Characterization and Targeting of the Aldehyde Dehydrogenase Subpopulation in Ovarian Cancer
Abstract
In the first year of our grant, we have demonstrated that ALDH-positive cells from the A2780cp20 and SKOV3TRip2 cell lines have approximately 50-fold increased tumorigenicity compared to ALDH-negative cells. Additionally, tumors that formed after ALDH-positive cells were injected were composed of both ALDH-positive and ALDH-negative cells, demonstrating multipotentiality of these cells. By contrast, tumors that formed after injection of ALDHnegative cells were composed of only ALDH-negative cells, demonstrating that tumorigenicity is not absolute, but ALDH-negative cells lack such differentiating capacity. In separate experiments, mice injected intraperitoneally with A2780cp20 or SKOV3TRip2 cells were treated with ALDH1A1-targeting siRNA incorporated into DOPC liposomes, with or without chemotherapy. While downregulation of ALDH1A1 alone did not have a significant effect on tumor growth, it did sensitize these normally-resistant cell lines to cisplatin or paclitaxel, respectively. Finally, a cohort of high-grade epithelial ovarian cancer patient specimens were examined, and we noted that patients with higher density of ALDH-positive cells had shorter progressive-free survival than those with smaller percentages of ALDH1A1. These studies demonstrate that ALDH1A1-positive cells are more aggressive, contribute to poor patient outcomes, and contribute to chemoresistance, but these effects can be reversed by downregulating ALDH1A1 expression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2011
- Accession Number
- ADA552747
Entities
People
- Charles N. Landen Jr.
Organizations
- University of Alabama