Survival niche for cancer cells

ScienceDaily (June 6, 2011) — Cancer cells do not grow equally well everywhere in the body. Often, they first create the conditions in which they can grow. Many years ago researchers discovered that solid tumors attract blood vessels to ensure their supply of nutrients by secreting specific factors. Now the immunologist Dr. Uta Höpken (Tumor and Immunogenetics Research Group at the Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch in the Helmholtz Association) and the hematologist Dr. Armin Rehm (Charité -- Virchow-Klinikum, Department of Hematology, Oncology and Tumor Immunology, MDC) have shown for the first time that specific forms of lymphoma also create their own survival niche.

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Lymphoma is the term used to describe a group of cancers of the lymphatic system. Lymphoma cells are abnormal immune cells (B cells or T cells), a specific group of white blood cells (lymphocytes). Using a mouse model, Dr. Rehm and Dr. Höpken demonstrated for the first time that the dissemination of lymphoma cells and their accumulation in the lymph nodes or spleen is dependent on specific signaling or growth substances, the chemokines CCL19 or CCL21.

Chemokines normally attract immune cells to a site of infection or inflammation. As former immune cells, lymphoma cells have special antennas (receptors) on their cell surface to which these signaling substances bind. If the lymphoma cells receive the signal via their CCR7 receptor, they migrate into the lymph nodes and into specific areas within the spleen.

Paradox

CCR7 not only mediates the migration of the lymphoma cells, it is also apparently crucial for their development and survival. As the two researchers showed in a next step, the lymphoma cells proliferate in the lymph nodes or in the spleen very slowly if this receptor is absent.

However, with the aid of CCR7 the cancer cells find their survival niche in the T-cell zones of the lymph nodes and the spleen. In these zones T cells are usually made fit for defense. "It is paradoxical that lymphoma cells as former B cells find an absolutely optimal microenvironment for their growth in these T-cell zones," Dr. Höpken said.

There the lymphoma cells crosstalk with stromal cells (connective tissue cells), which subsequently secrete increased quantities of the chemokines CCL19/CCL21. The CCR7 receptor not only mediates the homing of additional lymphoma cells to the lymph nodes or spleen, but also stimulates their proliferation.

On the other hand, the lymphoma cells themselves secrete a signaling substance (lymphotoxin) which induces the stromal cells to secrete more and more chemokines. In this way the lymphoma cells ensure their survival. This may also explain why some lymphomas are so aggressive.

In mice the researchers succeeded in breaking this vicious cycle. Using an active substance that blocks the binding of the lymphotoxins to the stromal cells, they were able to stop tumor growth. "In the future," Dr. Rehm said, "it may be that therapeutic strategies will not target the lymphoma cells directly, but rather the connective tissue so vital for their survival."

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Bankruptcy rates among cancer patients increase along with survival time, study finds

ScienceDaily (June 6, 2011) — An analysis linking federal bankruptcy court records to cancer registry data from nearly 232,000 adult cancer cases in western Washington during a 14-year period has found a hidden cost to survival: Insolvency rates increase along with the length of survival.

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"Patients diagnosed with cancer may face significant financial stress due to income loss and out-of-pocket costs associated with their treatment," said Scott Ramsey, M.D., Ph.D., a health care economist and internist at Fred Hutchinson Cancer Research Center who led the study. "On average, bankruptcy rates increased fourfold within five years of diagnosis." Ramsey presented the findings June 6 at the 2011 annual meeting of the American Society of Clinical Oncology in Chicago.

The study found that compared to the general population, bankruptcy rates were nearly twice as high among cancer patients one year after diagnosis, and that the median time to bankruptcy was two and a half years after diagnosis.

"The risk of bankruptcy for cancer patients is not well known, and previous studies have relied on individual self-reports about medically related reasons for bankruptcy filing," said Ramsey, a member of the Hutchinson Center's Public Health Sciences Division. "By linking two irrefutable government records of cancer and bankruptcy, we are able to determine how financial insolvency risk varies by cancer type, treatment and other factors," he said.

