Fibroblast phenotype plasticity: Relevance for understanding heterogeneity in "fibroblastic" tumors

Cellular transformations, reflecting phenotypic plasticity, characterize embryonic life, would-repair, physiological adaptation, and neoplasia. Fibroblastic tumors show a range of cellular differentiation, which can be rationalized in terms of phenotypic plasticity of the "normal" fibroblast. In this paper, the various kinds of fibroblast transformation are discussed, and some insights provided into the molecular mechanisms involved. Comparable molecular events may take place in neoplastic fibroblasts to produce the heterogeneous tumors nevertheless identified as fibroblastic. The following transformations are discussed: histiocytic, and fibrohistiocytic tumors; adipocytic, and lipogenic tumors; myofibroblastic, and myofibroblastic tumors. A definition of the fibroblast is required. This consists of spindle-cell morphology, vimentin-staining, and abundant rough endoplasmic reticulum. Transformation to histiocytic, lipogenic and myofibroblastic phenotypes requires the development of lysosomes, lipid droplets and lamina, and peripheral myofilaments and fibronexuses respectively. These occur in non-malignant transforming (transdifferentiating) fibroblasts, and also in tumors identified as fibrohistiocytic, lipogenic and myofibroblastic. The molecular basis of the myofibroblast transformation is probably the best studied. It is driven primarily by transforming growth factor beta. Investigations into the mechanisms of differentiation in normal fibroblasts could prove fertile ground for defining comparable differentiation in tumors. In this respect, there are very few publications on the presence of growth factors in tumors or tumor-like lesions. There is, however, increasing investigation into gene expression and gene products in tumors, which bear on the differentiation process. Ultimately, our understanding of the molecular events controlling differentiation in cancer will lead to control, cure and prevention.