The combination of estrogen plus progestin, which women stopped taking in droves following the news that it may increase their risk of breast cancer, may decrease their risk of colorectal cancer, according to a report published in the January issue of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research.

“Compared to women who had never taken these hormones, the use of estrogen plus progestin was associated with a reduced risk of colorectal cancer,” said Jill R. Johnson, M.P.H., a doctoral student at the University of Minnesota School of Public Health.

The largest risk reduction, approximately 45 percent, was seen among women who had completed use of estrogen plus progestin five or more years previously.

Johnson and her colleagues extracted data from 56,733 postmenopausal women who participated in the Breast Cancer Detection Demonstration Project follow-up study.  Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires between 1979 and 1998.  During an average 15 years of follow-up, Johnson and colleagues identified 960 new cases of colorectal cancer in this population.

Any use of estrogen therapy was associated with a 17 percent reduced risk in colorectal cancer.  Among those who used estrogen, the largest reductions were seen among those who were current users (25 percent reduced risk) and users of ten or more years duration (26 percent reduced risk).

Researchers also found a 22 percent reduced risk among those who had ever used estrogen plus progestin in combination.  They further found a 36 percent reduction in risk among those who had used progestin sequentially or less than 15 days per month.  Past users of estrogen plus progestin, who had stopped at least five years ago, had a 45 percent risk reduction.

Although Johnson’s study was not designed to look at biological mechanisms for the protective effect of estrogen therapy, she did say that previous research has suggested that hormones may play a role in decreasing levels of insulin-like growth factors, thereby reducing risk.  “The biological mechanism will need to be explored in further studies,” said Johnson.

A new study reveals that the metadherin gene (MTDH) plays a role in both cancer metastasis and resistance to chemotherapy.  The research, published by Cell Press in the January 6th issue of the journal Cancer Cell, identifies MTDH as a promising therapeutic target for high risk breast cancers.

“Most breast cancer patients resist currently available therapeutic regimens and succumb to recurrent tumors that spread to distant vital organs, such as lung, bone, liver and brain,” explains senior study author, Dr. Yibin Kang from the Department of Molecular Biology at Princeton University.  “Resistance to chemotherapy and metastasis remain major challenges to curative therapy.”

Previous research identified several clinically applicable genetic signatures associated with poor clinical outcomes of breast cancer.  However, the signatures differed between independent studies, making it difficult to identify overlapping, functionally relevant genes that might be useful for understanding, and eventually preventing, breast cancer metastasis and chemoresistance.

To further unravel the complex genetic events involved in breast cancer, Dr. Kang and colleagues developed a sophisticated computational algorithm designed to identify genomic changes in an extensive collection of breast tumor samples.  The researchers discovered abnormally high copy numbers of chromosomal region 8q22 in more than 30% of breast cancers examined.  Patients having this type of breast cancer often had a shorter survival time due to recurrent and metastatic cancers.

The researchers went on to find that among a handful of genes in the 8q22 region, MTDH was responsible for both increased metastasis and increased resistance to chemotherapeutics.  MTDH protein increased metastasis of breast cancers to distant organs by enhancing the binding of cancer cells to blood vessels in these organs.  In addition, MTDH protein promoted cell survival, allowing cancer cells to become more resistant to a wide variety of chemotherapeutic agents that are currently used to treat breast cancer.  Further, when the researchers genetically altered the cancer cells to reduce expression of MTDH, the tumor cells became less capable of metastasis and more likely to be eliminated by chemotherapeutic agents.

“These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk,” concludes Dr. Kang.  “Molecular targeting of MTDH may not only prevent the seeding of breast cancer cells to the lung and other vital organs but also sensitize tumor cells to chemotherapy, thereby stopping the deadly spread of breast cancer.”

A new study reveals critical molecular mechanisms associated with the development and progression of human neuroblastoma, the most common cancer in young children.  The research, published by Cell Press in the January 6th issue of the journal Cancer Cell, may lead to development of future strategies for treatment of this aggressive and unpredictable cancer.

Neuroblastoma cells are derived from migratory neural crest cells that give rise to the peripheral sympathetic nervous system.  During normal development, neural crest cells stop dividing and differentiate.  However, neuroblastoma cells seem to have lost this capacity.  Previous work has shown that amplification of the MYCN gene, which disrupts control of cell division and differentiation, is a strong predictor of poor prognosis in neuroblastoma.

“We speculated that genes that are expressed in a MYCN-dependent manner might be required specifically for the growth of MYCN-amplified neuroblastomas and that MYCN-amplified neuroblastomas might depend not only on N-Myc itself, but also on upstream regulatory factors or downstream target genes,” explains senior study author, Dr. Martin Eilers, from the University of Wurzburg in Germany.

