Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Stromal fibroblasts in cancer initiation and progression

Nature volume 432, pages 332–337 (2004)Cite this article

Abstract

It is widely accepted that the development of carcinoma — the most common form of human cancer — is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The stroma associated with the normal mammary gland differs profoundly from the stroma associated with a mammary carcinoma.
Figure 2: Epithelia can be reactive to a changing stromal environment.
Figure 3: Stromal–epithelial interactions in normal and tumour tissues.

Similar content being viewed by others

References

  1. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    ADS  CAS  PubMed  Google Scholar 

  2. Ronnov-Jessen, L., Petersen, O. W. & Bissell, M. J. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol. Rev. 76, 69–125 (1996).

    CAS  PubMed  Google Scholar 

  3. Tlsty, T. D. & Hein, P. W. Know thy neighbor: stromal cells can contribute oncogenic signals. Curr. Opin. Genet. Dev. 11, 54–59 (2001).

    CAS  PubMed  Google Scholar 

  4. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    CAS  PubMed  Google Scholar 

  5. Sandler, A. B., Johnson, D. H. & Herbst, R. S. Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin. Cancer Res. 10, 4258s–4262s (2004).

    CAS  PubMed  Google Scholar 

  6. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Weaver, V. M. et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J. Cell Biol. 137, 231–245 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ronnov-Jessen, L., Petersen, O. W., Koteliansky, V. E. & Bissell, M. J. The origin of the myofibroblasts in breast cancer. Recapitulation of tumour environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J. Clin. Invest. 95, 859–873 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Rev. Cancer 3, 422–433 (2003).

    CAS  Google Scholar 

  10. Cunha, G. R., Reese, B. A. & Sekkingstad, M. Induction of nuclear androgen-binding sites in epithelium of the embryonic urinary bladder by mesenchyme of the urogenital sinus of embryonic mice. Endocrinology 107, 1767–1770 (1980).

    CAS  PubMed  Google Scholar 

  11. Xin, L., Ide, H., Kim, Y., Dubey, P. & Witte, O. N. In vivo regeneration of murine prostate from dissociated cell populations of postnatal epithelia and urogenital sinus mesenchyme. Proc. Natl Acad. Sci. USA 100 (suppl. 1), 11896–11903 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cunha, G. R., Bigsby, R. M., Cooke, P. S. & Sugimura, Y. Stromal-epithelial interactions in adult organs. Cell Differ. 17, 137–148 (1985).

    CAS  PubMed  Google Scholar 

  13. Culig, Z. et al. Regulation of prostatic growth and function by peptide growth factors. Prostate 28, 392–405 (1996).

    CAS  PubMed  Google Scholar 

  14. Cunha, G. R. & Donjacour, A. A. Mesenchymal-epithelial interactions in the growth and development of the prostate. Cancer Treat. Res. 46, 159–75 (1989).

    CAS  PubMed  Google Scholar 

  15. Hayward, S. W. Approaches to modeling stromal–epithelial interactions. J. Urol. 168, 1165–1172 (2002).

    PubMed  Google Scholar 

  16. Hayward, S. W. & Cunha, G. R. The prostate: development and physiology. Radiol. Clin. North Am. 38, 1–14 (2000).

    CAS  PubMed  Google Scholar 

  17. Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nature Med. 10, 789–799 (2004).

    CAS  PubMed  Google Scholar 

  18. Dawe, C. J. in Tissue Interactions in Carcinogenesis. (ed. Tarin, D.) 305–358 (Academic, London, 1972).

    Google Scholar 

  19. Schor, S. L., Schor, A. M. & Rushton, G. Fibroblasts from cancer patients display a mixture of both foetal and adult-like phenotypic characteristics. J. Cell Sci. 90, 401–407 (1988).

    PubMed  Google Scholar 

  20. Schor, S. L., Schor, A. M., Rushton, G. & Smith, L. 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 (1985).

    CAS  PubMed  Google Scholar 

  21. Russell, P. J., Bennett, S. & Stricker, P. Growth factor involvement in progression of prostate cancer. Clin. Chem. 44, 705–723 (1998).

    CAS  PubMed  Google Scholar 

  22. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumour progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–11 (1999).

    CAS  PubMed  Google Scholar 

  23. Hayward, S. W. et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res. 61, 8135–8142 (2001).

    CAS  PubMed  Google Scholar 

  24. Barcellos-Hoff, M. H. & Ravani, S. A. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res. 60, 1254–1260 (2000).

    CAS  PubMed  Google Scholar 

  25. Ohuchida, K. et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumour–stromal interactions. Cancer Res. 64, 3215–3222 (2004).

