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.

  • Original Paper
  • Published:

Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks

Oncogene volume 24, pages 5053–5068 (2005)Cite this article

Abstract

Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell–cell interactions. To clarify the role of TGF-β signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-β type II receptor gene in mouse mammary fibroblasts (Tgfbr2fspKO). Tgfbr2fspKO mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2fspKO mammary fibroblasts transplanted with mammary carcinoma cells promote growth and invasion, which is associated with increased activating phosphorylation of the receptors: erbB1, erbB2, RON, and c-Met. Furthermore, the increased receptor phosphorylation correlates with increased secretion of the cognate ligands by Tgfbr2fspKO fibroblasts. Treatment of tumor cells with fibroblast-conditioned medium leads to increased tumor cell proliferation and motility, which are blocked by addition of pharmacologic inhibitors of TGF-α signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-β signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-α, MSP, and HGF signaling pathways.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Article 01 December 2022

Zixuan Zhao, Xinyi Chen, … Hanry Yu

Abbreviations

TβRII:

TGF-β type II receptor

PyVmT:

polyomavirus middle T antigen

MSP:

macrophage-stimulating protein

FSP1:

fibroblast-specific protein 1

GFP:

green fluorescent protein

ABS:

adult bovine serum

References

  • Akhurst RJ . (2002). J. Clin. Invest., 109, 1533–1536.

  • Akhurst RJ and Derynck R . (2001). Trends Cell Biol., 11, S44–S50.

  • Aslakson C and Miller FR . (1992). Cancer Res., 52, 1399–1405.

  • Bhowmick N, Chytiil A, Plieth D, Gorska A, Dumont N, Shappel S, Washington M, Neilson E and Moses H . (2004). Science, 303, 847–851.

  • Bitzer M, von Gersdorff G, Liang D, Dominguez-Rosales A, Beg AA, Rojkind M and Bottinger EP . (2000). Genes Dev., 2, 187–197.

  • Bottinger EP, Jakubczak JL, Haines DC, Bagnall K and Wakefield LM . (1997). Cancer Res., 57, 5564–5570.

  • Camps J, Chang S, Hsu T, Freeman M, hong S, Zhau H, von Eschenbach A and Chung L . (1990). Proc. Natl. Acad. Sci. USA, 87, 75–79.

  • Cardiff R . (2001a). Microsc. Res. Tech., 52, 224–230.

  • Cardiff R, Wagner U and Henninghausen L . (2001b). Vet. Pathol., 38, 357–358.

  • Chytil A, Magnuson MA, Wright CVE and Moses HL . (2002). Genesis, 32, 73–75.

  • Couldrey C, Moitra J, Vinson C, Anver M, Nagashima K and Green J . (2002). Dev. Dyn., 223, 459–468.

  • Cunha G and Hom Y . (1996). J. Mamm. Gland Biol., 1, 21–34.

  • Cunha G, Hom YK, Young P and Brody J . (2000). Methods in Mammary Gland Biology, Ip MM (ed). Kluwer Academic/Plenum Publishers: New York.

    Google Scholar 

  • Daniel CW, Robinson S and Silberstein GB . (2001). Bioactive Components of Human Milk. Plenum Publishers: New York, pp 61–69.

    Book  Google Scholar 

  • De Wever O and Mareel M . (2003). J. Pathol., 4, 429–447.

  • Derynck R, Akhurst RJ and Balmain A . (2001). Nature, 29, 117–129.

  • Gorska AE, Jensen RA, Shyr Y, Aakre ME, Bhowmick NA and Moses HL . (2003). Am. J. Pathol., 163, 1539–1549.

  • Graf T and Beug H . (1983). Cell, 34, 7–9.

  • Gregoire FM . (2001). Exp. Biol. Med., 226, 997–1002.

  • Grotendorst G, Soma Y, Takehara K and Charette M . (1989). Cell. Physiol., 139, 617–623.

  • Guy C, Cardiff R and Muller W . (1992). Mol. Cell. Biol., 12, 954–961.

