Medical staff confuse women with ductal carcinoma in situ

Women diagnosed with ductal carcinoma in situ (DCIS) need clear communication and tailored support to enable them to understand this complex breast condition, which has divided the medical profession when it comes to its perception and prognosis. That is the key finding of a study published in the April issue of the Journal of Advanced Nursing.

Research carried out at the University of the West of England, Bristol, UK, looked at how 45 women felt when they were diagnosed with DCIS and how their experiences changed over time. It found that many of the women were very confused about whether or not they had cancer and that medical staff often added to this confusion by providing conflicting messages.

“DCIS is a non-invasive condition where the cancer cells are contained in the ducts of the breast” explains lead author Dr Fiona Kennedy, now a research fellow at Sheffield Hallam University. “It currently makes up 20 per cent of breast cancers detected by UK screening programmes.

“However, uncertainty surrounds whether it will progress into invasive breast cancer and this has created two factions in the medical profession. Some view DCIS as a carcinoma in situ, emphasising that the majority of cases have a high risk of progression and need treatment to reduce the incidence of invasive breast cancer. Others view DCIS as a pre-cancerous condition.

“DCIS patients have an excellent prognosis, but treatment is controversial because it is similar to treatment for invasive breast cancer, including mastectomy and possibly radiotherapy and hormone treatment.

“This can be confusing for women diagnosed with DCIS. On the one hand they are being reassured that the condition is not life-threatening, yet on the other hand clinicians are recommending extensive, invasive treatment.”

The women, who were recruited from nine UK breast clinics, ranged from 34 to 84 years-of-age with an average age of 59. Seventy-six per cent had been diagnosed following screening and the rest had presented with symptoms. Some women had more than one surgical procedure, including wide local excision to remove the affected breast tissue (56%) or breast removal (44%).

Twenty-seven of the women took part in follow-up interviews nine to 13 months after diagnosis. All had completed their treatment and, during surgery, five had been diagnosed with DCIS in numerous sites (multifocal disease) or invasive breast cancer.

Key findings of the study, funded by the charity Breast Cancer Campaign, included:

Many women felt confused and conflicted by their diagnosis. Some were told it was cancer, some were told it wasn’t cancer and some medical staff used the terms DCIS, pre-cancer and early breast cancer. As one women said: “Sometimes they refer to it as breast cancer and then when I went to oncology last week they said it’s not breast cancer it’s pre-cancer…”Women spoke about the contradictions of being told it was pre-cancer or non- cancerous, their perceptions of what this meant and then being recommended extensive, invasive treatment. One woman’s surgeon said he didn’t know why she was so worried when she didn’t have cancer. “Well if I haven’t got cancer why am I having radiotherapy and why have you taken a 9cm by 6cm by 3cm chunk out of my breast?” she replied.Some women were more affected than others by their condition, especially if they had more extensive surgery. Many experienced mixed and fluctuating emotions. As one woman said: “At worst I feel mutilated and angry and upset…At best I feel relieved that it was nothing more.”One of the most enduring emotions was one of on-going risk, which ranged from fleeting concerns to significant, intrusive thoughts. They worried about DCIS reoccurring, or developing invasive breast cancer, and felt vulnerable and uncertain about the future.Body image was also a big issue and impacted on the women’s confidence and sexuality. “I felt that I wasn’t perfect in that area…I felt very exposed” said one woman. “I don’t know how I can go into a relationship and that makes me angry” said another after reconstructive surgery.  Women who were confused about their own diagnosis found telling others very challenging. “I wanted them to know that there was a cancer in the title…you need to justify why you’re having such major surgery” said one. “If I said I’ve got breast cancer she [mum] would have been hysterical” said another, adding that she chose instead to describe is as “a really, really, really tiny area of pre-cancerous cells”.

“It was clear from our research that women’s perceptions and experiences of DCIS shifted and developed over time during the diagnosis, treatment and post-treatment phases” says Dr Kennedy. “Confusion about their medical condition was also very common as they received mixed messages about their diagnosis and whether it was or wasn’t cancer.

“One of the key recommendations of this study is that clinicians should think carefully about the language they use to describe DCIS and that further work is needed to explore the potential for the development of clear, coherent and flexible communication guidelines. There is also a need for appropriate and tailored help, support and information to meet the specific and evolving needs of women diagnosed with DCIS.”

Baroness Delyth Morgan, Chief Executive of the Breast Cancer Campaign, has welcomed the findings. “A diagnosis of DCIS can leave women confused about their treatment options as currently even clinicians don’t know which cases will progress to invasive breast cancer” she says. “For now we must give clearer messages to patients about what their diagnosis means and the potential risks to them if it is left untreated. Improving awareness of DCIS when women attend routine breast screening appointments is a key part of this process.”

How a cancer drug leads to diabetes-like state

Scientists at Dana-Farber Cancer Institute have discovered why diabetic-like symptoms develop in some patients given rapamycin, an immune-suppressant drug that also has shown anti-cancer activity and may even slow aging.

Rapamycin is widely used to prevent organ rejection and is being tested as a cancer treatment in clinical trials. About 15 percent of patients, however, develop insulin resistance and glucose intolerance after taking the drug; until now, scientists had not identified the reason.

In a study published in Cell Metabolism, the researchers report that normal mice given rapamycin were more likely to have trouble regulating their blood sugar because of a drop in insulin signaling, which in turn was triggered by activity of a protein called Yin Yang 1, or YY1. But animals in which the YY1 protein was "knocked out" in their muscles had no such response to rapamycin -- they were protected against the development of diabetes-like symptoms. This result pinpointed YY1 as the target of rapamycin responsible for the loss of normal insulin function.

One of the finding's implications is that physicians should consider giving anti-diabetes drugs along with rapamycin, says Pere Puigserver, PhD, senior author of the report.

The results also raise a caution flag for researchers and non-scientists who are excited about the potential for rapamycin to extend life, based on recent studies in animals including mammals, he notes.

"The possibility of increased diabetes risk needs to be taken into account" in further research on the anti-aging properties of rapamycin and related compounds, says Puigserver.

Rapamycin is a drug derived from bacteria found on Easter Island, and was approved in 1999 by the FDA as an immunosuppressant in transplant patients.

One of its actions is to inhibit the important mTOR signaling pathway in cells (mTOR stands for "mammalian target of rapamycin"). The mTOR pathway is a critical factor in regulating the growth, proliferation, survival and motility of cells; elevated mTOR activity is a hallmark of many cancers.

In clinical trials rapamycin and a related drug are being evaluated in kidney cancer, brain tumors, and mantle cell lymphoma, among others. Intriguingly, rapamycin has been found in some experiments to extend healthy lifespan in yeast, flies and mammals, and delays age-related diseases, including cancer and atherosclerosis.

But the raised risk of deleterious pre-diabetes symptoms has been a concern and something of a mystery. In 2007, Puigserver and colleagues reported in Nature that mTOR causes an increase in mitochondria -- the cell's power plants -- in skeletal muscles; suppressing mTOR activity with rapamycin led to a diabetic state. That research also revealed that among the proteins "downstream" of mTOR in the signaling pathway is Yin Yang 1 (YY1), a transcription factor -- a protein that controls the expression of genes.

"We thought that maybe YY1 was responsible for the diabetic effects," says Puigserver. An increase in YY1 activity caused by rapamycin could suppress the production of insulin and related hormones which are necessary for muscles to take up glucose (sugar) for energy and keep blood sugar levels stable.

To test that idea, they bred mice that lacked the YYI gene and protein in their skeletal muscles. When these mice were given rapamycin, it didn't affect their muscles' glucose uptake or insulin signaling -- in effect, they were immune to the diabetic effects of rapamycin.

The investigators are continuing their studies: one goal is to discover why only a minority of human patients develop diabetes-like conditions with rapamycin treatment. One possibility that the risk is modulated by dietary factors, Puigserver says.

New clues to development of blood and other cancers

Scientists at Fox Chase Cancer Center have uncovered more details about how defects in components of the machinery that makes new proteins can lead to blood and other cancers. The findings may one day lead to new targeted therapies that address those problems.

"These findings help explain how mutations in one class of proteins can trigger the development of cancer," says Shuyun Rao, PhD, a scientific associate in the lab of David L. Wiest, PhD, also a co-author on the study, at Fox Chase Cancer Center in Philadelphia. "If we find a way to block the pathway activated by these mutations, this may cause tumors to regress."

The research focused specifically on ribosomal proteins. Previous research has linked mutations in ribosomal proteins to cancers such as leukemia and lymphoma, as well as myelodysplastic syndromes (MDS), which can lead to acute myelogenous leukemia (AML). However, this study represents the first insights into how mutations in ribosomal proteins might increase cancer risk.

To investigate further how an individual ribosomal protein might trigger cancer, Rao, Wiest and their colleagues focused on one known as L22. To begin, they looked at blood samples from a small number of leukemia patients -- approximately 50 -- and found that in 9%, L22 was either mutated or deleted entirely. This suggested that problems in L22 may have played a role in the development of their cancers.

Next, they deleted L22 in mice that were bred to be prone to develop lymphomas, and saw that their tumors developed faster, and the mice died faster than those who had intact forms of L22 -- further evidence of its important role in the disease.

Finally, in a sample of cells in the lab, the researchers inactivated L22 and saw that the cells experienced changes, signaling the early stages of lymphoma. Specifically, cells without L22 showed more activity in a pathway associated with inflammation known as NFkappaB, which other research has linked to cancer. "In theory, if we could find a way to block this pathway, we could add this to existing therapies to help treat the tumors it triggers," says Rao.

Although L22 is a ribosomal protein, and therefore helps build new proteins, previous research has found that eliminating L22 does not affect the rate with which cells make new proteins -- suggesting L22 has additional functions, says Rao.

