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JCI Insight. 2017 Aug 17;2(16). pii: 93076. doi: 10.1172/jci.insight.93076. eCollection 2017 Aug 17.

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.

Author information

1
Department of Gynecologic Oncology and Reproductive Medicine.
2
Center for RNAi and Non-Coding RNA.
3
Department of Experimental Therapeutics.
4
Department of Bioinformatics and Computational Biology.
5
Department of Systems Biology.
6
Department of Pathology, and.
7
Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
8
Departments of Psychological and Brain Sciences, Obstetrics and Gynecology, and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA.
9
Department of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles School of Medicine, UCLA Molecular Biology Institute, and Norman Cousins Center, Los Angeles, California, USA.
10
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Abstract

Adrenergic signaling is known to promote tumor growth and metastasis, but the effects on tumor stroma are not well understood. An unbiased bioinformatics approach analyzing tumor samples from patients with known biobehavioral profiles identified a prominent stromal signature associated with cancer-associated fibroblasts (CAFs) in those with a high biobehavioral risk profile (high Center for Epidemiologic Studies Depression Scale [CES-D] score and low social support). In several models of epithelial ovarian cancer, daily restraint stress resulted in significantly increased CAF activation and was abrogated by a nonspecific β-blocker. Adrenergic signaling-induced CAFs had significantly higher levels of collagen and extracellular matrix components than control tumors. Using a systems-based approach, we found INHBA production by cancer cells to induce CAFs. Ablating inhibin β A decreased CAF phenotype both in vitro and in vivo. In preclinical models of breast and colon cancers, there were increased CAFs and collagens following daily restraint stress. In an independent data set of renal cell carcinoma patients, there was an association between high depression (CES-D) scores and elevated expression of ACTA2, collagens, and inhibin β A. Collectively, our findings implicate adrenergic influences on tumor stroma as important drivers of CAFs and establish inhibin β A as an important regulator of the CAF phenotype in ovarian cancer.

KEYWORDS:

Cell Biology; Oncology

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