Dr. Eilers and colleagues performed a genetic screen of nearly 200 genes that are dependent on amplified MYCN in human neuroblastoma or are direct targets of Myc.  The researchers found that the oncogene AURKA is required for growth of MYCN-amplified neuroblastoma cells, but not cells lacking amplified MYCN.

AURKA encodes the kinase Aurora A which is dysregulated in multiple types of cancer cells.  Interestingly, Aurora A kinase activity was not required for N-Myc stabilization.  Instead, elevated Aurora A levels in MYCN-amplified neuroblastoma cells interfered with the PI3-kinase-dependent and mitosis-specific degradation of N-Myc.  This suggests that small molecule inhibitors of Aurora A kinase may not be effective at inhibiting the oncogenic functions of Aurora A.

“Our results show that stabilization of N-Myc is a critical oncogenic function of Aurora A in childhood neuroblastoma; the challenge will now be to find ways to interfere with this function in order to find new approaches for the therapy of these tumors,” says Dr. Eilers.  “The findings also suggest that the current views about why Aurora A is oncogenic may need to be re-evaluated.”

Researchers at the Salk Institute for Biological Studies have developed a versatile mouse model of glioblastoma—the most common and deadly brain cancer in humans—that closely resembles the development and progression of human brain tumors that arise naturally.

“Mouse models of human cancer have taught us a great deal about the basic principles of cancer biology,” says Inder Verma, Ph.D., a professor in the Laboratory of Genetics.  “By definition, however, they are just that: approximations that simulate a disease but never fully capture the molecular complexity underlying disease in humans.”

Trying to mimic randomly occurring mutations that lie at the heart of all tumors, the Salk researchers used modified viruses to shuttle cancer-causing oncogenes into a handful of cells in adult mice.  Their strategy, described in the Jan. 4, 2009 online issue of the journal Nature Medicine, could not only prove a very useful method to faithfully reproduce different types of tumors but also to elucidate the nature of elusive cancer stem cells.

The most frequently used mouse cancer model relies on xenografts: Human tumor tissue or cancer cell lines are transplanted in immuno-compromised mice, which quickly develop tumors.  “These tumors are very reproducible, but this approach ignores the fact that the immune system can make or break cancer,” says first author Tomotoshi Marumoto, Ph.D., a former postdoctoral researcher in the Verma lab and now an assistant professor at the Kobe Medical Center Hospital in Kobe, Japan.  Other animal models either express oncogenes in a tissue-specific manner or shut down the expression of tumor suppressor genes in the whole tissue.  “But we know that tumors generally develop from a single cell or a small number of cells of a specific cell type, which is one of the major determinants of the characteristics of tumor cells,” explains postdoctoral researcher and co-author Dinorah Friedmann-Morvinski.

To sidestep the shortcomings of currently used cancer models, the Salk team harnessed the power of lentiviral vectors to infect nondividing as well as dividing cells and ferry activated oncogenes into a small number of cells in adult, fully immunocompetent mice.  After initial experiments confirmed that the approach was working, Marumoto injected lentiviruses carrying two well-known oncogenes, H-Ras and Akt, into three separate brain regions of mice lacking one copy of the gene encoding the tumor suppressor p53: the hippocampus, which is involved in learning and memory; the subventricular zone, which lines the brain’s fluid-filled cavity; and the cortex, which governs abstract reasoning and symbolic thought in humans.

He specifically targeted astrocytes, star-shaped brain cells that are part of the brain’s support system.  They hold neurons in place, nourish them, digest cellular debris, and are suspected to be the origin of glioblastoma.  Within a few months, massive tumors that displayed all the histological characteristics of glioblastoma multiforme preferentially developed in the hippocampus and the subventricular zone.

The ability of adult stem cells to divide and generate both new stem cells (called self-renewal) as well as specialized cell types (called differentiation) is the key to maintaining healthy tissues.  The cancer-stem-cell hypothesis posits that cancers grow from stem cells in the same way healthy tissues do.  Known as tumor-initiating cells with stem like properties these cells have many characteristics in common with normal stem cells in that they are self-replicating and capable of giving rise to populations of differentiated cells.

To test whether the induced glioblastomas contained bona fide cancer stem cells, Marumoto isolated cultured individual tumor cells in the lab.  These cells behaved and looked just like neural stem cells.  They formed tiny spheres—often called tumor spheres—and expressed proteins typically found in immature neural progenitor cells.  When given the right chemical cues, these brain cancer stem cells matured into neurons and astrocytes.

“They displayed all the characteristics of cancer stem cells, and less than 100 and as few as 10 cells were enough to initiate a tumor when injected into immunodeficient mice,” says Friedmann-Morvinski.  Most xenograft models for brain tumors using tumor cell lines require at least 10,000 cells.

