Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement

Abstract

Surgery for the removal of a primary tumor presents an opportunity to eradicate cancer or arrest its progression, but is also believed to promote the outbreak of pre-existing micrometastases and the initiation of new metastases. These deleterious effects of surgery are mediated through various mechanisms, including psychological and physiological neuroendocrine and paracrine stress responses elicited by surgery. In this review we (i) describe the many risk factors that arise during the perioperative period, acting synergistically to make this short timeframe critical for determining long-term cancer recurrence, (ii) present newly identified potent immunocyte populations that can destroy autologous tumor cells that were traditionally considered immune-resistant, thus invigorating the notion of immune-surveillance against cancer metastasis, (iii) describe in vivo evidence in cancer patients that support a role for anti-cancer immunity, (iv) indicate neuroendocrine and paracrine mediating mechanisms of stress- and surgery-induced promotion of cancer progression, focusing on the prominent role of catecholamines and prostaglandins through their impact on anti-cancer immunity, and through direct effects on the malignant tissue and its surrounding, (v) discuss the impact of different anesthetic approaches and other intra-operative procedures on immunity and cancer progression, and (vi) suggest prophylactic measures against the immunosuppressive and cancer promoting effects of surgery.

Fig. 1

A schematic representation of the kinetics of several perioperative risk factors for the initiation of new metastases and the outbreak of preexisting micro-metastases in cancer patients (reviewed in section 1). Each risk factor is signified by a horizontal bar, and darker areas indicate higher levels of impact. *Not indicated are the direct effects of many of the soluble factors, including catecholamines (CA), prostaglandins (PG), and opiates/opioids on malignant tissue proliferation, invasion capacity, secretion of VEGF, etc, which are reviewed in sections 3 & 4. The curve represents the cumulative risk along the perioperative period.