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 Article
  • Published:

Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1

Oncogene volume 30, pages 4316–4326 (2011)Cite this article

Subjects

Abstract

The tumor microenvironment is emerging as an important target for cancer therapy. Fibroblasts (Fbs) within the tumor stroma are critically involved in promoting tumor growth and angiogenesis through secretion of soluble factors, synthesis of extracellular matrix and direct cell–cell interaction. In this work, we aim to alter the biological activity of stromal Fbs by modulating the Notch1 signaling pathway. We show that Fbs engineered to constitutively activate the Notch1 pathway significantly inhibit melanoma growth and tumor angiogenesis. We determine that the inhibitory effect of ‘Notch-engineered’ Fbs is mediated by increased secretion of Wnt-induced secreted protein-1 (WISP-1) as the effects of Notch1 activation in Fbs are reversed by shRNA-mediated blockade of WISP-1. When ‘Notch-engineered’ Fbs are co-grafted with melanoma cells in SCID mice, shRNA-mediated blockade of WISP-1 reverses the tumor-suppressive phenotype of the ‘Notch-engineered’ Fbs, significantly increases melanoma growth and tumor angiogenesis. Consistent with these findings, supplement of recombinant WISP-1 protein inhibits melanoma cell growth in vitro. In addition, WISP-1 is modestly expressed in melanoma-activated Fbs but highly expressed in inactivated Fbs. Evaluation of human melanoma skin biopsies indicates that expression of WISP-1 is significantly lower in melanoma nests and surrounding areas filled with infiltrated immune cells than in the adjacent dermis unaffected by the melanoma. Overall, our study shows that constitutive activation of the Notch1 pathway confers Fbs with a suppressive phenotype to melanoma growth, partially through WISP-1. Thus, targeting tumor stromal Fbs by activating Notch signaling and/or increasing WISP-1 may represent a novel therapeutic approach to combat melanoma.

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

Similar content being viewed by others

References

  • Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H et al. (2004). Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6: 17–32.

    Article  CAS  Google Scholar 

  • Anton K, Glod J . (2009). Targeting the tumor stroma in cancer therapy. Curr Pharm Biotechnol 10: 185–191.

    Article  CAS  Google Scholar 

  • Artavanis-Tsakonas S, Rand MD, Lake RJ . (1999). Notch signaling: cell fate control and signal integration in development. Science 284: 770–776.

    Article  CAS  Google Scholar 

  • Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I et al. (2005). Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. J Clin Invest 115: 3166–3176.

    Article  CAS  Google Scholar 

  • Bhowmick NA, Neilson EG, Moses HL . (2004). Stromal fibroblasts in cancer initiation and progression. Nature 432: 332–337.

    Article  CAS  Google Scholar 

  • Chen PP, Li WJ, Wang Y, Zhao S, Li DY, Feng LY et al. (2007). Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer. PLoS One 2: e534.

    Article  Google Scholar 

  • Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z et al. (2009). PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15: 21–34.

    Article  CAS  Google Scholar 

  • Davies SR, Watkins G, Mansel RE, Jiang WG . (2007). Differential expression and prognostic implications of the CCN family members WISP-1, WISP-2, and WISP-3 in human breast cancer. Ann Surg Oncol 14: 1909–1918.

    Article  Google Scholar 

  • Dufraine J, Funahashi Y, Kitajewski J . (2008). Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27: 5132–5137.

    Article  CAS  Google Scholar 

  • Hayward SW, Wang Y, Cao M, Hom YK, Zhang B, Grossfeld GD et al. (2001). Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res 61: 8135–8142.

    CAS  PubMed  Google Scholar 

  • Ishikawa Y, Onoyama I, Nakayama KI, Nakayama K . (2008). Notch-dependent cell cycle arrest and apoptosis in mouse embryonic fibroblasts lacking Fbxw7. Oncogene 27: 6164–6174.

    Article  CAS  Google Scholar 

  • Kalluri R . (2009). EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119: 1417–1419.

    Article  CAS  Google Scholar 

  • Kalluri R, Neilson EG . (2003). Epithelial–mesenchymal transition and its implications for fibrosis. J Clin Invest 112: 1776–1784.

    Article  CAS  Google Scholar 

  • Kalluri R, Zeisberg M . (2006). Fibroblasts in cancer. Nat Rev Cancer 6: 392–401.

    Article  CAS  Google Scholar 

  • Li Y, Song Y, Zhao L, Gaidosh G, Laties AM, Wen R . (2008). Direct labeling and visualization of blood vessels with lipophilic carbocyanine dye DiI. Nat Protoc 3: 1703–1708.

    Article  CAS  Google Scholar 

  • Liu ZJ, Herlyn M . Molecular Biology of Cutaneous Melanoma, 7th edn. Lippincott Williams & Wilkins: Philadelphia, (2005).

    Google Scholar 

  • Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP et al. (2003). Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23: 14–25.

    Article  Google Scholar 

  • Liu ZJ, Tian R, An W, Zhuge Y, Li Y, Shao H et al. (2010). Identification of E-selectin as a novel target for the regulation of postnatal neovascularization: implications for diabetic wound healing. Ann Surg 252: 625–634.

