Abstract ED07-02: Effects of chronic stress on cancer metastasis

Abstract

Abstract The notion that psychosocial factors can affect malignant progression has long been suspected. Clinical and epidemiological studies have recognized that specific psychosocial factors, such as stress, chronic depression, and lack of social support are risk factors for more rapid progression of cancer. However, the underlying mechanisms for this association are poorly understood. Cancer metastasis is a sequential and complex process that results in widespread dissemination of cancer cells. We have performed a series of in vitro and in vivo experiments using mechanistic manipulations to identify specific neuroendocrine signaling pathways that mediate direct effects of chronic stress on tumor cell biology. These studies focused on the effects of catecholamine neurotransmitters on angiogenic pathways that support the growth and progression of human ovarian carcinoma as well as other steps in the metastatic cascade. Findings indicate that chronic stress affects multiple steps during metastasis, resulting in greater tumor burden and more invasive growth in orthotopic mouse models. Moreover, catecholamines modulate the expression of genes encoding angiogenic factors (e.g., VEGF) via β-adrenergic receptors expressed on the human tumor cell surface. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the 2-adrenergic receptor. These data implicate β-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis and growth. At a clinical level, circulating levels of angiogenic factors such as VEGF and IL-6 are correlated with greater distress and inversely related to social support. Our recent studies demonstrate that relationships between psychosocial factors and angiogenic factors extend to the tumor microenvironment as well. Dissecting these pathways by which chronic stress provides support for angiogenesis and other steps in metastasis could have therapeutic implications for cancer management. Citation Information: Cancer Prev Res 2010;3(1 Suppl):ED07-02.