  • Hagedorn H, Bachmeir B and Nerlich A . (2001). Int. J. Oncol., 18, 669–681.

  • Haslam S and Woodward T . (2003). Breast Cancer Res., 5, 208–215.

  • Hayward S, Haughney PC, Rosen MA, Greulich KM, Weier HU, Dahiya R and Cunha GR . (1998). Differentiation, 63, 131–140.

  • Ihn H . (2002). Curr. Opin. Rheum., 14, 681–685.

  • Iwano M, Plieth D, Danoff T, Xue C, Okada H and Neilson E . (2002). J. Clin. Invest., 110, 341–350.

  • Joseph H, Gorska AE, Sohn P, Moses HL and Serra R . (1999). Mol. Biol. Cell, 10, 1221–1234.

  • Kanzler S . (2001). Oncogene, 16, 5015–5024.

  • Kuperwasser C, Chavarria T, Wu G, Gray JW, Carey L, Richardson A and Weinberg RA . (2004). Proc. Natl. Acad. Sci. USA, 101, 4966–4971.

  • Lei X, Bandyopadhyay A, Le T and Sun L . (2002). Oncogene, 21, 7514–7523.

  • Leonard E and Skeel AH . (1979). Adv. Exp. Med. Biol., 121B, 181–194.

  • Leonard J, Johnson D, Felsen R, Tanney LE, Royston I and Dillman R . (1987). Cancer Res., 47, 2899–2902.

  • Lin E, Jones J, Zhu L, Whitney K, Muller W and Pollard J . (2003). Am. J. Pathol., 163, 2113–2126.

  • Liu Y . (2004). Am. J. Physiol. Renal Physiol., 287, F7–F16.

  • Maglione J, Moghanak D, Young LJ, Manner CK, Ellies LG, Joseph SO, Nicholson B, Cardiff RD and MacLeod CL . (2001). Cancer Res., 61, 8298–8305.

  • Maguire HJ and Greene MI . (1989). Semin. Oncol., 16, 148–155.

  • Medina D and Kittrell F . (2000). Methods in Mammary Gland Biology and Breast Cancer Research, Ip MM, Asch BB (eds). Kluwer Academic/Plenum Publishers: New York, pp 137–147.

    Book  Google Scholar 

  • Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M and Tavassoli FA . (2000). Cancer Res., 60, 2562–2566.

  • Moulder S, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF and Arteaga CL . (2001). Cancer Res., 61, 8887–8895.

  • Mueller M and Fusenig N . (2002). Differentiation, 70, 486–497.

  • Pepper M, Soriano JV, Menoud PA, Sappino AP, Orci L and Montesano R . (1995). Exp. Cell. Res., 219, 204–210.

  • Pollard J . (2001). Breast Cancer Res., 3, 230–237.

  • Ronnov-Jessen L, Petersen O, Koteliansky V and Bissell M . (1995). J. Clin. Invest., 95, 859–873.

  • Roskoski Jr R . (2004). Biochem. Biophys. Res. Commun., 319, 1–11.

  • Sadlonova A, Novak Z, Johnson MR, Bowe DB, Gault SR, Page GP, Thottassery JV, Welch DR and Frost AR . (2004). Breast Cancer Res., 7, R46–R59.

  • Sakakura T, Sakagami Y and Nishizuka Y . (1981). J. Natl. Cancer Inst., 66, 953–959.

  • Schor AM, Rushton G, Ferguson JE, Howell A, Redford J and Schor SL . (1994). Int. J. Cancer, 59, 25–32.

  • Shekhar MP, Werdell J, Santner SJ, Pauley RJ and Tait L . (2001). Cancer Res., 61, 1320–1326.

  • Siegel P and Massague J . (2003). Nat. Rev. Cancer, 3, 807–821.

  • Silberstein G . (2001). Breast Cancer Res., 3, 218–223.

  • Simian M, Hirai Y, Navre M, Werb Z, Lochter A and Bissel MJ . (2001). Development, 128, 3117–3131.

