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<p>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<sup>+</sup> OSCCs. We describe a disease progression-driven shift of PNI<sup>−</sup> towards PNI<sup>+</sup> during the progression of early-stage OSCC (31%, <i>n =</i> 125) to late-stage OSCC (53%, <i>n =</i> 97), characterized by abundant CAFs and nerve demyelination. CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin <i>in vitro</i>, and this involved up-regulated ER stress and decreased MAPK signals. Moreover, CAFs also aggravated the paralysis of the hind limb and PNI <i>in vivo</i>. 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年2月25日

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  • Xinwen Zhang,
  • Yijia He,
  • Shixin Xie,
  • Yuxian Song,
  • Xiaofeng Huang,
  • Qingang Hu,
  • Yanhong Ni,
  • Yi Wang,
  • Yong Fu,
  • Liang Ding

摘要

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.