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

  • Seth L. Schor
  • Ann Marie Grey
  • Martino Picardo
  • Ana M. Schor
  • Anthony Howell
  • Ian Ellis
  • Graham Rushton
Chapter
Part of the Experientia Supplementum book series (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.

Keywords

Breast Cancer Patient Hyaluronic Acid Skin Fibroblast Familial Breast Cancer Hereditary Cancer Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Baird, A., and Durkin, T. (1986) Inhibition of endothelial cell proliferation by type-beta transforming growth factor: interactions with acidic and basic fibroblast growth factors. Biochem. Biophys. Res. Commun. 138: 476–482.CrossRefGoogle Scholar
  2. Balza, E., Borsi, L., Allemanni, G., and Zardi, L. (1988) Transforming growth factor-beta regulates the levels of different fibronectin isoforms in normal cultured fibroblasts. FEBS Lett. 228: 42–44.CrossRefGoogle Scholar
  3. Bartal, A. H., Lichtig, C., Cardo, C. C., Feit, C., Robinson, E., and Hirshaut, Y. (1986) Monoclonal antibody defining fibroblasts appearing in fetal and neoplastic tissues. J. Natl. Cancer Inst. 76: 415–419.Google Scholar
  4. BisScil, M. J., and Barcellos-Hoff, M. H. (1987) The influence of the extracellular matrix on gene expression. J. Cell Sci. suppl.: 327–343.Google Scholar
  5. Cantrella, M., McCarthy, T. L., and Canalis, E. (1987) Transforming growth factor-beta is a bifunctional regulator of replication and collagen synthesis in osteoblast-enriched cultures of fetal rat bone. J. Biol. Chem. 262: 2869–2874.Google Scholar
  6. Cheifetz, S., Weatherbee, J. A., Tsang, M. L., Anderson, J. K., Mole, J. E., Lucas, R., and Massague, J. (1987) The transforming growth factor-beta system: a complex pattern of cross-reactive ligands and receptors. Cell 48: 409–415.CrossRefGoogle Scholar
  7. Chen, J., Grant, M., Schor, A., and Schor, S. L. (1989) Differences between adult and foetal fibroblasts in the regulation of hyaluronate synthesis: correlation with migratory activity. J. Cell Sci. 94: 577–589.Google Scholar
  8. Colige, A., Nusgens, B., and Lapiere, C. M. (1988) Effect of EGF on human skin fibroblasts is modulated by the extracellular matrix. Arch. Dermatol. Res. 280 (suppl): S42-S46.Google Scholar
  9. Dabbous, M. K., Haney, L., Carter, L. M., Paul, A. K., and Reger, J. (1987) Heterogeneity of fibroblast response in host-tumor cell-cell interactions in metastatic tumors. J. Cell. Biochem. 35: 333–344.CrossRefGoogle Scholar
  10. Cunha, G., Bigsby, R. M., Cooke, P. S., and Sugimura, Y. (1985) Stromal-epithelial interactions in adult organs. Cell Different. 17: 137–148.CrossRefGoogle Scholar
  11. Docherty, R., Forreter, J. V., Lackie, J. M., and Gregory, D. W. (1989) Glycosaminoglycans facilitate the movement of fibroblasts through 3D collagen matrices. J. Cell Sci. 92: 263–267.Google Scholar
  12. Duming, P., Schor, S. L., and Sellwood, R. A. S. (1984) Fibroblasts from patients with breast cancer show abnormal migratory behaviour in vitro. Lancet ii: 890–892.Google Scholar
  13. Dvorak, H. F. (1986) Tumors; wounds that do not heal. New England J. Med. 315:1650–1659.CrossRefGoogle Scholar
  14. Elstad, C. A., and Hosick, H. L. (1987) Contribution of the extracellular matrix to growth properties of cells from a preneoplastic outgrowth: possible role of hyaluronic acid. Exp. Cell Biol. 55: 313–321.Google Scholar