“These findings show that our cancer model will not only allow us to start understanding the biology of glioblastoma but will also allow us to answer many questions surrounding cancer stem cells,” says Verma.  Although the work described to date pertains to glioblastoma, Verma and his team are currently using this methodology to investigate lung, pancreatic, and pituitary cancers.

Women who took beta carotene or vitamin C or E or a combination of the supplements had a similar risk of cancer as women who did not take the supplements, according to data from a randomized controlled trial in the December 30 online issue of the Journal of the National Cancer Institute.

Epidemiological studies have suggested that people whose diets are high in fruits and vegetables, and thus antioxidants, may have a lower risk of cancer.  Results from randomized trials that address the issue, however, have been inconsistent and have rarely supported that observation.

In the current study, Jennifer Lin, Ph.D., of the Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues tested the impact of antioxidant supplements on cancer incidence in a randomized controlled trial.  A total of 7,627 women who were at high risk of cardiovascular disease were randomly assigned to take vitamin C, vitamin E, or beta-carotene.

With an average of 9.4 years of follow-up time, there was no statistically significant benefit from antioxidant use compared with placebo in terms of disease risk or mortality due to cancer.  Overall, 624 women developed cancer and 176 died from cancer during the follow-up time.  Compared with placebo, the relative risk of a new cancer diagnosis was 1.11 for women who took vitamin C, 0.93 for women who took vitamin E, and 1.00 for women who took beta carotene.  None of these relative risks was statistically significantly different from 1.

“Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality,” the authors conclude.  “In our trial, neither duration of treatment nor combination of the three antioxidant supplements had effects on overall fatal or nonfatal cancer events.  Thus, our results are in agreement with a recent review of randomized trials indicating that total mortality was not affected by duration of supplementation and single or combined antioxidant regimens.”

In an accompanying editorial, Demetrius Albanes, M.D., of the National Cancer Institute, reviewed data from previous randomized controlled trials that examined supplement use and cancer incidence.  He noted that while the trial data reported by Lin are negative with respect to lowering cancer risk, there is valuable information uncovered that should not be overlooked.  There was a trend for a reduction in colon cancer with vitamin E supplementation, which has been observed in other studies.  Additionally, beta carotene use was associated with a modest excess of lung cancer, which is consistent with previous reports.

“Null trials or those with unexpected outcomes should not, however, be viewed as failures; they have and will con¬tinue to shed light on the causes of cancer and help us discover the means for its prevention,” the editorialist concludes.

New research in an animal model suggests that a diet high in inorganic phosphates, which are found in a variety of processed foods including meats, cheeses, beverages, and bakery products, might speed growth of lung cancer tumors and may even contribute to the development of those tumors in individuals predisposed to the disease.

The study also suggests that dietary regulation of inorganic phosphates may play an important role in lung cancer treatment.  The research, using a mouse model, was conducted by Myung-Haing Cho, D.V.M., Ph.D., and his colleagues at Seoul National University, appears in the first issue for January of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

“Our study indicates that increased intake of inorganic phosphates strongly stimulates lung cancer development in mice, and suggests that dietary regulation of inorganic phosphates may be critical for lung cancer treatment as well as prevention,” said Dr. Cho.

Lung cancer is the number one cause of cancer deaths in the world and is also the most frequently diagnosed solid tumor.  Non–small cell lung cancer (NSCLC) constitutes over 75 percent of lung cancers and has an average overall 35-year survival rate of 14 percent.  Earlier studies have indicated that approximately 90 percent of NSCLC cases were associated with activation of certain signaling pathways in lung tissue.  This study revealed that high levels of inorganic phosphates can stimulate those same pathways.

“Lung cancer is a disease of uncontrolled cell proliferation in lung tissue, and disruption of signaling pathways in those tissues can confer a normal cell with malignant properties,” Dr. Cho explained.  “Deregulation of only a small set of pathways can confer a normal cell with malignant properties, and these pathways are regulated in response to nutrient availability and, consequently, cell proliferation and growth.

“Phosphate is an essential nutrient to living organisms, and can activate some signals,” he added.  “This study demonstrates that high intake of inorganic phosphates may strongly stimulate lung cancer development by altering those (signaling) pathways.”

In the study, lung cancer-model mice were studied for four weeks and were randomly assigned to receive a diet of either 0.5 or 1.0 percent phosphate, a range roughly equivalent to modern human diets.  At the end of the four-week period, the lung tissue was analyzed to determine the effects of the inorganic phosphates on tumors.

“Our results clearly demonstrated that the diet higher in inorganic phosphates caused an increase in the size of the tumors and stimulated growth of the tumors,” Dr. Cho said.

Dr. Cho noted that while a moderate level of phosphate plays an essential role in living organisms, the rapidly increasing use of phosphates as a food additive has resulted in significantly higher levels in average daily diets.  Phosphates are added to many food products to increase water retention and improve food texture.