Previous research has found that L22 expression is strikingly reduced in a number of liquid and solid tumors including breast cancer, lung adenocarcinoma and ovarian carcinoma. "These findings don't just have implications for people with leukemia," Wiest says. "It is likely that L22 repression or inactivation will play a role in other cancer types as well"

Co-authors on the study include researchers at Fox Chase, Dana-Farber Cancer Institute in Boston, Massachusetts; St. Jude Children's Research Hospital in Memphis, Tennessee; and the University of Colorado Denver School of Medicine in Aurora, Colorado.

Breast cancer survival may improve by eating cruciferous vegetables

A study by Vanderbilt-Ingram Cancer Center and Shanghai Center for Disease Control and Prevention investigators reveals that breast cancer survivors who eat more cruciferous vegetables may have improved survival. The study of women in China was presented by postdoctoral fellow Sarah J. Nechuta, Ph.D., M.P.H., at the American Association for Cancer Research Annual Meeting in Chicago, Ill.

"Breast cancer survivors can follow the general nutritional guidelines of eating vegetables daily and may consider increasing intake of cruciferous vegetables, such as greens, cabbage, cauliflower and broccoli, as part of a healthy diet," said Nechuta.

Nechuta, Xiao Ou Shu, M.D., Ph.D., and colleagues investigated the role of cruciferous vegetables in breast cancer survival among women in the Shanghai Breast Cancer Survival Study, a prospective study of 4,886 Chinese breast cancer survivors who were diagnosed with stage 1 to stage 4 breast cancer from 2002 to 2006. Shu, Ingram Professor of Cancer Research, is the principal investigator of the Shanghai Breast Cancer Survival Study.

After adjusting for demographics, clinical characteristics and lifestyle factors, the researchers found cruciferous vegetable intake during the first 36 months after breast cancer diagnosis was associated with a reduced risk for total mortality, breast cancer-specific mortality and disease recurrence.

Survival rates were influenced by vegetable consumption in a dose-response pattern. As women ate more of these vegetables, their risk of death or cancer recurrence decreased.

Women who were in the highest quartiles of intake of vegetables per day had a 62 percent reduced risk of total mortality, 62 percent reduced risk of breast cancer mortality, and 35 percent reduced risk of breast cancer recurrence, compared to women with the lowest quartile of intake."

Nechuta noted that cruciferous vegetable consumption habits differ between China and the United States and suggested this fact be considered when generalizing these results to U.S. breast cancer survivors.

"Commonly consumed cruciferous vegetables in China include turnips, Chinese cabbage/bok choy and greens, while broccoli and Brussels sprouts are the more commonly consumed cruciferous vegetables in the United States and other Western countries," she said. "The amount of intake among Chinese women is also much higher than that of U.S. women."

Cruciferous vegetables contain phytochemicals known as isothiocyanates and indoles which appear to have a protective effect against some types of cancer.

Nechuta said the level of these bioactive compounds, proposed to play a role in the anticancer effects of cruciferous vegetables, depends on both the amount and type of cruciferous vegetables consumed.

She said there is a need for future studies that measure the bioactive compounds in these vegetables and the host factors that may influence the effects of these compounds to improve the understanding of the association between cruciferous vegetable consumption and breast cancer outcomes.

Scientists discovered how cancers override cellular growth controls

Rapidly dividing cancer cells are skilled at patching up damage that would stop normal cells in their tracks, including wear and tear of telomeres, the protective caps at the end of each chromosome.

Loss of telomeres forces cells out of the dividing game and into a growth arrest state called "senescence," but cancer cells evade this by employing an enzyme called telomerase to extend eroded telomeres.

If telomerase fails to activate, the tumor cells of about 10 percent of all human cancers have a back-up strategy to build serviceable telomeres and keep dividing. How that pathway, called ALT for alternative lengthening of telomeres, works is unclear, because researchers have had limited options to study it experimentally.

Now scientists at the at Salk Institute for Biological Studies have created roundworms that eke out an existence, and even manage to reproduce, relying solely on ALT to maintain telomeres. That study provides a valuable tool to tinker with the ALT pathway and learn how to block it, with a goal of forcing tumor cells to senesce.

"These worms are the first multicellular organisms we can study in the laboratory that maintain their telomeres through the ALT pathway and not through telomerase," says Jan Karlseder, a professor in Salk's Molecular and Cell Biology Laboratory and the study's senior author. "Up to now we could only study ALT in cell lines derived from tumor cells. Now we can screen for compounds and genes that suppress or regulate ALT in a whole organism, which in worms is fairly easy to do."

The components of telomere-building pathways are prime targets for cancer researchers. "There is a huge interest in drugs that block telomerase, since 90 percent of cancers use it for telomere maintenance," says Daniel Lackner, a postdoctoral fellow in the Karlseder lab and one of the study's first authors. "But these drugs won't work for the 10 percent of cancers that use the ALT pathway. In fact, some evidence suggests that drugs targeting telomerase might actually increase ALT, making the need for ALT inhibitors more pressing."

In contrast, the bottom rows show abnormally fused chromosomes found in genetically altered roundworms created by the Salk researchers.

Despite this irregularity, the Salk researchers' worms were able to reproduce, providing a new avenue for scientists to study a key pathway in the development of certain cancers.

The new study stems from a 2008 study from the Karlseder lab that was published in Cell. In that paper, they mutated a gene encoding a telomere-binding protein in roundworms. The resulting mutants displayed functional, but slightly scruffier-looking telomeres than those built by telomerase. That was a strong hint that when forced, worm cells, like human cells, can turn on the ALT pathway.

For the new study, the team pushed the mutant worms' survival capacity to the limit. This time they knocked out a second gene, telomerase itself, and found that these double mutants could reproduce continuously without undergoing senescence. Over the past 3 years a strain of double mutant worms has propagated for over 180 generations.

The group then used biochemistry to confirm that the worms depend totally on ALT for telomere maintenance. The telomeres of double mutants were more sloppily constructed than superior, telomerase-made caps and were similar in length and overall structure to chromosome caps displayed by human cancer cells that employ ALT.

The double mutant worms also contained wisps of telomeric DNA, called c-circles, that are unique by-products of ALT, further evidence that they were persisting via ALT.

Intriguingly, other investigators have reported that c-circles are present in the blood of human bone cancer patients and could potentially serve as a diagnostic for cancers that depend on the ALT rather than the telomerase pathway.

Although the worms are living long, species-wise, they are not quite prospering -- which is exactly what one would expect. The study reports that the double mutants have fewer offspring than normal worms, which is how roundworms exhibit "stress." And many have fused chromosomes, a likely outcome of having barely serviceable telomeres. But what counts is that the animals are viable, rely on ALT only, and their genome reflects aberrations seen in human tumor cells. In short, they are ready for analysis.

Currently, researchers cannot predict what mechanisms a cancer will to use to maintain the telomeres. "Cancers of the bones, stomach and soft tissues may be more efficient in activating ALT than telomerase pathways," says Karlseder, noting that indicators of ALT have also been observed in other cancer types. "We don't know why a tumor chooses one pathway over the other. All we know is that ALT may be switched on in response to telomerase inhibition, which means we must understand this pathway."

Marcela Raices, a former Salk postdoctoral fellow, now at University of California San Francisco, was co-first author with Lackner on the paper. Also contributing were Candy Haggblom of the Karlseder lab and Hugo Maruyama, a former graduate student in the lab, now at Osaka Dental University.

Human virus to treat head and neck cancer patients

A naturally-occurring harmless human virus may be able to boost the effects of two standard chemotherapy drugs in some cancer patients, according to early stage trial data published April 1 in Clinical Cancer Research. Cancers shrank for about one third of the patients who could be evaluated, and disease stabilized for a further third. For one patient, all signs of their cancer disappeared.

RT3D, trade name Reolysin, is a new drug developed by Oncolytics Biotech Inc with preclinical and clinical studies conducted at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital. It is based on a virus (reovirus type 3 Dearing) that is found in almost all adults' respiratory and gastrointestinal tracts without causing any symptoms.

RT3D has the ability to grow in and kill certain types of cancer cells, but does not grow in normal cells.

Previous trials injecting patients with the virus on its own showed limited effectiveness, but the team found that RT3D appeared to magnify the effects of platin and taxane-based chemotherapy on tumour cells.

Dr Kevin Harrington and colleagues in Leeds therefore started a clinical trial testing intravenous RT3D in combination with chemotherapeutics carboplatin and paclitaxel in 31 patients with advanced cancers who had stopped responding to standard treatments.

An initial Phase I study was carried out in patients with a range of advanced cancers, which showed the drug combination was safe. Side-effects were found to be generally mild, and consistent with chemotherapy alone.

Patients with head and neck cancers were found to have the best responses, so a Phase II expansion study at The Royal Marsden Hospital, London, and St James's Hospital, Leeds, was therefore targeted to patients with these types of cancers.

Cancers shrank for about one third of the patients who could be evaluated, and disease stabilised for a further third. For one patient, all signs of their cancer disappeared.

"We saw really very impressive response rates in these patients. These are patients whose cancers had grown despite a great deal of previous treatment, including platinum-based chemotherapy for many," Dr Harrington, Leader of the ICR's Targeted Therapy Team and Consultant Oncologist at The Royal Marsden, said. "Under those circumstances, we'd expect that the average response rate to chemotherapy alone might be as low as single digits figures and the average survival would be somewhere between three to four months. In our Phase I/II study we show this had been prolonged to an average of seven months, albeit not in a randomised trial."

"Based on the results of this study we've now started recruiting patients with advanced head and neck cancer to a randomised Phase III trial, in which all patients will receive chemotherapy and half will receive Reolysin as well. We are extremely excited about this progress."

The study also found the virus was not shed after treatment. This means people could be given the drug as outpatients as no risk was found that they could transmit the virus to others.

