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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.

Author information

1
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina.
2
Department of Genetics, University of Delhi, South Campus, India.
3
Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania.
4
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, and Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.
5
Department of Drug Discovery and Biomedical Sciences, School of Pharmacy, Ohio State University, Columbus, Ohio.
6
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio.
7
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina. Mythreye@sc.edu.
#
Contributed equally

Abstract

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.

PMID:
29535220
PMCID:
PMC6510404
DOI:
10.1158/0008-5472.CAN-17-2316
[Indexed for MEDLINE]
Free PMC Article

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