The effects of the neuroendocrine system and microenvironment on breast cancer metastasis remain largely unexplored.
Sympathetic nervous system (SNS) nerve fibers are present in organs that serve as key targets for breast cancer metastasis, including the lymph nodes, lung and bone but little is known about the effects of the SNS function or chronic stress on the dissemination of metastatic cancer cells from a primary tumor to distant target organs. To investigate the role of neuroendocrine activation in cancer progression, in this study, Erica K. Sloan and colleagues used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. The authors demonstrate that physical restraint, applied as a standardized stressor increased the metastasis of primary breast tumor cells to distant tissues by 38-fold, and stress increased metastasis in clinically relevant tissues, with a 37-fold increase in the lung and a 67% increase in the lymph nodes. The beta-adrenoreceptor-agonist isoproterenol increased metastasis to distant tissues by 22-fold, whereas treatment of stressed animals with the beta-adrenoreceptor antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. SNS effects were mediated through beta-adrenergic signaling, which acted to recruit alternatively activated macrophages into the primary tumor parenchyma and thereby induce a prometastatic gene expression signature. The study identifies SNS activation as a novel physiologic regulator of breast cancer metastasis to distant tissue sites, and the authors argue that a direct regulation of macrophage biology by the SNS seems to constitute a previously unrecognized pathway by which external conditions affecting the autonomic nervous system can activate a metastatic switch within a growing primary tumor. They suggest that pharmacologic inhibition of SNS activity could potentially constitute a novel adjunctive strategy for minimizing breast cancer metastasis. Furthermore, they also stress the importance of considering the patient''s overall physiology in the development of new therapeutic approaches to limit cancer progression and minimize metastatic rates in breast cancer.
SOURCE: Cancer Res 2010, 70: 7042