Head and neck cancers include tumours of the eye, nasal cavity, tongue, gums, lip, cheeks, voice box and esophagus. Around 650,000 people are diagnosed with squamous cell cancer of the head and neck each year worldwide, and around 350,000 die from the disease annually.

Notes to editors: Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies with first author Eleni M. Karapanagiotou from the ICR and The Royal Marsden publishes in the print edition of Clinical Cancer Research on April 1.

The Phase III trial is recruiting patients with head and neck cancer who have already been treated with platinum but not taxane.

Research gives hope to detecting cancer in early stages

Research from Queen Mary, University of London has uncovered the mechanism which causes normal cells to develop into cancer, giving hope in the fight against one of the UK's biggest killers.

The study, published in the online journal PLoS ONE on March 26, investigated the role of the notorious cancer gene FOXM1.

Lead investigator Dr Muy-Teck Teh from Queen Mary, University of London, said the team found that the FOXM1 gene "brain washes" normal cells so they adopt a 'memory' pattern similar to cancer cells.

"This research has important clinical implications for early cancer diagnosis, prevention and treatment.

"We knew the FOXM1 gene is present in almost all different types of human cancers so we wanted to understand how excessive levels of it cause normal cells to become cancer-like."

Dr Teh's team used a gene-chip microarray technology to investigate the DNA 'memory' patterns in cells.
Normal cells inherit specific instructions or 'memory' patterns by masking and unmasking parts of their DNA. Maintaining the correct memory patterns is important for normal cell function -- disturbing the memory pattern can lead to cancer formation.

"We knew that excess expression of FOXM1 can lead to cancer but its underlying mechanism was not clear," Dr Teh explained.

"We looked at normal human mouth cells and introduced high levels of FOXM1. The normal cells changed to adopt a memory pattern similar to those in mouth cancer cells and we identified a number of key pattern changes that may be responsible for initiating cancer formation.

"These pattern changes may lead to the identification of biomarkers which could be developed into new diagnostic tests. We are currently working towards developing a practical diagnostic test for detecting mouth cancer at very early stages."

The team's research, funded by the Wellcome Trust and the Facial Surgery Research Foundation, Saving Faces, means that it will be easier to detect changes in cells before they develop into cancer.

Consultant oral and maxillofacial surgeon Professor Iain Hutchison, founder of Saving Faces and co-author on the study, said: "We are excited about this finding as it means that we can now detect changes in cells way before they become cancer cells.

"Mouth cancer, if detected early when the disease is most receptive to surgical treatment, has a very high cure rate. Understanding how a gene such as FOXM1 can convert normal cells into cancer is an important step towards finding new diagnostic tests for early cancer detection."

This study builds on previous studies Dr Teh and his team has done on FOXM1. Published in 2009, Dr Teh found that nicotine could activate FOXM1 and that excessive levels could cause normal human mouth cells to develop into cancer. His research on FOXM1 was awarded 'Molecule of the Year 2010' by the International Society for Molecular and Cell Biology and Biotechnology Protocols and Research for its pivotal role in cancer stem-cell biology.

Researchers create cellular automation model to study complex tumor-host role in cancer

Cancer remains a medical mystery -- despite all of the research efforts devoted to understanding and controlling it. The most sought-after tumor model is one that would be able to formulate theoretical and computational tools to predict cancer progression and propose individual treatment strategies.

To better understand the role complex tumor-host interactions play in tumor growth, Princeton University researchers developed a cellular automation model for tumor growth in heterogeneous microenvironments. They then used this same model to investigate the effects of pressure on the growth of a solid tumor in a confined heterogeneous environment, such as a brain cancer growing in the cranium, and discovered that pressure accumulated during tumor growth can lead to a wide spectrum of growth dynamics and morphologies for both noninvasive and invasive tumors.

Depending on the magnitude of the pressure and the physical properties of the host environment, the types of tumor patterns that emerge range from strongly malignant tumors characterized by finger-like protrusions at the tumor surface to those in which fingering growth is diminished.

Nearly half of cancer survivors died from conditions other than cancer

Although cancer recurrence may be the overriding fear for many survivors, nearly half of survivors from a recently presented study died from other conditions.

These results indicate survivors could potentially benefit from a more comprehensive, less cancer-focused approach to their health, according to lead researcher Yi Ning, M.D., Sc.D., assistant professor in the department of epidemiology and community health at Virginia Commonwealth University (VCU) and associate research member at VCU Massey Cancer Center in Richmond, Va. Ning presented the results at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4.

"We realized that the mortality rates for some types of cancer, such as breast cancer, had declined," said Ning. "Cancer survivors live much longer than they did several decades ago. So with this large group of cancer survivors, we need to pay more attention to cancer survivors' overall health."

Ning and colleagues evaluated 1,807 cancer survivors who had participated in the National Health and Nutrition Examination Surveys (NHANES) study. The most common forms of cancer among the study group were breast, prostate, cervical, lung and colorectal.

When originally surveyed through NHANES, a large percentage of the study group suffered from conditions other than cancer, including cardiovascular conditions, hypertension and diabetes.

Researchers followed patients for more than 18 years. During the course of the study, 776 cancer survivors died. Fifty-one percent died from cancer and 49 percent died from other causes. Cardiovascular disease was the primary cause of noncancer deaths.

Researchers found that the longer patients survived after their initial cancer diagnosis, the more likely they were to die from another disease: 32.8 percent died from another condition within five years of diagnosis compared with 62.7 percent after 20 years.

With nearly half of cancer survivors dying from other causes, Ning said that physicians and patients must improve efforts to manage those risks.

"After the detection of cancer, clinicians and cancer survivors pay less attention to the prevention and treatment of other diseases and complications," said Ning. "We shouldn't neglect other aspects of health because we are focused on cancer and overlook other chronic conditions."

Tales from the crypt lead researchers to cancer discovery

Tales from the crypt are supposed to be scary, but new research from Vanderbilt University, the HudsonAlpha Institute for Biotechnology, and colleagues shows that crypts can be places of renewal too: intestinal crypts, that is. Intestinal crypts are small areas of the intestine where new cells are formed to continuously renew the digestive tract. By focusing on one protein expressed in our intestines called Lrig1, the researchers have identified a special population of intestinal stem cells that respond to damage and help to prevent cancer.

The research, published in the March 30 issue of Cell, also shows the diversity of stem cells in the intestines is greater than previously thought.

"Identification of these cells and the role they likely play in response to injury or damage will help advance discoveries in cancer," said Shawn Levy, Ph.D., faculty investigator at the HudsonAlpha Institute and an author on the study.

The intestines and colon are normally lined with a single layer of cells to absorb nutrients from food. There are regular small pockets in the intestines called crypts, where stem cells are gathered. Rapid turnover of the lining cells and replacement by new lining cells made in the crypt, keep the intestines and colon healthy and keep damaged cells from turning into cancerous ones.

The new paper demonstrates that, although the makeup of stem cells in the crypt is still controversial, one protein called Lrig1 can distinguish a group of long-lived cells at the base of the crypt. These Lrig1-positive stem cells do not regularly replace lining cells, but instead are only activated when there is damage or injury to the intestine.

In addition, the researchers show that the Lrig1 protein functions to prevent cancer as a tumor suppressor molecule. When the protein is completely absent from a mouse model, the mice all develop adenomas and then tumors. This suggests that Lrig1 is an important target for understanding and treating intestinal and colon cancer.

Levy added, "RNA sequencing work at HudsonAlpha found that the Lrig1-positive stem cells are molecularly different in multiple ways from previously identified crypt stem cells, in keeping with their role in responding to damage." Further work on genes expressed or silenced in this population of cells, he added, will increase understanding of both normal and cancer cell progression in the intestines.

Researchers discovered protein critical for tissue regeneration

A flatworm known for its ability to regenerate cells is shedding more light on how cancer could be treated and how regenerative medicine could better target diseases, according to researchers at the University of California, Merced.

In research, biology Professor Néstor Oviedo has shown that signaling by a protein called Target of Rapamycin (TOR) -- found in humans and most other mammals -- is crucial for planaria's unique tissue regeneration. Disabling the protein prevents the flatworm's regrowth, a sign that disabling it in abnormal cells could prevent the growth of a cancer.

"It's a new model in which we can study stem cell behavior by manipulating the signaling pathways," Oviedo said.

Researchers have recognized that the TOR protein plays a role in cancer, aging and degenerative diseases, but they haven't figured out how it works.

Oviedo's lab is approaching this question using tiny flatworms known as planaria. Long relegated as a scientific oddity, the planarian is now among the species that could be crucial in understanding the role of stem cells. The worm's ability to repair itself is unparalleled, and its secrets could help combat cancer and degenerative diseases.

For this study, Oviedo's lab disabled the TOR protein in planaria and then amputated parts of the flatworm. Under typical circumstances, the organism would be able to repair itself.

But researchers discovered the planaria's stem cells recognized they needed to regrow tissue but were unable to regenerate it in the correct place and instead formed tissues in abnormal places. This kind of regeneration hasn't been reported before. Additionally, the planaria with the disabled protein were unable to grow, even if nutrients were available.

In addition to stopping cancer, understanding TOR and its role in regulation could lead to the development of medicines to encourage tissue regeneration and to fight degenerative diseases, such as Alzheimer's.

Graduate student Harshani Peiris, who was the lead author on the paper, said the planaria gives researchers the ability to look at the reactions of an entire organism, rather than just looking at cells in a Petri dish.
"We have a cutting-edge look into what's happening at the system level," Peiris said.

HIV 'superinfection' boosts immune response

Women who have been infected by two different strains of HIV from two different sexual partners -- a condition known as HIV superinfection -- have more potent antibody responses that block the replication of the virus compared to women who've only been infected once.

These findings, by researchers at Fred Hutchinson Cancer Research Center in Seattle, are published online March 29 in PLoS Pathogens.

