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 ...