Implications of TP-positive CAFs as a possible inducer of bone invasion in the pathogenesis of oral squamous cell carcinoma

Objectives Recently, cancer-associated fibroblasts (CAFs) have been suggested as key cellular components of bone invasion in oral squamous cell carcinoma (OSCC). However, the underlying molecular mechanisms, as well as the subtypes related to their bone invasive function, are largely unknown. In this study, we aimed to investigate the implications of thymidine phosphorylase (TP)-positive CAFs (TP + CAFs) in OSCC bone invasion. Materials and Methods TP expression was determined in 116 patients with OSCC using immunohistochemistry. The influence of TP expression on the biological behavior of CAFs was investigated in vitro . The possible impact of TP + CAFs on bone invasion in OSCC was further evaluated using patient-derived xenograft (PDX) mouse models. Results In bone-invasive OSCC tissues, we found that TP + CAFs were mainly distributed on the surface of resorbed bone tissue rather than on the tumor side. High TP + CAFs were significantly associated with higher T-stage ( p = 0.002) and bone invasion ( p < 0.001), as well as worsened overall survival ( p = 0.013) and recurrence-free survival ( p = 0.029), in our study cohort. Multivariate analysis using variable clinicopathologic factors—with tumoral TP and TP + CAFs as cofactors—revealed that high TP + CAFs (hazard ratio: 3.140; p = 0.005) had independent impacts on worsened recurrence-free survival. Recombinant human TP promoted the proliferative and invasive abilities of CAFs and increased matrix metalloproteinase-9 mRNA expression in vitro , which is related to bone resorption. In the PDX mouse models, TP + CAFs were found in early bone resorption on the surface of resorbed bony tissues. Moreover, bone resorption occurred more frequently in the PDX models with TP + CAFs than in those without. Conclusion TP + CAFs were significantly associated with bone invasion and the prognosis of OSCC. This study provides information about cellular and molecular targets for the early diagnosis and treatment of bone-invasive OSCC.