Modulations of the epithelial phenotype during embryogenesis and cancer progression

Savagner, Pierre; Boyer, Brigitte; Vallés, Ana María; Jouanneau, Jacqueline; Thiery, Jean Paul

doi:10.1007/978-1-4615-2592-9_12

Cited by 58 publications

(53 citation statements)

References 89 publications

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“…Cytoplasmic up-regulation of vimentin in carcinoma cells, replacing the cytoskeleton network, is referred to as fibroblast-like transformation and is the classic example of EMT, for example, observed in sarcomatoid carcinomas (20). In our study, we found frequent expression of epithelial vimentin in the absence of morphologic transdifferentiation.…”

Section: Discussionsupporting

confidence: 66%

Prognostic Significance of Epithelial-Mesenchymal and Mesenchymal-Epithelial Transition Protein Expression in Non–Small Cell Lung Cancer

Soltermann¹,

Tischler²,

Arbogast³

et al. 2008

Clinical Cancer Research

241

224

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Purpose: In carcinomas, invasive tumor growth is accompanied by desmoplastic stroma reaction and facilitated by epithelial-mesenchymal transition (EMT) of cancer cells. We investigated the prognostic significance of the EMT indicator proteins periostin and vimentin in comparison with versican, a putative indicator of the opposite mechanism mesenchymal-epithelial transition (MET), and to the desmoplasia proteins collagen and elastin in non-small cell lung cancer (NSCLC). Experimental Design: Tumor of 533 patients with surgically resected NSCLC was used for analysis of stromal and epithelial protein expression by immunohistochemistry (EMT-MET proteins) and Elastica van Gieson histochemical staining (collagen and elastin). A semiquantitative sum scoring system was done on three tissue microarrays. Results: Of the 533 patients, 48% had squamous cell carcinoma, 47% adenocarcinoma, and 5% adenosquamous carcinoma. High expression of periostin in either stroma or tumor epithelia, independently scored by two pathologists, correlated with male gender, higher stage, higher pT category, and larger tumor size, and in only stroma with tumor relapse. High expression of versican in either stroma or epithelia as well as of stromal collagen had fewer but concordant associations with advanced tumor and periostin, respectively. High expression of elastin was oppositely associated with less advanced disease. Associations of high vimentin were inconsistent (all P values <0.05). High stromal periostin was found to be a prognostic factor for decreased progression-free survival on univariate analysis (P = 0.007). Conclusions: Because up-regulation is frequently observed in the stromal and epithelial tumor compartment, EMT-MET indicator proteins may be integrated in progression models of NSCLC.

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Section: Discussionsupporting

confidence: 66%

Prognostic Significance of Epithelial-Mesenchymal and Mesenchymal-Epithelial Transition Protein Expression in Non–Small Cell Lung Cancer

Soltermann¹,

Tischler²,

Arbogast³

et al. 2008

Clinical Cancer Research

241

224

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show abstract

“…Taken as a whole, our observations are not compatible with a general down-regulation of E-cadherin gene in breast carcinomas by transcription factors Snail or Slug. However, these observations do not preclude local and transient Slug or Snail overexpression at particular sites, potentially linked to E-cadherin and cytokeratin downregulation during epithelial-mesenchymal transition phases that could occur during the initiation of invasive events (1,31).…”

Section: Discussionmentioning

confidence: 85%

Snail and Slug Play Distinct Roles during Breast Carcinoma Progression

Côme¹,

Magnino²,

Bibeau³

et al. 2006

Clinical Cancer Research

Self Cite

225

170

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Purpose: Carcinoma progression is linked to a partially dedifferentiated epithelial cell phenotype.As previously suggested, this regulation could involve transcription factors, Snail and Slug, known to promote epithelial-mesenchymal transitions during development. Here, we investigate the role of Snail and Slug in human breast cancer progression. Experimental Design: We analyzed Snail, Slug, and E-cadherin RNA expression levels and protein localization in large numbers of transformed cell lines and breast carcinomas, examined the correlation with tumor histologic features, and described, at the cellular level, Snail and Slug localization in carcinomas using combined in situ hybridization and immunolocalization. Results: In contrast with transformed cell lines, Slug was found to colocalize with E-cadherin at the cellular level in normal mammary epithelial cells and all tested carcinomas. Snail also colocalized at the cellular level with E-cadherin in tumors expressing high levels of Snail RNA. In addition, Snail was significantly expressed in tumor stroma, varying with tumors. Slug and Snail genes were significantly overexpressed in tumors associated with lymph node metastasis. Finally, the presence of semidifferentiated tubules within ductal carcinomas was linked to Slug expression levels similar to or above normal breast samples. Conclusions: These results suggest that Snail or Slug expression in carcinoma cells does not generally preclude significant E-cadherin expression. They emphasize a link between Snail, Slug, and lymph node metastasis in a large sampling of mammary carcinomas, and suggest a role for Slug in the maintenance of semidifferentiated structures. Snail and Slug proteins seem to support distinct tumor invasion modes and could provide new therapeutic targets.

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“…EMTs occur during various developmental processes, including gastrulation and neural crest formation. During an EMT, epithelial cells lose cellcell contacts and cell polarity, acquire mesenchymal gene expression, and undergo major changes in their cytoskeleton that enables them to acquire a mesenchymal appearance with increased motility and invasiveness (2)(3)(4)(5).…”

Section: Epithelial-mesenchymal Transition ͉ Embryogenesis ͉ Twist Anmentioning

confidence: 99%

Mesenchyme Forkhead 1 ( FOXC2 ) plays a key role in metastasis and is associated with aggressive basal-like breast cancers

Mani

Yang

Brooks

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

527

489

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The metastatic spread of epithelial cancer cells from the primary tumor to distant organs mimics the cell migrations that occur during embryogenesis. Using gene expression profiling, we have found that the FOXC2 transcription factor, which is involved in specifying mesenchymal cell fate during embryogenesis, is associated with the metastatic capabilities of cancer cells. FOXC2 expression is required for the ability of murine mammary carcinoma cells to metastasize to the lung, and overexpression of FOXC2 enhances the metastatic ability of mouse mammary carcinoma cells. We show that FOXC2 expression is induced in cells undergoing epithelial-mesenchymal transitions (EMTs) triggered by a number of signals, including TGF-␤1 and several EMT-inducing transcription factors, such as Snail, Twist, and Goosecoid. FOXC2 specifically promotes mesenchymal differentiation during an EMT and may serve as a key mediator to orchestrate the mesenchymal component of the EMT program. Expression of FOXC2 is significantly correlated with the highly aggressive basal-like subtype of human breast cancers. These observations indicate that FOXC2 plays a central role in promoting invasion and metastasis and that it may prove to be a highly specific molecular marker for human basal-like breast cancers.epithelial-mesenchymal transition ͉ embryogenesis ͉ Twist and Snail

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Modulations of the epithelial phenotype during embryogenesis and cancer progression

Cited by 58 publications

References 89 publications

Prognostic Significance of Epithelial-Mesenchymal and Mesenchymal-Epithelial Transition Protein Expression in Non–Small Cell Lung Cancer

Prognostic Significance of Epithelial-Mesenchymal and Mesenchymal-Epithelial Transition Protein Expression in Non–Small Cell Lung Cancer

Snail and Slug Play Distinct Roles during Breast Carcinoma Progression

Mesenchyme Forkhead 1 ( FOXC2 ) plays a key role in metastasis and is associated with aggressive basal-like breast cancers

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