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Bone morphogenetic protein signalling in colorectal cancer

Nature Reviews Cancer volume 8, pages 806–812 (2008)Cite this article

Abstract

Much of the current understanding of colorectal cancer stems from the study of rare, inherited colorectal cancer syndromes. Mutations in the bone morphogenetic protein (BMP) pathway have been found in juvenile polyposis, an inherited polyposis syndrome that predisposes to colorectal cancer. The hamartomas that develop in these patients and in BMP pathway mutant mice have a remarkable mesenchymal component. Further evidence in mice suggests a primary role for mesenchymal loss of BMP signalling in hamartoma development. Here, we examine this evidence and question its relevance to sporadic colorectal carcinogenesis.

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Figure 1: Bone morphogenetic protein (BMP) pathway signalling.
Figure 2: The expression of components of the bone morphogenetic protein (BMP) pathway within normal colonic crypts.
Figure 3: Histological sections.
Figure 4: The adenoma–carcinoma sequence.

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References

  1. van den Brink, G. R. & Offerhaus, G. J. The morphogenetic code and colon cancer development. Cancer Cell 11, 109–117 (2007).

    Article  CAS  Google Scholar 

  2. Regula, J. et al. Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia. N. Engl. J. Med. 355, 1863–1872 (2006).

    Article  CAS  Google Scholar 

  3. Winawer, S. J. et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N. Engl. J. Med. 329, 1977–1981 (1993).

    Article  CAS  Google Scholar 

  4. Huang, C. S., O'Brien, M., J., Yang, S. & Farraye, F. A. Hyperplastic polyps, serrated adenomas, and the serrated polyp neoplasia pathway. Am. J. Gastroenterol. 99, 2242–2255 (2004).

    Article  CAS  Google Scholar 

  5. Chan, T. L., Zhao, W., Leung, S. Y. & Yuen, S. T. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 63, 4878–4881 (2003).

    CAS  PubMed  Google Scholar 

  6. Massague, J. TGF-β signal transduction. Annu. Rev. Biochem. 67, 753–791 (1998).

    Article  CAS  Google Scholar 

  7. Schmierer, B. & Hill, C. S. TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Nature Rev. Mol. Cell Biol. 8, 970–982 (2007).

    Article  CAS  Google Scholar 

  8. Kosinski, C. et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc. Natl Acad. Sci. USA 104, 15418–15423 (2007).

    Article  CAS  Google Scholar 

  9. Li, X. et al. Deconvoluting the intestine: molecular evidence for a major role of the mesenchyme in the modulation of signaling cross talk. Physiol. Genomics 29, 290–301 (2007).

    Article  CAS  Google Scholar 

  10. Haramis, A. P. et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303, 1684–1686 (2004).

    Article  CAS  Google Scholar 

  11. He, X. C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–β-catenin signaling. Nature Genet. 36, 1117–1121 (2004).

    Article  CAS  Google Scholar 

  12. Hardwick, J. C. et al. Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. Gastroenterology 126, 111–121 (2004).

    Article  CAS  Google Scholar 

  13. Auclair, B. A., Benoit, Y. D., Rivard, N., Mishina, Y. & Perreault, N. Bone morphogenetic protein signaling is essential for terminal differentiation of the intestinal secretory cell lineage. Gastroenterology 133, 887–896 (2007).

    Article  CAS  Google Scholar 

  14. Howe, J. R. et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nature Genet. 28, 184–187 (2001).

    Article  CAS  Google Scholar 

  15. Brosens, L. A. et al. Risk of colorectal cancer in juvenile polyposis. Gut 56, 965–967 (2007).

    Article  Google Scholar 

  16. Howe, J. R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).

    Article  CAS  Google Scholar 

  17. Sweet, K. et al. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294, 2465–2473 (2005).

    Article  CAS  Google Scholar 

  18. Howe, J. R. et al. ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis. Clin. Genet. 71, 91–92 (2007).

    Article  CAS  Google Scholar 

  19. Howe, J. R. et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J. Med. Genet. 41, 484–491 (2004).

    Article  CAS  Google Scholar 

  20. Woodford-Richens, K. et al. Analysis of genetic and phenotypic heterogeneity in juvenile polyposis. Gut 46, 656–660 (2000).

    Article  CAS  Google Scholar 

  21. Friedl, W. et al. Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum. Genet. 111, 108–111 (2002).

    Article  CAS  Google Scholar 

  22. Sayed, M. G. et al. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann. Surg. Oncol. 9, 901–906 (2002).

    Article  CAS  Google Scholar 

  23. Roth, S. I. & Helwig, E. B. Juvenile polyps of the colon and rectum. Cancer 16, 468–479 (1963).

    Article  CAS  Google Scholar 

  24. Mesiya, S. et al. Sporadic colonic hamartomas in adults: a retrospective study. Gastrointest. Endosc. 62, 886–891 (2005).

