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Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-? signaling.

ABSTRACT: Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelial homoeostasis. However, the underlying mechanisms remain to be elucidated. Here we report that deletion of the gene encoding TGF? receptor 2 (Tgfbr2) in the stromal fibroblasts (Tgfbr2(fspKO)) induces inflammation and significant DNA damage in the neighboring epithelia of the forestomach. This results in loss or down-regulation of cyclin-dependent kinase inhibitors p15, p16, and p21, which contribute to the development of invasive squamous cell carcinoma (SCC). Anti-inflammation treatment restored p21 expression, delayed tumorigenesis, and increased survival of Tgfbr2(fspKO) mice. Our data demonstrate for the first time that inflammation is a critical player in the epigenetic silencing of p21 in tumor progression. Examination of human esophageal SCC showed a down-regulation of TGF? receptor 2 (T?RII) in the stromal fibroblasts, as well as increased inflammation, DNA damage, and loss or decreased p15/p16 expression. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of T?RII in the stroma.

SUBMITTER: Achyut BR

PROVIDER: S-EPMC3567148 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling.

Achyut B R BR Bader David A DA Robles Ana I AI Wangsa Darawalee D Harris Curtis C CC Ried Thomas T Yang Li L

PLoS genetics 20130207 2

Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelial homoeostasis. However, the underlying mechanisms remain to be elucidated. Here we report that deletion of the gene encoding TGFβ receptor 2 (Tgfbr2) in the stromal fibroblasts (Tgfbr2(fspKO)) induces inflammation and significant DNA damage in the neighboring epithelia of the forestomach. This results in loss or down-regulation of cyclin-dependent k ...[more]

PMID: 23408900

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Project description:Specific deletion of Tgfbr2 in FSP1+ fibroblasts (Tgfbr2fspKO) induced development of SCC in forestomach with 100% penetrance. Tgfbr2fspKO mice die by 7 weeks with a median survival of 38 days (Log rank p<0.001). Examination of Tgfbr2fspKO forestomach between embryonic day 16 (E16) and 5 weeks of age suggested that hyperplasia began during week 3 and was followed by dysplasia, carcinoma in situ, and invasive squamous cell carcinoma (SCC). The aim of this study was to elucidate genetic aberrations in the tumor associated stroma and SCC tumor using array comparative genomic hybridization (CGH) analysis. Laser capture micro-dissection was performed using formalin-fixed, paraffin-embedded, 5 week old Tgfbr2fspKO forestomach tissues. Genetic loss of cyclin-dependent kinase inhibitor, Cdkn2a/ p16Ink4A was found in laser captured epithelia of all three Tgfbr2fspKO forestomachs. Surprisingly, no genetic change was seen in the tumor associated stroma. Examination of human esophageal SCC showed a down-regulation of TGFβ receptor 2 (TβRII) in the stromal fibroblasts as well as increased inflammation and DNA damage. Published literature showed that loss of Cdkn2a/p16Ink4A tumor suppressor is the common event in human ESCCs. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of TβRII in the stroma. Laser capture microdissection of Tgfbr2flox/flox (n=3) and Tgfbr2fspKO (n=3) forestomach tissues was performed using an Arcturus XT (Life Technologies, CA, USA). Mouse background strain is C57Bl6. Frozen tissue sections on PEN membrane frame slides (Applied Biosystems) were H&E stained followed by dehydration using the standard protocol to improve visualization of the cells at the microscope. The epithelia and stroma were identified by morphology, captured using a low-power infrared laser pulse, and transferred onto a cap (Capsure™ Macro LCM Caps, Life Technologies). The DNA was extracted using a QIAamp DNA micro kit (Qiagen, CA, USA). Array-CGH was performed using test DNA from laser captured epithelia and stroma from Tgfbr2fspKO mice. Reference DNA was laser captured from the epithelia of normal forestomach of Tgfbr2flox/flox mice. DNA was labeled with Cy3 (test) or Cy5 (control) fluorescent dyes (Perkin Elmer, MA, USA) according to the BioPrime array CGH genomic labeling protocol (Invitrogen, Carlsbad, CA) and cleaned using Microcon YM-30 filters (Millipore, Billerica, MA). Hybridization was carried out using Mouse Genome CGH Microarray 4x180 K format from Agilent Technologies (Santa Clara, CA) according to CGH Procedures for Genomic DNA Analysis (Agilent Technologies). Slides were hybridized for 20 hours, washed, and scanned with an Agilent microarray scanner. Data was analyzed using Feature Extraction® and CGH Analytics® software packages (Agilent Technologies).

Dataset Information

Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-? signaling.

Publications

Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling.

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