Abstract
Migration-stimulating factor (MSF), a soluble genetically truncated isoform of fibronectin, is a potent oncofoetal regulatory molecule. Its 2.1-kb message is generated from the fibronectin gene by a variant of standard alternative splicing involving premature intra-intronic cleavage. MSF is constitutively expressed by both epithelial and stromal cells during foetal development and in patients with cancer, but is generally not expressed in healthy adults. MSF affects the behaviour of a broad range of potential target cells (fibroblasts, vascular, and epithelial) in terms of stimulation of their migration/invasion, matrix remodelling and induction of angiogenesis. It also functions as an autocrine survival factor for the angiogenic endothelium. MSF expression by foetal and cancer patient cells adherent to an appropriate matrix may be persistently switched off by a transient exposure to TGF-β1; conversely, MSF expression by adult dermal fibroblasts adherent to other matrices may be persistently switched on by a transient exposure to TGF-β or various pharmacological agents known to alter gene expression by epigenetic mechanisms. The manifestation of MSF effects on target cells is similarly dependent on the inter-dependent signalling of soluble factors and matrix molecules. The significant association between elevated MSF expression and poor survival in patients with breast and oral cancer suggests that MSF may function as a driver of tumour progression. Accordingly, we suggest that the downregulation of MSF expression (eg, by siRNA or pharmacological agents) and/or inhibition of its bioactivities (by function-neutralising antibodies or MSF inhibitors) may provide a clinically efficacious means of improving treatment outcome in cancer patients.
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Acknowledgements
This study has been funded by grants from the Breast Cancer Campaign, Cancer Research UK, National Institutes of Health, USA (Grant no. 1 RO1 DK59144-01), Scottish Enterprise Proof of Concept Programme, Engineering and Physical Sciences Research Council and Biotechnology and Biological Sciences Research Council.
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Review presented at the 39th Cambridge Ophthalmological Symposium. Cambridge, 2–4 September 2009 to be published in Eye, March 2010
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Schor, A., Schor, S. Angiogenesis and tumour progression: migration-stimulating factor as a novel target for clinical intervention. Eye 24, 450–458 (2010). https://doi.org/10.1038/eye.2009.314
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DOI: https://doi.org/10.1038/eye.2009.314
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