Recent studies show that interleukin-6 (IL-6) plays an important role in cancer development and cancer stromal fibroblasts are necessary for steps in progression, such as angiogenesis. However, little is known about the prognostic significance of IL-6 to the biology and the carcinogenic potential of stromal fibroblasts for oral squamous cell carcinoma (OSCC). This study aimed to investigate the correlation between IL-6 and cancer stromal fibroblasts related angiogenesis and the utility of IL-6 as a therapeutic target in OSCC.
We evaluated expression levels of IL-6 in 53 OSCC tissues by immunohistochemical staining and established three pairs of normal fibroblast (NF) and cancer-associated fibroblast (CAF) cultures from OSCC surgical specimens and the normal counterparts. The expression levels of IL-6 and VEGF of NF and CAF were evaluated using quantitative RT-PCR and ELISA. We investigated the effect of an anti-human/anti-mouse IL-6 receptor antibody on the growth of OSCC cell line in vitro and vivo.
Serial immunohistochemical staining of OSCC specimens showed that the IL-6 was mainly limited to cancer stromal region. NF cells were positive for vimentin and negative for cytokeratin AE1/AE3 and α-SMA. CAF cells were vimentin and α-SMA positive and cytokeratin AE1/AE3 negative. We confirmed that CAF produced significant amounts of IL-6 and VEGF than NF. Moreover, IL-6 enhanced VEGF production in NF and CAF, thereby inducing angiogenesis. We examined the in vitro cell proliferation of OSCC cells and CAF cells by WST-8 assay. Neither humanized anti-IL-6 receptor monoclonal antibody nor exogenous IL-6 influenced the proliferation rate of SAS cells and CAF cells under condition of single culture. However, in vivo study the IL-6 antibody reduced tumor volume by 70%.
These data suggest that inhibition of the relationship between IL-6 and stromal fibroblasts offers new approaches to OSCC therapy.
Clinical trial identification
All authors have declared no conflicts of interest.