Abstract
BackgroundIn bone-invasive oral squamous cell carcinoma (OSCC), cancer-associated fibroblasts (CAFs) infiltrate into bony tissue ahead of OSCC cells. In the present study, we aimed to investigate the role of the Axin2-Snail axis in the biological behaviour of CAFs and bone invasion in OSCC.MethodsThe clinicopathological significance of Axin2 and Snail expression was investigated by immunohistochemistry in an OSCC cohort containing 217 tissue samples from patients with long-term follow-up. The influence of the Axin2-Snail axis on the biological behaviour of OSCC cells and CAFs was further investigated both in vitro and in vivo.ResultsAxin2 expression was significantly associated with Snail expression, the desmoplasia status, and bone invasion in patients with OSCC. In multivariate analysis, lymph node metastasis, desmoplasia, Axin2 expression, and Snail expression were independent poor prognostic factors in our cohort. Consistent with these findings, OSCC cells demonstrated attenuated oncogenic activity as well as decreased expression of Snail and various cytokines after Axin2 knockdown in vitro. Among the related cytokines, C-C motif chemokine ligand 5 (CCL5) and interleukin 8 (IL8) demonstrated a strong influence on the biological behaviour of CAFs in vitro. Moreover, both the desmoplastic reaction and osteolytic lesions in the calvaria were predominantly decreased after Axin2 knockdown in OSCC cells in vivo using a BALB/c athymic nude mouse xenograft model.ConclusionsOncogenic activities of the Axin2-Snail axis are not limited to the cancer cells themselves but rather extend to CAFs via regulation of the cytokine-mediated cancer-stromal interaction, with further implications for bone invasion as well as a poor prognosis in OSCC.
Highlights
In bone-invasive oral squamous cell carcinoma (OSCC), cancer-associated fibroblasts (CAFs) infiltrate into bony tissue ahead of OSCC cells
Clinicopathological significance of Axis inhibition protein 2 (Axin2) and snail expression in patients with OSCC In the present study, Axin2 expression was found in the cytoplasm of cancer cells in 168 (77.4%) patients with OSCC, and immunoreactivity against Axin2 was high in 101 OSCC tissue samples and low in 116
The results showed that when using age, sex, lesion site, T stage, lymph node metastasis, histologic grade, vascular invasion, perineural invasion, bone invasion, desmoplasia status, angiogenesis status, Axin2 expression, and Snail expression as cofactors, lymph node metastasis, desmoplasia status, Axin2 expression, and Snail expression were independent risk factors for OSCC prognosis, with hazard ratios of 3.424 (95% confidence interval, 1.466–7.998; p = 0.004), 2.491 (95% confidence interval, 1.240–5.004; Fig. 2 Clinicopathological significance of Axin2 and Snail expression in patients with OSCC. a Representative expression patterns for Axin2 and Snail in OSCC tissue samples (i)
Summary
In bone-invasive oral squamous cell carcinoma (OSCC), cancer-associated fibroblasts (CAFs) infiltrate into bony tissue ahead of OSCC cells. We aimed to investigate the role of the Axin2-Snail axis in the biological behaviour of CAFs and bone invasion in OSCC. Oral squamous cell carcinoma (OSCC) is the most common histological type of oral cancer. OSCC cells often penetrate underlying bone, and 12–56% of patients with. OSCC present with bone invasion [1]. According to the American Joint Committee on Cancer (AJCC) classification, the presence of bone invasion can upstage this type of cancer regardless of tumour size because bone invasion is a major poor prognostic indicator of OSCC [2,3,4]. The molecular mechanism underlying the invasion of adjacent bone by OSCC is not fully understood.
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