TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression

SIMPLE SUMMARY: Androgen deprivation therapy (ADT) is the principal therapy for advanced prostate cancer. ADT controls tumor growth by rapidly altering the prostate tumor microenvironment and subsequently inducing cancer cell death. ADT induces prostate vascular damage and thereby reduces intratumoral blood flow in the rodent and human prostate gland, but the mechanism whereby ADT induces vascular damage has long been elusive. This work describes studies that, for the first time, functionally define TNF as the mediator of castration-induced vascular damage in prostate tumors. ABSTRACT: The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. In addition to this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death, which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostates. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area, and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely by inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer microenvironment that mediates prostate cancer regression following androgen deprivation.