  15. Feinberg, R. N., and Beebe, D. C. (1983) Hyaluronate in vasculargenesis. Science 220: 1177–1179.CrossRefGoogle Scholar
  16. Goldberg, R., and Toole, B. P. (1987) Hyaluronate inhibition of cell proliferation. Arthritis Rheum. 30: 769–777.CrossRefGoogle Scholar
  17. Gospodarowicz, D., Greenburg, G., and Birdwell, C. R. (1978) Determination of cellular shape by the extracellular matrix and its correlation with the control of cellular growth. Cancer Res. 38: 4155–4171.Google Scholar
  18. Grey, A. M., Schor, A. M., Rushton, G., Ellis, I., and Schor, S. L. (1989) Purification of the migration stimulating factor produced by fetal and breast cancer patient fibroblasts. Proc. Natl. Acad. Sci. (USA) 86: 2438–2422.CrossRefGoogle Scholar
  19. Haggie, J., Schor, S. L., Howell, A., Birch, J. M., and Sellwood, R. A. S. (1987) Fibroblasts from relatives of hereditary breast cancer patients display foetal-like behaviour in vitro. Lancet i: 1455–1457.CrossRefGoogle Scholar
  20. Hassell, T. M., and Stanek, E. J. (1983) Evidence that the healthy human gingiva contains functionally heterogenous fibroblast subpopulations. Archs. Oral Biol. 28: 617–625.CrossRefGoogle Scholar
  21. Hay, E. D., and Svoboda, K. K. (1989) Extracellular matrix interactions with the cytoskeleton, in: Stein, W. D. and Bronner, F. (eds). Cell Shape: Determinants, Regulation and Regulatory Role. Academic Press, San Diego, pp. 147–172.Google Scholar
  22. Hronowski, L, and Anastassiades, T. P. (1980) The effect of cell density on net rates of glycosaminoglycan synthesis and secretion by cultured rat fibroblasts. J. Biol. Chem. 255: 10091–10099.Google Scholar
  23. Ignotz, R. A., and Massague, J. (1986) Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J. Biol. Chem 261: 4337–4345.Google Scholar
  24. Kleinman, H. K., Klebe, R. J., and Martin, G. R. (1981) Role of collagenous matrices in the adhesion and growth of cells. J. Cell Biol. 88: 473–485.CrossRefGoogle Scholar
  25. Knudson, A. G. (1977) Genetics and etiology of human cancer, in: Harris, H. and Hirchhorn, K. (eds). Advances in Human Genetics. Raven Press, New York, pp. 1–66.Google Scholar
  26. Knudson, W., Biswas, C., Li, X.-Q., Nemec, R. E., and Toole, B. P. (1989) The role and regulation of tumor-associated hyaluronan, in: The Biology of Hyaluronan, Ciba Foundation Symposium 143, John Wiley and Sons, Chichester, pp. 150–159.Google Scholar
  27. Kopelovich, L. (1982) Hereditary adenomatosis of the colon and rectum: relevance to cancer promotion and cancer control in humans. Cancer Gen. Cytogen. 5: 333–351.CrossRefGoogle Scholar
  28. Kujawa, M. J., Carrino, D. A., and Caplan, A. L (1986) Substrate-bonded hyaluronic acid exhibits a size-dependent stimulation of chondrogenic differentiation of stage 24 limb mesenchymal cells in culture. Dev. Biol. 114: 519–528.CrossRefGoogle Scholar
  29. Liotta, L., Mandler, R., Murano, G., Katz, D. A., Gordon, R. K., Chiang, P. K., and Schiffmann, E. (1986) Tumor cell autocrine motility factor. Proc. Natl. Acad. Sci. (USA) 83: 3302–3306.CrossRefGoogle Scholar
  30. Mintz, B., and Illmensee, K. (1975) Normal genetically mosaic mice produced from malignant teratócarcinoma cells. Proc. Natl. Acad. Sci. (USA) 72: 3585–3589.CrossRefGoogle Scholar
  31. Nakano, S., and Ts’ O P. O. (1981) Cellular differentiation and neoplasia: characterization of subpopulations of cells that have neoplasia related growth properties in Syrian hamster embryo cell cultures. Proc. Natl. Acad. Sci. (USA) 78: 4995–4999.CrossRefGoogle Scholar
