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Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma

An Author Correction to this article was published on 19 November 2021

This article has been updated

Abstract

Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)–protein kinase A (PKA) signaling pathway by the β2 adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify β-adrenergic activation of the cAMP–PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.

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Figure 1: Effect of chronic stress on in vivo ovarian cancer growth.
Figure 2: Angiogenesis is increased in chronically stressed animals.
Figure 3: Effects of chronic stress on angiogenesis.
Figure 4: Effect of VEGF on stress-induced tumor growth.

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Acknowledgements

The authors thank I.J. Fidler, J. Price, C. Bucana, G. Gallick and A. Johnson for their helpful input and discussions regarding this work. We thank D. Reynolds for assistance with immunohistochemistry. We also thank J. Johnson and E. Schrock for assistance with manuscript preparation. This work was supported by US National Institutes of Health (NIH) grants (CA-11079301 and CA-10929801), the Donna Marie Cimitile-Fotheringham Award for Ovarian Cancer Research, the U.T. M.D. Anderson Ovarian Cancer SPORE (2P50 CA083639-06A1), and a Program Project Development Grant from the Ovarian Cancer Research Fund, Inc. to A.K.S., NIH grant CA-104825 to S.K.L., and NIH grant A152737 to S.W.C.

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Authors and Affiliations

Authors

Contributions

P.H.T., L.Y.H. and A.A.K. designed and performed experiments and wrote portions of the manuscript. J.M.A. and R.T. designed and performed VEGF transcription and promoter assays and edited the manuscript. C.L., N.B.J., G.A.-P., W.M.M., Y.G.L., M.L., L.S.M., T.J.K., C.N.L. and Y.L. designed and performed experiments and edited the manuscript. E.F. and R.A.N. designed and performed catecholamine analyses and edited the manuscript. J.A.B., M.R. and V.K. designed and performed the imaging experiments and edited the manuscript. A.M.S. and G.L.-B. performed siRNA incorporations and edited the manuscript. R.L.C. and D.M.G. performed statistical analyses and edited the manuscript. S.K.L., S.W.C. and A.K.S. designed the overall study, analyzed data and edited the manuscript.

Corresponding author

Correspondence to Anil K Sood.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Characterization of chronic stress in a mouse model. (PDF 217 kb)

Supplementary Fig. 2

Effect of chronic stress on in vivo ovarian cancer growth. (PDF 93 kb)

Supplementary Fig. 3

Effet of chronic stress and social isolation on angiogenesis. (PDF 146 kb)

Supplementary Fig. 4

Chronic stress does not promote angiogenesis in the β-adrenoreceptor null tumors. (PDF 114 kb)

Supplementary Fig. 5

Angiogenic cytokine expression in tumors from stressed mice. (PDF 172 kb)

Supplementary Fig. 6

Effect of stress hormones and various antagonists on endothelial cell migration and proliferation. (PDF 129 kb)

Supplementary Fig. 7

Effect of VEGF inhibitors on mouse body weight. (PDF 93 kb)

Supplementary Fig. 8

Chronic stress effects on mouse cardiac physiology, lymphangiogenesis and tumor cell proliferation. (PDF 149 kb)

Supplementary Methods (PDF 132 kb)

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Thaker, P., Han, L., Kamat, A. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12, 939–944 (2006). https://doi.org/10.1038/nm1447

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