For the study, Ramsey and colleagues linked Washington state cancer registry data with federal bankruptcy court records in 13 western Washington counties. They measured the rate of bankruptcy after a first cancer diagnosis and identified factors that increased bankruptcy risk among people with common cancers.

They found that bankruptcy risk varies widely across cancer types. The risk is highest for lung, thyroid and leukemia/lymphoma cancer patients. In contrast, patients over 65, who are typically on Medicare, have a much lower risk of bankruptcy than younger patients. The researchers also found that bankruptcy rates among cancer patients have increased significantly since the U.S. financial crisis.

Ramsey and colleagues in the Hutchinson Center's Public Health Sciences Division, along with researchers at the University of Washington, conducted the study in collaboration with the U.S. Bankruptcy Court, Western District of Washington, Seattle.

The National Cancer Institute funded the research.

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Host Mta1 gene is required for optimal survival of schistosome parasites, a leading global cause of cancer

ScienceDaily (June 1, 2011) — By using mice lacking a crucial gene that controls the process of chromatin remodeling of cytokines including those responsible for inflammation and comparing them to normal wild type mice with the gene, researchers at the George Washington University School of Medicine and Health Sciences have shown that the gene, Mta1, is essential for the parasite Schistosoma haematobium to establish a productive infection and survival in the host.

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Schistosomes are flukes (helminth worms) that can infect people when they come into contact with water carrying the parasite. They proliferate and cause chronic inflammation and fibrosis in the liver, and many migrate to the bladder, causing inflammation, granulomas, and eventually, bladder cancer. S. haematobium is responsible for two-thirds of the world's 200 to 400 million cases of human schistosomiasis, resulting in an estimated 280,000 deaths per year.

Publishing in the July issue of the journal Hepatology, the researchers demonstrated the role of Mta1, the metastasis-associated protein-1 (MTA1) gene, in the survival of schistosomes. They infected two strains of mice with schistosome cercariae, a larval stage of the parasite, by immersing their tails in water containing cercariae, from which the cercariae penetrated the skin. The wild type mice had the intact Mta1 gene, and Mta1-/- mice lacked the gene but were normal in other respects.

At various times after infection, blood was taken from the portal circulatory system of the liver to look for worms, and parasite eggs were quantified from the liver tissue. "At the twelfth week of infection we found that the wild type mice, that is, the mice in which the gene was intact, had severe granulomatous lesions in the liver. The worm count was very high, and in the mice that did not have the gene, we did not have any worms. Neither did we have any eggs that we could collect from the portal perfusion," said lead author Sujit Nair, PhD, Assistant Research Professor in the department.

A total of 15 worms were recovered from the wild type mice but none from Mta1-/- mice. Similarly, wild type animals yielded 6556 eggs per gram of liver tissue while no eggs were evident in the Mta1-/- livers. The researchers confirmed that the Mta1-/- mice had been successfully infected with schistosomes by checking their serum antibody responses to the parasites. Both strains showed increasing antibody responses to antigen from the worms over the course of the infection. However, only the wild type mice made a strong antibody response to egg antigen, indicating a lack of egg production and full development to adulthood in the Mta1-/- mice.

The researchers concluded from these results that absence of the Mta1 gene does not compromise the mice's susceptibility to S. haematobium infection, but a lack of metastasis-associated protein-1 limits the survival and/or maturation of schistosomes in the host, and possibly egg release and deposition as well.

Senior author Rakesh Kumar, PhD, Professor and Chairman of the Department of Biochemistry and Molecular Biology in the School of Medicine and Health Sciences, explained that expression of MTA1, a nuclear protein, regulates the expression of inflammatory cytokines that are produced by Th1 and Th2 cells of the immune response. By increasing the expression of MTA1 in the wild type mice, the parasite "hijacks" MTA1, "which in turn will allow it to up-regulate pro-inflammatory cytokines, and these pro-inflammatory cytokines in turn will provide a favorable atmosphere for the pathogens to grow and cause a persistent inflammation. And it's the persistent inflammation over time which we believe can lead to cancer," he said. "If we take out MTA1, the entire inflammatory cascade will be significantly reduced."

