COX-2 inhibitors, which are being studied for the treatment of a wide range of cancers, appear to be able to promote as well as inhibit tumor growth and angiogenesis, according to research reported last week at the AACR annual meeting.
In the study, conducted by Dr. Guido E. Eibl and colleagues at the UCLA David Geffen School of Medicine, the selective COX-2 inhibitor nimesulide inhibited tumor growth and angiogenesis in tumors that were COX-2 positive in two different mouse models of pancreatic cancer. However, in tumors that were COX-2 negative - which, Dr. Eibl noted, previous research has found to be the case in anywhere from 10 to 40 percent of tumors - just the opposite held true: nimesulide stimulated tumor growth.
"When we looked more carefully at these tumors, we found that on the surface there were more and larger microvessels" as well as increased production of cancerous cells, Dr. Eibl said.
The researchers also conducted in vitro studies to elucidate the pathway by which nimesulide acted. They found that, in COX-2 negative tumors, nimesulide increased production of vascular endothelial growth factor (VEGF), a potent angiogenesis stimulant. This occurs, they determined, primarily through the direct activation on pancreatic cancer cells of the nuclear receptor PPAR Gamma.
This "surprising" finding, he added, "suggests...that maybe a certain subset of pancreatic cancer patients may respond differently to selective COX-2 inhibitors" and that use of these drugs should be based on the tumor's COX-2 expression profile. The research team is now going to test other selective COX-2 inhibitors in these same models to see if they achieve similar results, Dr. Eibl said.
In the March 17 issue of the Journal of the National Cancer Institute, NCI scientist Dr. Michael Waalkes and colleagues report a link in mice between estrogen signaling and hepatocellular carcinoma (HCC) caused by in utero exposure to arsenic. Tumors from HCC, a specific type of liver cancer, have previously been reported to be associated with arsenic exposure in humans.
The researchers found higher expression levels of the estrogen receptor-α (ER-α) gene - an indicator of changes in estrogen signaling - in the livers of adult male mice that had developed the tumors after the in utero arsenic exposure. Another gene, cyclin D1 - a cell cycle regulator that responds to estrogen signaling - also demonstrated increased expression levels when compared to levels found in control mice. The mice with HCC had decreased methylation of the promoter region of their ER-α gene, which may be the cause for these changes in expression levels. Furthermore, the scientists looked at human liver biopsy samples from men who were exposed to high levels of arsenic and found that ER-α and cyclin D1 were also overexpressed, compared to genes in samples from people not exposed to high levels of arsenic.
"Taken together," the study report concludes, "these data indicate that aberrant expression of the ER-α gene, as a result of changes in methylation, could be an important molecular event in carcinogenesis induced by inorganic arsenic, at least in the liver."
In the April 7 issue of the Journal of the American Medical Association, researchers report the results of a prospective cohort study suggesting that higher ejaculation frequency may correlate with a decreased risk of prostate cancer in white men aged 46 or older.
The 29,342 participants received a questionnaire in 1992 that included an assessment of current and past ejaculation frequency. The researchers followed the men from 1992 until 2000, during which time the subjects completed questionnaires every two years that asked whether they had been diagnosed with prostate cancer. By the time the study ended, 1,449 new cases of prostate cancer had been diagnosed.
The researchers found that men reporting 21 or more ejaculations per month had a lower relative risk of developing prostate cancer. They concluded that "each increment of three ejaculations per week across a lifetime" was associated with a fifteen percent reduction in total prostate cancer risk. Interestingly, the researchers found that men with the lowest ejaculation frequencies (three or fewer per month) between the ages of 40 and 49 also experienced a suggestive decreased risk of prostate cancer while men with ejaculation frequencies in the middle range showed no detectable change in risk status.
The researchers cautioned against over-interpreting their results. At most, the study indicates that an association possibly exists between higher ejaculation frequency and lower prostate cancer risk. The evidence does not definitively establish a causal linkage between ejaculation frequency and prostate cancer etiology. The study provides a direction for future research into identifying the possible biological mechanisms that give rise to prostate cancer. "
The major implications of our results are in stimulating future progress toward understanding the molecular mechanisms underlying the potential adverse effects of inhibited or suppressed ejaculation on prostate tumor growth," commented lead author Dr. Michael Leitzmann of NCI's Division of Cancer Epidemiology and Genetics. "Future research should focus on the chronic interaction of prostate glandular cells with the prostatic fluid they secrete."