Tumor stromal fibroblasts as factor of tumor progression

Malignant tumors are widely occurring in humans and they form a serious medical, economical and social problem. The aging of the population may be related to the increased incidence of such malignancies. However, despite the progress in cancer treatment, the prognosis for many patients is not optimistic. Remarkable achievements in stem cell research have delineated new horizons for possible future improvement in cancer treatment. A paradigm of the existence of cancer stem cells has been established for solid tumors where it is based on a parallel between tissue stem cells and a population of cancer cells responsible for tumor spread. Normal tissue stem cells require a highly specialized microenvironment, a so-called niche, necessary for the maintenance of their sternness. The positive role of tumor stroma in the course of the vascularisation of the tumor bed has already been well-described. The tumor stroma includes a large number of cell types (fibroblasts, leukocytes, endothelial cells). The evidence to date is that cancer stromal fibroblasts have an important role in cancer progression. Phenotype and functional differences between cancer stroma and normal tissue fibroblasts have been established in e.g. tumors of breast, pancreas, colon, prostatic gland, skin and oral cavity. We isolated stromal fibroblasts from basal and squamous cell carcinoma and compared them with normal human fibroblasts. When normal keratinocytes are co-cultured with basal/squamous cell carcinoma associated fibroblasts, the phenotype of keratinocytes is heavily altered to resemble epidermal stem cells and/or cancer cells in comparison to keratinocytes co-cultured with normal human fibroblasts. Modern analytic technologies such as DNA microarray analysis of transcriptoma (lllumina) used as screening method reveal differences in expression of genes encoding production of regulatory factors/cytokines/chemokines that are significant in the biological activity of cancer associated fibroblasts. The nature of these fibroblasts is not well-understood, but principally they can originate in local mesenchyme under the control of cancer cells or from tumor cells undergoing epithelial-mesenchymal transition. The participation of mesenchymal stem cells is also possible. Summarizing these data, like in embryonic development, mesenchymal-epithelial interaction can play an important role in tumor progression. Experiments involving blocking the activity of selected regulatory factors are enabling us to understand the role of the stroma in tumor biology. The management of the tumor microenvironment may be a promising future anti-cancer therapeutic approach.

Supported by the Ministry of Education Youth and Sports of the Czech Republic, projects No. 1M0538, NPVII 2B06106 and 0021620806