The paracrine effect of cancer-associated fibroblast-induced interleukin-33 regulates the invasiveness of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related death worldwide. The prognosis of HNSCC is usually poor because of its propensity for extensive invasion, local recurrence and frequent regional lymph node metastasis, even at initial diagnosis. Carcinoma-associated fibroblasts (CAFs), a major type of tumour-surrounding stromal cell, generate mediators through which they interact with tumours and contribute to cancer progression. The orchestration between CAFs and cancer cells is complex. Despite recent studies demonstrating the paracrine effect of stromal cells in the tumour microenvironment on initiation and progression of cancer cells, the major mediator related to CAFs and its underlying mechanism remain unknown. In the present study, we used organotypic culture to investigate CAFs that promote aggressive behaviour of HNSCC cells. Using microarray analysis, we detected abundant expression of interleukin-33 (IL-33) in CAFs and identified IL-33 as a critical mediator in CAF-induced invasiveness. Counteracting IL-33 activity diminished the aggressive phenotype of cancer cells induced by CAFs. Administration of IL-33 promoted cancer cell migration and invasion through induction of epithelial-to-mesenchymal transdifferentiation and increased IL-33 gene expression in cancer cells. In 40 patients with HNSCC, IL-33 expression in CAFs correlated with IL-33 expression in cancer cells. Most cases with a low invasion pattern grading score (IPGS) showed low or no expression of IL-33, whereas most HNSCC cases with high IPGS displayed over-expression of IL-33 in CAFs and cancer cells. High IL-33 expression associated with poor prognosis in terms of nodal metastasis-free survival. These results indicate that CAFs promote cancer invasiveness via paracrine and autocrine effects on microenvironmental IL-33 signalling, and suggest that IL-33 is a potential prognostic biomarker that could be considered in therapeutic strategies for the treatment of patients with HNSCC.