Fig. 2.

Four alternative models for cellular origins and evolution of myofibroblasts in the stroma of tumour. (1) Transdifferentiation into myofibroblasts. Populations of residual mesenchymal cells (e.g., stromal fibroblasts) might transdifferentiate into myofibroblasts without acquiring any significant genetic alterations; (2) differentiation into myofibroblasts. Stromal myofibroblasts are recruited from specialised circulating bone marrow-derived progenitor cell types, such as fibrocytes and MSCs, which differentiate into myofibroblasts within the tumour stroma; (3) selection of pre-existing myofibroblasts. A small population of pre-existing myofibroblasts may be clonally expanded in the tumour without acquiring any further phenotypic alterations; (4) selection of genetically altered fibroblasts. Acquisition of genetic alterations (e.g., p53 loss) may allow for the clonal selection from a small population of fibroblasts or progenitors that have undergone such alterations. The resulting fibroblasts may or may not then differentiate into myofibroblasts.