News Tips from The University of Texas M. D. Anderson Cancer Center
News Tips from The University of Texas M. D. Anderson Cancer Center
Published in the Proceeding for the 2003 Annual Meeting of the American Association for Cancer Research, Toronto, Ontario, Canada April 5–9, 2003
M. D. Anderson News Release 04/08/03
Researchers report that in laboratory animals, the combination of radiation and the anti-angiogenic drug, endostatin, appears to work synergistically together to stop development of new blood vessels that seek to grow and nourish damaged tumors.
Researchers at The University of Texas M. D. Anderson Cancer Center found that the regrowth of new blood vessels was reduced five-fold in mice with implanted squamous cell cancer treated with radiation and endostatin compared to diseased mice that had radiation or endostatin alone, says Satoshi Itasaka, M.D., a visiting postdoctoral fellow from Kyoto, Japan.
"Endostatin enhanced the anti-tumor effects of irradiation and 40% of mice in the combined treatment group achieved long-term survival and tumor control," says Itasaka.
The researchers then examined the tumors and found that expression of crucial proteins varied among the treatment groups. Specifically, a "sharp" increase in VEGF/VPF, IL-8 and MMP2 proteins were found in tumors that had been irradiated. These proteins are proangiogenic and invasive factors that are needed to "signal" blood vessels to grow to tumor cells, to nourish them. Radiation increased levels of these proteins, but then endostatin "blocked" them from acting.
"After radiation, there is a regrowth of blood vessels as well as tumor cells, and endostatin seems to work to stop blood vessel regrowth," says Itasaka. "Why the combination of irradiation and endostatin works well is not fully understood yet, but it appears they may overcome the limitations of each other."
Other studies have looked at the effect of a combination of radiation and anti-angiogenesis drugs on death of blood vessel cells, but this is the first to examine whether these blood vessel cells regrow after irradiation, and what effect endostatin has on that regrowth, he says.
Interim results of a large lung cancer case-control study suggest there is a genetic basis for development of lung cancer and other smoking related cancers, say researchers from The University of Texas M. D. Anderson Cancer Center.
The study, still ongoing, compared family histories of cancer in the immediate families of 806 lung cancer patients with that of a group of 663 control families, and provides indirect evidence that variation in individual susceptibility to smoking and cancer may be genetically-determined.
Aggregation of cancer in families can be due to shared exposures, shared genes, or a combination of both, says Carol Etzel, Ph.D., a statistician and instructor in the Department of Epidemiology. Previous studies at M. D. Anderson and other institutions have found similar results.
"Only about 15% of all smokers develop lung cancer, and in families of those smokers, our belief is that it is more likely other family members will be just as susceptible if they also smoke," says Etzel. "We all are familiar with someone who smoked for years and never got cancer, while another person who didn't smoke much developed the disease. It is those individual differences, expressed in genetic tendencies, that we are exploring."
In all, the study ascertained family cancer history in 6,430 first-degree relatives (parents, siblings and offspring) of patients and 5,505 relatives of control subjects.
The researchers interviewed patients and control participants, asking detailed questions about their smoking habits and those of their families, and whether any family members had developed smoking related cancers, such as lung, bladder, kidney, head and neck, and pancreas. Most of the cancer patients were over the age of 60 and were current or former smokers, Etzel notes, so the issue of second hand smoke was not a factor.
They found that there was a nearly two-fold increased risk of lung cancer among relatives of smokers, but no evidence of an increased risk among relatives of people who never smoked.
If the genes responsible for susceptibility to developing lung and other smoking-related cancers are found, it may be possible to identify high-risk subgroups of smokers and to develop tailored interventions or screening programs, says Etzel.
Possible genes that may affect a smoker's risk of developing cancer are being intensively studied, she says, including genes that help to detoxify the cancer causing agents in tobacco smoke — and so confer a protective effect — as well as genes that effect the ability to repair genetic damage, and thus to prevent the negative biological consequences of smoking.
Based on a large study of prostate cancer patients, researchers are finding that maintaining a normal body mass index, frequent physical activity and screening before diagnosis appear to be important in stopping prostate cancer from progressing.
