Molecular aspects of esophageal squamous cell carcinoma carcinogenesis

Lehrbach, Dárcio Matenhauer; Nita, Marcelo Eidi; Cecconello, Ivan

doi:10.1590/s0004-28032003000400011

Cited by 55 publications

(29 citation statements)

References 39 publications

(40 reference statements)

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“…The development of ESCC is a progressive multistep process, starting with increases in esophageal epithelial cell proliferation, leading to basal cell hyperplasia, dysplasia, carcinoma in situ, and finally advanced carcinoma (Lehrbach et al 2003). At the late stages of disease, tumor invasion plays a key role in influencing patient survival (Nair et al 2005).…”

Section: D Culture Model Of Esophageal Cancer Genes and Development 2797mentioning

confidence: 99%

The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation

Okawa¹,

Michaylira²,

Kalabis³

et al. 2007

Genes Dev.

157

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Esophageal cancer is a prototypic squamous cell cancer that carries a poor prognosis, primarily due to presentation at advanced stages. We used human esophageal epithelial cells as a platform to recapitulate esophageal squamous cell cancer, thereby providing insights into the molecular pathogenesis of squamous cell cancers in general. This was achieved through the retroviral-mediated transduction into normal, primary human esophageal epithelial cells of epidermal growth factor receptor (EGFR), the catalytic subunit of human telomerase (hTERT), and p53 R175H, genes that are frequently altered in human esophageal squamous cell cancer. These cells demonstrated increased migration and invasion when compared with control cells. When these genetically altered cells were placed within the in vivo-like context of an organotypic three-dimensional (3D) culture system, the cells formed a high-grade dysplastic epithelium with malignant cells invading into the stromal extracellular matrix (ECM). The invasive phenotype was in part modulated by the activation of matrix metalloproteinase-9 (MMP-9). Using pharmacological and genetic approaches to decrease MMP-9, invasion into the underlying ECM could be suppressed partially. In addition, tumor differentiation was influenced by the type of fibroblasts within the stromal ECM. To that end, fetal esophageal fibroblasts fostered a microenvironment conducive to poorly differentiated invading tumor cells, whereas fetal skin fibroblasts supported a well-differentiated tumor as illustrated by keratin "pearl" formation, a hallmark feature of well-differentiated squamous cell cancers. When inducible AKT was introduced into fetal skin esophageal fibroblasts, a more invasive, less-differentiated esophageal cancer phenotype was achieved. Invasion into the stromal ECM was attenuated by genetic knockdown of AKT1 as well as AKT2. Taken together, alterations in key oncogenes and tumor suppressor genes in esophageal epithelial cells, the composition and activation of fibroblasts, and the components of the ECM conspire to regulate the physical and biological properties of the stroma.[Keywords: Cell migration and invasion; tumor microenvironment; EGFR; p53; MMP-9; AKT] Supplemental material is available at http://www.genesdev.org. Received February 22, 2007; revised version accepted September 5, 2007. 8 These authors contributed equally to this work. 9Corresponding author. E-MAIL anil2@mail.med.upenn.edu; FAX (215) 573-5412. Article is online at http://www.genesdev.org/cgi

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Section: D Culture Model Of Esophageal Cancer Genes and Development 2797mentioning

confidence: 99%

The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation

Okawa¹,

Michaylira²,

Kalabis³

et al. 2007

Genes Dev.

157

View full text Add to dashboard Cite

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“…Most deaths from this disease are due to metastasis that is resistant to conventional therapies (Stoner and Gupta, 2001; Lehrbach et al, 2003). Great efforts have been taken to decipher this metastatic process.…”

Section: Introductionmentioning

confidence: 99%

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

et al. 2008

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xCT, the functional subunit of the cystine/glutamate transporter xc-system, plays a critical role in the maintenance of intracellular glutathione and redox balance. Disruption of xCT significantly inhibits the growth of a variety of carcinomas, including lymphoma, glioma, prostate and breast cancer. However, the role of xCT in tumor metastasis remains largely unknown. In this study, both xCT þ / þ and xCT À/À melanocytes were used to evaluate the role of xCT in adhesion. xCT activity was suppressed by an inhibitor, sulfasalazine (SASP), or by xCT siRNA in an esophageal cancer cell line, KYSE150. We found that disruption of xCT enhanced homotypic cell-cell adhesion and attenuated cell-extracellular matrix adhesion. SASP significantly inhibited both cell invasion of KYSE150 in vitro and its experimental metastasis in nude mice. Caveolin-1 was upregulated and b-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of b-catenin transcriptional activity. Further study revealed that the upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species-induced p38 MAPK activation. These results first establish the role of xCT in tumor metastasis and implicate a potential target for cancer therapy.

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“…The p53 tumor suppressor gene has an open reading frame of 393 amino acids in length, and is located at the short arm of human chromosome 17 (14). Normal p53 functions in cell cycle regulation, in the maintenance of genomic stability and in controlled cell death (apoptosis).…”

Section: Discussionmentioning

confidence: 99%

Genetic pathways of multiple esophageal squamous cell carcinomas

Kuwabara

Hiyama

Tanaka³

et al. 2011

Oncol Rep

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Abstract.Whether multiple esophageal squamous cell carcinomas (SCCs) in a patient develop through an identical genetic pathway is still unclear. We examined multiple esophageal SCCs for alterations of p53, p16, IRF and mitochondrial DNA (mtDNA) and microsatellite instability (MSI). Thirty patients with multiple superficial esophageal SCCs, 23 with double lesions and 7 with triple lesions, were enrolled. Loss of heterozygosity (LOH) of p53 (TP53), p16 (D9S171), IRF (IRF) and other microsatellite loci including D1S191, D17S858, D18S58 and D18S61 of the tumors was examined by microsatellite assay. Mutations of p16 and mtDNA were examined with PCR single-strand conformation polymorphism (SSCP) analysis. LOH of p53, p16 and IRF were detected in 16 of 50 (32%), 5 of 38 (13%) and 5 of 48 (10%) tumors, respectively. Mutations of p16 were detected in 4 of 67 (6%) tumors. Six of 67 (9%) tumors had mtDNA alterations and none of the tumors showed high-frequency MSI. All 30 patients showed one or more gene alterations in one or more genetic loci. Discordant genetic patterns among individual lesions within a patient were observed in 28 of the 30 (93%) patients. The most discordant locus was TP53, present in 11 of 29 (38%) informative cases, followed by D18S61, present in 11 of 30 (37%) informative cases. These results suggest that the genetic pathways of multiple esophageal SCCs may differ even within the same patient.

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Molecular aspects of esophageal squamous cell carcinoma carcinogenesis

Cited by 55 publications

References 39 publications

The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation

The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

Genetic pathways of multiple esophageal squamous cell carcinomas

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