Surgical Excision of a Primary Tumor Enhances Spontaneous Metastasis of Breast Cancer Through COX-2 and β-adrenergic Pathways

Evidence suggests that the surgical removal of a primary tumor in cancer patients elicits processes that promote the outbreak of pre-existing micrometastases and the initiation of new metastases. Indeed, the peri-operative period has been suggested to be pivotal in determining long-term cancer outcomes, despite of its relatively short duration in the course of cancer progression. Recent findings have pinpointed peri-operative surgical stress responses and inflammation as potential pro-metastatic mediators. Specifically, the excess secretion of catecholamines and prostaglandins was shown to suppress immunity and to affect the tumor and its microenvironment to acquire pro-metastatic characteristics. In this study we aimed at assessing the simultaneous blockade of catecholamines and prostaglandins during the perioperative period, as well as elucidating underlying mechanisms. To this end, we injected orthotopically the MDA-MB-231 breast cancer cell line to nude mice. Primary tumor and metastatic progression were monitored in vivo employing bioluminescent imaging. Once metastatic foci were detected, the primary tumor was excised, and half of the mice were subjected to laparotomy, simulating a more extensive surgical procedure. Additionally, mice were treated peri-operatively for 30 hrs with both a β-adrenergic blocker and a COX-2 inhibitor, or with vehicle. Our results indicate that an extensive surgical procedure significantly increases metastasis, and that our combined drug treatment completely abolish this deleterious effect of surgery. We are now examining the role of natural killer (NK) cells in this model, as surgery was shown to reduce their cytotoxicity through elevating catecholamines and prostaglandins, and as NK-depletion in nude mice significantly elevated tumor lung colonization as well as the growth of established micrometastases. Based on these and previous findings, a preliminary clinical trial is now conducted.