Inhibin is a novel paracrine factor for tumor angiogenesis and metastasis

Academic Article

Abstract

  • © 2018 American Association for Cancer Research. Inhibin is a heterodimeric TGFb 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 TGFb 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.
  • Digital Object Identifier (doi)

    Author List

  • Singh P; Jenkins LM; Horst B; Alers V; Pradhan S; Kaur P; Srivastava T; Hempel N; Gyorffy B; Broude EV
  • Start Page

  • 2978
  • End Page

  • 2989
  • Volume

  • 78
  • Issue

  • 11