Dr. Kumar said previous studies have used mice lacking aspects of their immune systems to study parasitic infections, but this is the first study to show a relationship between the host MTA1 and the schistosome parasite and the first "to show, using immune competent mice... that there is a deregulation of Th1 and Th2 responses in the Mta1-/- mice following parasite infection."

Co-author Peter Hotez, MD, PhD, Chair of the Department of Microbiology, Immunology, and Tropical Medicine at the University and President of the Sabin Vaccine Institute, said S. haematobium is one of the most important causes of cancer in the world but is often neglected in the developed world because it affects "the poorest regions of sub-Saharan Africa."

By providing insight into the mechanism by which worms cause inflammation, the current study has implications beyond the major cancer-causing flukes, and the findings may potentially extend to all worm parasites.

Furthermore, Dr. Hotez said the Schistosomes also cause granulomatous lesions on the cervix, uterus, and lower female genital tract. "Now we're just beginning to realize that this is an important problem for girls and women," he said. "Those granulomas are associated with a three- to four-fold increase in the horizontal transmission rate of HIV/AIDS. So this parasite may be one of the most important co-factors in the transmission of AIDS."

"From the on-going work in the laboratory, it is clear that the significance of MTA1 master coregulator is not going to be limited to Schistosoma as MTA1 appears to be equally important for the survival of liver fluke" said Dr. Kumar. "It is now possible for the team to start develop strategies to target MTA1 to reduce the global burden of diseases caused by parasite-induced inflammation."

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Drug combination extends survival in refractory lung cancer patients, study finds

ScienceDaily (June 2, 2011) — Scientists have identified a drug combination, when used in advanced lung cancer patients, shows a survival advantage in patients who no longer respond to existing therapies. They found that bexarotene and erlotinib can each repress the critical cell cycle regulator: cyclin D1. The drug combination also broadened the reach to include a specific subset of patients, such as those resistant due to the presence of a ras mutation in their cancer.

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The study was published in the June issue of Cancer Prevention Research.

"Erlotinib has been found to be most effective in women of Asian descent who are never smokers with bronchioalveolar carcinoma, and who tend to have activating mutations of the epidermal growth factor receptor," said Ethan Dmitrovsky, M.D., an Associate Scientific Director of the Samuel Waxman Cancer Research Foundation and a senior author on the study. "None of the patients in our study fit that demographic profile."

In fact, the patients in the cohort who exhibited the greatest response included non-Asian men who were smokers. Advanced lung cancer patients with refractory disease have a survival of four months or less with traditional chemotherapy. The results of the study showed a median survival of five and a half months and longer. Three patients from the trial are now living two to four years beyond the expected average.

The study's results were recently duplicated by a group of MD Anderson scientists, noted Konstantin Dragnev, M.D., who led this trial and is an associate professor at Dartmouth Medical School, in Hanover, N.H.

The most exciting part of the research, which was funded in part by the Samuel Waxman Cancer Research Foundation, "is that scientists were able to make a dent in the ras mutation subset of patients," said Dmitrovsky, who is a professor at Dartmouth Medical School. "This area is an unmet medical need. These are often times the most difficult lung cancers to treat."

"This study gives hope to a large group of lung cancer patients who currently have very few options," said Linda Wenger, the Executive Director of Uniting Against Lung Cancer. "It's critical for nonprofit foundations to continue supporting research in underserved areas to bring new ideas to the clinic."

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Therapeutic melanoma vaccine improves response rate, progression-free survival, study finds

ScienceDaily (June 2, 2011) — A vaccine for one of the most lethal cancers, advanced melanoma, has improved response rate and progression-free survival for patients when combined with the immunotherapy drug Interleukin-2, according to research led by scientists from The University of Texas MD Anderson Cancer Center and Indiana University Health Goshen Center for Cancer Care.

