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Cell Motility Factors pp 127–146Cite as

Heterogeneity amongst fibroblasts in the production of migration stimulating factor (MSF): Implications for cancer pathogenesis

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Part of the book series: Experientia Supplementum ((EXS,volume 59))

Summary

Fetal skin fibroblasts migrate into 3D collagen gels to a significantly greater extent than do adult cells. This enhanced motility of fetal fibroblasts appears to result from the production of a “migration stimulating factor” (MSF) which is not made by their normal adult counterparts. Adult skin fibroblasts retain responsiveness to MSF and cells exposed to this factor achieve the elevated levels of migration characteristic of fetal cells. MSF has been purified to homogeneity, has an apparent molecular mass of 70 kD and has been further characterized in terms of a number of biochemical parameters. Studies concerned with the mechanism of action of MSF indicate that it stimulates the production of a high molecular weight class of hyaluronic acid (HA). Concurrent exposure of cells to Streptomyces hyaluronidase blocks the stimulation of adult fibroblast migration by MSF. In a related series of experiments, we have shown that TGF-beta inhibits the effects of MSF on both cell migration and HA production. Taken together, these data suggest that the stimulation of fibroblast migration by MSF is dependent upon (and may directly result from) a primary induction of HA synthesis.

We have previously reported that skin fibroblasts obtained from patients with sporadic and familial breast cancer, as well as the unaffected first-degree relatives of familial breast cancer patients, commonly display a fetal-like migratory phenotype. Subsequent work has indicated that (a) these fetal-like cells also produce MSF, and (b) detectable levels of MSF are present in the serum of sporadic breast cancer patients both prior to and following surgical resection of the primary tumor mass. On the basis of these and related observations, we have put forward an hypothesis suggesting that the disruption in normal epithelial-mesenchymal interactions caused by the persistent production of MSF by fibroblasts in the adult may contribute directly to the pathogenesis of an epithelial cancer.

The demonstration of aberrant fibroblasts in sporadic cancer patients (both in our own and independent studies) is not consistent with the “germ-line genetic lesion” model commonly invoked to account for the presence of such cells in patients with hereditary cancer syndromes. We have proposed an alternative “clonal modulation” model in which we suggest that: (a) a high degree of phenotypic diversity exists within fibroblast populations, (b) a minority subpopulation of MSF-secreting fibroblasts is present in the normal adult, (c) these cells may undergo a transient clonal expansion as part of tissue homeostatic mechanisms, such as wound healing, and (d) the detection of MSF-secreting fibroblasts in cancer patients results from a persistent and inappropriate increase in their relative number in response to as yet unidentified stimuli; these may include interaction with emerging aberrant epithelial cell populations and/or environmental factors. Our recent data are consistent with this epigenetic model and indicate the existence of extensive interand intra-site heterogeneity amongst normal adult fibroblasts in terms of MSF production.

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Authors and Affiliations

  1. Department of Cell and Structural Biology, Coupland 3 Building, University of Manchester, M13 9PL, Manchester, UK

    Seth L. Schor, Ann Marie Grey, Martino Picardo & Ian Ellis

  2. CRC Department of Medical Oncology, Christie Hospital, Wilmslow Road, M20 9BX, Manchester, England

    Ana M. Schor, Anthony Howell & Graham Rushton

Authors
  1. Seth L. Schor
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  2. Ann Marie Grey
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  3. Martino Picardo
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  4. Ana M. Schor
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  6. Ian Ellis
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Editors and Affiliations

  1. Department of Radiation Oncology, Long Island Jewish Medical Center, 270-05 76th Avenue, 11042, New Hyde Park, NY, USA

    I. D. Goldberg M.D.

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Schor, S.L. et al. (1991). Heterogeneity amongst fibroblasts in the production of migration stimulating factor (MSF): Implications for cancer pathogenesis. In: Goldberg, I.D. (eds) Cell Motility Factors. Experientia Supplementum, vol 59. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7494-6_9

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  • DOI: https://doi.org/10.1007/978-3-0348-7494-6_9

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-0348-7496-0

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