The key findings from our study are that increased angiogenic processes mediated by surgical stress could promote ovarian cancer growth in vivo. This increase in tumor growth was abrogated by blocking ADRB-mediated angiogenesis and peri-operative use of propranolol could have preventive effects for the surgical stress-induced tumor growth.
Surgery, as a stressor, could increase the risk of postoperative metastases and their mechanisms can be divided as local or systemic effects. Some reports have suggested that the surgical wound has important roles in surgical stress as the source of the tumor-stimulating factors (10
). These reports suggested that growth factors or cytokines released by wounding could contribute to creating a suitable environment for tumor growth (10
). Wound healing and tumor progression both involve processes of cell proliferation, inflammation, and angiogenesis. In contrast to local effects, Ben-Eliyahu et al
. suggested that surgical stress results in activation of the hypothlamic-pituitary-adrenal axis and the SNS and influences the immune system, especially surgery-induced suppression of natural killer (NK) cell activity (28
). They reported that marginating pulmonary NK activity was suppressed by surgery and a combined use of a β-blocker and a prostagladin-synthesis inhibitor restored NK function (18
We recently reported that chronic (immobilization) stress promotes tumor development and progression via β-adrenergic activation of the cAMP-PKA signaling pathway in an orthotopic murine model of ovarian carcinoma (23
). In addition to chronic stress, understanding the mechanisms responsible for mediating the effects of surgical stress on human tumor tissues is crucial for determining the full impact of this stressor on tumorigenesis and for devising effective interventions.
Our results indicate that surgical stress likely results in systemic sympathetic responses that promote tumor growth, in part, by activating ADRB on tumor cells. Biologically, the acceleration in tumor growth is mediated by increased angiogenesis resulting from increased VEGF production. This premise is supported by our finding that even surgery at an extraperitoneal site (i.e., mastectomy) promoted intraperitoneal tumor growth (). Our findings related to the efficacy of a beta-blocker in abrogating the surgically-induced tumor growth suggest that such an approach may hold utility for cancer patients undergoing surgery (). Our findings regarding activation of angiogenesis by surgical stress are consistent with work from our and other groups demonstrating the effects of stress on angiogenic factors ( and ) (23
Although we focused on sympathetic influence and angiogenesis in the current study, it is possible that other mechanisms might be operative as well in mediating the effects of stress. Therefore, we analyzed several cytokines and chemokines in serum following surgery (). Indeed, several cytokines were elevated, which might also be involved in the effects of surgical stress on tumor growth (31
In summary, increased angiogenic processes mediated by surgical stress promote tumor growth in vivo. These effects can be effectively blocked by a β-blocker such as propranolol. These findings could have significant implications for the perioperative management of cancer patients.