“In the 1990s, phosphorous-containing food additives contributed an estimated 470 mg per day to the average daily adult diet,” he said.  “However, phosphates are currently being added much more frequently to a large number of processed foods, including meats, cheeses, beverages, and bakery products.  As a result, depending on individual food choices, phosphorous intake could be increased by as much as 1000 mg per day.”

“Although the 0.5 percent was defined as close to ‘normal,’ the average diet today is actually closer to the one percent diet and may actually exceed it,” Dr. Cho noted.  “Therefore, the 0.5 percent intake level is actually a reduced phosphate diet by today’s scale.”

Dr. Cho said future studies will help refine what constitutes a “safe” level of dietary inorganic phosphate, with recommendations that will be easily achievable in the average population.

“The results of this study suggest that dietary regulation of inorganic phosphates has a place in lung cancer treatment, and our eventual goal is to collect sufficient information to accurately assess the risk of these phosphates,” he said.

John Heffner, M.D., past president of the ATS, stated that this line of investigation in animals addresses the complex interactions between host factors and the environment that underlie cancer in man.  “We know that only some patients who smoke develop lung cancer but the reasons for this varying risk are unknown.  This study now provides a rationale for funding case-control studies in humans to determine the potential role of dietary phosphates in promoting cancer.”

Women who experience severe gestational hypertension may give birth to boys at lower risk for testicular cancer, although the exact reasons why are still unclear, according to a paper published in the November 1, 2008, issue of Cancer Research, a journal of the American Association for Cancer Research.

Andreas Pettersson, M.D., a doctoral student at Karolinska Institute in Sweden, said the protective effect of gestational hypertension may be due to the hormones that are released when a placenta malfunctions.

“Ironically, a malfunctioning placenta may lower the risk,” said Pettersson.  “One possible reason is that estrogens are lower in pregnancies that develop severe gestational hypertension or preeclampsia, and this lack of estrogens may lower the risk of testicular cancer.”

Pettersson and colleagues observed 293 cases of germ-cell testicular cancer in the Swedish Cancer Register and 861 controls in the Swedish Medical Birth Register.  They extracted data on maternal and pregnancy characteristics such as gestational hypertension, proteinuria, anemia and glucoseuria.

If women experienced severe gestational hypertension, their male offspring were 71 percent less likely to develop testicular cancer than those women who experienced no hypertension.  If the gestational hypertension was mild, there was a 62 percent increased risk of testicular cancer.

Beyond decreased estrogen, severe gestational hypertension and preeclampsia increases the level of human Chorionic Gonadotropin, another pregnancy-related hormone, which may also have a protective effect against testicular cancer.

Pettersson said that these findings add knowledge to the mechanisms behind testicular cancer, but he cautioned against reverse thinking.

“This study does not suggest that a woman who does not have gestational hypertension is going to give birth to a boy who is at increased risk for testicular cancer,” said Pettersson.

Scientific research shows that certain genes can influence a person’s likelihood to contract particular diseases, cancer for example. New research at the Masonic Cancer Center, University of Minnesota demonstrates that genetic markers may also show a person’s likelihood to survive the disease.

A research study led by Brian Van Ness, Ph.D., has successfully identified combinations of genes associated with early clinical relapse of multiple myeloma, a cancer of the white blood cells that produce antibodies. These results raise the possibility that a patient’s genetic background exerts an important influence on the patient’s prognosis and response to treatment.

“Ultimately, the goal of this research is to predict drug efficacy and toxicity based on a patient’s genetic profile, and develop individualized assessments and predictions for the right drug, at the right dose, for the right patient,” Van Ness said. This approach offers the dual benefits of avoiding unnecessary treatment for patients less likely to respond to a particular drug, and targeting treatments to those who will benefit most.

The findings are reported in the current issue of the research journal BMC Medicine. Van Ness heads the University’s Department of Genetics, Cell Biology, and Development, and conducts research through the Masonic Cancer Center.

In this study, Van Ness and his colleagues used genetic information that the International Myeloma Foundation has gathered from myeloma patients worldwide through its program, Bank On A Cure®. This first-of-its-kind program involves several of the major treatment and research centers for myeloma worldwide and thousands of myeloma patients who donate DNA samples to the bank. The University of Minnesota houses one of the program’s two DNA banks (the other is in London), and Van Ness is co-director of the program.

“Although myeloma is considered a fatal disease, individual patients have widely varied rates of disease progression and response to treatment because of attributes encoded in their DNA,” Van Ness said.

According to Van Ness, the research study findings demonstrate that cancer outcomes differ because patients vary in the ways they absorb, distribute, metabolize, and transport drugs across cell membranes. Individual variations in genes that regulate these biologic processes may not only affect the effectiveness of the drug, but also can result in adverse side effects.

