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Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens
Archana S. Nagaraja, … , Steve W. Cole, Anil K. Sood
Archana S. Nagaraja, … , Steve W. Cole, Anil K. Sood
Published August 17, 2017
Citation Information: JCI Insight. 2017;2(16):e93076. https://doi.org/10.1172/jci.insight.93076.
View: Text | PDF | Expression of Concern | Corrigendum
Research Article Cell biology Oncology

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

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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.

Authors

Archana S. Nagaraja, Robert L. Dood, Guillermo Armaiz-Pena, Yu Kang, Sherry Y. Wu, Julie K. Allen, Nicholas B. Jennings, Lingegowda S. Mangala, Sunila Pradeep, Yasmin Lyons, Monika Haemmerle, Kshipra M. Gharpure, Nouara C. Sadaoui, Cristian Rodriguez-Aguayo, Cristina Ivan, Ying Wang, Keith Baggerly, Prahlad Ram, Gabriel Lopez-Berestein, Jinsong Liu, Samuel C. Mok, Lorenzo Cohen, Susan K. Lutgendorf, Steve W. Cole, Anil K. Sood

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Figure 1

Chronic stress accelerates induction of the cancer-associated fibroblast (CAF) phenotype in ovarian carcinoma.

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Chronic stress accelerates induction of the cancer-associated fibroblast...
(A) Results from NetWalker analysis to identify networks of upregulated genes in ovarian cancer patients with high Center for Epidemiologic Studies Depression Scale [CES-D] (i.e., depression) scores and low social support. (B) Expression of α-smooth muscle actin (α-SMA, a CAF marker) in micrographs of representative tumors from control and restraint-stressed mice in adrenergic receptor–positive Skov3-ip1, HeyA8, and ID8-ip1 models. (C) Expression of α-SMA and CD31 (blood vessel marker) in micrographs of representative Skov3-ip1 tumors from control and stressed mice. (D) Expression of α-SMA in micrographs of representative tumors from mice subjected to short-term (7 days) or long-term (21 days) stress. Scale bars: 100 μm. n = 5/group for all data.

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