    Article  Google Scholar 

  25. Giardiello, F. M. et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119, 1447–1453 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Woodford-Richens, K. et al. Allelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium. Cancer Res. 60, 2477–2482 (2000).

    CAS  PubMed  Google Scholar 

  28. Woodford-Richens, K. L. et al. Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers. Am. J. Pathol. 159, 1293–1300 (2001).

    Article  CAS  Google Scholar 

  29. Beppu, H. et al. Stromal inactivation of BMPRII leads to colorectal epithelial overgrowth and polyp formation. Oncogene 27, 1063–1070 (2008).

    Article  CAS  Google Scholar 

  30. Kim, B. G. et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441, 1015–1019 (2006).

    Article  CAS  Google Scholar 

  31. Wagner, K. U. et al. Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res. 10, 545–553 (2001).

    Article  CAS  Google Scholar 

  32. Yan, C., Costa, R. H., Darnell, J. E. Jr, Chen, J. D. & Van Dyke, T. A. Distinct positive and negative elements control the limited hepatocyte and choroid plexus expression of transthyretin in transgenic mice. EMBO J. 9, 869–878 (1990).

    Article  CAS  Google Scholar 

  33. Suemori, S., Lynch-Devaney, K. & Podolsky, D. K. Identification and characterization of rat intestinal trefoil factor: tissue- and cell-specific member of the trefoil protein family. Proc. Natl Acad. Sci. USA 88, 11017–11021 (1991).

    Article  CAS  Google Scholar 

  34. Madison, B. B. et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283 (2002).

    Article  CAS  Google Scholar 

  35. Thiagalingam, S. et al. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nature Genet. 13, 343–346 (1996).

    Article  CAS  Google Scholar 

  36. Loh, K. et al. Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development. Genes Chromosomes Cancer 47, 449–460 (2008).

    Article  CAS  Google Scholar 

  37. Beck, S. E. et al. Bone morphogenetic protein signaling and growth suppression in colon cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G135–G145 (2006).

    Article  CAS  Google Scholar 

  38. Deng, H. et al. Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells. Exp. Cell Res. 313, 1033–1044 (2007).

    Article  CAS  Google Scholar 

  39. Motoyama, K. et al. Clinical significance of BMP7 in human colorectal cancer. Ann. Surg. Oncol. 15, 1530–1537 (2008).

    Article  Google Scholar 

  40. Kodach, L. L. et al. The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers. Gastroenterology 134, 1332–1341 (2008).

    Article  CAS  Google Scholar 

  41. Kodach, L. L. et al. The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer. Cancer 112, 300–306 (2008).

    Article  CAS  Google Scholar 

  42. Markowitz, S. et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

    Article  CAS  Google Scholar 

  43. Akiyama, Y. et al. Mutations of the transforming growth factor-β type II receptor gene are strongly related to sporadic proximal colon carcinomas with microsatellite instability. Cancer 78, 2478–2484 (1996).

    Article  CAS  Google Scholar 

  44. Manning, A. M., Williams, A. C., Game, S. M. & Paraskeva, C. Differential sensitivity of human colonic adenoma and carcinoma cells to transforming growth factor β (TGF-β): conversion of an adenoma cell line to a tumorigenic phenotype is accompanied by a reduced response to the inhibitory effects of TGF-β. Oncogene 6, 1471–1476 (1991).

    CAS  PubMed  Google Scholar 

  45. Fernandez-Peralta, A. M. et al. Significance of mutations in TGFBR2 and BAX in neoplastic progression and patient outcome in sporadic colorectal tumors with high-frequency microsatellite instability. Cancer Genet. Cytogenet. 157, 18–24 (2005).

    Article  CAS  Google Scholar 

  46. Broderick P et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nature Genet. 39, 1315–1317 (2007).

    Article  CAS  Google Scholar 

  47. Jaeger E et al. Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nature Genet. 40, 26–28 (2008).

    Article  CAS  Google Scholar 

  48. Fearon, E.R., Hamilton S.R. & Vogelstein, B. Clonal analysis of human colorectal tumors. Science 238, 193–197 (1991).

    Article  Google Scholar 

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Authors and Affiliations

  1. Liudmila L. Kodach and Gijs R. van den Brink are at the Department of Gastroenterology & Hepatology, James C. Hardwick, Leiden University Medical Center, Leiden, the Netherlands,

    James C. Hardwick, Liudmila L. Kodach & Gijs R. van den Brink

  2. G. Johan Offerhaus is at the Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.,

    G. Johan Offerhaus

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  1. James C. Hardwick
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  2. Liudmila L. Kodach
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  3. G. Johan Offerhaus
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  4. Gijs R. van den Brink
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Correspondence to James C. Hardwick.

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Hardwick, J., Kodach, L., Offerhaus, G. et al. Bone morphogenetic protein signalling in colorectal cancer. Nat Rev Cancer 8, 806–812 (2008). https://doi.org/10.1038/nrc2467

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