Ectopic Expression of P-Cadherin Correlates with Promoter Hypomethylation Early in Colorectal Carcinogenesis and Enhanced Intestinal Crypt Fission <i>In vivo</i>

Milicic, Anita; Harrison, Lea–Anne; Goodlad, R A; Hardy, Richard J.; Nicholson, Anna M.; Presz, Michal; Sieber, Oliver M.; Santander, Sonia; Pringle, James H.; Mandir, Nikki; East, Philip; Obszynska, Jolanta; Sanders, Scott; Piazuelo, Elena; Shaw, Jacqui; Harrison, Rebecca; Tomlinson, Ian; McDonald, Stuart; Wright, Nicholas; Jankowski, Janusz

doi:10.1158/0008-5472.can-08-0020

Cited by 62 publications

(54 citation statements)

References 41 publications

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“…Reinforcing our results, CDH3 promoter was also found hypomethylated in colonic aberrant crypt foci, in colorectal cancer, and, occasionally, in the normal epithelium adjacent to cancer (Milicic et al, 2008). This hypomethylation pattern was associated with the induction of P-cadherin expression in the neoplastic colon.…”

Section: Epigenetic Regulation Of P-cadherin Expressionsupporting

confidence: 88%

P-cadherin role in normal breast development and cancer

Albergaria

Ribeiro²,

Vieira³

et al. 2011

Int. J. Dev. Biol.

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P-cadherin is a cell-cell adhesion molecule, whose expression is highly associated with undifferentiated cells in normal adult epithelial tissues, as well as with poorly differentiated carcinomas. Its expression has been already reported in human embryonic stem cells and it is presumed to be a marker of stem or progenitor cells of some epithelial tissues. In normal breast, P-cadherin has an essential role during ductal mammary branching, being expressed by the monolayer of epithelial cap cells at the end buds. In mature mammary tissue, its expression is restricted to the myoepithelium; it has been postulated that it may also be present in early luminal progenitor cells. In breast cancer, P-cadherin is frequently overexpressed in high-grade tumours, being a well-established indicator of poor patient prognosis. It has been reported as an important inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloproteases to the extracellular media, and the cleavage of a P-cadherin soluble form with pro-invasive activity. Intracellularly, this protein interferes with the endogenous cadherin/catenin complex, inducing p120-catenin delocalization to the cytoplasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton. Considering P-cadherin's role in cancer cell invasion and metastasis formation, a humanized monoclonal antibody was recently produced to antagonize P-cadherin-associated signalling pathways, which is currently under Phase I clinical trials. In this review, the most important findings about the role of P-cadherin in normal breast development and cancer will be illustrated and discussed, with emphasis on the most recent data.

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Section: Epigenetic Regulation Of P-cadherin Expressionsupporting

confidence: 88%

P-cadherin role in normal breast development and cancer

Albergaria

Ribeiro²,

Vieira³

et al. 2011

Int. J. Dev. Biol.

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“…The role of P-cadherin in colorectal carcinogenesis has not been extensively studied, however, its increased expression has previously been reported based on immunohistochemical staining of AD (12) and AC (13). P-cadherin is classified as an oncogene due to its ability to increase crypt cell proliferation in the context of inflammation (14). In addition, two reports have suggested that CDH3 upregulation in cancer tissue is associated with gene promoter demethylation (14,15).…”

Section: Discussionmentioning

confidence: 99%

“…P-cadherin is classified as an oncogene due to its ability to increase crypt cell proliferation in the context of inflammation (14). In addition, two reports have suggested that CDH3 upregulation in cancer tissue is associated with gene promoter demethylation (14,15). However, using a quantitative approach, increased promoter hypomethylation was identified in only 77% of carcinomas (15), which does not account for the universal upregulation of the expression of this gene in AD and cancer.…”

