Fibroblast interaction with squamous cell carcinoma

Cancer microenvironment plays crucial role in tumor progression and metastasis of head and neck squamous cell carcinoma. A growing body of evidence indicates that fibroblasts are active participants in tumor progression. Preliminary results show that oral fibroblasts are capable to synthesize the chemokine CXCL12 (Stroma-Derived- Factor-1). Tumor cells of oral carcinoma carry the specific receptor (CXCR4) for this chemokine. In this study the SDF-1 - CXCR4 axis will be investigated as a model system of chemokine-mediated interaction of carcinoma- associated fibroblasts (CAFs) and tumor cells. The invasive phenotype of tumor cells supported by CAFs will be investigated in cell interaction systems, where comparative methodology will be used. Traces of epithelial- mesenchymal transdifferentiation (EMT) will be detected in squamous cell carcinoma cells as a consequence of SDF-1 - CXCR4 induction. By the usage of functional approach (synthetic inhibitors, neutralizing antibodies and RNA-inhibition) the SDF-1 - CXCR4 axis will be mechanistically challenged. Based on improved knowledge of the SDF-1 - CXCR4 axis in CAF - tumor cell interactions, this study aims to describe further mediator systems involved in tumor-host interaction, and to provide potential novel therapeutic targets.

In the project P22287-B13 Fibroblast interaction with squamous cell carcinoma we have hypothesized that tumor cells of head and neck squamous cell carcinoma interact with their microenvironment, which contributes to the invasion of cancer cells. The invasion is required for colonisation of lymph nodes, and distant organs (metastasis). The continuous communication between malignant tumor cells and their direct neighbours was the subject of our investigation. We have established an experimental model using oral fibroblasts and oral tumor cells. These cells were separated with a semi-permeable membrane. The cells were grown together for 5-7 days and it was investigated, which mediators are released from the tumor cells and from the oral fibroblasts, and what kind of changes can be observed in them in terms of gene expression, regulation and morphology. The experimental system reproduced characteristics of tumor cells observed in histological sections of head and neck cancer. Particularly, tumor cells suffered a major change in their nature; from epithelial cells they became mesenchymal. This change is known from embryonic development, and is related with a stem cell-like character. Indeed, the tumor cells gaining the mesenchymal morphology and gene expression profile were able to migrate through an 8 m pore size grid, moreover, they were also able to degrade a gel layered in their way. At the same time, fibroblasts have also changed and become adapted to the interactive tumor cells. In fact, the achievement of mesenchymal character in tumor cells happened with the contribution of fibroblasts. Tumor cells initially produced inflammatory factors and fibroblasts have answered to them by releasing growth factors inducing a mesenchymal differentiation and invasive function of tumor cells. The entire novelty is the achievement of a model, which explains the interaction between tumor cells and the adapted fibroblasts by growth factors that are originally known in neural system. Moreover, we have also found that curcumin, a natural compound derived from the Curcuma longa plant was able to inhibit the supporting function of adaptive fibroblasts, and the aggressive invasion of tumor cells. This project will have a significant impact on pharmaceutical drug development, as it provides therapeutic targets and a novel application potential of an already existing drug. We have also provided biomarkers for the routine clinical work, which has a therapy predictive potential.