Stromal Reaction to Invasive Cancer: The Cellular Origin of the Myofibroblast and Implications for Tumor Development

Many epithelial malignancies are associated with an extensive conversion of the surrounding normal stroma reminiscent of the transient activation seen during wound healing, albeit in a more chronic form. The most outstanding feature of the altered stroma is the accumulation of peritumoral myofibroblasts. Here, I have focused on the cellular origin of myofibroblasts in human breast cancer, the tumor cell-derived activity responsible for their occurrence, and the possible function of their most pronounced cytoskeletal change. In the field of myofibroblast research, the use of newly developed cell-culture based technologies have been instrumental. Stromal cells in short-term cultures have been thoroughly characterized using markers defined by their staining patterns in the tissue of origin. Efforts to purify non-activated fibroblasts prior to cultivation and the introduction of chemically defined culture conditions have allowed the elements of conversion to be studied at the molecular level. Furthermore, the development of a so called tumor environment assay, in which tumor cell-stromal cell interactions result in functional replicas of typical tumor histology, has proven a powerful tool in the search for the contribution of the individual stromal cell types to the complex scenario of peritumoral myofibroblasts. The cell-cell interactions seen in the tumor environment assay have been validated by in vivo coinoculation of tumor cells and myofibroblasts in nude mice. The most recent data point to the function of fibroblast cytoskeletal conversion in immobilizing the cells in close apposition to tumor cells. The comprehensive participation of normal fibroblasts in malignancies promise for future new therapeutic strategies directed against tumor cell-fibroblast interaction.?