The findings from this study pave the way for similar investigations into other cancers, neurological and cardiovascular conditions, organ transplants, and other diseases.

Scientists at Dana-Farber Cancer Institute have identified a previously undetected trigger point on a naturally occurring “death protein” that helps the body get rid of unwanted or diseased cells. They say it may be possible to exploit the newly found trigger as a target for designer drugs that would treat cancer by forcing malignant cells to commit suicide.Loren Walensky, MD, PhD, pediatric oncologist and chemical biologist at Dana-Farber and Children’s Hospital Boston, and colleagues report in the Oct. 23 issue of the journal Nature that they directly activated this trigger on the “executioner” protein BAX, killing laboratory cells by setting in motion their self-destruct mechanism.

The researchers fashioned a peptide (a protein subunit) that precisely matched the shape of the newly found trigger site on the killer protein, which lies dormant in the cell’s interior until activated by cellular stress. When the peptide docked into the binding site, BAX was spurred into assassin mode. The activated BAX proteins flocked to the cell’s power plants, the mitochondria, where they poked holes in the mitochondria’s membranes, killing the cells. This process is called apoptosis, or programmed cell death.

“We identified a switch that turns BAX on, and we believe this discovery can be used to develop drugs that turn on or turn off cell death in human disease by targeting BAX,” said Walensky, who is also an assistant professor of pediatrics at Harvard Medical School.

BAX is one of about two dozen proteins known collectively as the BCL-2 family. The proteins interact in various combinations leading to either the survival of a cell or its programmed self-destruction. Cancer cells have an imbalance of BCL-2 family signals that drives them to survive instead of dying on command.

The late Stanley Korsmeyer, MD, an apoptosis research pioneer and Walensky’s Dana-Farber mentor, had suggested that killer proteins like BAX could be activated directly by “death domains,” termed BH3, contained within a subset of BCL-2 family proteins. He hypothesized that this activating interaction was a fleeting “hit-and-run” event, making it especially challenging for scientists to study the phenomenon.

As suspected, the proposed BAX-activating interactions could not be captured by traditional methods. “When you tried to measure binding of the BH3 subunits to BAX, you couldn’t detect the interaction,” explained Walensky. He recognized, however, that the BH3 peptides being used in the laboratory didn’t retain the coiled shape of the natural BH3 domains that participate in BCL-2 family protein interactions. Walensky and his colleagues pioneered the design of “stapled” BH3 peptides, which contain a chemical crosslink that locks the peptides into their natural coiled shape. With biologically active shape restored, the stapled BH3 peptides bound directly to BAX and triggered its killer activity.

Defining how the activating peptides docked on BAX remained a formidable catch-22. In order to solve the structure of an interaction complex, it needed to be stable enough for analysis. In this case, the BH3 binding event itself triggers BAX to change its shape and self-associate to perform its killer function, rendering the activating interaction unstable by definition.

What if, Walensky proposed, you could set up the interaction of BH3 and BAX under laboratory conditions that caused it to be more stable or proceed in slow motion? The plan was to adjust the potency of the stapled BH3 peptide so that, according to Walensky, “it was good enough to bind BAX, yet activate it just a bit more slowly so that we could actually study the interaction.” The researchers would then look for any detectable shift in the three-dimensional structure of the BAX protein to help point them to the docking site.

The researchers used nuclear magnetic resonance (NMR) spectroscopy to monitor the arrangement of atoms in the protein. First authors of the Nature paper Evripidis Gavathiotis, PhD, of Walensky’s laboratory and Motoshi Suzuki, PhD, of Nico Tjandra, PhD,’s laboratory at the National Institutes of Health, succeeded in generating pure BAX protein that could be put into solution with the stapled BH3 peptide — the latter in increasing concentrations until it initiated a BH3-BAX interaction. Gavathiotis and Suzuki used the NMR technique to spot a group of BAX amino acids, the building blocks of proteins, which were affected by the addition of the stapled BH3 peptide.

“The discrete subset of amino acids that shifted upon exposure to the stapled BH3 peptide mapped to a completely unanticipated location on BAX,” said Walensky. The long-elusive binding site on BAX that initiates its killer activity was revealed. “Because BAX lies at the crossroads of the cell’s decision to live or die, drugs that directly activate BAX could kill diseased cells like in cancer and BAX-blocking drugs could potentially prevent unwanted cell death, such as in heart attack, stroke, and neurodegeneration,” said Walensky.

Working as part of a multi-institutional collaboration, scientists at Washington University School of Medicine in St. Louis have assembled the most complete catalog to date of the genetic changes underlying the most common form of lung cancer.  The research, published Oct. 23 in Nature, helps lay the foundation for more personalized diagnosis and treatment of a disease that is the leading cause of U.S. cancer deaths.

