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IGFBP7, a novel tumor stroma marker, with growth-promoting effects in colon cancer through a paracrine tumor–stroma interaction

Oncogene volume 34, pages 815–825 (2015)Cite this article

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Abstract

The activated tumor stroma participates in many processes that control tumorigenesis, including tumor cell growth, invasion and metastasis. Cancer-associated fibroblasts (CAFs) represent the major cellular component of the stroma and are the main source for connective tissue components of the extracellular matrix and various classes of proteolytic enzymes. The signaling pathways involved in the interactions between tumor and stromal cells and the molecular characteristics that distinguish normal ‘resting’ fibroblasts from cancer-associated or ‘-activated’ fibroblasts remain poorly defined. Recent studies emphasized the prognostic and therapeutic significance of CAF-related molecular signatures and a number of those genes have been shown to serve as putative therapeutic targets. We have used immuno-laser capture microdissection and whole-genome Affymetrix GeneChip analysis to obtain transcriptional signatures from the activated tumor stroma of colon carcinomas that were compared with normal resting colonic fibroblasts. Several members of the Wnt-signaling pathway and gene sets related to hypoxia, epithelial-to-mesenchymal transition (EMT) and transforming growth factor-β (TGFβ) pathway activation were induced in CAFs. The putative TGFβ-target IGFBP7 was identified as a tumor stroma marker of epithelial cancers and as a tumor antigen in mesenchyme-derived sarcomas. We show here that in contrast to its tumor-suppressor function in epithelial cells, IGFPB7 can promote anchorage-independent growth in malignant mesenchymal cells and in epithelial cells with an EMT phenotype when IGFBP7 is expressed by the tumor cells themselves and can induce colony formation in colon cancer cells co-cultured with IGFBP7-expressing CAFs by a paracrine tumor–stroma interaction.

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References

  1. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004; 303: 848–851.

    Article  CAS  Google Scholar 

  2. Mueller MM, Fusenig NE . Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 2004; 4: 839–849.

    Article  CAS  Google Scholar 

  3. Rasanen K, Vaheri A . Activation of fibroblasts in cancer stroma. Exp Cell Res 2010; 316: 2713–2722.

    Article  Google Scholar 

  4. Kunz-Schughart LA, Knuechel R . Tumor-associated fibroblasts (part I): Active stromal participants in tumor development and progression? Histol Histopathol 2002; 17: 599–621.

    CAS  PubMed  Google Scholar 

  5. Joyce JA, Pollard JW . Microenvironmental regulation of metastasis. Nat Rev Cancer 2009; 9: 239–252.

    Article  CAS  Google Scholar 

  6. Garin-Chesa P, Old LJ, Rettig WJ . Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA 1990; 87: 7235–7239.

    Article  CAS  Google Scholar 

  7. Desmouliere A, Guyot C, Gabbiani G . The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol 2004; 48: 509–517.

    Article  CAS  Google Scholar 

  8. Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E et al. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer research 2005; 65: 3772–3780.

    Article  CAS  Google Scholar 

  9. Ostman A, Heldin CH . PDGF receptors as targets in tumor treatment. Adv Cancer Res 2007; 97: 247–274.

    Article  Google Scholar 

  10. Orimo A, Weinberg RA . Heterogeneity of stromal fibroblasts in tumors. Cancer Biol Ther 2007; 6: 618–619.

    Article  CAS  Google Scholar 

  11. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  Google Scholar 

  12. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2004; 2: E7.

    Article  Google Scholar 

  13. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 2008; 14: 518–527.

    Article  CAS  Google Scholar 

  14. Navab R, Strumpf D, Bandarchi B, Zhu CQ, Pintilie M, Ramnarine VR et al. Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer. Proc Natl Acad Sci USA 2011; 108: 7160–7165.

    Article  CAS  Google Scholar 

  15. Herrera M, Herrera A, Dominguez G, Silva J, Garcia V, Garcia JM et al. Cancer-Associated Fibroblast and M2 Macrophage markers together predict outcome in colorectal cancer patients. Cancer Sci 2013; 104: 437–444.

    Article  CAS  Google Scholar 

  16. Ostermann E, Garin-Chesa P, Heider KH, Kalat M, Lamche H, Puri C et al. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res 2008; 14: 4584–4592.

    Article  CAS  Google Scholar 

  17. Santos AM, Jung J, Aziz N, Kissil JL, Pure E . Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest 2009; 119: 3613–3625.

    Article  CAS  Google Scholar 

  18. Pure E . The road to integrative cancer therapies: emergence of a tumor-associated fibroblast protease as a potential therapeutic target in cancer. Expert Opin Ther Targets 2009; 13: 967–973.