"We found that women who had been infected twice not only had more potent antibody responses, but some of these women had 'elite' antibody activity, meaning that they had a broad and potent ability to neutralize a wide variety of strains of HIV over a sustained period time," said senior author Julie Overbaugh, Ph.D., a member of the Hutchinson Center's Human Biology Division. It is estimated that only about 1 percent of people with HIV are so-called "elite neutralizers" who are able to potently neutralize multiple subtypes of the virus.

"Individuals who become superinfected with a second virus from a different partner represent a unique opportunity for studying the antibody response and may provide insights into the process of developing broad neutralizing antibodies that could inform HIV-vaccine design," she said.

The study suggests that harboring a mixture of different viral strains may be one way to promote a robust antibody response. The findings also suggest that being infected with two different HIV strains not only leads to a strong response, but also a more rapid response that is capable of recognizing many other HIV strains.

The researchers tracked the immune activity of 12 superinfected women from Mombasa, Kenya, over a five-year period and compared each to a control group of three singly infected women. Overbaugh and lead author Valerie Cortez, a doctoral student in her lab, assessed the ability of antibodies present in superinfected and singly infected women to neutralize a spectrum of circulating HIV-1 variants. In doing so they were able to determine whether the presence of two viruses compared to one made a difference in immune response. The researchers controlled for variables such as antibody response prior to superinfection and biomarkers of immunity such as CD4+ T cell count and viral load. The study found that superinfected women had, on average, 1.68 times more neutralizing antibodies than non-superinfected women, and they scored much higher in their ability to neutralize the virus -- superinfected women had 1.46 times greater potency than the singly infected women.

More than 1.1 million Americans are estimated to be living with HIV today, and every nine-and-a-half minutes someone in the U.S. becomes infected, according to the U.S. Department of Health and Human Services. An HIV vaccine is considered the best approach to long-term protection from HIV infection, but attempts to develop such a vaccine so far have meet with limited success.

"The holy grail of an HIV vaccine is to elicit antibodies to the virus because antibodies have been shown to block virus infection. But there has been little progress in determining how to elicit such antibodies with a vaccine. The study of individuals HIV infected who have developed strong antibody responses to the virus may shed light on the best approach to design a vaccine that will induce an effective immune response," Overbaugh said.

Dense breasts can nearly double the risk of breast cancer recurrence

Women aged 50 and over with breasts that have a high percentage of dense tissue are at greater risk of their breast cancer recurring, according to Swedish research presented at the eighth European Breast Cancer Conference (EBCC-8) in Vienna on March 21.

Dr Louise Eriksson and her colleagues from the Karolinska Institutet (Stockholm, Sweden) found that women with denser breasts had nearly double the risk of their cancer recurring, either in the same breast or in the surrounding lymph nodes, than women with less dense breasts. They warn that doctors should take breast density into account when making decisions about treatment and follow-up for these women.

When a woman has a mammogram, the resulting scan gives an image of the breast that shows areas of white and black. The white areas represent the dense tissue, made up of the epithelium and stroma [1]. The black areas are made up of fatty tissue, which is not dense. The percentage density (PD) of the breast is calculated by dividing the dense area by the area of the whole breast (dense and non-dense tissue included).

Breast density varies from woman to woman, and it also decreases with age. Dr Eriksson explained: "Density can vary greatly, even between postmenopausal women. In the group of women I studied, those with the lowest percentage density had breasts that were less than one percent dense, whereas those with highest PD had 75-80% dense breasts. The mean average PD was 18%. However, density does decrease with age. Studies have shown a decrease by approximately two percent per year. The largest decrease is seen at menopause when PD decreases by approximately 10%."

The researchers studied the mammograms and outcomes for 1,774 post-menopausal women who were aged 50-74 and who were part of a larger study of all women with breast cancer diagnosed between 1993-1995 in Sweden.

"We found that if you have a PD at diagnosis of 25% or more, you have an almost two-fold increased risk of local recurrence in the breast and surrounding lymph nodes than women with a PD of less than 25%. However, density does not increase the risk of distant metastasis and has no effect on survival. We also see that although mammographic density is one of the strongest risk factors for breast cancer it doesn't seem to influence tumour development in any specific way; for instance, it isn't more associated with oestrogen receptor positive tumours than oestrogen receptor negative tumours, but seems to act as a general stimulator of tumour development," said Dr Eriksson, who is a PhD student at the Karolinska, as well as a physician at the Stockholm South General Hospital.

"Our study shows that breast density before or at diagnosis should be taken into account even after diagnosis, for instance, when deciding on adjuvant treatment and follow-up routines; perhaps women with dense breasts should be followed more frequently or for a longer period of time in order to quickly spot any local recurrence.

"As far as screening programmes are concerned, it is already known that breast density is a risk factor for the occurrence of breast cancer and that it decreases the sensitivity of mammograms. Our study confirms the importance of taking breast density into account in the screening setting."

Until now, little was known about the association between density, tumour characteristics and prognosis once cancer had occurred, and results were conflicting. This study is important because of its size and detailed information on each woman. "This is one of the largest studies to date studying mammographic density, tumour characteristics, and prognosis, including almost 50% of all Swedish breast cancer cases diagnosed 1993-1995," said Dr Eriksson.

Cancer researchers do not know why breast density is a risk factor for breast cancer. "It could simply be due to higher density being associated with more cells, which means that more cells are at risk of developing cancer," she said. "Another hypothesis is that it is the relationship between mammographic density and the stroma (which has been shown to be the main compound of mammographic density) that is central to the increase in risk. There is no leading hypothesis on why an increased amount of stroma would increase breast cancer risk, but it is known that the interaction between the epithelial cells and the stroma is crucial to the development of breast cancer. Based on the results from our study, we propose that mammographic density creates a beneficial environment for epithelial cells to transform into cancer cells; much like fertile soil giving a planted seed the needed nutrients to grow and develop."

Professor David Cameron, from the University of Edinburgh (Edinburgh, UK), and chair of EBCC-8 said: "This study raises questions about how and why the appearance of normal breast tissue on a mammogram could influence the chances of a local recurrence of breast cancer. It is, therefore, more thought-provoking than practice-changing, since it is not clear what a patient, or her physician, should do if the mammogram shows a higher density of the normal breast tissue. A number of factors are known that influence mammographic breast density, but more research is needed to know which of these, if any, is responsible for this important observation."

[1] The breast epithelium is the cellular tissue lining the milk-producing ducts of the breast. The stroma is the supporting cells and connective tissue in the breast.

[2] The study was funded by Märit and Hans Rausing's Initiative against Breast Cancer, the Swedish Research Council, and the Swedish Cancer Society.

Levels of Ki67 in prostate cancer cells reduced by oral Vitamin D supplements

Higher oral doses of plain vitamin D raised levels of calcitriol in prostate tissue. Higher prostate levels of calcitriol, a hormone made from vitamin D, corresponded with lower levels of the proliferation marker Ki67 and increased levels of cancer growth-inhibitory microRNAs in prostate cancer cells, according to data presented at the AACR Annual Meeting 2012, held here March 31 -- April 4.

The results not only point to the mechanisms by which vitamin D affects the rate of prostate cancer growth, but also indicate that vitamin D may slow the growth of prostate cancer cells -- a key finding given that the role of vitamin D in prostate cancer has been "controversial, with some suggesting that higher levels of vitamin D should be avoided," said Reinhold Vieth, Ph.D., professor at the University of Toronto in Toronto, Ontario, Canada.

"This study shows calcitriol makes the foot come off the gas pedal of cancer growth. We are not able to prove that the speed of the car has slowed down, but it certainly is a good sign," said Vieth. "We expect that this early-phase clinical trial will open the door for more detailed clinical research into the usefulness of vitamin D in the treatment or prevention of prostate cancer."

Vieth and colleagues previously reported that in men who were being monitored regularly for prostate cancer, higher vitamin D levels slowed the rate of rise in prostate-specific antigen levels. They randomly assigned 66 men scheduled for radical prostatectomy to daily vitamin D in doses of 400, 10,000 or 40,000 IU for three to eight weeks before surgery.

Researchers found that calcitriol levels in the prostate increased progressively with each daily dose of vitamin D, with 40,000 IU showing the highest levels. These higher levels of calcitriol corresponded with lower prostate levels of Ki67, a protein that indicates prostate cancer cell growth, as well as higher levels of specific growth-inhibitory microRNAs.

Vieth stressed that he and his colleagues do not advocate vitamin D supplementation in doses higher than 4,000 IU daily. Patients were assigned to the 40,000 IU daily dose because of the short presurgical time frame available for study, not as a regular regimen.

"Plain vitamin D provides the raw material to permit the body to take care of its own needs," he said. "We showed here that plain vitamin D allows the prostate to regulate its own level of calcitriol, and at the doses we used, for the time frame we used, it has been safe with the hoped-for desirable outcomes."

The next step in this line of research will be to conduct a phase III clinical trial in which men who are being monitored for prostate cancer progression will be randomly assigned to placebo or to a "high" dose of plain vitamin D.

Stress management for breast cancer patients may affect disease course

A team of researchers led by Michael H. Antoni, director of the University of Miami's Center for Psycho-Oncology Research, has shown that a stress management program tailored to women with breast cancer can alter tumor-promoting processes at the molecular level. The new study is one of the first to link psychological intervention with genetic expression in cancer patients.

In the study, researchers found that a group-based intervention called Cognitive-Behavioral Stress Management (CBSM) can have an effect on which genes in the cells of the immune system are turned on and off and in ways that may facilitate better recovery during treatment for breast cancer.

"For the women in the CBSM groups, there was better psychological adaptation to the whole process of going through treatment for breast cancer and there were physiological changes that indicated that the women were recovering better," said Antoni, professor of psychology in the College of Arts and Sciences, professor of psychiatry and behavioral sciences, and program leader of biobehavioral oncology at the Sylvester Comprehensive Cancer Center. "The results suggest that the stress management intervention mitigates the influence of the stress of cancer treatment and promotes recovery over the first year."

