Tumor Biology

, Volume 37, Issue 2, pp 2243–2255 | Cite as

BMP pathway suppression is an early event in inflammation-driven colon neoplasmatogenesis of uPA-deficient mice

  • George S. Karagiannis
  • Hara Afaloniati
  • Elisavet Karamanavi
  • Theofilos Poutahidis
  • Katerina Angelopoulou
Original Article


The suppression of the bone morphogenetic protein (BMP) signaling pathway has been recently shown to promote adenoma-to-carcinoma transition in sporadic colon cancer. However, its role in the evolution of early preneoplastic changes to neoplasia remains elusive. In the present study, we aimed to investigate the gene expression levels of multiple extracellular BMP family constituents, including BMP ligands/receptors and inhibitors, during the early stages of inflammation-associated colon carcinogenesis. For that, we used the recently developed urokinase-type plasminogen activator (uPA)-deficient mouse model of colonic polypoidogenesis, in which adenomatous polyps arise several months after the induction of dextran sodium sulfate (DSS) colitis. In DSS-treated wild-type mice, the preneoplastic lesions which did not eventually evolve to adenomas resided in a colitic microenvironment characterized by a balanced upregulation of both BMP ligands, i.e., Bmp4/7 and BMP inhibitors, such as chordin, noggin, and gremlin-1. In the uPA-deficient tumor-promoting inflammatory microenvironment, however, there was a clear evidence for BMP pathway suppression. By contrast to DSS-treated wild-type controls, the inflammation-associated Bmp4 upregulation was abolished, and the BMP signaling suppression was further enhanced by a particularly high increase of gremlin-1 expression. These findings propose that BMP pathway suppression in colon cancer could be associated with very early stages of the preneoplasia-to-neoplasia sequence of events.


BMP GREM1 uPA Colorectal cancer Colitis Mouse 



The authors are grateful to the Bodossaki Foundation for the kind donation of the real-time PCR instrumentation.