    Article  CAS  Google Scholar 

  19. Rupp C, Dolznig H, Puri C, Schweifer N, Sommergruber W, Kraut N et al. Laser capture microdissection of epithelial cancers guided by antibodies against fibroblast activation protein and endosialin. Diagn Mol Pathol 2006; 15: 35–42.

    Article  CAS  Google Scholar 

  20. Pen A, Moreno MJ, Durocher Y, Deb-Rinker P, Stanimirovic DB . Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-beta signaling. Oncogene 2008; 27: 6834–6844.

    Article  CAS  Google Scholar 

  21. Ruan W, Xu E, Xu F, Ma Y, Deng H, Huang Q et al. IGFBP7 plays a potential tumor suppressor role in colorectal carcinogenesis. Cancer Biol Ther 2007; 6: 354–359.

    Article  CAS  Google Scholar 

  22. Evdokimova V, Tognon CE, Benatar T, Yang W, Krutikov K, Pollak M et al. IGFBP7 binds to the IGF-1 receptor and blocks its activation by insulin-like growth factors. Sci Signal 2012; 5 ra92.

    Article  Google Scholar 

  23. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  Google Scholar 

  24. Christian S, Ahorn H, Novatchkova M, Garin-Chesa P, Park JE, Weber G et al. Molecular cloning and characterization of EndoGlyx-1, an EMILIN-like multisubunit glycoprotein of vascular endothelium. J Biol Chem 2001; 276: 48588–48595.

    Article  CAS  Google Scholar 

  25. Ozerdem U, Grako KA, Dahlin-Huppe K, Monosov E, Stallcup WB . NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn 2001; 222: 218–227.

    Article  CAS  Google Scholar 

  26. Ahmed S, Jin X, Yagi M, Yasuda C, Sato Y, Higashi S et al. Identification of membrane-bound serine proteinase matriptase as processing enzyme of insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1/angiomodulin/mac25). FEBS J 2006; 273: 615–627.

    Article  CAS  Google Scholar 

  27. Ahmed S, Yamamoto K, Sato Y, Ogawa T, Herrmann A, Higashi S et al. Proteolytic processing of IGFBP-related protein-1 (TAF/angiomodulin/mac25) modulates its biological activity. Biochem Biophys Res Commun 2003; 310: 612–618.

    Article  CAS  Google Scholar 

  28. Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA . Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 2008; 68: 3645–3654.

    Article  CAS  Google Scholar 

  29. Dolznig H, Rupp C, Puri C, Haslinger C, Schweifer N, Wieser E et al. Modeling colon adenocarcinomas in vitro a 3D co-culture system induces cancer-relevant pathways upon tumor cell and stromal fibroblast interaction. Am J Pathol 2011; 179: 487–501.

    Article  Google Scholar 

  30. Smith JJ, Deane NG, Wu F, Merchant NB, Zhang B, Jiang A et al. Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. Gastroenterology 2010; 138: 958–968.

    Article  CAS  Google Scholar 

  31. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6: 1–6.

    Article  CAS  Google Scholar 

  32. Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A et al. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 2006; 3: e47.

    Article  Google Scholar 

  33. Sato N, Maehara N, Goggins M . Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res 2004; 64: 6950–6956.

    Article  CAS  Google Scholar 

  34. Gallagher PG, Bao Y, Prorock A, Zigrino P, Nischt R, Politi V et al. Gene expression profiling reveals cross-talk between melanoma and fibroblasts: implications for host-tumor interactions in metastasis. Cancer Res 2005; 65: 4134–4146.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Casey T, Bond J, Tighe S, Hunter T, Lintault L, Patel O et al. Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer. Breast Cancer Res Treat 2009; 114: 47–62.

    Article  CAS  Google Scholar 

  37. Gregg JL, Brown KE, Mintz EM, Piontkivska H, Fraizer GC . Analysis of gene expression in prostate cancer epithelial and interstitial stromal cells using laser capture microdissection. BMC Cancer 2010; 10: 165.

    Article  Google Scholar 

  38. Massoner P, Haag P, Seifarth C, Jurgeit A, Rogatsch H, Doppler W et al. Insulin-like growth factor binding protein-3 (IGFBP-3) in the prostate and in prostate cancer: local production, distribution and secretion pattern indicate a role in stromal-epithelial interaction. Prostate 2008; 68: 1165–1178.

    Article  CAS  Google Scholar 

  39. Pilewski JM, Liu L, Henry AC, Knauer AV, Feghali-Bostwick CA . Insulin-like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition. Am J Pathol 2005; 166: 399–407.

    Article  CAS  Google Scholar 

  40. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141: 69–80.