Previous research has shown that during times of adversity, our nervous and endocrine systems send signals to the immune system, which defends us from disease. In response, our body activates specific genes inside immune cells called white blood cells or leukocytes, Antoni explains.

"For the women who participated in the intervention groups, the genes that signal the production of molecules associated with a healthy immune response, such as type I interferon, were up-regulated -- meaning they were producing more of these substances compared with levels seen in the control group," Antoni said. "At the same time, the genes responsible for the production of substances involved in cancer progression, such as pro-inflammatory cytokines, chemokines, and matrix metalloproteinases were down-regulated."

CBSM is a ten-week group-based program developed at UM that combines relaxation, imagery, and deep breathing, along with cognitive behavior therapy, which is designed to help patients reduce bodily tension, change the way they deal with intrusive stressful thoughts, decrease negative moods, and improve their interpersonal communication skills. In the study, 79 women undergoing primary treatment for stage III breast cancer were randomized into a ten-week CBSM program or a psychoeducational control group in the weeks following surgery. Six-month and 12-month follow-up assessments were conducted.

"You essentially have this timeframe in a woman's life where she is getting diagnosed with breast cancer, followed by surgery, then chemotherapy or radiation, and it's very stressful," Antoni said. "This can be an emotionally and physically exhausting period offering little opportunity for recovery. If stress affects the immune system in a negative way, then their recovery could be slowed down, and those patients taking longer to recover may be at risk for poorer health outcomes. Conversely, if stress management intervention can reduce the impact of stress on the immune system, then recovery may be hastened."

The research team plans to follow the women in this cohort to see if CBSM intervention and its effects on leukocyte gene expression are predictive of recurrence and/or long-term health outcomes.

Diabetes drug appeared to slow prostate cancer growth

The use of metformin in men with prostate cancer before prostatectomy helped to reduce certain metabolic parameters and slow the growth rate of the cancer, according to the results of a phase II study.

Anthony M. Joshua, M.B.B.S., Ph.D., staff medical oncologist at the Princess Margaret Hospital, University Health Network in Toronto, Ontario, Canada, presented the data at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4.

Metformin is the most commonly prescribed medication for diabetes. Prior laboratory research has suggested that metformin may also help to improve prognosis in patients with prostate cancer by slowing the growth of the cancerous cells.

To follow up on the laboratory clues, Joshua and colleagues evaluated 22 men with confirmed prostate cancer who had been assigned up to 500 mg of metformin three times a day prior to undergoing prostatectomy.

"This gave us the ability to compare what the prostate cancer looked like when it was first diagnosed to what it looked like when the prostate cancer was removed from the body," said Joshua. "We were able to directly measure the effect of metformin on the prostate cancer."

Patients were assigned metformin for a median duration of 41 days. During that time, none of the men reported grade 3 adverse events, and all of them underwent prostatectomy with no adverse effect related to use of metformin.

The researchers found that metformin significantly reduced fasting glucose, insulin growth factor-1, body mass index and waist-to-hip ratio.

In addition, "although these are preliminary results, metformin appeared to reduce the growth rate of prostate cancer in a proportion of men," Joshua said. "Also, it appeared to reduce one of the main growth pathways that may have contributed to the overall growth of the tumor."

These results may have implications for men with prostate cancer who also have diabetes or early undiagnosed diabetes and for men with prostate cancer whose tumors have characteristics that make them sensitive to metformin, according to Joshua.

"This research builds on the hypothesis that metformin has a role in prostate cancer," he said. "Exactly what that role will be will depend on the results of the analysis currently being completed by our study team and others worldwide."

Joshua is particularly interested in better defining the precise mechanism of action and the subpopulation of patients with prostate cancer for whom metformin has the potential to improve outcomes.

New endoscope technology paves the way for 'molecular-guided surgery' for cancer

With more than 15 million endoscope procedures done on patients each year in the U.S. alone, scientists have reported evidence that a new version of these flexible instruments for diagnosing and treating disease shows promise for helping surgeons more completely remove cancerous tumors. Their report on technology that combines the endoscope with the phenomenon responsible for the eerie blue glow in the cooling water of nuclear reactors was part of the 243rd National Meeting & Exposition of the American Chemical Society (ACS).

"The advance marries endoscopes to one of the newest and most exciting fields of medical imaging," said Zhen Cheng, Ph.D., who led the research. "Endoscopes are medical devices consisting of a long, thin, flexible tube of optical fibers fitted with a light and a video camera. Doctors can insert them through natural openings in the body or small surgical incisions to diagnose and treat a wide range of diseases. The new approach expands the use of those fibers to include molecular-guided surgery to remove more of a cancerous tumor than is currently possible."

Conventional endoscopic methods allow doctors to see inside the stomach or colon, for instance, and take biopsy samples for tests. The new imaging technology -- called Cerenkov Luminescence Endoscopy (CLE) -- has advantages over both traditional endoscopic and imaging techniques, like MRI, in also providing information about the functioning of the tissue, Cheng added.

Cheng, who is with Stanford University, explained that CLE relies on the same phenomenon responsible for the soft blue glow in the cooling water in the core of nuclear power reactors. It results from interactions that occur when invisible particles from the nuclear reaction in the core zip through the water faster than the speed of light in water. The glow was named for its discoverer, a Russian scientist, who won the 1958 Nobel Prize.

Cerenkov Luminescence Imaging (CLI) emerged just a few years ago when scientists discovered ways to harness the effect in devices that do not involve nuclear power reactors. Excitement grew when laboratory experiments established that CLI could produce images of organs and guide surgery in laboratory animals to remove remaining cancer cells that otherwise would have been invisible to surgeons. Scientists also found that CLI could dramatically improve the resolution of PET scans, enabling PET scanners to detect smaller objects than previously possible. Cerenkov luminescence was especially exciting because the light used to reveal diseased tissue is visible light that can be detected with simple optical sensors. It also is compatible with commercially available optical imaging instruments and a wide selection of the nuclear imaging agents that doctors use to make structures in the body visible.

"One drawback however, is that the weak blue light -- unlike the X-rays in other medical scans -- barely penetrates through deep tissues," Cheng said. "This limits the usefulness of the technology in humans, where many tumors develop in areas deep inside the body. Our marriage of Cerenkov luminescence with the endoscope may be the perfect solution. With endoscopy, we can get close enough to the diseased tissue to take advantage of this technology."

Cheng pointed out that CLE's transition from laboratory to operating room, which may occur during the next few years, should be relatively smooth because of its similarity to traditional endoscopy. "Since the CLE system is an upgraded version of endoscopy, it is highly compatible with conventional endoscopic imaging requirements," he said.

Scientists identify novel pathway for T-cell activation in leprosy

UCLA researchers pinpointed a new mechanism that potently activates T-cells, the group of white blood cells that play a major role in fighting infections.

Published March 25 online in Nature Medicine, the team specifically studied how dendritic cells, immune cells located at the site of infection, become more specialized to fight the leprosy pathogen known as Mycobacterium leprae. Dendritic cells, like scouts in the field of a military operation, deliver key information about an invading pathogen that helps activate the T-cells in launching a more effective attack.

It was previously known that dendritic cells were important for a strong immune response and the number of such cells at an infection site positively correlated with a robust reaction. However, until now it was poorly understood how dendritic cells become more specialized to address specific types of infections.

The researchers found that a protein called NOD2 triggers a cell-signaling molecule called interleukin-32 that induces general immune cells called monocytes to become specialized information-carrying dendritic cells.

"This is the first time that this potent infection-fighting pathway with dendritic cells has been identified, and demonstrated to be important in fighting human disease," said the study's first author Mirjam Schenk, postdoctoral scholar, division of dermatology, David Geffen School of Medicine at UCLA.

In conducting the study, scientists used monocytes taken from the blood of healthy donors and leprosy patients and incubated the cells with the pathogen M. Leprae or specific parts of the mycobacteria, known to trigger NOD2 and TLR2, both associated with immune system activation.

Scientists wanted to investigate how these proteins might trigger mechanisms that turn on different immune receptors that recognize specific parts of the microbe in an infection. The NOD2 interleukin-32 pathway was the most effective and caused monocytes to develop into dendritic cells that carry critical information about the pathogen to the T-cells.

The team studied the gene expression profiles of the protein-triggered pathways and then also examined how the monocytes of leprosy patients responded to NOD2. Scientists found that NOD2 worked to induce moncytes to dendritic cells in tuberloid leprosy, a milder infection that is more easily contained. The NOD2 pathway was inhibited and could not be activated in lepromatous leprosy, which is more serious and causes widespread infection throughout the body.

"We were surprised to find the high potency of the dendritic cells in triggering certain specific T-cell responses, which may be useful in developing new therapeutic strategies for infectious diseases and cancer," said senior investigator Dr. Robert Modlin, UCLA's Klein Professor of Dermatology and chief of dermatology at the Geffen School of Medicine.

Leprosy, one of the world's oldest known diseases, is a chronic infectious disease that affects the skin, the peripheral nerves, the upper respiratory tract and the eyes and can lead to disfigurement of the hands, face and feet. In 2008, approximately 249,000 new cases of leprosy were reported worldwide, according to the World Health Organization.

Modlin adds that leprosy is a good model to study immune mechanisms in host defense since it presents as a clinical spectrum that correlates with the level and type of immune response of the pathogen.

The next stage of research will involve trying to further understand how to manipulate the innate immune system to induce a potent immune response in human infections and possibly for cancer immunotherapy as well.

Rearchers provides insights for treatments of brain disease by tracking protiens behaving badly

A research team led by the University of Melbourne has developed a novel technique that tracks diseased proteins behaving badly by forming clusters in brain diseases such as Huntington's and Alzheimer's.

The technique recently published in Nature Methods is the first of its kind to rapidly identify and track the location of diseased proteins inside cells and could provide insights into improved treatments for brain diseases and others such as cancer.

