Fibroblasts as Turned Agents in Cancer Progression

SIMPLE SUMMARY: Normal epithelial cells in our organs are surrounded by stroma, which is an ecosystem made up of a variety of cells and proteins that support their intended functions. When normal epithelial cells go through a series of genetic steps that transform them into cancer cells, the cancer cells, in turn, change the character of the stroma. The stroma co-evolves with the cancer to become an autonomous tumor organ with its own ecosystem. Initially, stromal cells try to maintain normal epithelial cell function and suppress malignant changes. However, during their co-evolution, the cancer cells recruit supporting cells to actively promote their growth, invasion, metastasis, and treatment resistance. Here, I outline how cancer cells change the character of the most abundant cells in the stroma, called fibroblasts, and how the altered fibroblasts, in turn, make cancers more aggressive. I also outline efforts to use these changed fibroblasts as new targets for cancer treatment. ABSTRACT: Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G(0) differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer “wounds” the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches.