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Objective To identify FN1 transcripts associated with OA pathophysiology and investigate the downstream effects of modulating FN1 expression and relative transcript ratio. Methods FN1 transcriptomic data was obtained from our previously assessed RNA-seq dataset of lesioned and preserved OA cartilage samples from the Research osteoArthritis Articular Cartilage (RAAK) study. Differential transcript expression analysis was performed on all 27 FN1 transcripts annotated in the Ensembl database. Human primary chondrocytes were transduced with lentiviral particles containing short hairpin RNA (shRNA) targeting full-length FN1 transcripts or non-targeting shRNA. Subsequently, matrix deposition was induced in our 3D in vitro neo-cartilage model. Effects of changes in the FN1 transcript ratio on sulphated glycosaminoglycan (sGAG) deposition were investigated by Alcian blue staining and dimethylmethylene blue assay. Moreover, gene expression levels of 17 cartilage-relevant markers were determined by reverse transcription quantitative polymerase chain reaction. Results We identified 16 FN1 transcripts differentially expressed between lesioned and preserved cartilage. FN1-208, encoding migration-stimulating factor, was the most significantly differentially expressed protein coding transcript. Downregulation of full-length FN1 and a concomitant increased FN1-208 ratio resulted in decreased sGAG deposition as well as decreased ACAN and COL2A1 and increased ADAMTS-5, ITGB1 and ITGB5 gene expression levels. Conclusion We show that full-length FN1 downregulation and concomitant relative FN1-208 upregulation was unbeneficial for deposition of cartilage matrix, likely due to decreased availability of the classical RGD (Arg-Gly-Asp) integrin-binding site of fibronectin.

Migration Stimulating Factor (MSF) is a 70 kDa truncated isoform of fibronectin (FN); its mRNA is generated from the FN gene by an unusual two-stage processing. Unlike full-length FN, MSF is not a matrix molecule but a soluble protein which displays cytokine-like activities not displayed by any other FN isoform due to steric hindrance. There are two isoforms of MSF; these are referred to as MSF+aa and MSF-aa, while the term MSF is used to include both.

Migration Stimulating Factor (MSF) is a novel oncofetal biomarker previously identified in a number of human tumours. The aim of this study was to evaluate the possible association between MSF expression and disease progression in breast cancer. Archival breast tissues examined included malignant tumours (T; n=23), benign tumours or pathologies (B; n=8) and histologically normal breast from either reduction mammoplasties (NB; n=19) or from tumour patients (NB-T; n=18). Sections were stained with MSF-specific antibodies and assessed by consensus of 3-4 independent observers in terms of various MSF indices, which represented overall, epithelial and stromal MSF expression. MSF was heterogeneously expressed by epithelial and stromal cells, with significant inter-group quantitative differences in the sequence NB

Migration stimulating factor (MSF) is a novel angiogenic factor previously identified in breast tumours and their associated stroma. The aim of this study was to determine the possible diagnostic and prognostic value of MSF expression in these tumours and its effects on breast-derived cells in vitro.

Publisher Summary Cancer progression is also invariably accompanied by the reexpression of fetal isoforms of various structural and regulatory proteins not normally present in healthy adult tissues. Recent technological advances have fueled an explosion in our detailed understanding of the epigenetic mechanisms controlling this process. Different models involving both genetic and epigenetic mechanisms have been proposed to account for the observed “oncofetal” pattern of gene expression. Migration stimulating factor (MSF) is an oncofetal regulatory molecule constitutively expressed by epithelial and stromal cells during fetal development. This chapter reviews MSF in terms of its molecular characterization and spectrum of bioactivities, including the role of hyaluronan (HA) in mediating the motogenic response of certain target cells and the oncofetal pattern of its local and systemic expression. It also discusses the tissue level control of target cell response to MSF and the postulated epigenetic control of MSF expression within the context of an “extended” oncofetal model of cancer inception and progression. Finally, the chapter concludes with a brief discussion of the potential clinical implications of these concepts for improving the management of patients with cancer.

Objective of the project was to evaluate the impact of migration-stimulating factor expression for breast cancer diagnosis and prognosis.

Tumor progression is a relatively indolent process, with many years commonly intervening between the inception of an initiating genetic lesion and the development of overt malignant disease. We suggest that the perturbation of normal epithelial-mesenchymal interactions caused by the inappropriate presence of fibroblast subpopulations displaying various ‘fetal-like’ phenotypic characteristics may significantly alter the kinetics of tumor progression and hence enhance susceptibility to cancer development. In this communication, we review our own data indicating the presence of fetal-like fibroblasts in cancer patients and put these observations in the context of similar published reports. We then discuss our interpretation of these findings, emphasising the possible direct involvement of fetal-like fibroblasts in cancer pathogenesis and putting forward an epigenetic ‘clonal modulation’ model to account for their presence in cancer patients.

MSF isoforms are present in most breast tumours and are secreted by breast tumour cell lines. MSF stimulates tumour cell invasion in an autocrine and paracrine manner, modulated by the type of isoform expressed and by the presence of MSFI.