Developed by Dr Danny Hatters and his team of the Department of Biochemistry and Molecular Biology at the Bio21 Institute, University of Melbourne, the technique uses a flow cytometer to track the protein clusters in cells at a rate of 1000s per minute. In addition, cells with clustered proteins can be recovered for further study -- neither of which had been possible before.

"Being able to identify locations of diseased proteins in cells enables drugs to be developed to target different stages of disease development," he said.

He said the technique has application to many neurological diseases, which are characterized by formations of proteins clustering such as in Alzheimer's, Parkinson's and Huntington's diseases.

"A challenge for researchers has been trying to understand how proteins cluster and cause damage in diseases like Huntington's and Alzheimer's. This is the first approach which could enable us to answer those questions."

"Now we can see how the proteins form clusters inside a cell and can examine which cell functions are being damaged at different steps of the clustering process."

"No drugs at this stage can stop the clustering process in Huntington's disease for example. This sets up platforms to develop drugs that block the formation of clusters," Dr Hatters said.

The technique can also be used to examine how signaling processes occur such as when genes are switched on and off.

"It has application to track events of abnormal gene signaling such as in cancer " Dr Hatters said.
"This technique offers hope in improving treatments for a range of neurological and other conditions," he said.

Scientists unlock cancer cell death mystery

An international team of scientists has announced a new advance in the ability to target and destroy certain cancer cells. A group led by the University of Leicester has shown that particular cancer cells are especially sensitive to a protein called p21. This protein usually forces normal and cancer cells to stop dividing but it was recently shown that in some cases it can also kill cancer cells.

However, scientists have been unclear about how this happens.

Researcher Salvador Macip, from the University of Leicester Department of Biochemistry, said: "If we could harness this 'killing power' that p21 has, we could think of designing new therapies aimed at increasing its levels in tumours. This is what motivated us to look into it."

Now the team from the universities of Leicester and Cardiff in the UK, University of South Carolina, USA and Karolinska Institutet, Sweden has discovered that cells from sarcomas tend to die in response to p21 and that this is determined by the sensitivity of their mitochondria to oxidants.

They have published their findings in The Journal of Biological Chemistry. The research was funded by the MRC, the NIH, CONACYT and the Swedish Cancer Society.

Dr Macip added: "Our research also showed that p21 can kill cells even in the absence of p53, a protein that is in the main responsible for cell death but is inactivated in most cancers.

"This shows that certain types of cancer, sarcomas for instance, but maybe also others, should respond well to drugs that increase the levels of p21, even if they don't have an active p53. The side effects of these therapies should be minimal, since our experiments show that normal cells would arrest but not die in response to p21.

"There are already drugs available that selectively increase p21. Our results provide a rationale for testing them in certain types of cancers, which could be identified using the experiments we describe."

First Volume Of The Cancer Cell Line Encyclopedia Made Public

The goal of cancer treatment is to match the right drug to the right target in the right patient. But before such "personalized" drugs can be developed, more knowledge is needed about specific genomic alterations in cancers and their sensitivity to potential therapeutic agents.

Now an academic-industry collaboration is releasing the first results from a new and freely available resource that marries deeply detailed cancer genome data with predictors of drug response, information that could lead to refinements in cancer clinical trials and future treatments. The Cancer Cell Line Encyclopedia (CCLE), authored by scientists at the Broad Institute, Dana-Farber Cancer Institute, the Genomics Institute of the Novartis Foundation, and the Novartis Institutes for Biomedical Research, is described in the March 29 issue of the journal Nature. In a proof of principle, the researchers also report that genomic predictors of drug sensitivity revealed three novel candidate biomarkers of response.

"We hope that the Cancer Cell Line Encyclopedia will be a preclinical resource that could guide clinical trials," said Levi A. Garraway, a senior associate member of the Broad Institute, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School, and a co-corresponding author of the paper.

"The CCLE is a public resource that we think will catalyze discoveries throughout the cancer research community," said Todd Golub, director of the Broad's Cancer Program, Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute, and a co-author of the paper. "With this initial effort, we have taken some critical first steps. The challenge now is to greatly expand the number of compounds tested across the panel of cell lines."

The CCLE integrates gene expression, chromosomal copy number, and massively parallel sequencing data from almost 1,000 human cancer cell lines together with pharmacological profiles for 24 anticancer drugs across roughly half of these cell lines. The scale of the project allows greater depth of genetic characterization and pharmacological annotation than previously possible with fewer cell lines. A separate effort by scientists at Massachusetts General Hospital and the Sanger Institute appears in the same issue of Nature.

To accomplish such a feat, the team of scientists relied on the genetics, computational biology, and drug-screening capabilities at the Broad, Dana-Farber, and Novartis. They chose 947 of the nearly 1,200 commercially available cancer cell lines to reflect the genomic diversity of human cancers.

"One of the strengths of the CCLE lies in the number of cell lines it surveys," said Nicolas Stransky, a computational biologist in the Cancer Program at the Broad and a co-first author of the paper. "We can focus on rare cancer subtypes and still have sufficient statistical power for analyses."

Cancer cell lines are malignant cells that have been removed from tumor tissue and cultured in the laboratory. Under controlled conditions, they can grow indefinitely. This near-immortality is an advantage for performing repeated experiments, but it can be a potential pitfall if the cells differ markedly from tumors because they lack typical surroundings. However, with relatively few exceptions, the CCLE cell lines proved to be representative genetic proxies for primary tumor subsets across multiple different cancer types.

Correlating the more than 50,000 genetic and molecular features that emerged from these cell lines created a computational challenge that the scientists met by adapting algorithms to the biological data. They tested this tool against genetic alterations known to predict sensitivity to cancer drugs, and confirmed the value of their systematic approach. Then they applied the predictive modeling methodology to genetic subtypes of cancer known to pose challenges for current treatment modalities.

For example, a variety of cancers have mutations in the NRAS gene, which activates signaling pathways important in tumor growth. Some NRAS-mutant cancers, including a subset of melanomas, may prove vulnerable to drugs that block a protein also involved in signaling, called MEK. The scope of the CCLE enabled the investigators to study approximately 40 cancer cell lines with this mutation to see if they could predict sensitivity to MEK inhibitor drugs, some of which are being studied in clinical trials.

One of the genetic features that rose to the top of their analysis was expression of the aryl hydrocarbon receptor (AHR) gene in cell lines that were highly sensitive to MEK inhibitors. This suggested that high levels of AHR may indicate higher sensitivity to MEK inhibitor drugs. Additional experiments suggested that some of these same cell lines might also depend on AHR activity, and that MEK inhibitors might simultaneously intercept AHR function in some instances.

Armed with this kind of knowledge from the CCLE, researchers may have a much clearer idea of which tumors are most likely to respond to particular drugs before using them in clinical trials, the scientists say. Patients could therefore be selected for such studies based on how likely they are to respond, given the genetic and molecular makeup of their cancers.

"Knowing that kind of information very early might help to improve the success rate of drug development, compared to a genetically 'agnostic' approach that includes any patient with advanced cancer without knowledge of a genetic profile," said Garraway.

The scientists also found new predictors of sensitivity to existing chemotherapy drugs in other cancer cell lines. Elevated levels of SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Another analysis indicates that multiple myeloma may respond to IGF1 receptor inhibitors. Formal clinical studies will be required to learn if these features will hold true in patients.

"We can ask questions not only about emerging targeted therapies, but also about standard chemotherapy drugs," Garraway said. "There may be ways to identify patients who are more likely to respond to conventional chemotherapy versus those who might not. The predicted 'non-responders' may be better off trying a different regimen."

There are more volumes to be written in this encyclopedia.

"From a computational biology perspective, it's a clean, complex data set that allows many more analyses," Stransky said. "We are only scratching the surface of what can be done."

In the CCLE's next phase, analyses based on deeper sequencing, profiles of metabolic activity, and epigenetic modifications - changes in chromatin organization - will also be added.

"This is really the tip of the iceberg," Garraway said. "With these predictive modeling algorithms and with data sets of this size, their study could become an entire discipline in its own right. "

Side effects after HPV vaccine more likely experienced by younger girls

Younger girls are more likely than adult women to report side effects after receiving Gardasil, the human papillomavirus vaccine. The side effects are non-serious and similar to those associated with other vaccines, according to a new study funded by the Centers for Disease Control and Prevention and published in the Journal of Women's Health.

As part of an ongoing study and evaluation of this relatively new vaccine, researchers surveyed 899 girls and young women (ages 11-26) within two weeks after they received the Gardasil vaccine injection in the upper arm. The survey, which took place in 2008, also found that while most girls and young women did know that the vaccine can prevent cervical cancer, and that three doses are recommended, many didn't know that the vaccine can also prevent genital warts and abnormal pap smears.

"Gardasil is an important cancer-prevention vaccine, but too few girls are getting it. Our study found that young girls do have some knowledge about the vaccine, but they need to know more. If these girls and their parents know what to expect, they will likely be less afraid of getting the vaccine," said study lead author Allison Naleway, PhD, a senior investigator with the Kaiser Permanente Center for Health Research in Portland, Ore.

Since 2006, the CDC has recommended Gardasil for girls ages 11-12, and for older girls and women (ages 13-26) who did not receive the vaccine when they were younger. The CDC also recently recommended Gardasil for boys ages 11-12, and for older boys and men (ages 13-21) who did not receive the vaccine when they were younger.

Information about side effects has been reported by the manufacturer, the CDC, and by the federal government's Vaccine Adverse Event Reporting System, but this study is one of the first to survey girls themselves shortly after they received the vaccine. Many other studies have relied on information reported by health care providers and parents.