    PubMed  PubMed Central  Google Scholar 

  • Liu ZJ, Xiao M, Balint K, Smalley KS., Brafford P, Qiu R et al. (2006). Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase–Akt pathways and upregulating N-cadherin expression. Cancer Res 66: 4182–4190.

    Article  CAS  Google Scholar 

  • Liu ZJ, Zhuge Y, Velazquez OC . (2009). Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem 106: 984–991.

    Article  CAS  Google Scholar 

  • Lorusso G, Ruegg C . (2008). The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol 130: 1091–1103.

    Article  CAS  Google Scholar 

  • Lynch CC, Matrisian LM . (2002). Matrix metalloproteinases in tumor–host cell communication. Differentiation 70: 561–573.

    Article  CAS  Google Scholar 

  • Mailhos C, Modlich U, Lewis J, Harris A, Bicknell R, Ish-Horowicz D . (2001). Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 69: 135–144.

    Article  CAS  Google Scholar 

  • Meier F, Nesbit M, Hsu MY, Martin B, Van Belle P, Elder DE et al. (2000). Human melanoma progression in skin reconstructs: biological significance of bFGF. Am J Pathol 156: 193–200.

    Article  CAS  Google Scholar 

  • Midwood KS, Williams LV, Schwarzbauer JE . (2004). Tissue repair and the dynamics of the extracellular matrix. Int J Biochem Cell Biol 36: 1031–1037.

    Article  CAS  Google Scholar 

  • Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW et al. (2006). Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444: 1032–1037.

    Article  CAS  Google Scholar 

  • Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR . (1999). Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59: 5002–5011.

    CAS  Google Scholar 

  • Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121: 335–348.

    Article  CAS  Google Scholar 

  • Orimo A, Weinberg RA . (2006). Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 5: 1597–1601.

    Article  CAS  Google Scholar 

  • Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J et al. (1998). WISP genes are members of the connective tissue growth factor family that are upregulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci USA 95: 14717–14722.

    Article  CAS  Google Scholar 

  • Pinnix CC, Lee JT, Liu ZJ, McDaid R, Balint K, Beverly LJ et al. (2009). Active Notch1 confers a transformed phenotype to primary human melanocytes. Cancer Res 69: 5312–5320.

    Article  CAS  Google Scholar 

  • Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y et al. (2006). Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444: 1083–1087.

    Article  CAS  Google Scholar 

  • Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M et al. (2002). The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem 277: 29399–29405.

    Article  CAS  Google Scholar 

  • Sappino AP, Skalli O, Jackson B, Schurch W, Gabbiani G . (1988). Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int J Cancer 41: 707–712.

    Article  CAS  Google Scholar 

  • Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM . (2003). Overexpression of WISP-1 downregulated motility and invasion of lung cancer cells through inhibition of Rac activation. J Biol Chem 278: 11465–11470.

    Article  CAS  Google Scholar 

  • Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M et al. (2001). A novel variant of WISP1 lacking a von Willebrand type C module overexpressed in scirrhous gastric carcinoma. Oncogene 20: 5525–5532.

    Article  CAS  Google Scholar 

  • Thurston G, Noguera-Troise I, Yancopoulos GD . (2007). The delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 7: 327–331.

    Article  CAS  Google Scholar 

  • Urs S, Roudabush A, O'Neill CF, Pinz I, Prudovsky I, Kacer D et al. (2008). Soluble forms of the Notch ligands Delta1 and Jagged1 promote in vivo tumorigenicity in NIH3T3 fibroblasts with distinct phenotypes. Am J Pathol 173: 865–878.

    Article  CAS  Google Scholar 

  • Yin L, Velazquez OC, Liu ZJ . (2010). Notch signaling: emerging molecular targets for cancer therapy. Biochem Pharmacol 80: 690–701.

    Article  CAS  Google Scholar 

  • Zeisberg M, Kalluri R . (2008). Fibroblasts emerge via epithelial–mesenchymal transition in chronic kidney fibrosis. Front Biosci 13: 6991–6998.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr M Herlyn for providing the melanoma cells (1205Lu, WM35, WM3248, Sbcl2, WM278 and WM3899) and Dr G McNamara for laser-scanning confocal microscopy. The work of Dr Liu was supported by grants from the James & Esther King Biomedical Research Program (08KN-10) and the Bankhead-Coley Cancer Research Program (09BN-11).

Author information

Authors and Affiliations

  1. Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA

    H Shao, L Cai, A S Livingstone, O C Velazquez & Z-J Liu

  2. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    J M Grichnik, O C Velazquez & Z-J Liu

  3. Hangzhou Red-Cross Hospital, Zhejiang Province, China

    L Cai

  4. Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA

    J M Grichnik

Authors
  1. H Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J M Grichnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A S Livingstone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O C Velazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z-J Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z-J Liu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shao, H., Cai, L., Grichnik, J. et al. Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1. Oncogene 30, 4316–4326 (2011). https://doi.org/10.1038/onc.2011.142

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.142

Keywords

This article is cited by

Search

Advanced search

Quick links