Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis.
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) 1alpha 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 HIF1alpha 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 HIF1alpha. 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.
Giles
R H
RH
Laboratory of Experimental Oncology, Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands.
Lolkema
M P
MP
Snijckers
C M
CM
Belderbos
M
M
van der Groep
P
P
Mans
D A
DA
van Beest
M
M
van Noort
M
M
Goldschmeding
R
R
van Diest
P J
PJ
Clevers
H
H
Voest
E E
EE
D000230:Adenocarcinoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D004921:Erythropoietin / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007668:Kidney; D007739:L Cells; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000494:pharmacology / Q000502:physiology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C090743:Tcf4 protein, mouse; C544895:Tcf7l2 protein, mouse; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; C494469:VHL protein, mouse