Chronic stress increases experimental pancreatic cancer growth, reduces survival and can be antagonised by beta-adrenergic receptor blockade.

Abstract

Chronic stress could promote tumour growth and reduce survival of pancreatic cancer patients via beta-adrenergic receptors of tumour cells. We have tested the impact of chronic acoustic and restraint stress on tumour development in an orthotopic syngeneic murine model of pancreatic cancer. Tumour-bearing C57BL/6 mice exposed to chronic stress had 45% (p=0.0138) higher circulating steroid and 111% (p=0.0052) higher adrenal tyrosine hydroxylase levels. Their immune response was significantly suppressed: The invitro LPS response of splenocytes was significantly reduced regarding Th1- and Th2-cytokines including IFN-gamma, IL-6, IL-10 and MCP-1 (0.0011<p<0.043). Also, tumours of stressed mice showed a tendency towards fewer total CD4 cells, more regulatory T cells (Treg), less T cell/tumour cell contacts and a reduction of CTLA-4 in CD4 cells (p>0.05). TGF-beta invitro was increased by 23.4% using catecholamines (p<0.012) and invivo employing chronic stress (p<0.001). After 5 weeks tumour volumes were 130% (p=0.0061) larger and median survival reduced by 13.5% (p=0.0058). Tumours expressed more VEGF (p=0.0334), had greater microvessel densities (p=0.047), and an increased MMP-9 expression (p=0.0456). Beta-catecholamines increased proliferation in tumour cells by 18% (p<0.0001) and migration by 78% (p=0.0348) whereas the beta-blocker propranolol reduced these effects by 25% (p<0.0001) and 53% (p=0.045), respectively. When stressed tumour-bearing animals were treated with propranolol tumour volumes were reduced by 69% (p=0.0088) and survival improved by 14% (p<0.0058). The potential treatment with beta-blockers of patients with pancreatic cancer or other malignancies should be further evaluated as an adjuvant anti-neoplastic agent in clinical trials.