The role of tumor stroma and cancer associated fibroblasts in tumor growth through cytokines

Development of a tumor is a parallel event with the expansion of tumor microenvironment. Although most of the treatment strategies target only malignant cells, advanced understanding of the stromal contribution in cancer progression may enhance our knowledge and allow us to develop better treatments. Tumor stroma consists of different types of cells such as a heterogenous population of fibroblasts, immune cells, pericytes, endothelial cells and other noncellular components like extracellular matrix. Studies have shown that the interaction between malignant cells and stromal components through cytokine secretion has a crucial role in cancer progression. Moreover, these stromal cells and components can be recruited, manipulated, and altered by cancer cells to provide a permissive environment rather than a defensive one. One of the major components of tumor stroma is cancer associated fibroblasts (CAFs). In normal tissues, fibroblasts are found in a quiescent state and they become activated upon stimulations such as wound healing and fibrosis. Their activation is a reversible process and most of the activated fibroblasts are removed by apoptosis after wound healing. However, recent studies showed that CAFs differ from normal activated fibroblasts in terms of proliferation, migratory capacity, and secretory phenotype. In vitro and animal studies reveal that they enhance tumor growth and progression. In this study, we present that CAFs can enhance the growth of MCF7 and T47D breast cancer cells in vitro when they are co-cultured. Our co-culture experiments showed that this tumor promoting effect of CAFs is not dependent on cell-to-cell contact and it is caused by their crosstalk through cytokine secretion. We found that Activin A, Interleukin 5 and Angiogenin are present in higher levels in the cell culture media of CAF co-culture and similarly their expression in human breast cancer tumor samples are increased. Moreover, we showed that tumor growth due to CAFs can be reversed using specific neutralizing antibodies. Additionally, recombinantly produced cytokines were able to enhance the growth of MCF7 and T47D cells without the presence of CAFs in the culture. Therefore, we propose that CAFs induce tumor growth by their interaction with malignant cells through the secretion of specific cytokines and targeting this interaction can be developed as a new strategy in cancer treatmen