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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

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...

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Published in:Genes & development 2007-11, Vol.21 (21), p.2788-2803
Main Authors: Okawa, Takaomi, Michaylira, Carmen Z, Kalabis, Jiri, Stairs, Douglas B, Nakagawa, Hiroshi, Andl, Claudia D, Johnstone, Cameron N, Klein-Szanto, Andres J, El-Deiry, Wafik S, Cukierman, Edna, Herlyn, Meenhard, Rustgi, Anil K
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cited_by cdi_FETCH-LOGICAL-c410t-4af8d6886ab04a8a5145c5fa84d34989227e7f1fc77140437ee2ae7e38c8b663
cites cdi_FETCH-LOGICAL-c410t-4af8d6886ab04a8a5145c5fa84d34989227e7f1fc77140437ee2ae7e38c8b663
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creator Okawa, Takaomi
Michaylira, Carmen Z
Kalabis, Jiri
Stairs, Douglas B
Nakagawa, Hiroshi
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El-Deiry, Wafik S
Cukierman, Edna
Herlyn, Meenhard
Rustgi, Anil K
description 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.
doi_str_mv 10.1101/gad.1544507
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subjects Animals
Cell Transformation, Neoplastic - genetics
Epithelial Cells - metabolism
Epithelial Cells - pathology
Esophageal Neoplasms - genetics
Esophageal Neoplasms - pathology
Esophagus - metabolism
Esophagus - pathology
Female
Gene Expression Regulation, Neoplastic
Genes, erbB-1 - physiology
Genes, p53 - physiology
Humans
Mice
Mice, Nude
Mutation - physiology
Neoplasm Invasiveness
Neoplasms, Squamous Cell - genetics
Neoplasms, Squamous Cell - pathology
Research Paper
Stromal Cells - pathology
Telomerase - metabolism
Tumor Cells, Cultured
title 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
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