Impact of stress on cancer metastasis

Abstract

The influence of psychosocial factors on the development and progression of cancer has been a longstanding hypothesis since ancient times. In fact, epidemiological and clinical studies over the past 30 years have provided strong evidence for links between chronic stress, depression and social isolation and cancer progression. By contrast, there is only limited evidence for the role of these behavioral factors in cancer initiation. Recent cellular and molecular studies have identified specific signaling pathways that impact cancer growth and metastasis. This article provides an overview of the relationship between psychosocial factors, specifically chronic stress, and cancer progression.

Figure 1. Norepinephrine-, dopamine- and glucocorticoid-mediated signaling pathways in tumor, endothelial and endothelial progenitor cells

(A) In ovarian cancer cells, NE acting through ADRBs induces synthesis and release of the proangiogenic cytokines IL-6, IL-8 and VEGF. NE also induces synthesis of MMPs and stimulates migration and invasion of ovarian, colon and head and neck cancer cells; in breast, cervical and lung cancer cells, GCs acting through the GC receptor inhibit chemotherapy-induced apoptosis and promote cancer cell survival. (B) DA acting through DR2 receptors in tumor endothelial cells inhibits proliferation of these cells by inhibiting phosphorylation of VEGFR-2, MAPK and FAK. (C) DA decreases ERK1/ERK2-mediated MMP-9 synthesis and release by endothelial progenitor cells and thereby inhibits their mobilization from the bone marrow. Thus, DA prevents the participation of EPCs in tumor neovascularization. ADRB: β-adrenergic receptor; DA: Dopamine; EC: Endothelial cell; EPC: Endothelial progenitor cell; FAK: Focal adhesion kinase; GC: Glucocorticoid; GCR: Glucocorticoid receptor; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase; NE: Norepinephrine; VEGFR: VEGF receptor.

Figure 2. Main steps in the formation of a metastasis

The process of cancer metastasis consists of sequential selective steps. The outcome of each step is influenced by the interaction of metastatic cells with homeostatic factors. Failure of a tumor cell to complete any step effectively terminates the process. Therefore, the formation of clinically relevant metastases represents the survival and growth of unique subpopulations of cells that pre-exist in primary tumors. (A) Cellular transformation and tumor growth. (B) Extensive vascularization must occur if a tumor mass exceeds 1–2 mm in diameter. The synthesis and secretion of angiogenic factors establish a capillary network from the surrounding host tissue. (C) Migration and invasion of the host stroma by some tumor cells occurs by several parallel mechanisms. Lymphatic channels offer very little resistance to penetration by tumor cells and provide the most common route for tumor cell entry into the circulation. (D) Next, detachment and embolization of single tumor cells or aggregates occurs; most circulating tumor cells are rapidly destroyed. (E) After cancer cells have survived the circulation, they become trapped in the capillary beds of distant organs by adhering either to capillary endothelial cells or to the subendothelial basement membrane. (F) Extravasation then occurs, probably by mechanisms similar to those that operate during invasion. (G) Proliferation within the organ parenchyma completes the metastatic process. To continue growing, the micrometastasis must develop a vascular network and evade destruction by host defenses. The cells can then invade blood vessels, enter the circulation and produce additional metastases.