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The findings, published in the June 2 New England Journal of Medicine, mark the first vaccine study in the disease -- and one of the first in cancer overall -- to show clinical benefit in a randomized Phase III clinical trial. It's also the first cancer vaccine to show an improved response rate in patients.

The research was first presented on the plenary session of 2009 American Society of Clinical Oncology.

According to the American Cancer Society, melanoma has one of the fastest growing incidence rates of all cancers. In 2010, more than 68,130 people in the U.S. were diagnosed with melanoma and 8,700 died from the disease. The five-year survival rates for those with regional and metastatic disease are 65 percent and 16 percent, respectively.

"Obviously, this is a disease, in its advanced setting, in need of better therapies for patients," said Patrick Hwu, M.D., professor and Chair of the Department of Melanoma Medical Oncology and the study's senior author. "This study serves as a proof-of-principle for the role of vaccines in melanoma and in cancer therapy overall. If we can use the body's own defense system to attack tumor cells, we provide a mechanism for ridding the body of cancer without destroying healthy tissue."

During their tenure at the National Cancer Institute NCI), Hwu and Douglas Schwartzentruber, M.D., the medical director of the Goshen Center for Cancer Care, were involved in the vaccine's development and early basic and clinical studies. The peptide vaccine, known as gp100:209-217 (200M), works by stimulating patients' T cells, known for controlling immune responses.

"This vaccine activates the body's cytotoxic T cells to recognize antigens on the surface of the tumor. The T cells then secrete enzymes that poke holes in the tumor cell's membrane, causing it to disintegrate," explained Schwartzentruber, the study's principal investigator and corresponding author.

After an NCI-led Phase II study combining the vaccine with Interleukin-2 (IL-2) showed response rates of 42 percent in metastatic melanoma patients, a Phase III randomized trial with the two agents opened more than a decade ago.

Conducting a large, multi-institutional trial with IL-2, however, had its own set of unique challenges, explained Hwu, as not all cancer centers and community hospitals are capable of administering the immunotherapy. A highly specialized therapy associated with such significant side effects as low blood pressure and capillary leak syndrome, which poses risks to the heart and lung, IL-2 is often delivered in intensive care units. MD Anderson is one of the few centers with a dedicated in-patient unit exclusively designed for the drug's delivery; before, the institution was offering the therapy in its ICU.

In the Phase III trial, 185 patients at 21 centers across the country were enrolled in the study. All had advanced metastatic melanoma and were stratified for cutaneous metastasis, a known indicator of response to IL-2. Patients were randomized to receive either high dose IL-2, or IL-2 and vaccine. In the IL-2 arm, 94 patients were enrolled and 93 were treated and evaluated for response; 91 were enrolled and 86 treated and 85 were evaluated for response in the IL-2 and vaccine arm. The primary endpoint of the study was clinical response; the secondary endpoints were toxic effects and progression-free survival.

The study found that those who received the vaccine had a response rate of 16 percent, and progression-free survival of 2.2 months, compared to 6 percent and 1.6 months respectively in those that did not. The study was not powered to look at overall survival, but for those receiving the vaccine, it trended positive, 17.8 months vs. 11.1 months.

"This is one of the first positive randomized vaccine trials in cancer and the findings represent a significant step forward for treatment of advanced melanoma," said Schwartzentruber. "However, the vaccine only can be given to half of those with melanoma because it has to match a patient's tissue type, or HLA. A major priority for us is to figure out ways to broaden our approach and use mixtures of peptides, for example, so that more patients are eligible."

The researchers would like to improve upon it by including other immune-stimulatory agents, such as newer vaccine adjuvants, other cytokines and antibodies that further activate immune cells.

"This is a very exciting time for the field of melanoma. During the last few years, the entire landscape has changed -- with the addition of targeted therapies such as those that target BRAF as well as those that stimulate the immune system. Still, these drugs work in a small number of patients, and/or resistance often develops," said Hwu. "Now, our focus will need to turn toward studying these novel therapies in combination and continue our quest for better vaccines, as well as researching ways to make the study inclusive of more metastatic melanoma patients."