The investigators, from The University of Texas M. D. Anderson Cancer Center researchers, used standard clinical criteria for predicting the risk of treatment failure in patients treated for localized prostate cancer (cancer that is confined within the prostate) to assign the patients to different groups according to the likelihood that their cancer would progress. These criteria included pre-treatment PSA levels and biopsy Gleason scores (a score assigned by a pathologist to determine the aggressiveness of the cancer) and clinical T stage (the size of the tumor).
A total of 1,117 patients with localized prostate cancer were recruited over a six-year period and surveyed on their lifestyle, and these answers were then matched to their risk of progression.
The researchers found that patients with a high-risk of progression were significantly more likely to be obese, to exercise less than twice a week, and not to have had prior annual prostate cancer screenings. Those with the lowest risk kept their body weight down, exercised regularly and had routine screenings.
"What we are finding has positive implications for prostate cancer prevention," says the lead author, Mfon Cyrus-David, M. D., a postdoctoral fellow in the Department of Epidemiology. "It appears to be important that men maintain a low body mass index, exercise to the point of sweating at least two times a week, and be screened regularly for prostate cancer."
Although researchers say their conclusions are preliminary and that their findings need further validation with a follow-up study, the study is among the first to attempt to quantify the predictive risk that lifestyle factors have on whether or not prostate cancer will recur in patients who have been treated.
For the first time, researchers are characterizing the molecular processes that turn brain cancer deadly, and their work may result in a diagnostic test that can predict patient survival.
The research, by scientists at The University of Texas M. D. Anderson Cancer Center demonstrates that degree of loss of a crucial tumor suppressor gene, the AP-2a transcription factor, correlates with progression of different human gliomas.
For example, researchers found that normal brain tissue, as well as grade II gliomas, maintained expression of AP-2a, whereas 96% of grade III glioma, and almost 99% of grade IV glioma had lost AP-2a.
“Although previous molecular markers have been identified in malignant gliomas, none have exhibited such a strong correlation with progression, indicating the pivotal role of this gene,” says Amy Heimberger, M.D., assistant professor in the Department of Neurosurgery.
The findings one day may be clinically important, says Eric McGary, M.D., Ph.D., a clinical fellow.
If validated through further study, the results can help scientists devise a diagnostic test to check for loss of function of the AP-2a gene, which can help doctors and patients know about treatment options. "No such test exists like that now," he says. Heimberger is following the long-term survival of patients within the various grades of gliomas to determine if loss of the AP-2a confers a more serious prognosis.
McGary led the effort to characterize how cancer develops when the AP-2a gene, which normally protects against cancer development, is lost. They have found that other tumors such as melanoma become increasingly deadly when the gene is no longer active, and have described its role in breast and prostate cancer as well.
The AP-2a transcription factor controls the expression of many genes, including c-Kit, which regulates cellular proliferation and differentiation, MUC18, an adhesion molecule involved in angiogenesis, and MMP2, which is involved in invasion. When AP-2a is lost, less c-Kit, but more MUC18 and MMP2 are produced, resulting in an increased potential of the cell to grow and divide uncontrollably.
"As such, AP-2a acts as a tumor suppressor gene," says Menashe Bar-Eli, PhD, professor in the Division of Cancer Medicine and a senior member of the research team.
Looking at tumor samples taken from 279 patients with different kinds of brain cancer, the research team used a tissue array constructed by Dr. Gregory Fuller, associate professor in the Department of Pathology, to look for AP-2a gene expression.
In addition to their findings of different stages of gliomas, they found that 21.5% of oligodendrogliomas did not express AP-2a, but this increased to 66% in cases of anaplastic oligodendrogliomas.
The team also looked at glioblastomas, which are the most common malignant brain tumors in adults and are the most resistant and deadly of all brain cancers to treat. They found that none of the four different glioblastoma cell lines they tested expressed any detectable levels of AP-2a.
“The discovery of the ubiquitous loss of AP-2a in high-grade malignant gliomas provides a unique target for new therapies aimed at restoring the function of that gene," says Heimberger. "We are already looking at trying to replace AP-2a function in animal models with gene therapy in order to slow down growth of the tumor," McGary added.