Bistable switch in migration stimulating factor expression: Regulation by the concerted signalling of transforming growth factor‐β1 and the extracellular matrix

Abstract

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-b1 (TGF-b1). As the bioactivities of both MSF and TGF-b1 are modulated by the extracellular matrix, we investigated whether the induction of MSF expression by TGF-b1 is also matrix dependent. We now report that adult fibroblasts are induced to express MSF by a transient treatment with TGF-b1 (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-b1 and irrespective of the substratum. Such ''activated'' MSF expression may, however, be persistently switched off again by a second transient exposure to TGF-b1 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-b1 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-b1 as both a tumour suppressor and tumour promoter.Migration stimulating factor (MSF) is a motogenic and angiogenic cytokine exhibiting an oncofetal expression profile. [1][2][3][4][5] Skin fibroblasts derived from more than 90% of healthy adults do not express MSF and display a low baseline level of migration into three-dimensional (3D) gels of native type I collagen fibres. In contrast, more than 90% of fetal fibroblasts and 50-90% of cancer patient fibroblasts express MSF and consequently migrate to a significantly greater extent than do their healthy adult-derived counterparts. Although not expressing MSF, healthy adult fibroblasts remain responsive to it, as evidenced by the stimulation of their migration by either recombinant human MSF (rhMSF) or conditioned medium (CM) from fetal or cancer patient fibroblasts. 1,[6][7][8][9] MSF is a genetically truncated isoform of fibronectin. 2 Approximately 20 ''full-length'' fibronectin isoforms had been identified when MSF was cloned, all of which consisted of two peptide chains (250-280 kDa each) covalently linked by disulfide bonds at their respective C-termini. 10 In contrast, MSF (with a molecular mass of 70 kDa) is a soluble single chain protein identical to the N-terminus of the fibronectin monomer up to and including the amino acid sequence coded by exon III-1a (Fig. 1a). MSF expression by fibroblasts is controlled by a two-step process in which the primary fibronectin gene transcript is foreshortened as a result of read-through of...

Migration Stimulating Factor (MSF): A Novel Biomarker of Breast Cancer Progression

“…The assessment of MSF expression in tumours may inform the development of novel MSF-targeted adjuvant therapies, these designed to inhibit its expression and/or manifestation of its bioactivity [7,33,34,42]. Such a targeted "theranostic" approach has the potential of enhancing therapeutic efficacy.…”

“…The difference between older and younger patients was determined by unpaired two-tailed Mann Whitney test is consistent with this paradigm. It should accordingly be noted that the expression of MSF and its precise effect on target cells is profoundly modulated by both the nature of the macromolecular matrix to which the cells are adherent and the presence of cell-produced soluble factors, including TGF-β and neutrophil-associated lipocalin [7,13,33,34]. The complexity of this hierarchy of autocrine and paracrine regulatory circuits underscores the importance of achieving a holistic appreciation of the factors collectively contributing to the dynamic process of tumour progression [35,36].…”

Engineering a Cell Home for Stem Cell Homing and Accommodation

“…Notably, both the denatured and native collagen substrata used in these investigations were composed of the same chemical species, i.e., type I collagen; they differed only in topological organization and spatial conformation. Recently, MSF expressed by epithelial l cells was shown to be switched on or off by transient treatment with TGF‐β1 in a manner critically dependent on the nature of the matrix substratum …”

Migration Stimulating Factor (MSF): Its Role in the Tumour Microenvironment

“…In different studies, the presence of MSF has been determined by in-situ hybridisation, RT-PCR, immunohistochemistry (IHC) and biochemical methods. In our laboratory, the presence of bioactive MSF has been defined by the expression of its motogenic activity on target cells attached to native collagen substrata (either collagen gel or transmembrane assay), in combination with other methods, such as (i) abolition of the motogenic activity with MSFfunction-neutralising antibodies, (ii) removal of the activity by immunoprecipitation or affinity chromatography to MSF-identification antibodies, (iii) separation of MSF from other molecules by gel filtration chromatography and SDS-PAGE [Grey et al 1989;Schor et al 2003Schor et al , 2012Jones et al 2007].…”