Autophagic Schwann cells promote perineural invasion mediated by the NGF/ATG7 paracrine pathway in pancreatic cancer

Abstract

Background Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated. Methods To investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion (DRG) coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08–2750(RO) and the autophagy inhibitor Chloroquine (CQ) were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples. Results SC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model. Conclusions PanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a “nerve-repair like effect”, induce a high level of autophagy of cancer cells, provide a “beacon” for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.

Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target

“…Further support from the TME involves an interesting relationship between autophagy and invasion in local pancreatic Schwann cells. The PDAC cells were found to promote autophagy in Schwann cells by a paracrine signal pathway involving NGF and ATG7 [ 274 ]. The “recruited” Schwann cells then: (1) promote aggressive perineural invasion in the PDAC cells; (2) migrate towards the tumor; and (3) promote neoplastic invasion via chemotaxis towards the nerve [ 274 ].…”

“…The PDAC cells were found to promote autophagy in Schwann cells by a paracrine signal pathway involving NGF and ATG7 [ 274 ]. The “recruited” Schwann cells then: (1) promote aggressive perineural invasion in the PDAC cells; (2) migrate towards the tumor; and (3) promote neoplastic invasion via chemotaxis towards the nerve [ 274 ]. The combination of these outcomes can significantly enhance the aggressiveness and metastatic potential of PDAC cells.…”

Schwann Cells in Digestive System Disorders

“…These are out of the scope of this review since we focus only on the response of normal non-mutated SCs in various physiological and pathological situations. Hypoxia-induced GM-CSF activates SCs and forces their migration to promote PNI [76] Possible role in migration SCs activate the STAT3 pathway in PDAC and promote EMT [77] and MMP production [78] by tumour cells IL-6 [77] and L1CAM [78] SCs influence tumour microenvironment by recruiting macrophages and promoting PNI [79] CCL2 Tumour fibroblasts activate SCs via N-cadherin/b-catenin and STAT3 pathways to promote neural remodelling [80,81] Possible roles in differentiation and migration PDAC cells activate autophagy in SCs via NGF/ATG7 pathway [82] Autophagy Bowel Regeneration SCPs perform neurogenesis in post-embryonic small [26,27] and large intestine [26][27][28] of mice and in zebrafish [83] Differentiation to ENS neurons and glia…”

“…GM-CSF expression was elevated in patient tumour samples and was correlated with PNI incidence [76]. Autophagy, a process that activated SCs use in nerve repair to reduce cell membrane size and clear myelin debris [158], is also implicated in PDAC [82]. Murine PNI and cell culture models were used to demonstrate that tumour cells produce NGF, which acts through ATG7 (activated in autophagy 7) to induce autophagy in SCs and promote invasion of the nerve.…”

Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment

“…In addition to neurons, glial cells, such as Schwann cells and oligodendrocytes, play a non-negligible role in neuro-tumor communications. A recent example in pancreatic cancer indicates that the autophagy of Schwann cells is activated and promotes perineural invasion (PNI) [ 62 ]. Collagen synthesis induced by proline hydroxylase was previously inferred to be the primary mechanism of VitC promotion of myelin formation.…”