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

Abstract

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.

Analgesics promote welfare and sustain tumour growth in orthotopic 4T1 and B16 mouse cancer models

“…Such changes have previously been attributed to removal of anti-angiogenesis control, growth factor release, or metabolic, neuroendocrine and immunological suppression. 6 , 11 , 13 Several previous studies have also shown stress due to anaesthesia, pain or hypothermia 12 , 32 – 34 can promote many types of cancer. 10 – 16 Although it is unknown which aspect contributed most to the present 4T1 acceleration, because it was partially neutralised by buprenorphine, stress again seems the most likely candidate.…”

Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor

“…25, 27-31 CRF is also found in the periphery where it is involved in inflammation 32-38 and cancer, 39-51 and it has been suggested that CRF may be one of the links between stress and cancer. 48, 52-59 …”

Corticotropin-releasing hormone receptors mediate apoptosis via cytosolic calcium-dependent phospholipase A2 and migration in prostate cancer cell RM-1

“…Some evidence both in favor (Arranz et al 2010, Im et al 2010, Jo et al 2011 and against (Im et al 2010, Rassouli et al 2011) the involvement of CRH family peptides in migration has been presented. Our previous studies showed that CRH inhibited migration of breast cancer cells mainly via CRHR1.…”