  • Skeel A and Leonard EJ . (1994). J. Immunol., 152, 4618–4623 152, 4618–4623.

  • Soriano P . (1999). Nat. Genet., 21, 70–71.

  • Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE and Neilson EG . (1995). J. Cell. Biol., 130, 393–405.

  • Sun L . (2004). Front Biosci., 1, 1925–1935.

  • Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver M and Wakefield LM . (2003). J. Clin. Invest., 112, 1116–1124.

  • Tolstonog GV, Shoeman RL, Traub U and Traub P . (2001). DNA Cell Biol., 20, 509–529.

  • Tuxhorn J, Ayala G, Smith M, Smith V, Dang T and Rowley D . (2002a). Clin. Cancer Res., 8, 2912–2923.

  • Tuxhorn J, McAlhany S, Yang F, Dang T and Rowley D . (2002b). Cancer Res., 62, 6021–6025.

  • Wakeling A, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ and Gibson KH . (2002). Cancer Res., 62, 5749–5754.

  • Wang D, Shen Q, Chen YQ and Wang MH . (2004). Oncogene, 23, 1668–1680.

  • Wang MH, Zhou YQ and Chen YQ . (2002). Scand. J. Immunol., 56, 545–553.

  • Webster M, Hutchinson JN, Rauh MJ, Muthuswamy SK, Anton A, Tortorice CG, Cardiff RD, Graham FL, Hassell JA and Muller WJ . (1998). Mol. Cell. Biol., 18, 2344–2359.

  • Wiseman BS and Werb Z . (2002). Science, 296, 1046–1049.

  • Zangani D, Darcy KM, Shoemaker S and Ip MM . (1999). Exp. Cell. Res., 247, 399–409.

  • Zhang Y, Su Y, Volpert OV and Vande Woude GF . (2003). Proc. Natl. Acad. Sci. USA, 100, 12718–12723.

Download references

Acknowledgements

This work was supported by grants number CA102162 and CA85492 (to HLM) from the National Cancer Institute DHHS, and by the TJ Martell Foundation. The following Shared Resources of the Vanderbilt-Ingram Cancer Center provided outstanding assistance and are supported by grant number P30 CA68485: Statistics and Human Acquisition and Pathology Cores. The Mouse Pathology Core is supported by the NIH grant AR41943. We thank Bonnie LaFleur for biostatistical assistance, Dana Brantley-Sieders, and Jin Chen for critical reading of this manuscript.

Author information

Author notes

  1. Nikki Cheng

    Present address: Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA

Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, 37232-6838, TN, USA

    Nikki Cheng, Neil A Bhowmick, Anna Chytil, Agnieszka E Gorksa, Kimberly A Brown, Rebecca Muraoka, Carlos L Arteaga, Simon W Hayward & Harold L Moses

  2. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, 37232-6838, TN, USA

    Nikki Cheng, Neil A Bhowmick, Anna Chytil, Agnieszka E Gorksa, Carlos L Arteaga, Eric G Neilson, Simon W Hayward & Harold L Moses

  3. Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, 37232-6838, TN, USA

    Neil A Bhowmick & Simon W Hayward

  4. Department of Medicine, Vanderbilt University School of Medicine, Nashville, 37232-6838, TN, USA

    Carlos L Arteaga & Eric G Neilson

  5. Department of Pathology, Vanderbilt University School of Medicine, Nashville, 37232-6838, TN, USA

    Harold L Moses

Authors
  1. Nikki Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil A Bhowmick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Chytil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Agnieszka E Gorksa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kimberly A Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rebecca Muraoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carlos L Arteaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eric G Neilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Simon W Hayward
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Harold L Moses
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harold L Moses.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, N., Bhowmick, N., Chytil, A. et al. Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks. Oncogene 24, 5053–5068 (2005). https://doi.org/10.1038/sj.onc.1208685

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208685

Keywords

This article is cited by

Search

Advanced search

Quick links