Dataset Information

Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

ABSTRACT:

Aims

Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC).

Methods and results

We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment-naïve high-grade columnar dysplasia (HGD) or EAC, and 23 non-EAC oesophagectomy cases. A gastrointestinal pathologist assessed haematoxylin and eosin-stained ESMG images by using a scoring system that assigns individual ESMG acini to five histological types (mucous, serous, oncocytic, dilated, or ductal metaplastic). In our model, ductal metaplastic acini were more common in patients with HGD/EAC (12.7%) than in controls (3.5%) (P = 0.006). We also identified greater proportions of acini with dilation (21.9%, P < 0.001) and, to a lesser extent, ductal metaplasia (4.3%, P = 0.001) in non-EAC oesophagectomy cases than in controls. Ductal metaplasia tended to occur in areas of mucosal ulceration or tumour.

Conclusions

We found a clear association between ductal metaplastic ESMG acini and HGD/EAC. Non-EAC cases had dilated acini and some ductal dilation. Because ESMGs and ducts harbour putative progenitor cells, these associations could have significance for understanding the pathogenesis of EAC.

SUBMITTER: Garman KS

PROVIDER: S-EPMC4592376 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

Garman Katherine S KS Kruger Leandi L Thomas Samantha S Swiderska-Syn Marzena M Moser Barry K BK Diehl Anna Mae AM McCall Shannon J SJ

Histopathology 20150604 6

<h4>Aims</h4>Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC).<h4>Methods and results</h4>We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment-naïve high-grade columnar dysplasia (HGD) or EA ...[more]

PMID: 25847432

Similar Datasets

Project description:Background & aimsActivating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs.MethodsWe performed studies in adult mice with conditional disruption of Klf5 (Klf5fl/fl) and/or expression of KrasG12D (LSL-KrasG12D) via CreERTM recombinase regulated by an acinar cell-specific promoter (Ptf1a). Activation of KrasG12D and loss of KLF5 was achieved by administration of tamoxifen. Pancreatitis was induced in mice by administration of cerulein; pancreatic tissues were collected, analyzed by histology and immunohistochemistry, and transcriptomes were compared between mice that did or did not express KLF5. We performed immunohistochemical analyses of human tissue microarrays, comparing levels of KLF5 among 96 human samples of PDAC. UN-KC-6141 cells (pancreatic cancer cells derived from Pdx1-Cre;LSL-KrasG12D mice) were incubated with inhibitors of different kinases and analyzed in proliferation assays and by immunoblots. Expression of KLF5 was knocked down with small hairpin RNAs or CRISPR/Cas9 strategies; cells were analyzed in proliferation and gene expression assays, and compared with cells expressing control vectors. Cells were subcutaneously injected into flanks of syngeneic mice and tumor growth was assessed.ResultsOf the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-CreERTM;LSL-KrasG12D mice contained ADM and PanIN lesions, which contained high levels of nuclear KLF5 within these structures. In contrast, Ptf1a-CreERTM;LSL-KrasG12D;Klf5fl/fl mice formed fewer PanINs. After cerulein administration, Ptf1a-CreERTM;LSL-KrasG12D mice formed more extensive ADM than Ptf1a-CreERTM;LSL-KrasG12D;Klf5fl/fl mice. Pancreata from Ptf1a-CreERTM;LSL-KrasG12D;Klf5fl/fl mice had increased expression of the tumor suppressor NDRG2 and reduced phosphorylation (activation) of STAT3, compared with Ptf1a-CreERTM;LSL-KrasG12D mice. In UN-KC-6141 cells, PI3K and MEK signaling increased expression of KLF5; a high level of KLF5 increased proliferation. Cells with knockdown of Klf5 had reduced proliferation, compared with control cells, had reduced expression of ductal markers, and formed smaller tumors (71.61 ± 30.79 mm3 vs 121.44 ± 34.90 mm3 from control cells) in flanks of mice.ConclusionLevels of KLF5 are increased in human PDAC samples and in PanINs of Ptf1a-CreERTM;LSL-KrasG12D mice, compared with controls. KLF5 disruption increases expression of NDRG2 and reduces activation of STAT3 and reduces ADM and PanINs formation in mice. Strategies to reduce KLF5 activity might reduce progression of acinar cells from ADM to PanIN and pancreatic tumorigenesis.

Dataset Information

Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

Aims

Methods and results

Conclusions

Publications

Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets