L1CAM promotes epithelial to mesenchymal transition and formation of cancer initiating cells in human endometrial cancer

Chen, Jinlong; Gao, Fufeng; Liu, Naifu

doi:10.3892/etm.2018.5747

Cited by 32 publications

(32 citation statements)

References 48 publications

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“…It is intriguing to speculate that Fbxw7 -mutant endometrioid adenocarcinomas (were they left in the body) might have a propensity to progress into UCS, perhaps through the acquisition of Tp53 mutations. This is further suggested by the fact that UCSs are more likely to harbor p53 mutations, and our finding that Fbxw7 -mutant endometrioid adenocarcinomas are more likely to express L1CAM, a marker of EMT (59) frequently overexpressed in UCS (58). However, further investigations will be required to better define the natural history, precursors, and histologic intermediates for UCS.…”

Section: Discussionmentioning

confidence: 52%

“…We studied 28 cases harboring canonical Fbxw7 mutations (WD40 hotspot or definite null mutations) and 20 cases without Fbxw7 single nucleotide variants leading to amino acid alterations ( SI Appendix , Table S3). All cases were subjected to IHC for L1CAM, a well-established marker for EMT in human ECs (58, 59). Notably, only Fbxw7-mutant tumors expressed L1CAM, and all of these were also p53-positive by IHC, although not all p53-positive cases harbored Fbxw7 mutations ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 99%

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Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

Cuevas

Sahoo

Kumar

et al. 2019

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

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Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such asTp53andPten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressorFbxw7in endometrial cancer through defined genetic model systems. Inactivation ofFbxw7andPtenresulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquiredTrp53mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial–mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.

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Section: Discussionmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

Cuevas

Sahoo

Kumar

et al. 2019

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

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“…The authors suggest that ALK-related cascades could participate in divergent sarcomatous differentiation through the induction of EMT and inhibition of apoptosis [87]. In contrast, although the expression of L1CAM is a strong predictor of poor outcome in endometrial cancer and overexpression of L1CAM has been related to EMT in endometrial cancer cell lines [88], in clinical samples of ECS, only the epithelial component was positive in 65% of the cases, while no expression was seen in the mesenchymal part. Thus in ECS, L1CAM is not a marker for the mesenchymal phenotype [89].…”

Section: Epithelial-to-mesenchymal Transitionmentioning

confidence: 99%

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma

Leskelä

Pérez-Míes

Rosa-Rosa

et al. 2019

Cancers

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Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) components that can include heterologous tissues, such as skeletal muscle, cartilage, or bone. Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the TP53 mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as CCNE1 and c-MYC. However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as PTEN, PI3KCA, or ARID1A), after the acquisition of the TP53 mutations. Only a few ECS belong to the microsatellite-unstable hypermutated molecular type and the POLE-mutated, ultramutated molecular type. A common characteristic of all ECSs is the modulation of genes involved in the epithelial to mesenchymal process. Thus, the acquisition of a mesenchymal phenotype is associated with a switch from E- to N-cadherin, the up-regulation of transcriptional repressors of E-cadherin, such as Snail Family Transcriptional Repressor 1 and 2 (SNAI1 and SNAI2), Zinc Finger E-Box Binding Homeobox 1 and 2 (ZEB1 and ZEB2), and the down-regulation, among others, of members of the miR-200 family involved in the maintenance of an epithelial phenotype. Subsequent differentiation to different types of mesenchymal tissues increases tumor heterogeneity and probably modulates clinical behavior and therapy response.

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“…In summary, a lot of miRNAs, cellular and circulating, have been found dysregulated in endometrial cancer and a comprehensive list and the relative references are reported in Table 2 [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ].…”

Section: Ncrnas and Endometrial Cancermentioning

confidence: 99%

Non-Coding RNAs in Endometrial Physiopathology

Ferlita

Battaglia

Andronico

et al. 2018

IJMS

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The Human Genome Project led to the discovery that about 80% of our DNA is transcribed in RNA molecules. Only 2% of the human genome is translated into proteins, the rest mostly produces molecules called non-coding RNAs, which are a heterogeneous class of RNAs involved in different steps of gene regulation. They have been classified, according to their length, into small non-coding RNAs and long non-coding RNAs, or to their function, into housekeeping non-coding RNAs and regulatory non-coding RNAs. Their involvement has been widely demonstrated in all cellular processes, as well as their dysregulation in human pathologies. In this review, we discuss the function of non-coding RNAs in endometrial physiology, analysing their involvement in embryo implantation. Moreover, we explore their role in endometrial pathologies such as endometrial cancer, endometriosis and chronic endometritis.

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L1CAM promotes epithelial to mesenchymal transition and formation of cancer initiating cells in human endometrial cancer

Cited by 32 publications

References 48 publications

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma

Non-Coding RNAs in Endometrial Physiopathology

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