Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth

Abstract

Interleukin‐6 (IL‐6) is one of the major inflammatory interleukins that has been linked to cancer progression. In our model for human skin squamous cell carcinoma (SCC), IL‐6 expression is strongly upregulated upon progression from benign tumors to highly malignant, metastasizing SCCs. We now demonstrate that IL‐6 promotes malignant and invasive tumor growth in human skin SCCs by inducing cell type specific cytokine profiles in tumor keratinocytes and stromal fibroblasts, activating the latter towards a tumor associated fibroblast (TAF) phenotype. In three‐dimensional organotypic cocultures in vitro invasive growth of IL‐6 overexpressing tumor keratinocytes, is associated with increased expression of matrix metalloproteinase‐2 (MMP‐2), MMP‐14 and tissue inhibitor of metalloproteinases‐2, and clearly depends on IL‐6 activated fibroblasts. IL‐6‐induced secretion of monocyte chemotactic protein‐1 (MCP‐1) in tumor keratinocytes and of hepatocyte growth factor in fibroblasts is crucial for regulating expression and activation of MMP‐2. This functional role of IL‐6 is confirmed in vivo. Here MMP‐14 and MMP‐2 expression occur exclusively in surface transplants of IL‐6 overexpressing keratinocytes and fibroblasts are identified as important source of MMP‐2. Our data indicate that tumor keratinocytes derived IL‐6 activates stromal fibroblasts towards a TAF phenotype, promoting tumor invasion via enhanced expression and activation of MMP‐2.

Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature

“…The overall dependence of tumor angiogenesis on the expression of various MMPs is still in the spotlight of experimental and clinical cancer research, deeply focusing on unraveling the precise interrelations between different regulatory molecules and proteolytic activities of specific MMPs (Al Rawashdeh et al, 2014; Barillari et al, 2014; Depner et al, 2014; Gong et al, 2014; Kahlert et al, 2014; Zhang et al, 2014). In this review, however, we attempted to summarize the data on the mechanisms whereby various MMPs, characterized by different substrate specificities, e.g.…”

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

“…Invasive growth is defined as a complex biological program concomitantly instructing cells to migrate, invade, proliferate, and survive (27). IL6 was shown to induce invasive growth of tumor cells in skin cancer (39) and breast carcinomas (40) and was identified as a central driver of PDAC initiation and progression (29,30). IL6 mediates its potent effects in PDAC progression via STAT3 activation and both, ablation of IL6 and of STAT3 are essential drivers of pancreatic tumor formation in Kras G12D -driven pancreatic carcinogenesis (29).…”

In Silico Analysis Validates Proteomic Findings of Formalin-fixed Paraffin Embedded Cutaneous Squamous Cell Carcinoma Tissue

“…The roles of upstream regulators including EGF, JUN, ERK, IL6 and TGFB1 in cSCC carcinogenesis is well-established (76,(85)(86)(87)91), and are of potential diagnostic and prognostic value for cSCC management. The expression and role of other upstream regulators, PRL, NFE2L2, XBP1, PPARGC1A, TRIM24, MGEA5, SOX2 and ACOX1, have not been described in cSCC, and further research is required to confirm their role in cSCC as well as their potential for use as biomarkers.…”