Inhibin is a novel paracrine factor for tumor angiogenesis and metastasis

Priyanka Singh, Laura M. Jenkins, Ben Horst, Victoria Alers, Shrikant Pradhan, Prabhjot Kaur, Tapasya Srivastava, Nadine Hempel, Balazs Gyorffy, Eugenia V. Broude, Nam Y. Lee, Karthikeyan Mythreye

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2978-2989
Number of pages12
JournalCancer Research
Volume78
Issue number11
DOIs
StatePublished - Jun 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Singh, P., Jenkins, L. M., Horst, B., Alers, V., Pradhan, S., Kaur, P., Srivastava, T., Hempel, N., Gyorffy, B., Broude, E. V., Lee, N. Y., & Mythreye, K. (2018). Inhibin is a novel paracrine factor for tumor angiogenesis and metastasis. Cancer Research, 78(11), 2978-2989. https://doi.org/10.1158/0008-5472.CAN-17-2316