Inhibin Is a Novel Paracrine Factor for Tumor Angiogenesis and Metastasis

Singh, P. and Jenkins, L. M. and Horst, B. and Alers, V. and Pradhan, S. and Győrffy, Balázs (2018) Inhibin Is a Novel Paracrine Factor for Tumor Angiogenesis and Metastasis. CANCER RESEARCH, 78 (11). pp. 2978-2989. ISSN 0008-5472

Text 2018_CancerResMythreye.pdf Restricted to Repository staff only Download (2MB) | Request a copy

Abstract

Inhibin is a heterodimeric TGF beta family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers; however, its tumor-specific functions remain unknown. Here, we demonstrate that the a subunit of inhibin (INHA), which is critical for the functionality of dimeric inhibin A/B, correlates with microvessel density in human ovarian tissues and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that inhibin-regulated angiogenesis is necessary for metastasis. Although inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis in vitro and in vivo. Inhibin-induced angiogenesis was abrogated via anti-inhibin a antibodies. The endothelial-specific TGF beta receptor complex comprising ALK1 and endoglin was a crucial mediator of inhibin signaling, offering a molecular mechanism for inhibin-mediated angiogenesis. These results are the first to define a role for inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting inhibin therapeutically. Significance: Inhibin is a predictor of poor patient survival in multiple cancers and is a potential target for antiangiogenic therapies. (C) 2018 AACR.

Actions (login required)

Edit Item