The research team identified 26 genes that are frequently mutated in a type of cancer called lung adenocarcinoma, a finding that more than doubles the number of genes already known to be linked to the deadly disease.  What’s more, by casting a wide net in their search for genetic alterations, the scientists are now beginning to see intriguing relationships.  They found that some of the same genes associated with lung tumors are also defective in other cancers, that smokers and non-smokers with lung cancer have distinct genetic defects and that several molecular pathways underlie most of the mutations.

“This genomic approach has given us a completely different view of lung cancer,” says Richard K. Wilson, Ph.D., director of Washington University’s Genome Sequencing Center and one of the study’s lead authors.  “This broad view will allow scientists to more accurately categorize tumors, which should speed efforts to develop more targeted therapies to fight the disease.”

More than 1 million people worldwide die of lung cancer each year, including more than 160,000 in the United States.  About 40 percent of them are adenocarcinoma, a type of non-small cell lung cancer and one that is exceedingly difficult to treat.  Only about 15 percent of patients are still alive five years after diagnosis.

“By harnessing the power of genomic research, this pioneering work has painted the clearest and most complete portrait yet of lung cancer’s molecular complexities,” says Alan E. Guttmacher, M.D., acting director of the National Human Genome Research Institute, the agency that funded the research.

The Nature study was conducted as part of the Tumor Sequencing Project, a collaborative effort to assemble a genome-wide catalog of the genetic mutations in lung adenocarcinoma.  Like most cancers, lung adenocarcinoma arises from changes that accumulate in people’s DNA over the course of their lives.  However, little is known about the precise nature of these genetic alterations, how they occur and how they disrupt biological pathways to cause cancer’s unfettered cell growth.

Working with lung cancer samples donated by 188 patients from across the United States, the group sequenced 623 suspect genes and compared them to the same genes in healthy tissues from the same patients.  Initially, they found more than 1,000 mutations across the samples.  Looking more closely, the researchers identified 26 genes mutated in a significant number of samples.  Most of the genes had not previously been associated with lung cancer but are found in other tumors.

The new genes fingered in lung adenocarcinoma include:

* Neurofibromastosis 1: Mutations in this gene cause a rare inherited neurological disorder that increases the risk of tumors that form on nerve tissues, including the brain, spinal cord and individual nerves;

* Ataxia telangiectasia mutated (ATM): Mutations of this gene have been found in a rare inherited neurological disorder and in various types of leukemia and lymphoma;

* Retinoblastoma 1: Mutations in this gene have linked to a rare childhood cancer that begins in the retina;

* Adenomatosis polyposis coli (APC): Mutations of this gene are common in colon cancer.

The team also examined the effects of the genetic mutations on biological pathways and determined which of the pathways is most crucial to lung adenocarcinoma.  This line of discovery is essential to efforts to develop new and better treatments for cancer.

For example, the researchers discovered that more than 70 percent of the 188 tumors had at least one mutation affecting the mitogen-activated protein kinase (MAPK) pathway, indicating it plays a pivotal role in lung cancer.  Based on those findings, the researchers suggested new treatment strategies for some subtypes of lung adenocarcinoma might include compounds that affect this pathway.  One such group of compounds, the MEK inhibitors, has produced promising results in mouse models of lung cancer.

“Looking at the pathways helps simplify the picture,” Wilson explains.  “Generally, we found that each mutation only occurs in a small percentage of the tumor samples, but when we looked at all the mutations that intersect a particular signaling pathway, we were surprised to find a lot of overlap in only a handful of pathways.  This gives us a much better idea of what goes wrong in cells when they become cancerous.”

Additionally, the finding that more than 30 percent of tumors had mutations affecting the rapamycin (mTOR) pathway raises the possibility that the drug rapamycin might be tested in lung adenocarcinoma.  The drug, which inhibits mTOR, is approved for use in organ transplants and renal cancer.

The researchers also analyzed the patterns of genetic changes in both smokers and non-smokers with lung cancer.  About 90 percent of lung cancer is linked to smoking, but 10 percent of patients diagnosed with the disease have never smoked.  They found that the number of mutations detected in tumor samples from smokers was significantly higher than in tumors from never-smokers.  Smokers’ tumors contained as many as 49 mutations, while none of the never-smokers’ tumors had more than five.

More work is needed to determine the clinical significance of these differences.  However, doctors do know that in some other types of cancer, high mutation levels may cause a tumor to spread rapidly or be resistant to treatment.

The study also confirmed previous observations that indicated lung cancer in never-smokers may be triggered by different genetic mutations than those in smokers.  For example, mutations in the epidermal growth factor (EGFR) gene were prevalent in tumors from non-smokers, while mutations in the KRAS and Src tyrosine kinase 11 genes were common in tumors from smokers.

“Our findings underscore the value of systematic, large-scale genome studies for exploring cancer.  We now must move forward to apply this approach to even larger groups of samples and a wider range of cancers,” Wilson says.

