Endoglin is an accessory receptor for transforming growth factor-β (TGF-β) that has been implicated in prostate cancer cell detachment, migration and invasiveness. However, the pathophysiological significance of endoglin to prostate tumorigenesis has yet to be fully established. In this study we addressed this question by investigation of endoglin-dependent prostate cancer progression in a TRAMP mouse model where endoglin was genetically deleted. In this model, endoglin was haploinsufficient such that its allelic deletion slightly increased the frequency of tumorigenesis, yet produced smaller, less vascularized, and less metastatic tumors than TRAMP control tumors. Most strikingly, TRAMP:eng+/− tumors lacked the pronounced infiltration of carcinoma-associated fibroblasts (CAFs) that characterize TRAMP prostate tumors. Studies in human primary prostate-derived stromal fibroblasts (PrSC) confirmed that suppressing endoglin expression decreased cell proliferation, the ability to recruit endothelial cells, and the ability to migrate in response to tumor cell-conditioned medium. We found increased levels of secreted insulin-like growth factor binding proteins (IGFBPs) in the conditioned media from endoglin-deficient PrSCs, and that endoglin-dependent regulation of IGFBP-4 secretion was crucial for stromal cell-conditioned media to stimulate prostate tumor cell growth. Together, our results firmly establish the pathophysiological involvement of endoglin in prostate cancer progression, and they show how endoglin acts to support the viability of tumor infiltrating CAFs in the tumor microenvironment to promote neovascularization and growth.

It is well accepted that complex biological processes such as angiogenesis are not controlled by a single family of molecules or individually isolated signaling pathways. In this regard, new insight into the interconnected mechanisms that regulate angiogenesis might be gained by examining this process from a more global network perspective. The coordination of signaling cues from both outside and inside many different cell types is required for the successful completion of angiogenesis. Evidence is accumulating that the multifunctional integrin family of cell adhesion receptors represent an important group of molecules that play active roles in sensing, integrating, and distributing a diverse set of signals that regulate many cellular events required for angiogenesis. Given the ability of integrins to bind numerous extracellular ligands and transmit signals in a bi-directional fashion, we will discuss the multiple ways by which integrins may serve as a functional hub during pathological angiogenesis. In addition, we will highlight potential imaging and therapeutic strategies based on the expanding new insight into integrin function.