For this study, researchers used electronic health records to identify 3,490 Oregon and Washington girls and young women (ages 11-26) who received their first dose of HPV vaccine between February and September of 2008. Within a week of vaccination, researchers sent out surveys to young women ages 18-26. For girls under 18, researchers notified parents that their daughters would be receiving the surveys the following week, and gave the parents a choice to opt out. The survey included 50 questions about vaccine side effects, the girls' knowledge of the vaccine and the HPV virus, and about what kind of information their doctors shared with them before vaccine administration.

Of the 899 girls and women who responded to the survey, 78 percent reported pain when receiving the vaccine. Seventeen percent reported bruising or discoloration, 14 percent said they had swelling at the injection site, 15 percent reported dizziness, and 1 percent of the girls reported fainting.

Younger girls were more likely to have received other vaccines such as tetanus, meningitis and hepatitis A at the same time they received the HPV vaccine, and they were also more likely to report side effects. For example, 84 percent of girls aged 11-12 reported pain with the injection vs. 74 percent of women aged 18-26. Nineteen percent of girls aged 11-12 reported feeling dizzy after receiving the vaccine, but fewer than half that many (8 percent) of women aged 18-26 reported dizziness.

"These side effects are non-serious and very manageable," said Mike Wilmington, MD, a Kaiser Permanente pediatrician in Vancouver, Wash., who was not involved in the study. "The main complaint I hear about is pain with the injection, but there are ways to lessen the pain. Some girls will feel dizzy after this and other vaccines, so I follow CDC guidelines and have them sit or lie down for a few minutes after receiving the vaccine."

Eighty-four percent of girls and young women said they knew that the HPV virus can cause cervical cancer, but only half reported knowing that it can also cause genital warts and abnormal pap smears. Most respondents said their providers told them they needed three doses of the vaccine, and most also said their providers talked with them about the vaccine's benefits, possible side effects, and about HPV infection. Most girls, however, said their providers did not discuss genital warts or abnormal pap smears, and only one-fifth of girls said their provider asked them to sit and rest after receiving the vaccination.

Dramatic rise in skin cancer

Even as the rates of some cancers are falling, Mayo Clinic is seeing an alarming trend: the dramatic rise of skin cancer, especially among people under 40. According to a study by Mayo Clinic researchers published in the April issue of Mayo Clinic Proceedings, the incidence of melanoma has escalated, and young women are the hardest hit.

"We anticipated we'd find rising rates, as other studies are suggesting, but we found an even higher incidence than the National Cancer Institute had reported using the Surveillance, Epidemiology and End Result database, and in particular, a dramatic rise in women in their 20s and 30s," says lead investigator Jerry Brewer, M.D., a Mayo Clinic dermatologist. Researchers conducted a population-based study using records from the Rochester Epidemiology Project, a decades-long database of all patient care in Olmsted County, Minn. They looked for first-time diagnoses of melanoma in patients 18 to 39 from 1970 to 2009. The study found the incidence of melanoma increased eightfold among young women and fourfold among young men. The lifetime risk of melanoma is higher in males than females, but the opposite is true in young adults and adolescents, Dr. Brewer says.

Researchers also found mortality rates from the disease have improved over the years, likely due to early detection of skin cancer and prompt medical care.

"People are now more aware of their skin and of the need to see a doctor when they see changes," Dr. Brewer says. "As a result, many cases may be caught before the cancer advances to a deep melanoma, which is harder to treat."

The researchers speculate that the use of indoor tanning beds is a key culprit in the rising cancer rate in young women.

"A recent study reported that people who use indoor tanning beds frequently are 74 percent more likely to develop melanoma, and we know young women are more likely to use them than young men," Dr. Brewer says. Despite abundant information about the dangers of tanning beds, he adds, young women continue to use them. "The results of this study emphasize the importance of active interventions to decrease risk factors for skin cancer and, in particular, to continue to alert young women that indoor tanning has carcinogenic effects that increase the risk of melanoma."

Janey Helland, of Mapleton, Minn., didn't think twice when tanning in high school and college.

"I used tanning beds to get ready for homecoming and prom," she says. "In college, I tanned before a trip to Barbados because I didn't want to get sunburned." At age 21, Helland noticed an abnormal spot on her leg. It was melanoma, and the diagnosis changed Helland's life. "I really didn't know what my future was going to look like, or if I'd even have one."

Two years later, she is cancer-free and dedicated to educating others. "I would advocate that it's better to be safe than sorry," she says. "My advice is to educate yourself and research the risk factors."

Childhood sunburns and ultraviolet exposure in adulthood may also contribute to melanoma development, the researchers say.

Cancerous cells in mice treated using nanoparticles and magnatic current

Using nanoparticles and alternating magnetic fields, University of Georgia scientists have found that head and neck cancerous tumor cells in mice can be killed in half an hour without harming healthy cells.

The findings, published recently in the journal Theranostics, mark the first time to the researchers' knowledge this cancer type has been treated using magnetic iron oxide nanoparticle-induced hyperthermia, or above-normal body temperatures, in laboratory mice.

"We show that we can use a small concentration of nanoparticles to kill the cancer cells," said Qun Zhao, lead author and assistant professor of physics in the Franklin College of Arts and Sciences. Researchers found that the treatment easily destroyed the cells of cancerous tumors that were composed entirely of a type of tissue that covers the surface of a body, which is also known as epithelium.

Several researchers around the globe are exploring the use of heated nanoparticles as a potential cancer treatment. Previous studies also have shown that high temperatures created by combining magnetic iron oxide nanoparticles with strong alternating magnetic currents can create enough heat to kill tumor cells. Zhao said he is optimistic about his findings, but explained that future studies will need to include larger animals before a human clinical trial could be considered.

For the experiment, researchers injected a tiny amount -- a tenth of a teaspoon, or 0.5 milliliter -- of nanoparticle solution directly into the tumor site. With the mouse relaxed under anesthesia, they placed the animal in a plastic tube wrapped with a wire coil that generated magnetic fields that alternated directions 100,000 times each second. The magnetic fields produced by the wire coil heated only the concentrated nanoparticles within the cancerous tumor and left the surrounding healthy cells and tissue unharmed.

Zhao said the study paves the way for additional research that might investigate how to use a biodegradable nanoparticle material similar to magnetic iron oxide for other roles in fighting cancer, such as carrying and delivering anti-cancer drugs to the tumor site.

"When the cancer cell is experiencing this heated environment, then it becomes more susceptible to drugs," Zhao said.

Magnetic iron oxide nanoparticles could be useful in improving the contrast in magnetic resonance imaging at a cancer site, he said. In other words, the nanoparticles could help physicians detect cancer even if the cancer is not visible to the naked eye with an MRI scan.

"The reason I am interested in using these magnetic nanoparticles is because we hope to one day be able to offer diagnosis and therapeutics, or theranostics, using a single agent," Zhao said.

Embryonic stem cells shift metabolism in cancer-like way upon implanting in uterus

Shortly after a mouse embryo starts to form, some of its stem cells undergo a dramatic metabolic shift to enter the next stage of development, Seattle researchers have reported. These stem cells start using and producing energy like cancer cells.

"These findings not only have implications for stem cell research and the study of how embryos grow and take shape, but also for cancer therapy," said the senior author of the study, Dr. Hannele Ruohola-Baker, University of Washington professor of biochemistry. The study was collaborative among several research labs in Seattle.

The metabolic transition they discovered occurs very early as the mouse embryo, barely more than a speck of dividing cells, implants in the mother's uterus. The change is driven by low oxygen conditions, Ruohola-Baker explained.

The researchers also saw a specific type of biochemical slowdown in the stem cells' mitochondria -- the cells' powerhouses. The phenomenon previously was associated with aging and disease. This was the first example of the same downshift controlling normal early embryonic development.

"This downshift coincides with the time when the germ line, the keeper of the genome for the next generation, is set aside," Ruohola-Baker said.. "Hence reduction of mitochondrial reactive oxygen species may be nature's way to protect the future."

Embryonic stem cells are called pluripotent because they have the ability to renew themselves and have the potential to become any cell in the body. Self-sustaining and versatile are qualities necessary for the growth, repair and maintenance of the body -- and for regenerative medicine therapies.

Although they share these sought-after qualities, "Pluripotent stem cells come in several flavors," Ruohola-Baker explained. They differ in subtle ways that expand or shrink their capacities as the raw living material from which animals are shaped.

There's a big reason why the researchers wanted to understand the distinction between the stem cells that make up the inner cell mass of the free-floating mouse embryo, and those in the epiblast, or implantation stage. Mouse embryonic cells at the epiblast stage more closely resemble human embryonic stem cells -- and cancer cells.

Human stem cells and mouse epiblast stem cells have lower mitochondrial respiration activity than do earlier stage mouse stem cells. This reduction occurs despite the fact that the later stage stem cells have more mature mitochondria. The researchers confirmed that certain genes that control mitochondria are turned down during the transition from inner cells mass to epiblast cells.

Instead, the transitioning cells obtain their energy exclusively from breaking down a sugar, glucose. In contrast, the earlier stage mouse embryonic stem cells have more energy options, dynamically switching from mitochondrial respiration to glucose breakdown on demand.

As the embryo enlarges from a few dividing cells to a dense mass that buries into uterus for further development, oxygen comes at a premium.

The researchers discovered that the low-oxygen conditions activate a transcription factor called hypoxia-inducible factor 1alpha. This factor is sufficient to drive mouse embryonic stem cells to rely exclusively on glucose metabolism for their energy. The next challenge is to reveal whether the metabolic switch is deterministic for the fate of these stem cells, in normal as well as in cancer development.

This forced metabolic switch may determine the functional fate of some of the tiny mass of cells making up the primordial embryo. They transition first into epiblast stem cells and, afterward produce the entire developing embryo.

In cancer cells, the shift to a sugar-busting metabolism is known as the Warburg effect, the researchers explain. The Warburg effect sets in motion the biochemical activities that provide the fuel and materials required for rapid tumor cell growth and division.