The study was funded, in part, by the National Cancer Institute.

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C-reactive protein levels predict breast cancer survival rates, study finds

ScienceDaily (June 1, 2011) — Levels of C-reactive protein (CRP) are increased in response to acute inflammation, infection and tissue damage. There are also reports that CRP levels are elevated because of cancer. New research published in BioMed Central's open access journal Breast Cancer Research shows that elevated CRP levels are predictive of a poor prognosis for breast cancer sufferers.

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C-reactive protein is produced by the liver, in response to infection or injury, when stimulated by the cytokine IL-6. Tumor sites are often associated with inflammation and this inflammation contributes to tumor growth, invasion and metastasis. While elevated CRP has been found associated with a poor outcome for many solid tumors, including endometrial, cervical, prostate and colorectal cancer, there has been some discussion about whether this is true for breast cancer.

Researchers from Denmark looked at data from over 2000 breast cancer patients and followed their progress for up to seven years from diagnosis (average follow up was three years). The researchers found that regardless of lifestyle, menopause status and presence of cardiovascular disease, increasing levels of CRP resulted in increasingly poor prognosis. The five-year survival decreased from 90% for low CRP to 74% for high levels of CRP, disease-free survival reduced from 87% to 74%, and deaths from breast cancer increased from 11% to 20%.

Dr Kristine Allin, from Herlev Hospital, said, "Elevated CRP at time of diagnosis remained predictive of overall survival rates regardless of patient's age, tumor size, lymph node status, or presence of metastasis, and whether or not the patient was estrogen receptor positive. It was still true even when we excluded patients which we believed to have bacterial infections because of their very high CRP levels."

Dr Allin continued, "While measuring CRP levels gives a general indication of health and longevity, measuring CRP levels for breast cancer patients seems to be an easy way to predict the severity of the patient's disease. This may allow clinicians to alter their treatment tactics and improve cancer survival rates."

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Vaccine extends recurrent glioblastoma survival rates by 2 to 3 times, study finds

ScienceDaily (June 3, 2011) — In data presented at The American Society of Clinical Oncology (ASCO) Annual Meeting, cancer researchers found that the brain tumor vaccine HSPPC-96 for treating recurrent glioblastoma (GBM) has a favorable safety profile and extends survival by two to three times more than the current median survival rate.

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Patients in the study, conducted at University Hospitals Case Medical Center, University of California, San Francisco and Columbia University, were found to have a median survival of 11 months compared to current three to five month survival.

"The findings are very favorable for patients with this deadly form of brain cancer," said Andrew Sloan, MD, one of the authors of the study presented at ASCO and Director of the Brain Tumor and Neuro-Oncology Center at University Hospitals Case Medical Center. "The vaccine is one of the few immune therapies designed specifically for patients who are not newly diagnosed, and these encouraging results make this a promising therapy for a more extensive Phase 3 trial."

HSPPC-96 isolates the heat shock protein, which is part of the immune system. The protein from the patient's tumor is then reinjected into the skin with an adjuvant, or an agent added to a drug to increase its effect.

The vaccine was developed by Andrew Parsa, MD, PhD, principal investigator of the Brain Tumor Research Center at the University of California, San Francisco. He is collaborating with the Lexington, Massachusetts biotech company called Agenus. Columbia University also is part of the ongoing Phase 2 study designed to evaluate overall survival and immunologic response with HSPPC-96 in patients with first or subsequent recurrence of GBM.

All patients underwent surgery prior to vaccine therapy. However, since the vaccine is made from the patient's own tumor, the surgery had to be performed at one of the participating sites. The vaccine therapy begins within 5 weeks after surgery and consists of four weekly injections, followed by bi-weekly injections for up to 52 weeks.

"The vaccine is made from a patient's own cells, so it takes into account what is unique about the patient's particular tumor -- it's the ultimate in 'personalized medicine'," said Dr. Sloan who also is the Peter D. Cristal Chair in Neurosurgery and an Associate Professor of Neurological Surgery at Case Western Reserve University School of Medicine.