    CAS  PubMed  Google Scholar 

  26. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Allinen, M. et al. Molecular characterization of the tumour microenvironment in breast cancer. Cancer Cell 6, 17–32 (2004).

    CAS  PubMed  Google Scholar 

  28. Tucker, R. F., Shipley, G. D., Moses, H. L. & Holley, R. W. Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science 226, 705–777 (1984).

    ADS  CAS  PubMed  Google Scholar 

  29. Moses, H. L. et al. Type β transforming growth factor is a growth stimulator and a growth inhibitor. Cancer Cells 3, 65–71 (1985).

    CAS  Google Scholar 

  30. Pierce, D. F. Jr et al. Mammary tumour suppression by transforming growth factor beta 1 transgene expression. Proc. Natl Acad. Sci. USA 92, 4254–4258 (1995).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bottinger, E. P., Jakubczak, J. L., Haines, D. C., Bagnall, K. & Wakefield, L. M. Transgenic mice overexpressing a dominant–negative mutant type II transforming growth factor beta receptor show enhanced tumorigenesis in the mammary gland and lung in response to the carcinogen 7, 12-dimethylbenz-[a]-anthracene. Cancer Res. 57, 5564–5570 (1997).

    CAS  PubMed  Google Scholar 

  32. Gorska, A. E. et al. Transgenic mice expressing a dominant–negative mutant type II TGF-β receptor have impaired mammary development and enhanced mammary tumour formation. Am. J. Pathol. 163, 1539–1549 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Amendt, C., Schirmacher, P., Weber, H. & Blessing, M. Expression of a dominant negative type II TGF-beta receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development. Oncogene 17, 25–34 (1998).

    CAS  PubMed  Google Scholar 

  34. Akhurst, R. J. & Derynck, R. TGF-beta signalling in cancer–a double-edged sword. Trends Cell Biol. 11, S44–S51 (2001).

    CAS  PubMed  Google Scholar 

  35. Gold, L. I. The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit. Rev. Oncog. 10, 303–360 (1999).

    CAS  PubMed  Google Scholar 

  36. Tsushima, H. et al. Circulating transforming growth factor beta 1 as a predictor of liver metastasis after resection in colorectal cancer. Clin. Cancer Res. 7, 1258–1262 (2001).

    CAS  PubMed  Google Scholar 

  37. Shariat, S. F. et al. Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy. J. Clin. Oncol. 19, 2856–2864 (2001).

    CAS  PubMed  Google Scholar 

  38. Shariat, S. F. et al. Preoperative plasma levels of transforming growth factor beta(1) strongly predict clinical outcome in patients with bladder carcinoma. Cancer 92, 2985–2992 (2001).

    CAS  PubMed  Google Scholar 

  39. Bhowmick, N. A. et al. TGF-beta signalling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).

    ADS  CAS  PubMed  Google Scholar 

  40. Kuperwasser, C. et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc. Natl Acad. Sci. USA 101, 4966–4971 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nakamura, T., Matsumoto, K., Kiritoshi, A. & Tano, Y. Induction of hepatocyte growth factor in fibroblasts by tumour-derived factors affects invasive growth of tumour cells: in vitro analysis of tumour–stromal interactions. Cancer Res. 57, 3305–3313 (1997).

    CAS  PubMed  Google Scholar 

  42. Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis, motility and more. Nature Rev. Mol. Cell Biol. 4, 915–925 (2003).

    CAS  Google Scholar 

  43. Michieli, P. et al. Targeting the tumour and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 6, 61–73 (2004).

    CAS  PubMed  Google Scholar 

  44. Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003).

    PubMed  Google Scholar 

  45. Massague, J., Blain, S. W. & Lo, R. S. TGF-beta signalling in growth control, cancer, and heritable disorders. Cell 103, 295–309 (2000).

    CAS  PubMed  Google Scholar 

  46. Koskinen, P. J., Sistonen, L., Bravo, R. & Alitalo, K. Immediate early gene responses of NIH 3T3 fibroblasts and NMuMG epithelial cells to TGF beta-1. Growth Factors 5, 283–293 (1991).

    CAS  PubMed  Google Scholar 

  47. Lynch, C. C. & Matrisian, L. M. Matrix metalloproteinases in tumour-host cell communication. Differentiation 70, 561–573 (2002).

    CAS  PubMed  Google Scholar 

  48. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2, 161–174 (2002).

    CAS  Google Scholar 

  49. Itoh, T. et al. Reduced angiogenesis and tumour progression in gelatinase A-deficient mice. Cancer Res. 58, 1048–1051 (1998).