The Warburg effect in embryonic cells, the researcher proposed, "may serve a similar function in preparation for the dramatic burst of embryonic growth and for the formation of the layers of the early embryo that later will become organs and other body structures."

Identifying specific cancers using molecular analysis

Researchers from Huntsman Cancer Institute (HCI) at the University of Utah report they have discovered a method to identify cancer-causing rearrangements of genetic material called chromosomal translocations quickly, accurately, and inexpensively. A description of the method and the research results appear online in this month's issue of the EMBO Molecular Medicine journal.

Many cancers result from chromosomal translocations in tumor cells. Hundreds of cancer-causing translocations have been discovered, but current methods for detecting them have significant shortcomings.

The technique, developed in the lab of Stephen Lessnick, M.D., Ph.D., director of the Center for Children's Cancer Research at HCI, combines microarray technology, which can look for thousands of translocations in a single test, with a novel antibody that is used to detect the presence of the translocation . "We're moving past the age when a pathologist looking through the microscope at a tumor sample is the best way to diagnose what type of cancer it is," said Lessnick. "The molecular tests currently available are slow, inefficient, and expensive, and one of the biggest issues is that you need high-quality tumor samples, not always available in the clinical setting, to do them." According to Lessnick, his method tolerates real-life specimens much better than the current standard techniques.

"Originally, this method was used in HCI's Cairns lab (headed by Bradley R. Cairns, Ph.D.) to study RNA in yeast. We took their method and applied it to our study of chromosomal translocations in human tissue," Lessnick said. He said the next task is to find a commercial partner to develop this research from a 'proof of principle' into a diagnostic test that doctors can use to help their patients.

"With this method, there's potential to develop a single array that could test for every known cancer-causing translocation simultaneously. Currently, a clinician has to decide beforehand which specific cancer to test," he said.

The research used Ewing's sarcoma (a rare childhood cancer) as the case study for developing the method, but Lessnick maintains that the technology can be easily applied to any type of cancer caused by a translocation.

Experts say that more than half of all cancer disease is preventable

More than half of all cancer is preventable, and society has the knowledge to act on this information today, according to Washington University public health researchers at the Siteman Cancer Center in St. Louis.

In a review article published in Science Translational Medicine March 28, the investigators outline obstacles they say stand in the way of making a huge dent in the cancer burden in the United States and around the world.

"We actually have an enormous amount of data about the causes and preventability of cancer," says epidemiologist Graham A. Colditz, MD, DrPH, the Niess-Gain Professor at the School of Medicine and associate director of prevention and control at the Siteman Cancer Center. "It's time we made an investment in implementing what we know."

What we know, according to Colditz and his co-authors, is that lifestyle choices people make and that society can influence in a number of ways -- from tobacco use to diet and exercise -- play a significant role in causing cancer. Specifically, the researchers cite data demonstrating that smoking alone is responsible for a third of all cancer cases in the United States. Excess body weight and obesity account for another 20 percent.

But beyond individual habits, they argue that the structure of society itself -- from medical research funding to building design and food subsidies -- influences the extent of the cancer burden and can be changed to reduce it.

The obstacles they see to implementing broad cancer prevention strategies are:

Skepticism that cancer can be prevented. Smoking rates in different states demonstrate that 75 percent of lung cancer in the United States could be prevented with elimination of cigarette smoking.

The short-term focus of cancer research. Benefits of prevention may be underestimated because they take decades to show up, and research funding often spans five years or less.

Intervening too late in life to prevent cancer. Strategies like vaccination against cancer-causing viruses, such as the human papilloma virus that causes cervical cancer, work best when begun early, in this case before young people begin sexual activity.

Research focuses on treatment, not prevention. Treatments focus only on a single organ after diagnosis but behavioral changes reduce cancer and death rates from many chronic diseases.

Debate among scientists. They say health experts have a moral responsibility to highlight cancer risk factors even without knowing the biological mechanism by which they cause cancer.

Societal factors that affect health. Tobacco policy and government subsidies don't do enough to discourage unhealthy behavior, and in some cases they make the unhealthy options more accessible, especially in low-income communities.

Lack of collaboration across disciplines. Scientists and health experts must work together to learn what causes cancer, communicate that to the public and work with community leaders to implement policies that help people lead healthier lives, they say.

The complexity of implementing broad changes. With so many players involved, from health-care providers to government regulators to individuals, it will be difficult to implement broad change over the long term.

According to the American Cancer Society, an estimated 1,638,910 new cancer cases will be diagnosed this year in the United States. Also this year, 577,190 Americans are expected to die of cancer. Only heart disease kills more people in this country. And Colditz's research has shown that these cancer prevention strategies would reduce the burden of heart disease and other chronic conditions as well.

Despite the obstacles, Colditz and his colleagues point to some successes that they say demonstrate that broad change is possible. One example is the relatively quick elimination of unhealthy trans fats from the national diet. And the National Cancer Institute (NCI) has reported that lung cancer rates are declining in both men and women, supporting the benefits of tighter tobacco control policy.

"After working in public health for 25 years, I've learned that if we want to change health, we need to change policy," says co-author Sarah J. Gehlert, PhD, the E. Desmond Lee Professor of Racial and Ethnic Diversity at the Brown School of Social Work and the School of Medicine. "Stricter tobacco policy is a good example. But we can't make policy change on our own. We can tell the story, but it requires a critical mass of people to talk more forcefully about the need for change."

To combat skin cancer researchers are building melanoma vaccine

Mayo Clinic researchers have trained mouse immune systems to eradicate skin cancer from within, using a genetic combination of human DNA from melanoma cells and a cousin of the rabies virus. The strategy, called cancer immunotherapy, uses a genetically engineered version of the vesicular stomatitis virus to deliver a broad spectrum of genes derived from melanoma cancer cells directly into tumors. In early studies, 60 percent of tumor-burdened mice were cured in fewer than three months and with minimal side effects.

"We believe that this new technique will help us to identify a whole new set of genes that encode antigens that are important in stimulating the immune system to reject cancer. In particular, we have seen that several proteins need to be expressed together to generate the most effective rejection of the tumors in mice," says Richard Vile, Ph.D., a Mayo Clinic researcher in the Department of Molecular Medicine and a coauthor of the study, along with Jose Pulido, M.D., a Mayo Clinic ophthalmologist and ocular oncologist.

Dr. Vile's success with melanoma adds to Mayo Clinic's growing portfolio of experimental cancer vaccines, which includes an active clinical trial of vesicular stomatitis vaccines for liver cancers. Future studies could include similar vaccines for more aggressive cancers, such as lung, brain and pancreatic.

"I do believe we can create vaccines that will knock them off one by one," Dr. Vile says. "By vaccinating against multiple proteins at once, we hope that we will be able to treat both the primary tumor and also protect against recurrence."

The immune system functions on a seek-and-destroy platform and has fine-tuned its capacity to identify viral invaders such as vesicular stomatitis virus. Part of the appeal of building cancer vaccines from the whole spectrum of tumor DNA is that tumors can adapt to the repeated attacks of a healthy immune system and display fewer antigens (or signposts) that the immune system can identify.

Cancers can learn to hide from a normal immune system, but appear unable to escape an immune system trained by the vesicular stomatitis virus with the wide range of DNA used in the library approach.

"Nobody knows how many antigens the immune system can really see on tumor cells," says Dr. Vile. "By expressing all of these proteins in highly immunogenic viruses, we increased their visibility to the immune system. The immune system now thinks it is being invaded by the viruses, which are expressing cancer-related antigens that should be eliminated."

Much immunotherapy research has slowed because of researchers' inability to isolate a sufficiently diverse collection of antigens in tumor cells. Tumors in these scenarios are able to mutate and reestablish themselves in spite of the body's immune system.

Link between inflammation and breast cancer metastases identified

The incidence of breast cancer-associated metastasis was increased in animal models of the chronic inflammatory condition arthritis, according to results of a preclinical study presented at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4. The results indicate that inflammatory cells known as mast cells play a key role in this increase and that interfering with mast cells reduces the occurrence of bone and lung metastases.

"The most devastating aspect of breast cancer is the emergence of tumor cells that grow to distant organs," said Lopamudra Das Roy, Ph.D., research assistant professor at the University of North Carolina in Charlotte, N.C. "It has been reported that sites of chronic inflammation are associated with the establishment and growth of tumor cells."

Prior research conducted by Das Roy established that the incidence of breast cancer metastasis to the bone and lungs was increased in arthritic mice. Because both breast cancer and arthritis are prevalent in women, specifically postmenopausal women, the researchers conducted an additional study using two groups of mice to identify what might be causing the association between arthritis and breast cancer metastases.

The first group of mice had spontaneous arthritis and was induced to have breast cancer. The second group of mice had spontaneous breast cancer and was induced to have arthritis. Because mice in both groups had enhanced numbers of mast cells within the bone and lung, Das Roy and colleagues focused on understanding how these cells might influence breast cancer metastasis.

"We found that there were many proinflammatory factors that are upregulated in the arthritic microenvironment and several of these proinflammatory factors known to influence metastases are produced by mast cells, which are activated by tumor-derived stem cell factor (SCF) binding to its receptor c-Kit," Das Roy said.

A subsequent key finding was that SCF/c-Kit signaling was increased in arthritic mice with breast cancer versus nonarthritic mice with breast cancer. This set the stage for examining the effects of blocking this signaling.

When the mice were treated with a therapy to target the c-Kit mast cell receptor in combination with celecoxib (a drug used to treat autoimmune arthritis), the incidence of breast cancer metastasis to the bone and lung was greatly reduced.

"The clinical implications of this research are huge," Das Roy said. "We already have data that show that women with breast cancer and arthritis have lower survival as compared with women with breast cancer and no arthritis. This research indicates that we may be able to design a therapy to block SCF/c-Kit signaling, which could help reduce metastases to the bone and lungs."