The impact of stress on tumor growth: peripheral CRF mediates tumor-promoting effects of stress

Molecular Cancer

Research

Rosa P Gomariz¹  Andrew N Margioris²  Christos Tsatsanis²  Berber Mol²  Maria Venihaki²  Erini Dermitzaki²  Ariadne Androulidaki²  Alicia Arranz²  Olga Rassouli²  Efstathios N Stathopoulos³  Jorge Ripoll⁴ 

[1] Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain;Department of Clinical Chemistry, School Of Medicine, University of Crete, 71003, Heraklion, Greece;Department of Pathology, School Of Medicine, University of Crete, 71003, Heraklion, Greece;Institute for Electronic Structure and Laser, Foundation for Research and Technology-Hellas, 71110, Heraklion, Greece;

关键词: Corticotropin Releasing Hormone;    stress;    4T1;    breast cancer;   

DOI  :  10.1186/1476-4598-9-261

 received in 2010-03-30, accepted in 2010-09-27,  发布年份 2010

来源: Springer

【 摘 要 】

IntroductionStress has been shown to be a tumor promoting factor. Both clinical and laboratory studies have shown that chronic stress is associated with tumor growth in several types of cancer. Corticotropin Releasing Factor (CRF) is the major hypothalamic mediator of stress, but is also expressed in peripheral tissues. Earlier studies have shown that peripheral CRF affects breast cancer cell proliferation and motility. The aim of the present study was to assess the significance of peripheral CRF on tumor growth as a mediator of the response to stress in vivo.MethodsFor this purpose we used the 4T1 breast cancer cell line in cell culture and in vivo. Cells were treated with CRF in culture and gene specific arrays were performed to identify genes directly affected by CRF and involved in breast cancer cell growth. To assess the impact of peripheral CRF as a stress mediator in tumor growth, Balb/c mice were orthotopically injected with 4T1 cells in the mammary fat pad to induce breast tumors. Mice were subjected to repetitive immobilization stress as a model of chronic stress. To inhibit the action of CRF, the CRF antagonist antalarmin was injected intraperitoneally. Breast tissue samples were histologically analyzed and assessed for neoangiogenesis.ResultsArray analysis revealed among other genes that CRF induced the expression of SMAD2 and β-catenin, genes involved in breast cancer cell proliferation and cytoskeletal changes associated with metastasis. Cell transfection and luciferase assays confirmed the role of CRF in WNT- β-catenin signaling. CRF induced 4T1 cell proliferation and augmented the TGF-β action on proliferation confirming its impact on TGFβ/SMAD2 signaling. In addition, CRF promoted actin reorganization and cell migration, suggesting a direct tumor-promoting action. Chronic stress augmented tumor growth in 4T1 breast tumor bearing mice and peripheral administration of the CRF antagonist antalarmin suppressed this effect. Moreover, antalarmin suppressed neoangiogenesis in 4T1 tumors in vivo.ConclusionThis is the first report demonstrating that peripheral CRF, at least in part, mediates the tumor-promoting effects of stress and implicates CRF in SMAD2 and β-catenin expression.

【 授权许可】

Unknown   
© Arranz et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.