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In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a preinvasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal fluorescence lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to detect and grade murine PanIN lesions in real time in vivo. Our diagnostic approach is highly sensitive and specific and proved superior to clinically established fluorescein-enhanced imaging. Translation of this endoscopic technique into the clinic should tremendously improve detection of pancreatic neoplasia, thus reforming management of patients at risk for PDAC.

SUBMITTER: Eser S

PROVIDER: S-EPMC3116402 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging.

Eser Stefan S Messer Marlena M Eser Philipp P von Werder Alexander A Seidler Barbara B Bajbouj Monther M Vogelmann Roger R Meining Alexander A von Burstin Johannes J Algül Hana H Pagel Philipp P Schnieke Angelika E AE Esposito Irene I Schmid Roland M RM Schneider Günter G Saur Dieter D

Proceedings of the National Academy of Sciences of the United States of America 20110531 24

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a preinvasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal fluorescence lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to ...[more]

PMID: 21628592

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Project description:AimTo investigate the differentiated whole genome expression profiling of gastric high- and low-grade intraepithelial neoplasia and early-stage adenocarcinoma.MethodsGastric specimens from an upper magnifying chromoendoscopic targeted biopsy were collected from March 2010 to May 2013. Whole genome expression profiling was performed on 19 low-grade intraepithelial neoplasia (LGIN), 20 high-grade intraepithelial neoplasia (HGIN), 19 early-stage adenocarcinoma (EGC), and 19 chronic gastritis tissue samples using Agilent 4 × 44K Whole Human Genome microarrays. Differentially expressed genes between different types of lesions were identified using an unpaired t-test and corrected with the Benjamini and Hochberg false discovery rate algorithm. A gene ontology (GO) enrichment analysis was performed using the GeneSpring software GX 12.6. The differentially expressed gene was verified using a real-time TaqMan® PCR assay with independent tissue samples, including 26 LGIN, 15 HGIN, 14 EGC, and 20 chronic gastritis. The expression of G0S2 were further validated by immunohistochemical staining (IHC) in 24 LGIN, 40 HGIN, 30 EGC and 61 chronic gastritis specimens.ResultsThe gene expression patterns of LGIN and HGIN tissues were distinct. There were 2521 significantly differentially expressed transcripts in HGIN, with 951 upregulated and 1570 downregulated. A GO enrichment analysis demonstrated that the most striking overexpressed transcripts in HGIN compared with LGIN were in the category of metabolism, defense response, and nuclear factor κB (NF-κB) cascade. While the vast majority of transcripts had barely altered expression in HGIN and EGC tissues, only 38 transcripts were upregulated in EGC. A GO enrichment analysis revealed that the alterations of the immune response were most prominent in the progression from HGIN to EGC. It is worth noting that, compared with LGIN, 289 transcripts were expressed at higher levels both in HGIN and EGC. A characteristic gene, G0/G1 switch 2 (G0S2) was one of the 289 transcripts and related to metabolism, the immune response, and the NF-κB cascade, and its expression was validated in independent samples through real-time TaqMan® PCR and immunohistochemical staining. In real-time PCR analysis, the expression of G0S2 was elevated both in HGIN and EGC compared with that in LGIN (P < 0.01 and P < 0.001, respectively). In IHC analysis, G0S2 immunoreactivity was detected in the cytoplasmic of neoplastic cells, but was undetectable in chronic gastritis cells. The G0S2 expression in HGIN was higher than that of LGIN (P = 0.012, χ (2) = 6.28) and EGC (P = 0.008, χ (2) = 6.94).ConclusionA clear biological distinction between gastric high- and low-grade intraepithelial neoplasia was identified, and provides molecular evidence for clinical application.

Project description:Background and aimsDevelopment of pancreatic ductal adenocarcinoma (PDAC) is a multistep process intensively studied; however, precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially, as both cancer-promoting and cancer-antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary. Here, we focused on RBPJ, the receiving transcription factor in the Notch pathway, examined its expression pattern in PDAC, and characterized its function in mouse models of pancreatic cancer development and in the regeneration process after acute pancreatitis.MethodsConditional transgenic mouse models were used for functional analysis of RBPJ in the adult pancreas, initiation of PDAC precursor lesions, and pancreatic regeneration. Pancreata and primary acinar cells were tested for acinar-to-ductal metaplasia together with immunohistology and comprehensive transcriptional profiling by RNA sequencing.ResultsWe identified reduced RBPJ expression in a subset of human PDAC specimens. Ptf1α-CreERT-driven depletion of RBPJ in transgenic mice revealed that its function is dispensable for the homeostasis and maintenance of adult acinar cells. However, primary RBPJ-deficient acinar cells underwent acinar-to-ductal differentiation in ex vivo. Importantly, oncogenic KRAS expression in the context of RBPJ deficiency facilitated the development of pancreatic intraepithelial neoplasia lesions with massive fibrotic stroma formation. Interestingly, RNA-sequencing data revealed a transcriptional profile associated with the cytokine/chemokine and extracellular matrix changes. In addition, lack of RBPJ delays the course of acute pancreatitis and critically impairs it in the context of KRASG12D expression.ConclusionsOur findings imply that downregulation of RBPJ in PDAC patients derepresses Notch targets and promotes KRAS-mediated pancreatic acinar cells transformation and desmoplasia development.

Dataset Information

In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging.

Publications

In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging.

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