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The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer

  1. Liudmila L. Kodach MD1,
  2. Sylvia A. Bleuming PhD1,
  3. Alex R. Musler2,
  4. Maikel P. Peppelenbosch MD, PhD3,
  5. Daniel W. Hommes MD, PhD4,
  6. Gijs R. van den Brink MD, PhD4,
  7. Carel J. M. van Noesel MD, PhD2,
  8. G. Johan A. Offerhaus MD, PhD5,
  9. James C. H. Hardwick MD, PhD4,†,*

Article first published online: 15 NOV 2007

DOI: 10.1002/cncr.23160

Issue

Cancer

Cancer

Volume 112, Issue 2, pages 300–306, 15 January 2008

Additional Information

How to Cite

Kodach, L. L., Bleuming, S. A., Musler, A. R., Peppelenbosch, M. P., Hommes, D. W., van den Brink, G. R., van Noesel, C. J. M., Offerhaus, G. J. A. and Hardwick, J. C. H. (2008), The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer. Cancer, 112: 300–306. doi: 10.1002/cncr.23160

Author Information

  1. 1

    Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands

  2. 2

    Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands

  3. 3

    Department of Cell Biology, University Medical Center Groningen, University of Groningen, the Netherlands

  4. 4

    Department of Gastroenterology and Hepatology, Leiden University Hospital, Leiden, the Netherlands

  5. 5

    Department of Pathology, University Medical Center Utrecht, the Netherlands

  1. †

    Fax: (011) 31 71-5248115

*Department of Gastroenterology and Hepatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, the Netherlands

Publication History

  1. Issue published online: 4 JAN 2008
  2. Article first published online: 15 NOV 2007
  3. Manuscript Accepted: 9 AUG 2007
  4. Manuscript Revised: 7 AUG 2007
  5. Manuscript Received: 28 MAR 2007

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Keywords:

  • colorectal cancer;
  • SMAD proteins;
  • bone morphogenetic protein receptors;
  • tissue microarray;
  • adenoma-carcinoma sequence

Abstract

BACKGROUND.

Transforming growth factor β (TGFβ) is important in colorectal cancer (CRC) progression. Bone morphogenetic proteins (BMPs), a subgroup within the TGFβ superfamily, recently also have been implicated in CRC, but their precise role in CRC has yet to be investigated.

METHODS.

The authors used a tissue microarray and immunohistochemistry of BMP receptors and signal transduction elements in adenomas and CRC specimens to elucidate the role of BMP signaling in CRC carcinogenesis.

RESULTS.

The adenoma specimens expressed all 3 BMP receptors (BMPRs) (BMPR type 1a [BMPR1a], BMPR1b, and BMPR2) and expressed SMAD family member 4 (SMAD4); and 20 of 22 adenomas (90.9%) exhibited active BMP signaling, as determined by nuclear phosphorylated SMAD1,5,8 (pSMAD1,5,8) expression. In contrast, pSMAD1,5,8 nuclear staining was present in 5 CRC specimens (22.7%) but was lost in 17 CRC specimens (77.3%; cancer vs adenoma; P < .0001). The earliest loss of pSMAD1,5,8 nuclear staining was detected in regions of high-grade dysplasia/carcinoma in situ within adenomas. CRCs showed frequent loss of BMPR2 (P < .0001) and SMAD4 (P < .01) compared with adenomas. Negative expression of BMPR2 was observed more frequently in earlier stage cancers (Dukes stage B) than in advanced cancers (Dukes stage C; P < .05).

CONCLUSIONS.

Taken together, the current results indicated that loss of BMP signaling correlates tightly with progression of adenomas to cancer and occurs relatively early during cancer progression. Cancer 2008. © 2007 American Cancer Society.

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