Abstract. Cancer cells have a variety of interactions with neighboring connective tissue, and this activity primarily involves fibroblasts. Co-culture of fibroblasts derived from human skin with cancer cells results in the conversion of fibroblasts into cancer-associated fibroblasts, which are known to support tumor growth and invasiveness. To evaluate the effect of radiation on tumor-fibroblast interactions, the present study co-cultivated fibroblasts from pre-irradiated and non-irradiated human skin with FaDu head and neck squamous cell carcinoma cells for 3 days. Subsequently, cells were analyzed for tumor viability, apoptosis, and secretion of interleukin (IL)-6 and -8 by performing an MTT assay, Annexin V-propidium iodide test and enzyme-linked immunosorbent assay, respectively. Co-culture of FaDu cells with pre-irradiated fibroblasts resulted in a significant decrease in tumor viability, a notable increase in apoptosis and significantly lower levels of IL-8 compared with FaDu cells cultured with non-irradiated fibroblasts. Therefore, we propose that pre-irradiation changes the properties of fibroblasts and their effects on co-cultivated tumor cells, and, thus may lead to an improved understanding of the therapeutic options for patients that have already undergone irradiation.
IntroductionSquamous cell carcinoma is a major cause of cancer morbidity and mortality, and is one of the most commonly occurring malignancies worldwide. The incidence of head and neck squamous cell carcinoma (HNSCC) is estimated at 500,000 per year in the United States (1). Changes have been made regarding the therapeutic strategies applied for such patients, including different surgical approaches, radiotherapy and chemotherapy either in alone or in various combinations; however, despite this multi-modal treatment strategy, survival rates have not improved significantly over the past several decades, with an overall 5-year survival rate of 40-50% (2).There is increasing evidence that tumor growth is not only determined by malignant cancer cells, but also by the tumor stroma (3). The tumor stroma is partially composed of fibroblasts and the connective tissue they produce. Physiologically, due to their close proximity, continuous crosstalk between the stroma and epithelia controls tissue differentiation (4). In the pathology of a tissue wound, the stroma takes on the role of repair, while paracrine signaling alters epithelial proliferation and differentiation (4,5). As cancer functionally resembles a chronic wound, these mechanisms of wound repair are useful to examine from an oncological point of view. In this regard, fibroblasts, which are the primary component of tumor stroma, have been shown to be prominent modifiers of cancer progression (6). It has also become increasingly clear that there are different subpopulations of fibroblasts, as a result of their continuous interaction with epithelial or cancer cells. One of these subpopulations, termed cancer-associated fibroblasts (CAFs), has been shown to be an important promoter of t...