A normal developmental protein that sometimes goes awry has been implicated in breast cancer.  This discovery indicates the mechanism by which inappropriate expression of the Notch pathway may contribute to breast cancer.

The breast cancer team at WEHI, led by Drs Jane Visvader and Geoff Lindeman from the Victorian Breast Cancer Research Consortium, have identified important roles for Notch genes in regulating breast development and function.

This discovery has important implications for breast cancer, since elevated levels of Notch have been linked to breast cancer.  The advance builds on the group’s 2006 discovery of the breast stem cell in mice.

Research carried out by Drs Toula Bouras and Bhupinder Pal has uncovered dual functions for Notch in breast tissue.

First, Notch helps restrict breast stem cell number, so that when Notch is ’switched off’, there is a resultant expansion in breast stem cells.

Second, Notch is important for ensuring that stem cells produce the sleeve of cells that normally line breast ducts.  These ‘luminal’ cells may be the cells that give rise to common types of breast cancer.

Thus, Notch helps to orchestrate the formation of breast tissue: it plays an important role in controlling stem cell number and instructs stem cells to produce luminal cells.

Significantly, Dr Bouras and colleagues found that errant activation of Notch resulted in uncontrolled growth of luminal precursors, leading to the formation of breast tumours.

The work has spotlighted the potential importance of deregulated Notch in ductal precursor cells as a forerunner to breast cancer.

The researchers say that it is too early to speculate on whether the design of anti-Notch therapies could help patients facing breast cancer.

Moderate consumption of red wine may decrease the risk of lung cancer in men, according to a report in the October issue of Cancer Epidemiology, Biomarkers & Prevention¸ a journal of the American Association for Cancer Research.

“An antioxidant component in red wine may be protective of lung cancer, particularly among smokers,” said Chun Chao, Ph.D., a research scientist at Kaiser Permanente Department of Research and Evaluation in Pasadena, California.

Chao analyzed data collected through the California Men’s Health Study, which linked clinical data from California’s health system with self-reported data from 84,170 men aged 45 to 69 years. Researchers obtained demographics and lifestyle data from surveys computed between 2000 and 2003, and identified 210 cases of lung cancer.

Researchers measured the effect of beer, red wine, white wine and liquor consumption on the risk of lung cancer. Adjustments were made for age, race/ethnicity, education, income, body mass index, history of chronic obstructive pulmonary disease or emphysema, and smoking history.

Among the study participants, there was on average a two percent lower lung cancer risk associated with each glass of red wine consumed per month. The most substantial risk reduction was among smokers who drank one to two glasses of red wine per day. The researchers reported a 60 percent reduced lung cancer risk in these men. Researchers warned men to stop smoking as the best way to reduce lung cancer risk; noting that even men who drank one to two glasses of red wine per day still face higher lung cancer risk than do non-smokers.

No clear associations with lung cancer were noted for consumption of white wine, beer, or liquor. “Red wine is known to contain high levels of antioxidants. There is a compound called resveratrol that is very rich in red wine because it is derived from the grape skin. This compound has shown significant health benefits in preclinical studies,” Chao said.

Chao said their findings should not be construed to recommend heavy alcohol consumption.

New research suggests that the identification and examination of key cell signaling events required for initiation and progression of cancer might be best accomplished at the single cell level.  The research, published by Cell Press in the October issue of the journal Cancer Cell, provides new insight that may lead to better diagnosis and treatment of some complex cancers.

Recent advances in flow cytometry, a technique that allows detailed examination of individual cells, have enabled simultaneous measurement of cell type and signaling pathways.  Lead study authors Dr. Garry P. Nolan from the Stanford University School of Medicine and Dr. Mignon L. Loh from the UCSF Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center were interested in determining whether examination of cellular signaling abnormalities caused by genetic mutations associated with cancer could provide a precise correlation between aberrant signaling events and disease physiology.

“We had a strong hunch that we could use ‘deranged’ cellular signaling to track how cancer cell populations behave at diagnosis through therapy, as well as during remission or return of the cancer,” explains Dr. Nolan.  “By measuring how signaling proteins respond to certain stimuli at diagnosis and which are modified by resistant cancers, we are essentially monitoring key highways that cancers use to drive their own growth.  The advantage of diagnosing a patient’s cancer at the single cell level provides us an approach for early detection of cancer and yield insights into how cancer cells are responding or adapting to therapy.  A byproduct of the single cell technique, when appropriately extended, is that we should eventually be able to predict those pathways cancer cells might be using to circumvent current therapies and more intelligently direct the patient towards alternative treatments.”

