Neuropilin 2: Novel Biomarker and Therapeutic Target for Aggressive Prostate Cancer
Abstract
VEGF/NRP2 signaling is critical for the function of prostate cancer stem cells and a prime target for therapy. Surprisingly, however, we observed that that CSCs isolated from prostate tumors are resistant to anti-VEGF (bevacizumab) therapy. To understand this discrepancy, we generated prostate cancer cells that are resistant to bevacizumab and observed that resistant cells exhibit properties of CSCs compared to sensitive cells. Resistance is mediated by VEGF/NRP2 signaling, which is not inhibited by bevacizumab, and it involves the induction of PRex1, a Rac GEF, and consequent Rac1-mediated ERK activation. CSCs isolated from the PTENpc-/- transgenic model of prostate cancer exhibit Rac1-dependent resistance to bevacizumab. Rac1 inhibition or P-Rex1 down-regulation increases the sensitivity of prostate tumors to bevacizumab. Thus, prostate tumors harbor cells with CSC properties that are resistant to inhibitors of VEGF/VEGFR signaling. Combining the use of available VEGF/VEGFR-targeted therapies with Rac1 inhibition should improve the efficacy of these therapies significantly.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2015
- Accession Number
- AD1003800
Entities
People
- Arthur M Mercurio
Organizations
- University of Massachusetts Medical School