Omega-6 Fatty Acid Activates Genes Linked to Prostate Cancer Development
Researchers have identified specific intracellular signaling pathways via which a type of omega-6 fatty acid influences the growth rate of prostate tumor cells.
In a study published in the February 1 Cancer Research, investigators from the San Francisco Veterans Affairs Medical Center found that, in laboratory tests, the addition of the omega-6 fatty acid arachidonic acid to prostate tumor cells doubled the cells' growth rate compared with cells to which arachidonic acid was not added.
Further testing revealed that arachidonic acid appeared to activate two signaling pathways critical to cancer cell proliferation, PI3-kinase (PI3K) and Akt. This, in turn, fueled activity by the anti-apoptotic gene NF-κB. The researchers also found that many other inflammatory genes regulated by NF-κB were activated in tumor cells to which arachidonic acid was added, including COX-2, which previous research has implicated in prostate cancer development.
"The changes in gene expression point to a probable PI3K/Akt pathway activation by arachidonic acid, where COX-2 and 11 other NF-κB regulated genes are induced by the presence of omega-6 fatty acids," wrote lead author Dr. Millie Hughes-Fulford and colleagues.
Finally, when the researchers treated prostate tumor cells to which arachidonic acid had been added with a COX-2 inhibitor, PI3K activation was decreased. And treatment with an experimental PI3K inhibitor reduced the proliferation of tumor cells caused by arachidonic acid and reduced expression of the genes that arachidonic acid had activated.
Dietary intake of omega-6 acids, found in corn oil, as compared with omega-3 fats, which have been associated with many health benefits, has increased exponentially over the past five decades, the authors noted. Given the study's results, they concluded, "Reduction of omega-6 fatty acids intake and anti-PI3K/Akt inhibitors may be worth considering as future therapeutic approaches to battle prostate cancer."
Cetuximab Enhances Radiotherapy for Head and Neck Cancer
Results from a new study in the February 9 New England Journal of Medicine (NEJM) show that adding cetuximab (Erbitux) to high-intensity radiotherapy for locoregionally advanced head and neck cancer improved overall survival and extended the duration of local control, without exacerbating adverse effects such as mucositis.
Cetuximab controlled disease for nearly 10 months longer, improving progression-free survival by 30 percent over radiation alone. After a follow-up of 54 months, cetuximab patients survived an average of 49 months - nearly 20 months longer than those on radiation alone - which was a 26-percent reduction in mortality. The only cost appeared to be an increase in acneiform rash and infusion reactions; other toxic effects, especially mucositis, were comparable. The multicenter trial enrolled 424 patients in the United States and Europe.
Cetuximab is a monoclonal antibody that binds to and inhibits the epidermal growth factor receptors commonly overexpressed in epithelial cancers, which include most head and neck cancers. Dr. James Bonner, of the University of Alabama at Birmingham, and colleagues say it is "exceptional" to find a survival advantage with a molecular targeting agent.
In an accompanying editorial, Drs. Marshall Posner and Lori Wirth, of the Dana-Farber Cancer Institute and Harvard University, say a survival gain in this type of cancer that doesn't increase toxicity "immediately draws the attention of clinicians." They emphasized the need for more phase III trials, however, pointing out that all studies utilizing the current standard of care, platinum-based chemoradiotherapy, "have shown greater improvement" in patients than the results of this study, which compared radiotherapy, with or without cetuximab.
Colonoscopies Drive Higher Rates of Colorectal Cancer Screening
Rates of colorectal cancer screening are rising for both men and women in the United States, and the change is being driven by a sharp increase in the use of colonoscopy, according to a new study. Although rates are improving, less than half of those eligible undergo screening, and the prevalence is higher among men than women, according to findings in the February Cancer Epidemiological Biomarkers & Prevention.
