Foetal-to-adult transitions in fibroblast phenotype: their possible relevance to the pathogenesis of cancer.

Abstract

We have previously shown that the migration of foetal, adult and transformed fibroblasts into three-dimensional collagen gels is differentially affected by plating cell density. We now present data indicating that the migration of these fibroblasts is also differentially affected by local cell density in microdomains of the gel surface. In this article we discuss the possible biochemical and behavioural mechanisms that may contribute to the different migratory phenotypes expressed by foetal, adult and transformed fibroblasts; these include: (1) cell-induced alterations in the orientation and or packing density of collagen fibres in the gel; (2) deposition of specific matrix macromolecules by the fibroblasts; (3) social interactions between the cells; and (4) secretion of soluble factors affecting cell migration. We show that foetal fibroblasts secrete a migration stimulating factor (MSF) not produced by adult cells. Incubation of adult fibroblasts in the presence of MSF induces these cells to express a foetal-like migratory phenotype. Foetal fibroblasts undergo a spontaneous foetal-to-adult transition in migratory phenotype after prolonged passage in vitro; this transition is accompanied by a cessation in MSF production. MSF appears to promote fibroblast migration at high cell density by stimulating the deposition of hyaluronic acid in the extracellular matrix. Recent studies have indicated that skin fibroblasts from cancer patients display certain behavioural abnormalities characteristic of transformed and/or foetal cells. In this regard, we have shown that skin fibroblasts from cancer patients commonly express a foetal-like phenotype with respect to migratory behaviour and secretion of MSF: it is of interest to note that these cancer patient fibroblasts are indistinguishable from normal adult cells in other respects, such as morphology in confluent culture. On the basis of these observations, we suggest that: (1) fibroblasts in certain individuals fail to undergo normal foetal-to-adult transitions in a number of phenotypic characteristics; and that (2) the disruption in epithelial-mesenchymal interactions caused by the continued presence of these foetal-like fibroblasts in the adult significantly increases the risk of cancer development.