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Cancer Res. 2018 Jun 1;78(11):2978-2989. doi: 10.1158/0008-5472.CAN-17-2316. Epub 2018 Mar 13.

Inhibin Is a Novel Paracrine Factor for Tumor Angiogenesis and Metastasis.

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Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina.
Department of Genetics, University of Delhi, South Campus, India.
Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania.
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, and Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.
Department of Drug Discovery and Biomedical Sciences, School of Pharmacy, Ohio State University, Columbus, Ohio.
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio.
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina.
Contributed equally


Inhibin is a heterodimeric TGFβ 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 α 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 α antibodies. The endothelial-specific TGFβ 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. Cancer Res; 78(11); 2978-89. ©2018 AACR.

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