2. Academic Validation
  3. Cancer-Associated Fibroblasts Interact with Schwann Cells for Tumor Perineural Invasion by Oral Squamous Cell Carcinoma

Cancer-Associated Fibroblasts Interact with Schwann Cells for Tumor Perineural Invasion by Oral Squamous Cell Carcinoma

  • Neurosci Bull. 2025 Feb 25. doi: 10.1007/s12264-025-01364-w.
Xinwen Zhang # 1,  Yijia He # 1,  Shixin Xie # 1,  Yuxian Song 1,  Xiaofeng Huang 2,  Qingang Hu 1,  Yanhong Ni 3,  Yi Wang 4,  Yong Fu 5,  Liang Ding 6
Affiliations

Affiliations

  • 1 Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210093, China.
  • 2 Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210093, China.
  • 3 Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210093, China. yanhong.ni@nju.edu.cn.
  • 4 Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210093, China. athrun0528@126.com.
  • 5 Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210093, China. fy114@foxmail.com.
  • 6 Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210093, China. damoyu90@163.com.
  • # Contributed equally.
PMID: 39998796 DOI: 10.1007/s12264-025-01364-w
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

Cancer-associated fibroblasts; Leukemia inhibitory factor; Oral squamous cell carcinoma; Perineural invasion; Schwann cells.

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