  32. Nielson, M., Thomsen, J. L., Primdahl, S., Dyreborg, U., and Anderson, J. A. (1987) Breast cancer and atypia among young and middle aged women. Br. J. Cancer 56: 814–819.CrossRefGoogle Scholar
  33. Nowell, P. C. (1976) The clonal evolution of tumor cell populations. Science 194: 23–28.CrossRefGoogle Scholar
  34. Ottman, R., Pike, M. C., King, M.-C., and Henderson, B. E. (1983) Practical guide for estimating risk in familial breast cancer. Lancet ii: 556–558.CrossRefGoogle Scholar
  35. Picardo, M., Schor, S. L., Grey, A. M., Howell, A., Laidlaw, L, Redford, J., and Schor, A. M. (1990) The presence of migration stimulating activity in serum of breast cancer patients. Lancet 337: 130–133.CrossRefGoogle Scholar
  36. Pierce, G. B. (1970) Differentiation of normal and malignant cells. Fed. Proc. 29: 1248–1254.Google Scholar
  37. Prehm, P. (1989) Identification and regulation of the eukaryotic hyaluronate synthease; in: The Biology of Hyaluronan, Ciba Foundation Symposium 143, John Wiley and Sons, Chichester, pp. 21–31.Google Scholar
  38. Rifkin, D. B., and Moscatelli, D. (1989) Recent developments in the cell biology of basic fibroblast growth factor. J. Cell Biol. 109: 1–6.CrossRefGoogle Scholar
  39. Rodriguez-Boulan, E., and Nelson, W. J. (1989) Morphogenesis of the polarized epitheHal cell phenotype. Science 245: 719–725.CrossRefGoogle Scholar
  40. Rubin, H. (1985) Cancer as a dynamic disorder. Cancer Res. 45: 2935–2942.Google Scholar
  41. Saiag, P., Coulomb, B., Lebreton, C., Bell, E., and Dubertret, L. (1985) Psoriatic fibroblasts induce hyperproliferation of normal keratinocytes in a skin equivalent model in vitro. Science 230: 669–672.CrossRefGoogle Scholar
  42. Sakakura, T. (1983) Epithelial-mesenchymal interactions in mammary gland development and its perturbation in tumorigenesis, in: Understanding Breast Cancer, eds M. A. Rich, J. C. Hager and P. Furmanski. Marcel Dekker, Inc., New York, pp. 261–284.Google Scholar
  43. Schor, S. L. (1980) Cell proHferation and migration within three-dimensional collagen gels. J. Cell Sci. 41: 159–175.Google Scholar
  44. Schor, S. L., and Schor, A. M. (1987) Clonal heterogeneity in fibroblast phenotype: implications for the control of epithelial-mesenchymal interactions. BioEssays 7: 200–204.CrossRefGoogle Scholar
  45. Schor, S. L., Schor, A. M., Winn, B., and Rushton, G. (1982) The use of three-dimensional collagen gels for the study of tumour cell invasion in vitro: experimental parameters influencing cell migration into the gel matrix. Int. J. Cancer 29: 57–62.CrossRefGoogle Scholar
  46. Schor, S. L., Schor, A. M., Rushton, G., and Smith, L. (1985a) Adult, foetal and transformed fibroblasts display different migratory phenotypes on collagen gels: Evidence for an isoformic transition during foetal development. J. Cell Sci. 73: 221–234.Google Scholar
  47. Schor, S. L., Schor, A. M., Duming, P., and Rushton, G. (1985b) Skin fibroblasts obtained from cancer patients display foetal-like migratory behaviour on collagen gels. J. Cell Sci. 73: 235–244.Google Scholar
  48. Schor, S. L., Haggie, J., Durning, P., Howell, A., Sellwood, R. A. S., and Crowther, D. (1986) The occurrence of a foetal fibroblast phenotype in familial breast cancer. Int. J. Cancer 37: 831–836.CrossRefGoogle Scholar