    CAS  PubMed  Google Scholar 

  50. Brauchle, M., Angermeyer, K., Hubner, G. & Werner, S. Large induction of keratinocyte growth factor expression by serum growth factors and pro-inflammatory cytokines in cultured fibroblasts. Oncogene 9, 3199–3204 (1994).

    CAS  PubMed  Google Scholar 

  51. Yan, G., Fukabori, Y., Nikolaropoulos, S., Wang, F. & McKeehan, W. L. Heparin-binding keratinocyte growth factor is a candidate stromal-to-epithelial-cell andromedin. Mol. Endocrinol. 6, 2123–2128 (1992).

    CAS  PubMed  Google Scholar 

  52. Lu, W., Luo, Y., Kan, M. & McKeehan, W. L. Fibroblast growth factor-10. A second candidate stromal to epithelial cell andromedin in prostate. J. Biol. Chem. 274, 12827–12834 (1999).

    CAS  PubMed  Google Scholar 

  53. Jin, C. et al. Directionally specific paracrine communication mediated by epithelial FGF9 to stromal FGFR3 in two-compartment premalignant prostate tumours. Cancer Res. 64, 4555–4562 (2004).

    CAS  PubMed  Google Scholar 

  54. Furuhashi, M. et al. Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumours and an associated increase in tumour growth rate. Cancer Res. 64, 2725–2733 (2004).

    CAS  PubMed  Google Scholar 

  55. Jue, S. F., Bradley, R. S., Rudnicki, J. A., Varmus, H. E. & Brown, A. M. The mouse Wnt-1 gene can act via a paracrine mechanism in transformation of mammary epithelial cells. Mol. Cell. Biol. 12, 321–328 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Derksen, P. W. et al. Illegitimate WNT signalling promotes proliferation of multiple myeloma cells. Proc. Natl Acad. Sci. USA 101, 6122–6127 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  57. Marnett, L. J., Riggins, J. N. & West, J. D. Endogenous generation of reactive oxidants and electrophiles and their reactions with DNA and protein. J. Clin. Invest. 111, 583–593 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Moinfar, F. et al. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res. 60, 2562–2566 (2000).

    CAS  PubMed  Google Scholar 

  59. Kurose, K. et al. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nature Genet. 32, 355–357 (2002).

    CAS  PubMed  Google Scholar 

  60. Xue, C., Plieth, D., Venkov, C., Xu, C. & Neilson, E. G. The gatekeeper effect of epithelial–mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res. 63, 3386–3394 (2003).

    CAS  PubMed  Google Scholar 

  61. Jacoby, R. F. et al. A juvenile polyposis tumour suppressor locus at 10q22 is deleted from nonepithelial cells in the lamina propria. Gastroenterology 112, 1398–1403 (1997).

    CAS  PubMed  Google Scholar 

  62. Wirtzfeld, D. A., Petrelli, N. J. & Rodriguez-Bigas, M. A. Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations. Ann. Surg. Oncol. 8, 319–327 (2001).

    CAS  PubMed  Google Scholar 

  63. Waite, K. A. & Eng, C. From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family. Nature Rev. Genet. 4, 763–773 (2003).

    ADS  CAS  PubMed  Google Scholar 

  64. Yang, Y. A. et al. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J. Clin. Invest. 109, 1607–1615 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Trusolino, L. & Comoglio, P. M. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nature Rev. Cancer 2, 289–300 (2002).

    CAS  Google Scholar 

  66. Wessells, N. K. Mammalian lung development: interactions in formation and morphogenesis of tracheal buds. J. Exp. Zool. 175, 455–466 (1970).

    CAS  PubMed  Google Scholar 

  67. Bellusci, S. et al. Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. Development 124, 53–63 (1997).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a DOD USAMRMC grant (N.A.B.), NIH grants (H.L.M), and a Vanderbilt-Ingram Cancer Center Support Grant. We thank J. Pietenpol and S. Hayward for critical review of the manuscript and helpful advice.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    Neil A. Bhowmick & Harold L. Moses

  2. Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    Neil A. Bhowmick

  3. The Vanderbilt–Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    Neil A. Bhowmick, Eric G. Neilson & Harold L. Moses

  4. Department of Medicine, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    Eric G. Neilson & Harold L. Moses

Authors
  1. Neil A. Bhowmick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric G. Neilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harold L. Moses
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harold L. Moses.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bhowmick, N., Neilson, E. & Moses, H. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004). https://doi.org/10.1038/nature03096

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03096

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing