Interleukin-33-Enhanced CXCR4 Signaling Circuit Mediated by Carcinoma-Associated Fibroblasts Promotes Invasiveness of Head and Neck Cancer.

Yu-Chun Lin,Yi-Ming Chang,Shin Nieh,Tsai-Yu Lee,Yaoh-Shiang Lin,Su-Feng Chen,Wen-Yen Huang

doi:10.3390/cancers13143442

Abstract

Despite recent advances, treatment for head and neck squamous cell carcinoma (HNSCC) has limited efficacy in preventing tumor progression. We confirmed previously that carcinoma-associated fibroblasts (CAF)-induced interleukin-33 (IL-33) contributed to cancer progression. However, the molecular mechanisms underlying the complex communication network of the tumor microenvironment merited further evaluation. To simulate the IL-33-induced autocrine signaling, stable clones of IL-33-overexpressing HNSCC cells were established. Besides well-established IL-33/ST2 and SDF1/CXCR4 (stromal-derived factor 1/C-X-C motif chemokine receptor 4) signaling, the CAF-induced IL-33 upregulated CXCR4 via cancer cell induction of IL-33 self-production. The IL-33-enhanced-CXCR4 regulatory circuit involves SDF1/CXCR4 signaling activation and modulates tumor behavior. An in vivo study confirmed the functional role of IL-33/CXCR4 in tumor initiation and metastasis. The CXCR4 and/or IL-33 blockade reduced HNSCC cell aggressiveness, with attenuated invasions and metastases. Immunohistochemistry confirmed that IL-33 and CXCR4 expression correlated significantly with disease-free survival and IL-33-CXCR4 co-expression predicted a poor outcome. Besides paracrine signaling, the CAF-induced IL-33 reciprocally enhanced the autocrine cancer-cell self-production of IL-33 and the corresponding CXCR4 upregulation, leading to the activation of SDF1/CXCR4 signaling subsequent to cancer progression. Thus, targeting the IL-33-enhanced-CXCR4 regulatory circuit attenuates tumor aggressiveness and provides a potential therapeutic option for improving the prognosis in HNSCC patients.

Highlights

Head and neck squamous cell carcinoma (HNSCC) was the seventh most common cancer in 2018 accounting for over 890,000 new cases and 450,000 deaths worldwide [1]
We aimed to establish stable clones of the IL-33-overexpressing head and neck squamous cell carcinoma (HNSCC) cells and an animal model to confirm whether IL-33 exerts an autocrine effect on cancer cells in addition to the paracrine effect of carcinomaassociated fibroblasts (CAF)-induced IL-33, which increases the aggressiveness of HNSCC
PCR and Western blotting analysis demonstrated that stable clones of the IL-33-overexpressing HNSCC cells with ample functional IL-33 were related to the enhanced expression of the corresponding ST2 (Figure 1a,b)

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) was the seventh most common cancer in 2018 accounting for over 890,000 new cases and 450,000 deaths worldwide [1]. While most early-stage HNSCCs can be cured with surgical resections, advanced HNSCCs are difficult to eliminate using surgery alone, and multiple combined treatments that include chemotherapy and radiotherapy combined with surgery are required. CSCs are a promising target for cancer treatment, based on their therapeutic resistance; identifying CSCs within the heterogenic malignant tumor can be difficult, and there is currently no simple biomarker for their identification [3]. These drawbacks necessitate novel treatment strategies to target the tumor stroma and the tumor itself. The tumor stroma offers an attractive target for cancer therapy and may provide a new path for therapeutic intervention

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