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Interplay between VHL/HIF1α and Wnt/β-catenin pathways during colorectal tumorigenesis

Oncogene volume 25, pages 3065–3070 (2006)Cite this article

Abstract

Activation of the Wnt signaling pathway initiates the transformation of colorectal epithelial cells, although the transition to metastatic cancer requires angiogenesis. We have investigated the expression of the von Hippel–Lindau (VHL) tumor suppressor in the intestines from humans and mice. Here, we show that VHL expression is regulated by TCF4 and is restricted to the proliferative compartment at the bottom of intestinal crypts. Accordingly, VHL is completely absent from the proliferative intestinal pockets of Tcf4−/− perinatal mice. We observed complementary staining of the hypoxia-inducible factor (HIF) 1α to VHL in normal intestinal epithelium as well as in all stages of colorectal cancer (CRC). To the best of our knowledge, this is the first report demonstrating the presence of nuclear HIF1α in normoxic healthy adult tissue. Although we observed upregulated levels of VHL in very early CRC lesions from sporadic and familial adenomatous polyposis patients – presumably due to activated Wnt signaling – a clear reduction of VHL expression is observed in later stages of CRC progression, coinciding with stabilization of HIF1α. As loss of VHL in later stages of CRC progression results in stabilization of HIF, these data provide evidence that selection for VHL downregulation provides a proangiogenic impulse for CRC progression.

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Acknowledgements

We wish to thank Anita Jorna and Tim Wijgerde for technical assistance. RHG (VIDI award 016.066.354) and MPL (Grant 920-03-179) are funded by the Netherlands Organization for Scientific Research (NWO). This work was supported by a grant from the Dutch Cancer Society (NKB/KWF 99-1879).

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Authors and Affiliations

  1. Department of Medical Oncology, Laboratory of Experimental Oncology, University Medical Center, Utrecht, The Netherlands

    R H Giles, M P Lolkema, C M Snijckers, M Belderbos, D A Mans, M van Beest & E E Voest

  2. Department of Pathology, University Medical Center, Utrecht, The Netherlands

    P van der Groep, R Goldschmeding & P J van Diest

  3. Department of Urology, University Medical Center, Utrecht, The Netherlands

    M van Noort

  4. Hubrecht Laboratory/NIOB, Utrecht, The Netherlands

    H Clevers

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  1. R H Giles
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  2. M P Lolkema
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Correspondence to E E Voest.

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Giles, R., Lolkema, M., Snijckers, C. et al. Interplay between VHL/HIF1α and Wnt/β-catenin pathways during colorectal tumorigenesis. Oncogene 25, 3065–3070 (2006). https://doi.org/10.1038/sj.onc.1209330

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