The researchers focused on juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative disorder of young children.  JMML is difficult to diagnose and has a complex molecular profile.  Although genetic lesions impacting Ras signaling and alterations downstream of the activated GM-CSF receptor (both linked with inappropriate cell growth and survival) have been linked with JMML, there are very few methods for identifying therapeutic agents and assessing efficacy in JMML patients.

The researchers used flow cytometry to profile signaling at the single cell level, including molecules associated with GM-CSF and Ras signaling, for the presence of primary JMML cells with altered signaling behavior that correlated with disease physiology.  Cells samples came from JMML patients, healthy individuals and patients with other myeloproliferative disorders, some who had initially been diagnosed with JMML.  An unexpected STAT5 signaling signature was seen in most of the JMML patients, suggesting a critical role for JAK-STAT signaling in the biological mechanism of this cancer and suggesting potential targets for future therapies.

“This work successfully used single-cell profiling to follow patients over time and show that disease status in JMML – at diagnosis, remission, relapse and transformation – was indicated by a subset of cells with an abnormal signaling profile,” says Dr. Loh.  “Revealing cell subpopulations, even rare cells, that are associated with disease opens additional avenues for measuring minimal residual disease, assessing biochemical effects of targeted therapies at the single cell level and understanding drug actions and mechanisms of diseases of heterogeneous origins and manifestations in diverse patient populations.”

Some bacteria may help protect against the development of a type of esophageal cancer, known as adenocarcinoma, according to a new review of the medical literature.  These bacteria, which are called Helicobacter pylori, live in the stomachs of humans.

The review, published in the October issue of Cancer Prevention Research, a journal of the American Association for Cancer Research, found that people who had H. pylori strains carrying a gene called CagA were almost half as likely to get adenocarcinoma of the esophagus, a cancer that develops in the tube that passes food from the throat to the stomach.

“CagApositive strains of H. pylori may decrease the risk of adenocarcinoma by reducing acid production in the stomach and, therefore, reducing acid reflux to the esophagus,” said study co-author Farin Kamangar, M.D., Ph.D., a research fellow at the National Cancer Institute.  “It may also work by decreasing the production of the hormone ghrelin, which is secreted from the stomach to stimulate appetite.  A reduction in the level of ghrelin may lead to lower rates of obesity, an important risk factor for adenocarcinoma.”

H. pylori, estimated to be present in about half the world’s population, is a known cause of stomach cancer and ulcers.  Advancements in sanitation and antibiotics have made H. pylori less common and have consequently lowered the incidence stomach cancer and ulcers.  However, as H. pylori, including CagA-positive H. pylori, has become less common, esophageal adenocarcinomas have increased.  The study suggests that the declining rates of H. pylori in developed populations may be partly responsible for this increase.  Once a rare cancer, esophageal adenocarcinomas now constitute approximately half of all esophageal cancers cases in Western Countries like the U.S. and United Kingdom.

Although H. pylori was first discovered in the early 1980s, Kamangar says humans already had been living with the bacteria for 60,000 years.  The bacteria were once present in the stomachs of just about everyone.  Despite its potential for causing stomach cancer and ulcers, H. pylori’s long history of co-existence with humans suggests it also may have some beneficial effects, including possible roles in reducing diarrheal diseases and asthma, Kamangar said.

For the study, Kamangar and co-author Farhad Islami of the University of Tehran in Iran analyzed results from 19 published studies examining the associations of H. pylori with esophageal adenocarcinoma and esophageal squamous cell carcinoma, another type of esophageal cancer.

Caswell et al.report in the Journal of Cell Biology how the altered behavior of integrins can prompt metastatic movement in tumor cells.

On 2D surfaces, cells may migrate randomly, or be strongly unidirectional.  Integrins, which link the cell to the extracellular matrix, are known to influence the mode of migration, but exactly how has been unclear.  Recent work has suggested that an integrin called a5b1 drives random movement, while an integrin called avb3 has been associated with unidirectional migration—the balance of activity between the two determining the type of movement.  To further explore the contribution of a5b1 to random migration, the authors thus blocked avb3.

The treated cells changed their mode of migration from unidirectional to random, and their ability to invade 3D gels increased.  The changed behavior correlated with an increase in trafficking of a5b1 from intracellular compartments to anterior membrane protrusions.  But this increase in trafficking did not significantly alter a5b1’s contribution to cell adhesion—the ease with which cells were dislodged from a spinning disk increased as the amount of avb3 was reduced, but was not correlated with any change in a5b1.  This suggested that the cells’ increased invasive ability was due to alteration in some other property.  That property turned out to be activation of a proinvasive pathway headed by a kinase called Akt.

In avb3-blocked cells, a5b1 became associated with epidermal growth factor receptor 1 (EGFR1), which increased EGFR1’s abundance at the membrane protrusions, as well as its autophosphorylation.  Because EGFR1 is an activator of the Akt pathway, hey presto, the cells took on some new moves.