  49. Schor, S. L., Schor, A. M., Howell, A., and Crowther, D. (1987) Hypothesis: persistent expression of fetal phenotypic characteristics by fibroblasts is associated with an increased susceptibility to neoplastic disease. Exp. Cell. Biol. 55: 11–17.Google Scholar
  50. Schor, S. L., Schor, A. M., Grey, A. M., and Rushton, G. R. (1988a) Foetal and cancer patient fibroblasts produce an autocrine migration-stimulating factor not made by normal adult cells. J. Cell Sci. 90: 391–399.Google Scholar
  51. Schor, S. L., Schor, A. M., and Rushton, G. (1988b) Fibroblasts from cancer patients display a mixture of both foetal and adult-like phenotypic characteristics. J. Cell Sci. 90: 401–407.Google Scholar
  52. Schor, S. L., Schor, A. M., Grey, A. M., Chen, J., Rushton, G., Grant, M. E., and Ellis, I. (1989) Mechanism of action of the migration stimulating factor (MSF) produced by fetal and cancer patient fibroblasts: Effect on hyaluronic acid synthesis. In Vitro Cell. Develop. Biol. 25: 737–746.CrossRefGoogle Scholar
  53. Sporn, M. B., and Roberts, A. B. (1988) Peptide growth factors are multifunctional. Nature 332: 217–219.CrossRefGoogle Scholar
  54. Sporn, M. B., and Roberts, A. B. (1990) Peptide Growth Factors And Their Receptors (vols I and II): Handbook of Experimental Pharmacology, vol 95/1, Springer-Verlag, Heidelberg.CrossRefGoogle Scholar
  55. Stoker, A. W., Hatier, C., and Bissell, M. J. (1990) The embryonic environment strongly attenuates v-src oncogenesis in mesenchymal and epithelial tissues, but not in endothelia. J. Cell Biol. 111: 217–228.CrossRefGoogle Scholar
  56. Toole, B. P., Biswas, C., and Gross, J. (1979) Hyaluronate and invasiveness of the rabbit V2 carcinoma. Proc. Natl. Acad. Sci. USA 76: 6299–6303.CrossRefGoogle Scholar
  57. Toole, B. P., and Trelstad, R. L. (1971) Hyaluronate production and removal during corneal development in the chick. Dev. Biol. 26: 28–35.CrossRefGoogle Scholar
  58. Trelstad, R. L. (1984) Role of the extracellular matrix in development. Academic Press, New York.Google Scholar
  59. Turley, E. A., and Torrance, J. (1984) Locahzation of hyaluronate and hyaluronate-binding protein on motile and non-motile fibroblasts. Epl. Cell Res. 161: 17–28.CrossRefGoogle Scholar
  60. Valverius, E. M., Ciardiello, F., Heldin, N E., Blondel, B., Merio, G., Smith, G., Stampfer, M. R., Lippman, M. E., Dickson, R. B., and Salomon, D. S. (1990) Stromal influences on transformation of human manmiary epithelial cells overexpressing c-myc and SV40T. J. Cell. Physiol. 145: 207–216.CrossRefGoogle Scholar
  61. Zajicek, G. (1990a) Progress against cancer: are we winning the war? Cancer J. 3: 2.Google Scholar
  62. Zajicek, G. (1990b) Clinical manifestations of transgenic cancer. Cancer J. 3: 3.Google Scholar
  63. Zetter, B. R., and Brightman, S. E. (1990) Cell motihty and the extracellular matrix. Curr. Opin. Cell Biol. 2: 850–856.CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 1991

Authors and Affiliations

  • Seth L. Schor
    • 1
  • Ann Marie Grey
    • 1
  • Martino Picardo
    • 1
  • Ana M. Schor
    • 2
  • Anthony Howell
    • 2
  • Ian Ellis
    • 1
  • Graham Rushton
    • 2
  1. 1.Department of Cell and Structural Biology, Coupland 3 BuildingUniversity of ManchesterManchesterUK
  2. 2.CRC Department of Medical OncologyChristie HospitalManchesterEngland

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