"The good news is that test use is going up," says lead researcher Dr. Helen Meissner of NCI. "The bad news is that the use of colorectal cancer screening lags behind other types of cancer screening," such as mammography and Pap tests. Statistics on test use came from the National Health Interview Survey for the years 1987, 1998, 2000, and 2003, the most recent periods for which data are available.
The rise in colonoscopy use has been accompanied by a decline in sigmoidoscopy use, while the use of fecal occult blood testing (FOBT) has remained about the same. In other findings, the study supports previous research showing that rates of colorectal cancer screening use are lower for those of Hispanic ethnicity, at a lower education level, lacking health insurance, without a usual source of health care, and who have not talked with a doctor in the past year.
That the recent increase was almost exclusively driven by colonoscopy has implications for public health practice in the United States, the researchers say. Colonoscopy is an expensive, invasive, and relatively time-consuming test that currently must be done by a physician. The promotion of colonoscopy as the "preferred" colorectal screening test may widen socioeconomic disparities, the researchers suggest.
"Technology is changing rapidly," notes Dr. Meissner. "In the next several years, we hope that molecular markers and other less invasive ways of detecting colon cancer early will be validated."
Disruption of Adhesion Molecule Leads to Cancer Cell Death
Focal adhesion kinase (FAK), a protein found at the points where cells join to the extracellular matrix, is overexpressed in several types of cancer. The research team at the University of Florida who first identified the overexpression of FAK in human tumors has now found evidence that vascular endothelial growth factor receptor-3 (VEGFR-3), a signaling protein required for lymphatic vessel growth, binds to FAK in tumor cells, leading to suppression of apoptosis. Blocking the binding of the two proteins can cause cell death. These results were published in the February 1 Cancer Research.
The investigators showed both in vivo and in breast cancer cell lines that VEGFR-3 binds to the focal adhesion targeting domain within the carboxyl terminus region of FAK, which is involved in apoptotic signaling. They also identified overexpression of both VEGFR-3 and FAK in several breast cancer cell lines.
A short, 12 amino-acid fragment of VEGFR-3 called AV3 was used to disrupt the binding of VEGFR-3 to FAK. Cells that overexpressed FAK and were treated with AV3 showed displacement of FAK from adhesion sites. This led to an increased dose-dependent detachment of cells, a decrease in cell proliferation, and an increase in apoptosis. These effects were not seen in normal breast cells.
The authors state that the results from this study "could be used as a basis for the development of novel molecular therapeutics that target the signaling between FAK and VEGFR-3 and cause apoptosis in breast cancer."
Saw Palmetto Fails to Improve Benign Prostatic Hyperplasia
An extract of the saw palmetto plant was no more effective than a placebo in reducing symptoms associated with benign prostatic hyperplasia (BPH), a randomized clinical trial has found. BPH is caused by an enlarged prostate gland, and millions of older men, particularly in Europe, use over-the-counter saw palmetto products to treat the condition.
The double-blind, randomized trial included 225 men over age 49; half took 160 mg of saw palmetto twice daily, and the others a placebo. After a year, the groups were similar in lower urinary tract symptoms and other objective measures of BPH, the researchers report in the February 9 NEJM.
The study, led by Dr. Stephen Bent of the University of California, San Francisco, was funded by NIH and the National Center for Complementary and Alternative Medicine. The negative results contrast with a number of earlier studies suggesting that saw palmetto may improve urinary symptoms caused by BPH.
To explain the discrepancy between the positive and negative findings, the researchers point out that some earlier studies had design flaws. In addition, the patients in the new study may have shared attributes that made them unlikely to respond to saw palmetto. Alternatively, the level of the active ingredient in their extract may have been too low to be effective (the active ingredient, if one exists, is not known).
The study was well designed, adequately powered, and avoided the pitfalls of previous studies by treating participants for a year, optimizing the consistency of the herbal product, and measuring the adequacy of blinding, an accompanying editorial notes. The authors raise the possibility, however, that a different preparation or dose of saw palmetto might have been effective.
