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Intestinal adenomagenesis involves core molecular signatures of the epithelial–mesenchymal transition

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Abstract

The epithelial–mesenchymal transition (EMT) occurs commonly during carcinoma invasion and metastasis, but not during early tumorigenesis. Microarray data demonstrated elevation of vimentin, a mesenchymal marker, in intestinal adenomas from Apc Min/+ (Min) mice. We have tested the involvement of EMT in early tumorigenesis in mammalian intestines by following EMT-associated markers. Elevated vimentin RNA expression and protein production were detected within neoplastic cells in murine intestinal adenomas. Similarly, vimentin protein was detected in both adenomas and invasive adenocarcinomas of the human colon, but not in the normal colonic epithelium or in hyperplastic polyps. Expression of E-cadherin varied inversely with vimentin. In addition, the expression of fibronectin was elevated while that of E-cadherin decreased. Canonical E-cadherin suppressors, such as Snail, were not elevated in the same tumor. Elevated vimentin expression in the adenoma was not correlated with persistent Ras signaling, but was strongly correlated with reduced proliferation indices, active Wnt signaling, and TGF-β signaling, as demonstrated by its dependence on Smad3. We designate our observations of expression of only some of the canonical features of EMT as “truncated EMT”. These unexpected observations are interpreted as reflecting the involvement of a core of the EMT system during the tissue remodeling of early tumorigenesis.

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Abbreviations

1638N:

Apc1638N insertion allele

129:

129S6

AOM:

Azoxymethane

BTBR:

BTBR/Pas

B6:

C57BL/6J

BR:

C57BR/cdcJ

DAB:

3,3′-Diaminobenzidine

EMT:

Epithelial–mesenchymal transition

IF:

Immunofluorescence

IHC:

Immunohistochemistry

ISH:

In situ hybridization

Min:

Apc Min/+

MMP7:

Matrix metalloproteinase 7

pMAPK:

Phosphorylated-p44/42 mitogen-activated protein kinase

pSmad2:

Phosphorylated Smad2

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Acknowledgements

We thank our colleagues in the Mouse Models for Human Cancer Consortium for the microarray analysis that has provided the starting point for this investigation. We thank Ismo Virtanen for providing the antibody to Snail. David Threadgill has generously provided sections of appropriately fixed AOM tumors for our ISH analysis. Jose Torrealba has generously provided sections of human colonic lesions. The Histotechnology Facility of the McArdle Laboratory (Jane Weeks, leader) has provided sections of high quality for this study. Cheri Pasch and Kathy Helmuth have provided fastidious assistance in ISH and Dawn Albrecht in the maintenance of pedigreed mouse kindreds and Alexandra Shedlovsky for BTBR Min tumors. Linda Clipson has provided both skilled assistance in organizing the manuscript but also, in conjunction with Alexandra Shedlovsky, detailed critique. Finally, we thank other members of the Dove laboratory for helpful discussion. Our research was supported by grants R37-CA63677 and U01-CA84227 from the NCI to WFD. This is publication #3638 from the Laboratory of Genetics, University of Wisconsin-Madison.

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Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, WI, 53706, USA

    Xiaodi Chen, Richard B. Halberg, Ryan P. Burch & William F. Dove

  2. Laboratory of Genetics, University of Wisconsin, Madison, WI, 53706, USA

    William F. Dove

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  1. Xiaodi Chen
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  2. Richard B. Halberg
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  4. William F. Dove
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Correspondence to William F. Dove.

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Chen, X., Halberg, R.B., Burch, R.P. et al. Intestinal adenomagenesis involves core molecular signatures of the epithelial–mesenchymal transition. J Mol Hist 39, 283–294 (2008). https://doi.org/10.1007/s10735-008-9164-3

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  • DOI: https://doi.org/10.1007/s10735-008-9164-3

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