Neuroimmune Regulation of Surgery-Associated Metastases

Abstract

Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has renewed interest been taken in the mechanism by which metastasizing of cancer occurs following operative procedures. It is well proven now that surgery constitutes a risk factor for the promotion of pre-existing, possibly dormant micrometastases and the acceleration of new metastases through several mechanisms, including the release of neuroendocrine and stress hormones and wound healing pathway-associated immunosuppression, neovascularization, and tissue remodeling. These postoperative consequences synergistically facilitate the establishment of new metastases and the development of pre-existing micrometastases. While only in recent years the role of the peripheral nervous system has been recognized as another contributor to cancer development and metastasis, little is known about the contribution of tumor-associated neuronal and neuroglial elements in the metastatic disease related to surgical trauma and wound healing. Specifically, although numerous clinical and experimental data suggest that biopsy- and surgery-induced wound healing can promote survival and metastatic spread of residual and dormant malignant cells, the involvement of the tumor-associated neuroglial cells in the formation of metastases following tissue injury has not been well understood. Understanding the clinical significance and underlying mechanisms of neuroimmune regulation of surgery-associated metastasis will not only advance the field of neuro-immuno-oncology and contribute to basic science and translational oncology research but will also produce a strong foundation for developing novel mechanism-based therapeutic approaches that may protect patients against the oncologically adverse effects of primary tumor biopsy and excision.

Keywords: metastasis; neoneurogenesis; neuroglia; neuroimmune axis.

Figure 1

Pathways and mechanisms of accelerated locoregional and distant tumor recurrence after surgical interventions on primary tumors. Resection and biopsy cause unavoidable tissue distraction, damage of blood and lymph vasculature, and injury and trauma of the peripheral neurons. Central systemic effects of surgical stress, together with its psychological components, result in the hypothalamic-pituitary-adrenal (HPA) axis activation and stimulation of the sympathetic branch of the peripheral nervous system (sPNS). Locally, tissue injury and regional hemorrhage, followed by different levels of hypoxemic cellular stress, inflammation, and ischemia, initiate a cascade of tissue repair pathways including wound healing and Wallerian degeneration. The wound healing, after the initial hemostasis and inflammation phases, incorporates extracellular matrix reorganization for remaking new tissue, neoangiogenesis/lymphogenesis for a new network of blood/lymph vessels, and attraction and polarization of regulatory immune cells, such as macrophages (alternatively activated type 2 or M2), for resolving inflammation and augmentation of tissue and vasculature restoration. These pathways phenotypically and functionally resemble the tumor microenvironment characteristics and thus may promote reactivation of dormant malignant cells, the formation of premetastatic niches and the survival and motility of residual and “in-transit” cancerous cells. Wallerian degeneration, prompted by the axonal injury, involves Schwann cell activation–denervation, de-differentiation, and proliferation (‘repair’ phenotype), which is required for the attraction of macrophages (Mф), cleaning the myelin and dead neuronal debris, and axonal regeneration. Resent data revealed that the repair Schwann cells functionally resemble the tumor-activated Schwann cells that can attract and activate myeloid-derived suppressor cells (MDSC), attract conventional dendritic cells (DC) and polarize them into regulatory immunosuppressive DC (regDC), and attract and polarize T cells into the regulatory phenotype (Treg). This pathway also supports local and systemic tumor-associated environments, which favor the establishment and growth of local and distant micrometastases. In addition, activated Schwann cells have been reported to induce the epithelial-mesenchymal transition (EMT) of malignant cells suggesting that tumor pre-activated, as well as axon injury-activated, Schwann cells may boost motility and invasiveness of residual and “in-transit” cancerous cells supporting the formation of the locoregional and distant metastases after surgical excision of primary tumors. (Cancerous cells and their migratory pathways are shown in blue font and blue arrows; immune cells and their effects on malignant cells are shown in brown font and brown arrows; neuroglial Schwann cells and their effects on immune and malignant cells are shown in green font and green arrows. Common pathways connected with primary tumor invasive procedures and tissue injury and repair, and their influences on malignant, neuroglial, and immune cells are shown in black font and black arrows.).