    Article  CAS  Google Scholar 

  41. Firth SM, Baxter RC . Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 2002; 23: 824–854.

    Article  CAS  Google Scholar 

  42. Vizioli MG, Sensi M, Miranda C, Cleris L, Formelli F, Anania MC et al. IGFBP7: an oncosuppressor gene in thyroid carcinogenesis. Oncogene 2010; 29: 3835–3844.

    Article  CAS  Google Scholar 

  43. Tomimaru Y, Eguchi H, Wada H, Kobayashi S, Marubashi S, Tanemura M et al. IGFBP7 downregulation is associated with tumor progression and clinical outcome in hepatocellular carcinoma. Int J Cancer 2012; 130: 319–327.

    Article  CAS  Google Scholar 

  44. Lin J, Lai M, Huang Q, Ruan W, Ma Y, Cui J . Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer Biol Ther 2008; 7: 1896–1900.

    Article  CAS  Google Scholar 

  45. Chen Y, Cui T, Knosel T, Yang L, Zoller K, Petersen I . IGFBP7 is a p53 target gene inactivated in human lung cancer by DNA hypermethylation. Lung Cancer 2011; 73: 38–44.

    Article  Google Scholar 

  46. Sullivan L, Murphy TM, Barrett C, Loftus B, Thornhill J, Lawler M et al. IGFBP7 promoter methylation and gene expression analysis in prostate cancer. J Urol 2012; 188: 1354–1360.

    Article  CAS  Google Scholar 

  47. Jiang W, Xiang C, Cazacu S, Brodie C, Mikkelsen T . Insulin-like growth factor binding protein 7 mediates glioma cell growth and migration. Neoplasia 2008; 10: 1335–1342.

    Article  CAS  Google Scholar 

  48. Degeorges A, Wang F, Frierson HF Jr., Seth A, Chung LW, Sikes RA . Human prostate cancer expresses the low affinity insulin-like growth factor binding protein IGFBP-rP1. Cancer Res 1999; 59: 2787–2790.

    CAS  PubMed  Google Scholar 

  49. van Beijnum JR, Dings RP, van der Linden E, Zwaans BM, Ramaekers FC, Mayo KH et al. Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature. Blood 2006; 108: 2339–2348.

    Article  CAS  Google Scholar 

  50. Bieche I, Lerebours F, Tozlu S, Espie M, Marty M, Lidereau R . Molecular profiling of inflammatory breast cancer: identification of a poor-prognosis gene expression signature. Clin Cancer Res 2004; 10: 6789–6795.

    Article  CAS  Google Scholar 

  51. Adachi Y, Itoh F, Yamamoto H, Arimura Y, Kikkawa-Okabe Y, Miyazaki K et al. Expression of angiomodulin (tumor-derived adhesion factor/mac25) in invading tumor cells correlates with poor prognosis in human colorectal cancer. Int J Cancer 2001; 95: 216–222.

    Article  CAS  Google Scholar 

  52. Sato Y, Chen Z, Miyazaki K . Strong suppression of tumor growth by insulin-like growth factor-binding protein-related protein 1/tumor-derived cell adhesion factor/mac25. Cancer Sci 2007; 98: 1055–1063.

    Article  CAS  Google Scholar 

  53. Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP . Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 2003; 31: e15.

    Article  Google Scholar 

  54. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004; 5: R80.

    Article  Google Scholar 

  55. Smyth GK . Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004; 3: Article3.

    Article  Google Scholar 

  56. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I . Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001; 125: 279–284.

    Article  CAS  Google Scholar 

  57. Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 1999; 154: 385–394.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Boehringer Ingelheim Austria. We are grateful to Christina Puri, Daniela Milovanovic, Oliver Bergner and Jakob Schnabl for help with immunohistochemistry, cell culture and in vitro assays.

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Author notes

  1. C Rupp

    Present address: 6Current address: Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/4 A-1030, Vienna, Austria.,

  2. H Dolznig and P Garin-Chesa: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Institute for Pathology, Medical University of Vienna, Vienna, Austria

    C Rupp, D Kerjaschki & P Garin-Chesa

  2. Institute of Medical Genetics, Center of Pathobiology and Genetics, Medical University of Vienna, Vienna, Austria

    M Scherzer, C Unger, M Hengstschläger & H Dolznig

  3. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

    A Rudisch, C Haslinger, N Schweifer, W Sommergruber & P Garin-Chesa

  4. Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria

    M Artaker

  5. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    H Nivarthi & R Moriggl

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Rupp, C., Scherzer, M., Rudisch, A. et al. IGFBP7, a novel tumor stroma marker, with growth-promoting effects in colon cancer through a paracrine tumor–stroma interaction. Oncogene 34, 815–825 (2015). https://doi.org/10.1038/onc.2014.18

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