Cancer’s got nerve: Schwann cells drive perineural invasion

Abstract

C o m m e n t a r y The nerve microenvironment and cancer progressionWhile the involvement of blood and lymphatic vessels in tumor growth and progression is well established, the role of nerves in the tumor microenvironment has been largely underappreciated. Increasing evidence suggests that activation of nerve growth into tumors, termed neoneurogenesis, is another key driver of cancer progression. In addition, chronic activation of the sympathetic nervous system via increased norepinephrine levels has been observed in the tumor microenvironment (1, 2), and this activation has been demonstrated to promote tumor growth and progression via β-adrenergic receptor signaling on tumor cells and subsequent upregulation of tumor-promoting chemokines (3-6). However, it was the hallmark paper from Magnon et al. (7) that clearly demonstrated that neuronal involvement promotes cancer progression. Specifically, this group showed that autonomic nerve formation is important for regulating primary prostate cancer growth and metastasis in mouse models and that inhibition of stromal β-adrenergic receptor and type 1 muscarinic receptor signaling inhibits tumor development and improves survival. Similarly, Zhao et al. (8) recently demonstrated that stomach denervation in mouse models of gastric cancer reduces tumor incidence and growth while improving chemotherapy response and that muscarinic acetylcholine M3 receptor loss inhibits tumorigenesis. Together, these groundbreaking studies also revealed that high tumor neural fiber density strongly correlates with tumor stage and worse clinical outcome, further implicating neuronal involvement as a key driver in cancer. Perineural invasion is the growth and invasion of cancer cells around and into nerves present in the tumor microenvironment (9). This is believed to promote tumor progression by providing a conduit for cancer cell spread. Patients who experience perineural invasion, which has been described in many cancer types, often have poor prognoses, higher risk of local recurrence, and often suffer from severe pain (10, 11). In this issue, Deborde et al. uncover a key mechanism of perineural invasion that is mediated by direct contact between Schwann cells and cancer cells (12). Schwann cell-mediated perineural invasion requires contactSchwann cells regulate neuronal growth, survival, and repair (13, 14) and undergo dedifferentiation into a more migratory subtype to promote neuronal guidance through matrix remodeling, paracrine signaling, and induction of neuron axonal extensions via direct cellular contact (15-18). A bundle of Schwann cells can also invaginate between individual axons to isolate them from one another (14). In this issue, Deborde et al. demonstrate that cancer exploits some of these canonical functions of Schwann cells in neuronal repair and regulation to promote cancer cell perineural invasion (12). Their findings suggest that the dedifferentiated subtype of Schwann cells associated with nerve repair is activated in cancer, as they observed a substantial increase ...

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“…The process of PNI is directed by complex bidirectional interactions between the tumor and adjacent nerves, 15 and nerves might provide a favorable microenvironment for tumor PNI. 38 The directed movement of cells is regulated by different classes of cytokines and growth factors; however, the prime cell movers are chemokines. 27 The expression of chemokine receptors can affect the behavior of cancer cells, and their corresponding ligands in the target organs can serve as cues for the directional migration.…”

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“…Decreased E-cadherin protein expression after contact of Schwann cells with the tumor resembles the mechanism followed by cells during axonal repair process [8]. The loss of E-cadherin during the epithelialmesenchymal transition in cancer is associated with a positive regulation of NCAM1 and CDH2 [1,3,4,8]. When E-cadherin is suppressed, NCAM1 and CDH2 are upregulated; they associate with the p59fyn protein, whose subsequent activation leads to inhibition of focal adhesion and an increase in cell migration.…”

“…It has been reported that Schwann cells are induced to migrate to the region close to the tumor at the beginning of the carcinogenic process. It was also suggested that Schwann cells promote neoplastic invasion by direct contact with cancer cells, since paracrine signaling and matrix remodeling are not yet sufficient to induce the migration process [4,23]. Cellcell contact between Schwann cells and tumor tissue is necessary to potentiate the ability of neoplastic cells to penetrate into the underlying tissue [1,3].…”

“…After the nerve damage, Schwann cells become dedifferentiated, lose their capacity to myelinate and, promote neuronal orientation during repair [3]. This is accompanied by the reexpression of proteins lost during the myelinizing differentiation program, such as the glial fibrillary acidic protein (GFAP) and the neural cell adhesion molecule 1 (NCAM1) [1,4]. Paracrine signaling has been implicated in perineural invasion, with factors secreted by nerves, including glial cell line derived neurotrophic factor (GDNF), increasing the invasion of tumor cells along the nerves [5,6].…”

“…Schwann cells were identified in the tumor surrounding area prior to initiate the invasion process underlying connective tissue. These cells promote cancer invasion through direct contact, while paracrine signaling and matrix remodeling are not sufficient to proceed [4]. These cells stimulate tumor cells at the cell-cell contact sites and promote detachment and spread of individual cancer cells from neighboring tissue.…”