Cancer-Associated Fibroblasts Interact with Schwann Cells for Tumor Perineural Invasion by Oral Squamous Cell Carcinoma
Xinwen Zhang1 · Yijia He1 · Shixin Xie1 · Yuxian Song1 · Xiaofeng Huang2 · Qingang Hu1 · Yanhong Ni1 · Yi Wang1 · Yong Fu1 · Liang Ding1 Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Afliated Hospital of Medical School, Nanjing University, Nanjing 210093, China
2 Department of Oral Pathology, Nanjing Stomatological Hospital, Afliated Hospital of Medical School, Nanjing University, Nanjing 210093, China
Abstract
Perineural invasion (PNI) by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma (OSCC). Since Schwann cells (SCs) and fibroblasts maintain the physiological homeostasis of the peripheral nervous system, and we have focused on cancer-associated fibroblasts (CAFs) for decades, it’s imperative to elucidate the impact of CAFs on SCs in PNI+ OSCCs. We describe a disease progression-driven shift of PNI− towards PNI+ during the progression of early-stage OSCC (31%, n = 125) to late-stage OSCC (53%, n = 97), characterized by abundant CAFs and nerve demyelination. CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro, and this involved up-regulated ER stress and decreased MAPK signals. Moreover, CAFs also aggravated the paralysis of the hind limb and PNI in vivo. Unexpectedly, leukemia inhibitory factor (LIF) was exclusively expressed on CAFs and up-regulated in metastatic OSCC. The LIF inhibitor EC330 restored CAF-induced SC inactivation. Thus, OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.
Keywords
Oral squamous cell carcinoma; Perineural invasion; Cancer-associated fbroblasts; Schwann cells; Leukemia inhibitory factor