Conflicts of interest



  1. 1.
    Reddi AH, Reddi A. Bone morphogenetic proteins (BMPs): from morphogens to metabologens. Cytokine Growth Factor Rev. 2009;20:341–2.CrossRefPubMedGoogle Scholar
  2. 2.
    Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors. 2004;22:233–41.CrossRefPubMedGoogle Scholar
  3. 3.
    Sieber C, Kopf J, Hiepen C, Knaus P. Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev. 2009;20:343–55.CrossRefPubMedGoogle Scholar
  4. 4.
    Singh A, Morris RJ. The yin and yang of bone morphogenetic proteins in cancer. Cytokine Growth Factor Rev. 2010;21:299–313.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6(7):506–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Ehata S, Yokoyama Y, Takahashi K, Miyazono K. Bi-directional roles of bone morphogenetic proteins in cancer: another molecular Jekyll and Hyde? Pathol Int. 2013;63:287–96.CrossRefPubMedGoogle Scholar
  7. 7.
    Hardwick JC, Kodach LL, Offerhaus GJ, van den Brink GR. Bone morphogenetic protein signalling in colorectal cancer. Nat Rev Cancer. 2008;8:806–12.CrossRefPubMedGoogle Scholar
  8. 8.
    Kodach LL, Bleuming SA, Musler AR, Peppelenbosch MP, Hommes DW, van den Brink GR, et al. The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer. Cancer. 2008;112:300–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Kodach LL, Wiercinska E, de Miranda NF, Bleuming SA, Musler AR, Peppelenbosch MP, et al. The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers. Gastroenterology. 2008;134:1332–41.CrossRefPubMedGoogle Scholar
  10. 10.
    Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J, et al. Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature. 1999;401:480–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Ali IH, Brazil DP. Bone morphogenetic proteins and their antagonists: current and emerging clinical uses. Br J Pharmacol. 2014;171:3620–32.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Walsh DW, Godson C, Brazil DP, Martin F. Extracellular BMP-antagonist regulation in development and disease: tied up in knots. Trends Cell Biol. 2010;20:244–56.CrossRefPubMedGoogle Scholar
  13. 13.
    Tocharus J, Tsuchiya A, Kajikawa M, Ueta Y, Oka C, Kawaichi M. Developmentally regulated expression of mouse HtrA3 and its role as an inhibitor of TGF-beta signaling. Dev Growth Differ. 2004;46:257–74.CrossRefPubMedGoogle Scholar
  14. 14.
    Yao Y, Zebboudj AF, Shao E, Perez M, Bostrom K. Regulation of bone morphogenetic protein-4 by matrix GLA protein in vascular endothelial cells involves activin-like kinase receptor 1. J Biol Chem. 2006;281:33921–30.CrossRefPubMedGoogle Scholar
  15. 15.
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;65:392–401.CrossRefGoogle Scholar
  16. 16.
    Del Rosso M, Margheri F, Serrati S, Chilla A, Laurenzana A, Fibbi G. The urokinase receptor system, a key regulator at the intersection between inflammation, immunity, and coagulation. Curr Pharm Des. 2011;17:1924–43.CrossRefPubMedGoogle Scholar
  17. 17.
    Karamanavi E, Angelopoulou K, Lavrentiadou S, Tsingotjidou A, Abas Z, Taitzoglou I, et al. Urokinase-type plasminogen activator deficiency promotes neoplasmatogenesis in the colon of mice. Transl Oncol. 2014;7:174–87.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gonzalez DM, Medici D. Signaling mechanisms of the epithelial–mesenchymal transition. Sci Signal. 2014;7, re8.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Dendooven A, van Oostrom O, van der Giezen DM, Leeuwis JW, Snijckers C, Joles JA, et al. Loss of endogenous bone morphogenetic protein-6 aggravates renal fibrosis. Am J Pathol. 2011;178:1069–79.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lin Z, Gao C, Ning Y, He X, Wu W, Chen YG. The pseudoreceptor BMP and activin membrane-bound inhibitor positively modulates Wnt/beta-catenin signaling. J Biol Chem. 2008;283:33053–8.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Sammar M, Stricker S, Schwabe GC, Sieber C, Hartung A, Hanke M, et al. Modulation of GDF5/BRI-b signalling through interaction with the tyrosine kinase receptor Ror2. Genes Cells. 2004;9:1227–38.CrossRefPubMedGoogle Scholar
  22. 22.
    Lehmann K, Seemann P, Silan F, Goecke TO, Irgang S, Kjaer KW, et al. A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am J Hum Genet. 2007;81:388–96.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Brazil DP, Church RH, Surae S, Godson C, Martin F. BMP signalling: agony and antagony in the family. Trends Cell Biol. 2015;25:249–64.CrossRefPubMedGoogle Scholar
  24. 24.
    Karagiannis GS, Musrap N, Saraon P, Treacy A, Schaeffer DF, Kirsch R, et al. Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression. Biol Chem. 2015;396:163–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Sneddon JB, Zhen HH, Montgomery K, van de Rijn M, Tward AD, West R, et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc Natl Acad Sci U S A. 2006;103:14842–7.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Laurila R, Parkkila S, Isola J, Kallioniemi A, Alarmo EL. The expression patterns of gremlin 1 and noggin in normal adult and tumor tissues. Int J Clin Exp Pathol. 2013;6:1400–8.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Karagiannis GS, Berk A, Dimitromanolakis A, Diamandis EP. Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin-1. Mol Oncol. 2013;7:826–39.CrossRefPubMedGoogle Scholar
  28. 28.
