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

A. M. Schor (Lead / Corresponding author), A. M. Woolston, K. Kankova, K. Harada, L. E. Aljorani, S. Perrier, P. A. Felts, R. P. Keatch, S. L. Schor

Research output: Chapter in Book/Report/Conference proceedingChapter (peer-reviewed)peer-review

Abstract

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.MSF was first identified as a motogen secreted by foetal and cancer-associated fibroblasts in tissue culture. It is also produced by sprouting (angiogenic) endothelial cells, tumour cells and activated macrophages. Keratinocytes and resting endothelial cells secrete inhibitors of MSF that have been identified as NGAL and IGFBP-7, respectively. MSF+aa and MSF-aa show distinct functionality in that only MSF+aa is inhibited by NGAL.MSF is present in 70-80% of all tumours examined, expressed by the tumour cells as well as by fibroblasts, endothelial cells and macrophages in the tumour microenvironment (TME). High MSF expression is associated with tumour progression and poor prognosis in all tumours examined, including breast carcinomas, non-small cell lung cancer (NSCLC), salivary gland tumours (SGT) and oral squamous cell carcinomas (OSCC). Epithelial and stromal MSF carry independent prognostic value. MSF is also expressed systemically in cancer patients, being detected in serum and produced by fibroblast from distal uninvolved skin. MSF-aa is the main isoform associated with cancer, whereas MSF+aa may be expressed by both normal and malignant tissues.The expression of MSF is not invariant; it may be switched on and off in a reversible manner, which requires precise interactions between soluble factors present in the TME and the extracellular matrix in contact with the cells. MSF expression in fibroblasts may be switched on by a transient exposure to several molecules, including TGFβ1 and MSF itself, indicating an auto-inductive capacity.Acting by both paracrine and autocrine mechanisms, MSF stimulates cell migration/invasion, induces angiogenesis and cell differentiation and alters the matrix and cellular composition of the TME. MSF is also a survival factor for sprouting endothelial cells. IGD tri- and tetra-peptides mimic the motogenic and angiogenic activities of MSF, with both molecules inhibiting AKT activity and requiring αvβ3 functionality. MSF is active at unprecedently low concentrations in a manner which is target cell specific. Thus, different bioactive motifs and extracellular matrix requirements apply to fibroblasts, endothelial cells and tumour cells. Unlike other motogenic and angiogenic factors, MSF does not affect cell proliferation but it stimulates tumour growth through its angiogenic effect and downstream mechanisms.The epithelial-stromal pattern of expression and range of bioactivities displayed puts MSF in the unique position of potentially promoting tumour progression from both the "seed" and the "soil" perspectives.

Original languageEnglish
Title of host publicationTumor Microenvironment
Subtitle of host publicationNovel Concepts
EditorsAlexander Birbrair
Place of PublicationSwitzerland
PublisherSpringer
Pages351-397
Number of pages47
Edition1
ISBN (Electronic)9783030731199
ISBN (Print)9783030731182, 9783030731212
DOIs
Publication statusPublished - 2021

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1329
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Keywords

  • Carcinoma, Non-Small-Cell Lung
  • Cytokines
  • Endothelial Cells
  • Humans
  • Lung Neoplasms
  • Tumor Microenvironment
  • NGAL
  • Sprouting (angiogenic) endothelial cells
  • IGFBP-7
  • Migration Stimulating Factor (MSF)
  • Macrophages
  • IGD peptides
  • Tumour microenvironment (TME)
  • Angiogenesis
  • Oncofoetal protein
  • TGFβ1
  • Prognostic factor
  • Cancer-associated fibroblasts (CAF)
  • Cell migration
  • Fibronectin isoforms
  • Tumour cells

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