Section: Discussionmentioning

confidence: 99%

Expression changes of cell-cell adhesion-related genes in colorectal tumors

et al. 2015

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Abstract. Epithelial tissues achieve a highly organized structure due to cell-cell junction complexes. Carcinogenesis is accompanied by changes in cell interactions and tissue morphology, which appear in the early stages of benign tumors and progress along with invasive potential. The aim of the present study was to analyze the changes in expression levels of genes encoding intercellular junction proteins that have been previously identified to be differentially expressed in colorectal tumors compared with normal mucosa samples (fold change, >2.5) in genome-wide expression profiling. The expression of 20 selected genes was assessed using quantitative reverse transcription polymerase chain reaction in 26 colorectal cancer, 42 adenoma and 24 normal mucosa samples. Between these tissue types, differences were observed in the mRNA levels of genes encoding adherens junction proteins (upregulation of CDH3 and CDH11, and downregulation of CDH19 and PTPRF), tight junction proteins (upregulation of CLDN1 and CLDN2, and downregulation of CLDN5, CLDN8, CLDN23, CLDN15, JAM2 and CGN) and desmosomes (upregulation of DSC3 and DSG3, and downregulation of DSC2), in addition to a decrease in the expression of certain other genes involved in intercellular connections: PCDHB14, PCDH7, MUPCDH and NEO1. The differences between tissue types were statistically significant, and separate clustering of normal adenoma and carcinoma samples was observed in a hierarchical clustering analysis. These results indicate that the morphological changes in neoplastic colon tissue that occur during the 'adenoma-carcinoma sequence' are accompanied by specific changes in the expression of multiple genes encoding the majority of cell-cell junction complexes. The particular differential expression patterns appear to be consistent among patients with cancer and adenoma, in addition to normal mucosa samples.

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“…Crypt fission is of interest because it represents increased stem cell clonal expansion in intestinal dysplasia and models of familial adenomatous polyposis (40,46).…”

Section: Discussionmentioning

confidence: 99%

Functional Cftr in crypt epithelium of organotypic enteroid cultures from murine small intestine

Liu

Walker

Cook

et al. 2012

American Journal of Physiology-Cell Physiology

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Physiological studies of intact crypt epithelium have been limited by problems of accessibility in vivo and dedifferentiation in standard primary culture. Investigations of murine intestinal stem cells have recently yielded a primary intestinal culture in three-dimensional gel suspension that recapitulates crypt structure and epithelial differentiation (Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, Van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Nature 459: 262–265, 2009). We investigated the utility of murine intestinal crypt cultures (termed “enteroids”) for physiological studies of crypt epithelium by focusing on the transport activity of the cystic fibrosis transmembrane conductance regulator Cftr. Enteroids had multiple crypts with well-differentiated goblet and Paneth cells that degranulated on exposure to the muscarinic agonist carbachol. Modified growth medium provided a crypt proliferation rate, as measured by 5-ethynyl-2′-deoxyuridine labeling, which was similar to proliferation in vivo. Immunoblots demonstrated equivalent Cftr expression in comparisons of freshly isolated crypts with primary and passage 1 enteroids. Apparent enteroid differences in mRNA expression of other transporters were primarily associated with villous epithelial contamination of freshly isolated crypts. Microelectrode analysis revealed cAMP-stimulated membrane depolarization in enteroid epithelium from wild-type (WT) but not Cftr knockout (KO) mice. Morphological and microfluorimetric studies, respectively, demonstrated Cftr-dependent cell shrinkage and lower intracellular pH in WT enteroid epithelium in contrast to Cftr KO epithelium or WT epithelium treated with Cftr inhibitor 172. We conclude that crypt epithelium of murine enteroids exhibit Cftr expression and activity that recapitulates crypt epithelium in vivo. Enteroids provide a primary culture model that is suitable for physiological studies of regenerating crypt epithelium.

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Ectopic Expression of P-Cadherin Correlates with Promoter Hypomethylation Early in Colorectal Carcinogenesis and Enhanced Intestinal Crypt Fission In vivo

Cited by 62 publications

References 41 publications

P-cadherin role in normal breast development and cancer

P-cadherin role in normal breast development and cancer

Expression changes of cell-cell adhesion-related genes in colorectal tumors

Functional Cftr in crypt epithelium of organotypic enteroid cultures from murine small intestine

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