    Karagiannis GS, Petraki C, Prassas I, Saraon P, Musrap N, Dimitromanolakis A, et al. Proteomic signatures of the desmoplastic invasion front reveal collagen type XII as a marker of myofibroblastic differentiation during colorectal cancer metastasis. Oncotarget. 2012;3:267–85.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Karagiannis GS, Treacy A, Messenger D, Grin A, Kirsch R, Riddell RH, et al. Expression patterns of bone morphogenetic protein antagonists in colorectal cancer desmoplastic invasion fronts. Mol Oncol. 2014;8:1240–52.CrossRefPubMedGoogle Scholar
  30. 30.
    Deng H, Makizumi R, Ravikumar TS, Dong H, Yang W, Yang WL. Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells. Exp Cell Res. 2007;313:1033–44.CrossRefPubMedGoogle Scholar
  31. 31.
    Motoyama K, Tanaka F, Kosaka Y, Mimori K, Uetake H, Inoue H, et al. Clinical significance of BMP7 in human colorectal cancer. Ann Surg Oncol. 2008;15:1530–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res. 2012;10:1403–18.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Jin X, Chen Z, Xiang L, Luo Q, Guo Z, Ding X, et al. Colorectal polyp model established by transplacental BMP4 RNAi. Mol Med Rep. 2014;10:33–8.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Kotzsch A, Nickel J, Seher A, Heinecke K, van Geersdaele L, Herrmann T, et al. Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome. J Biol Chem. 2008;283:5876–87.CrossRefPubMedGoogle Scholar
  35. 35.
    Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet. 2001;28:184–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Fajardo M, Liu CJ, Egol K. Levels of expression for BMP-7 and several BMP antagonists may play an integral role in a fracture nonunion: a pilot study. Clin Orthop Relat Res. 2009;467:3071–8.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tarragona M, Pavlovic M, Arnal-Estape A, Urosevic J, Morales M, Guiu M, et al. Identification of NOG as a specific breast cancer bone metastasis-supporting gene. J Biol Chem. 2012;287:21346–55.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Stabile H, Mitola S, Moroni E, Belleri M, Nicoli S, Coltrini D, et al. Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor. Blood. 2007;109:1834–40.CrossRefPubMedGoogle Scholar
  39. 39.
    Chen MH, Yeh YC, Shyr YM, Jan YH, Chao Y, Li CP, et al. Expression of gremlin 1 correlates with increased angiogenesis and progression-free survival in patients with pancreatic neuroendocrine tumors. J Gastroenterol. 2013;48:101–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Mitola S, Ravelli C, Moroni E, Salvi V, Leali D, Ballmer-Hofer K, et al. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood. 2010;116:3677–80.CrossRefPubMedGoogle Scholar
  41. 41.
    Ravelli C, Mitola S, Corsini M, Presta M. Involvement of alphavbeta3 integrin in gremlin-induced angiogenesis. Angiogenesis. 2013;161:235–43.CrossRefGoogle Scholar
  42. 42.
    Canfield AE, Hadfield KD, Rock CF, Wylie EC, Wilkinson FL. HtrA1: a novel regulator of physiological and pathological matrix mineralization? Biochem Soc Trans. 2007;35:669–71.CrossRefPubMedGoogle Scholar
  43. 43.
    Sharma B, Albig AR. Matrix Gla protein reinforces angiogenic resolution. Microvasc Res. 2013;85:24–33.CrossRefPubMedGoogle Scholar
  44. 44.
    Katoh M. WNT signaling in stem cell biology and regenerative medicine. Curr Drug Targets. 2008;9:565–70.CrossRefPubMedGoogle Scholar
  45. 45.
    Enomoto M, Hayakawa S, Itsukushima S, Ren DY, Matsuo M, Tamada K, et al. Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling. Oncogene. 2009;28:3197–208.CrossRefPubMedGoogle Scholar
  46. 46.
    de Lau W, Barker N, Clevers H. WNT signaling in the normal intestine and colorectal cancer. Front Biosci. 2007;12:471–91.CrossRefPubMedGoogle Scholar
  47. 47.
    Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13:69–80.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    van Vlodrop IJ, Baldewijns MM, Smits KM, Schouten LJ, van Neste L, van Criekinge W, et al. Prognostic significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear cell renal cell carcinoma. Am J Pathol. 2010;176:575–84.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Suzuki M, Shigematsu H, Shames DS, Sunaga N, Takahashi T, Shivapurkar N, et al. DNA methylation-associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers. Br J Cancer. 2005;93:1029–37.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Suzuki M, Shigematsu H, Shivapurkar N, Reddy J, Miyajima K, Takahashi T, et al. Methylation of apoptosis related genes in the pathogenesis and prognosis of prostate cancer. Cancer Lett. 2006;242:222–30.CrossRefPubMedGoogle Scholar
  51. 51.
    Yoshino M, Suzuki M, Tian L, Moriya Y, Hoshino H, Okamoto T, et al. Promoter hypermethylation of the p16 and Wif-1 genes as an independent prognostic marker in stage IA non-small cell lung cancers. Int J Oncol. 2009;35:1201–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • George S. Karagiannis
    • 1
  • Hara Afaloniati
    • 2
  • Elisavet Karamanavi
    • 3
    • 4
  • Theofilos Poutahidis
    • 3
  • Katerina Angelopoulou
    • 2
  1. 1.Department of Anatomy and Structural Biology, Albert Einstein College of MedicineYeshiva UniversityBronxUSA
  2. 2.Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health SciencesAristotle University of ThessalonikiThessalonikiGreece
  3. 3.Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health SciencesAristotle University of ThessalonikiThessalonikiGreece
  4. 4.Department of Cardiovasular Sciences, Cardiovascular Research Centre, Glenfield General HospitalUniversity of LeicesterLeicesterUK

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