Bistable switch in migration stimulating factor expression: regulation by the concerted signalling of transforming growth factor-β1 and the extracellular matrix
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Migration stimulating factor (MSF) is an oncofetal motogenic/angiogenic cytokine constitutively expressed by epithelial and stromal cells in fetal and neoplastic tissues. Fibroblasts derived from healthy adult skin do not express MSF but can be induced to do so by treatment with transforming growth factor-ß1 (TGF-ß1). As the bioactivities of both MSF and TGF-ß1 are modulated by the extracellular matrix, we investigated whether the induction of MSF expression by TGF-ß1 is also matrix dependent. We now report that adult fibroblasts are induced to express MSF by a transient treatment with TGF-ß1 (as short as 2 hr) but only when the cells are adherent to a "wound" matrix, such as denatured type I collagen, fibrin or plastic tissue culture dishes. Unexpectedly, this induction of MSF expression persists unabated for the entire subsequent lifespan of the treated cells in the absence of further TGF-ß1 and irrespective of the substratum. Such "activated" MSF expression may, however, be persistently switched off again by a second transient exposure to TGF-ß1 but this time only when the cells are adherent to a "healthy" matrix of native type I collagen. Significantly, the constitutive expression of MSF by fetal and cancer patient fibroblasts could also be persistently switched off by this means. We conclude that TGF-ß1 may both switch on and switch off MSF expression in a manner critically determined by the nature of the matrix substratum and suggest that this may be a possible mechanism underlying the observed dual functionality of TGF-ß1 as both a tumour suppressor and tumour promoter.