Role of IKKalpha and STAT3 in the Emergence of Castration-Resistant Prostate Cancer
Abstract
A major complication of androgen ablation therapy for prostate cancer (PC) is the development of castration resistant PC (CRPC) that is more aggressive and more prone to metastatic spread. We previously demonstrated that CRPC development is accelerated by infiltrating B cells that are recruited into regressing androgen-deprived tumors by the chemokine CXCL13, whose expression was found to correlate with clinical severity in human PC. Here we describe how androgen ablation leads to CXCL13 expression. In both subcutaneously transplanted tumors and spontaneous PC in mice CXCL13 is expressed by tumor-associated myofibroblasts that are activated upon androgen ablation. Myofibrolast activation and CXCL13 expression are also induced upon castration within the normal prostate and CXCL13 and myofibroblast markers are co-expressed in human PC. Androgen ablation results in appearance of hypoxic regions and nuclear HIF-1 within the regressing tumors and hypoxia leads to myofibroblast activation and CXCL13 induction in a HIF-1 -dependent manner. Myofibroblast activation and CXCL13 induction are also dependent on signaling by TGF family members, whose expression induced in response to hypoxia and androgen ablation. Immunodepletion of myofibroblasts or inhibition of TGF signaling retard the development of CRPC in transplanted tumors and block it completely in the TRAMP model of spontaneous PC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2013
- Accession Number
- ADA601839
Entities
People
- Massimo Ammirante
Organizations
- University of California, San Diego