Characterization and Targeting of the Aldehyde Dehydrogenase Subpopulation in Ovarian Cancer.

摘要

Despite a common outstanding response to primary therapy, most ovarian cancer patients will experience recurrence due to what is often microscopic undetectable disease. One possible cause of this is a chemoresistant population of cells with stem cell characteristics. We have examined one potential population in particular, the ALDH-positive population. We have shown that ALDH1A1-positive cells are more tumorigenic than ALDH1A1- negative cells, contribute to poor patient outcomes, and contribute to chemoresistance. These effects can be reversed by downregulating ALDH1A1 expression with nanoparticle-delivered siRNA. Additionally, we have shown that CSCs are clinically significant, in that chemoresistant tumors have increased density of ALDH and CD133 cells. Importantly, they do not seem to explain the entire story, as there are still many CSC-negative cells present at the conclusion of treatment. Specifically, endoglin (CD105) and hedgehog family members (Gli1 and Gli2) appear to play important roles in chemotherapy resistance, and when targeted enhance response to chemotherapy. To further identify other important players, we have further developed the patient-derived xenograft (PDX) model where patient samples are directly implanted into mice, and when formed, treated with chemotherapy. The treated tumors, like patient specimens, are enriched with ALDH1-positive cells. Further characterization of the surviving population is underway, in conjunction with separately-funded protocols.