The neuroendocrine impact of chronic stress on cancer

Behavioral processes have long been suspected to influence many health processes including effects on cancer. However, mechanisms underlying these observations are not fully understood. Recent work has demonstrated that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden, and a more invasive pattern of ovarian cancer growth in an orthotopic mouse model. These effects are mediated primarily through the β₂ adrenergic receptor (ADRB2) activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway. Additionally, tumors in stressed animals have increased vascularization and enhanced expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) -2 and -9. In this review, we highlight the importance of the neuroendocrine stress response in tumor biology and discuss mechanisms by which the β-adrenergic receptors on ovarian cancer cells enhance angiogenesis and tumor growth.