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Advanced-stage prostate cancer patients experience 20-year survival rates with surgery, study suggests

ScienceDaily (May 15, 2011) — Long-term survival rates for patients with advanced prostate cancer suggest they can be good candidates for surgery, Mayo Clinic researchers have found. Their study found a 20-year survival rate for 80 percent of patients diagnosed with cancer that has potentially spread beyond the prostate, known as cT3 prostate cancer, and treated with radical prostatectomy, or surgery to remove the prostate gland. Previously, patients found to have cT3 prostate cancer were offered radiation or hormone treatment, but not radical prostatectomy.

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The researchers presented their findings during the American Urological Association Annual Meeting in Washington.

"We are doing a much better job of identifying and expanding candidates for surgery, which results in better, longer outcomes for so many of our patients," says R. Jeffrey Karnes, M.D., of Mayo Clinic's Department of Urology. "We have confirmed that patients diagnosed with locally advanced prostate cancer can enjoy a long, cancer-free interval."

The 80 percent survival rate for cT3 diagnoses at 20 years compares to 90 percent for cT2, or cancer confined to the prostate. This long-term follow-up of patients who underwent surgery between 1987 and 1997 is an important advance in understanding the quality outcomes for cT3 patients. The study sample included patients diagnosed and operated on between 1987 and 1997. Ongoing research will examine contemporary data.

Other study investigators include Christopher Mitchell, M.D., Eric Umbreit, M.D., Rachel Carlson and Laureano Rangel, all of Mayo Clinic.

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DNA repair system affects colon cancer recurrence and survival

ScienceDaily (May 20, 2011) — Colorectal cancer patients with defects in mismatch repair--one of the body's systems for repairing DNA damage--have lower recurrence rates and better survival rates than patients without such defects, according to a study published online May 19th in the Journal of the National Cancer Institute.

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About 15% of colorectal cancers are associated with mismatch repair defects. Some defects are caused by the inherited gene mutations found in Lynch syndrome and others occur by chance, or "sporadically." But it has never been clear whether mismatch repair defects are linked to cancer recurrence rates, time-to-recurrence and site of recurrence and whether such defects influence response to chemotherapy.

To explore these questions, Frank A. Sinicrope, M.D., of the Mayo Clinic in Rochester, Minn., and colleagues analyzed data from more than 2,000 clinical trial patients who had been treated after surgery with chemotherapy that included 5-fluorouracil (5-FU), a standard drug used in colorectal cancer. All patients had stage II or III colon cancer.

The patients with defective mismatch repair had lower rates of tumor recurrence, longer remissions, fewer metastases, and better survival rates compared to those without the defects. Both overall survival and disease-free survival were improved.

Whether mismatch repair status influences response to 5-FU therapy has been a subject of some debate. In this study treatment with 5-FU reduced recurrence rates in stage III, regardless of mismatch repair status, but not stage II patients.

The researchers also compared the effects of 5-FU-based therapy in patients thought to have inherited mismatch repair defects versus those whose defects occurred sporadically. They suggest that 5-FU appeared to reduce recurrences only in those with inherited defects.

"In conclusion," they write, "our data demonstrate that patients with defective mismatch repair colon cancers have a statistically significant reduction in their rates of tumor recurrence, a delayed time to recurrence, and better survival rates" than those without the defects. They note that the difference between inherited and sporadic tumors, though a preliminary finding, warrants further study.

In an accompanying editorial, Sabine Tejpar,M.D., Ph.D., of University Hospital Gasthuisberg, Leuven, Belgium, and colleagues note that the influence of mismatch repair defects on patients' prognosis and response to 5-FU has long been a contentious issue. They say that this study, with its large number of samples, provides "valuable information about the prognostic and certainly the predictive role" of mismatch repair defects. The editorialists conclude that it will be important to validate whether patients should have their mismatch repair defects identified as hereditary or sporadic before deciding on chemotherapy with 5-FU.

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