Link Between Cell Survival Proteins, Ovarian Cancer Aggressiveness
Scientific team has found that the elevated levels of certain proteins typically associated with keeping cancer cells alive may actually correspond with improved patient survival in ovarian cancer.
These proteins, all members of cellular networks that regulate apoptosis (programmed cell death) and responses to stress together form a prognostic protein signature that provides key information about the tumor. If additional research verifies these findings, clinicians may be able to use this protein signature to gauge the aggressiveness of a woman's ovarian tumor at the time of diagnosis, as well as to identify patients who could benefit from various therapies. The findings are published in the November 15, 2007, issue of Clinical Cancer Research.
"We selected these proteins for study assuming that, because of their known abilities to promote the survival of cancer cells, they would likely correlate with worse clinical outcomes and high tumor aggressiveness," said Elise Kohn, M.D., head of the Molecular Signaling Section at NCI's Center for Cancer Research and the study's senior author. "We did not expect to find that increased expression of these proteins would actually be linked with better survival." The degree to which the information encoded in a gene is translated into a protein is a measure of expression.
An estimated 22,430 women will be diagnosed with ovarian cancer in the United States in 2007. Approximately 70 percent of them will succumb to the disease, a sobering statistic linked primarily to the fact that most women are not diagnosed until the cancer has reached an advanced stage. Also, there are few therapeutic options available to women with ovarian cancer, so any research leading to therapeutic targets would be a great advance for ovarian cancer patients.
The research team, which included scientists at the Rikshospitalet-Radiumhospitalet Medical Centre in Oslo, Norway, set out to understand the relationships between clinical aggressiveness in ovarian tumors and expression levels of both proteins within the BAG protein family (a collection of proteins that block apoptosis and promote cell survival) and proteins with which they interact, namely members of the Bcl-2 (another group of anti-apoptotic proteins) and Hsp (proteins expressed in response to cellular stress) families. Kohn and her collaborators examined the protein expression patterns in 28 tumor samples collected from women treated at NCI for stage III or IV ovarian cancer and 170 tissue samples archived at the Gynecological Oncology Group tissue bank (Columbus Children's Hospital, Columbus, Ohio).
Unexpectedly, the team found that elevated expression of BAG-4 localized outside the nucleus (that is, in the cytoplasm) was strongly and positively associated with long-term patient survival (both overall and progression-free survival) in newly diagnosed patients who were treated with chemotherapy that included a platinum-based drug. Conventional wisdom holds that because BAG-4 normally interferes with apoptosis, or cell death, its expression would correlate with worse survival.
Similarly, Kohn and her colleagues found that the cytoplasmic level of Bcl-2 ( a protein that is the namesake of the Bcl-2 family and binds directly to BAG proteins) was inversely related to tumor grade and stage at diagnosis. Of note, the opposite is true for other cancers; for instance, a higher Bcl-2 level in lymphomas correlates with cancer aggressiveness. The team also found a correlation between increased nuclear accumulation of the protein Hsp70 (which also binds to BAG-4), a lower cytoplasmic level of Bcl-2, and higher tumor grade at diagnosis, suggesting that the baseline Hsp70 level could also be tied to a tumor's aggressiveness at diagnosis.
Together, these findings draw a fairly complex picture of ovarian cancer. For this cancer, it is possible that high cytoplasmic levels of BAG-4 and Bcl-2, together with a low nuclear level of Hsp70, predict a relatively good prognosis for a woman diagnosed with ovarian cancer. These clinical data also add a new twist to the body of thought on the mechanisms of apoptosis by suggesting that some anti-apoptotic proteins, namely BAG-4 and Bcl-2, may not block cell suicide in ovarian cancer. The data also open up new avenues of investigation for understanding the molecular biology of chemotherapy resistance, provide additional insights into the signaling networks underlying cancer cell survival, and highlight potentially attractive targets for new ovarian cancer therapeutics.