Pathology of genetically engineered mouse models of pancreatic exocrine cancer: Consensus report and recommendations

Louisiana State University in Shreveport, Shreveport, Louisiana, United States
Cancer Research (Impact Factor: 9.33). 02/2006; 66(1):95-106. DOI: 10.1158/0008-5472.CAN-05-2168
Source: PubMed


Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held from December 1 to 3, 2004 with the goal of establishing an internationally accepted uniform nomenclature for the pathology of genetically engineered mouse models of pancreatic exocrine neoplasia. The pancreatic pathology in 12 existing mouse models of pancreatic neoplasia was reviewed at this workshop, and a standardized nomenclature with definitions and associated images was developed. It is our intention that this nomenclature will standardize the reporting of genetically engineered mouse models of pancreatic exocrine neoplasia, that it will facilitate comparisons between genetically engineered mouse models and human pancreatic disease, and that it will be broad enough to accommodate newly emerging mouse models of pancreatic neoplasia.

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    • "Amylase-positive area/pancreas area was measured manually with ImageJ using the freehand selection tool. PanINs were defined according to previously published guidelines for reporting of these lesions in genetically engineered mouse models.6 Briefly, to be defined as PanIN, a lesion must arise in native pancreatic ducts measuring <1 mm and should not arise on a background of acinar-ductal metaplasia. "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is often lethal because it is highly invasive and metastasizes rapidly. The actin-bundling protein fascin has been identified as a biomarker of invasive and advanced PDAC and regulates cell migration and invasion in vitro. We investigated fascin expression and its role in PDAC progression in mice. We used KRas(G12D) p53(R172H) Pdx1-Cre (KPC) mice to investigate the effects of fascin deficiency (FKPC mice) on development of pancreatic intraepithelial neoplasia (PanIn), PDAC, and metastasis. We measured levels of fascin in PDAC cell lines and 122 human resected PDAC samples, along with normal ductal and acinar tissues; we associated levels with patient outcomes. Pancreatic ducts and acini from control mice, and early-stage PanINs from KPC mice, were negative for fascin, but approximately 6% of PanIN3 and 100% of PDAC expressed fascin. FKPC mice had longer survival times, delayed onset of PDAC, and a lower PDAC tumor burdens than KPC mice; loss of fascin did not affect invasion of PDAC into bowel or peritoneum in mice. Levels of slug and fascin correlated in PDAC cells; slug was found to regulate transcription of Fascin along with the epithelial-mesenchymal transition. In PDAC cell lines and cells from mice, fascin concentrated in filopodia, and was required for their assembly and turnover. Fascin promoted intercalation of filopodia into mesothelial cell layers and cell invasion. Nearly all human PDAC samples expressed fascin, and higher fascin histoscores correlated with poor outcome, vascular invasion, and time to recurrence. The actin-bundling protein fascin is regulated by slug and involved in late-stage PanIN and PDAC formation in mice. Fascin appears to promote formation of filopodia and invasive activities of PDAC cells. Its levels in human PDAC correlate with outcome and time to recurrence, indicating it might be a marker or therapeutic target for pancreatic cancer.
    Gastroenterology 01/2014; 146(5). DOI:10.1053/j.gastro.2014.01.046 · 16.72 Impact Factor
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    • "This mice model is used to study tumor development and tumor angiogenesis. Even pancreatic tumor pathology of those model mice was standardized nomenclature with definitions 6, 7. Generally the Rip1-Tag2 mice is not regard as metastasis animal model, however, we unexpectedly observed the micrometastasis in Rip1-Tag2 mice in tumor advanced stage that is not reported before. It is of great significance for studying the process of metastasis of cancer cell or the characteristics of metastasis cell. "
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    ABSTRACT: Rip1-Tag2 mice is one overt pancreatic β-cell tumor model, which is widely used for studying pancreas tumor angiogenesis and tumor development. However, tumor metastasis in Rip1-Tag2 mice had rarely been reported, in this present study, we find some micrometastasis in lung and spleen of the Rip1-Tag2 mice at advanced stage, which is important for uncovering metastasis cell characteristics and exploring how to survive in cancer microenvironment. To study the micrometastasis of Rip1-Tag2 mice in advanced pancreatic cancer, we first observed the pathology process of β cell tumor in Rip1-Tag2 mice through HE staining, then we performed immunohistochemistry with insulin antibody, T-antigen antibodies and C-petide antibody on lung and spleen tissues sections from advanced stage, comparing with background wild-type C57BL/6 mice sections. The results indicated that micrometastasis expressing insulin was found in the Rip1-Tag2 mice lung, and spleen. Further evidences demonstrate pathology structure of lung and spleen are damaged. Interestingly and importantly, the expression of T antigen and insulin antibodies are all decreased in advanced stage of primary β cell tumor, which suggest that the at least partly micrometastasis is derived from the early stage or from advanced stage of β cell tumor then return to undifferentiated state like cancer stem cell. The findings contributed to the study of cancer metastasis and cancer stem cell.
    International journal of biological sciences 01/2014; 10(2):136-41. DOI:10.7150/ijbs.7515 · 4.51 Impact Factor
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    • "The development of genetically engineered mouse models with pancreatic cancer [9] [10], specifically the progress in PanIN and PDAC mouse models [11] [12] [13], has significantly contributed to our understanding of the genetics of pancreatic neoplasia [14] [15]. Previous studies have isolated cell lines from the pancreas of genetically engineered mutant mice with PanIN and PDAC [11] [12]. "
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    ABSTRACT: Pancreatic intraepithelial neoplasia (PanIN) is the most common premalignant lesion of the pancreas. Further understanding of the biological behavior and molecular genetic alterations in the stepwise progression of PanINs is necessary toward the development of pancreatic ductal adenocarcinoma (PDAC) interventions. In this study, we analyzed the morphological characteristics, molecular alterations, and biological behavior of pancreatic wild-type and neoplasia tissues, including analysis of PanIN cell line SH-PAN (isolated from Pdx-1-Cre; LSL-Kras(G12D/+) mouse) and PDAC cell line DT-PCa (isolated from Pdx1-Cre; LSL-Kras(G12D/+); LSL-Tp53(R172H/+) mouse). Results show that Kras(G12D) induces ductal lesion PanINs. Increased expression of EGFR, Her-s/Neu, p-MAPK and β-Catenin was observed in low-grade PanINs. Tp53 was not expressed in wild-type and low-grade PanINs, however, increased expression was observed in high-grade PanINs. Furthermore, SH-PAN cells did not exhibit any colony formation and showed significantly lower migration and invasion ability compared with DT-PCa cells. Notably, we first found PPP2R2A (protein phosphatase 2, regulatory subunit B, alpha) expression was significantly higher in SH-PAN cells than DT-PCa cells, and was high in 96 of 172 peritumoral normal human pancreatic tissues and 20 of 36 human low- or middle-grade PanIN tissues, whereas, was weak or negligible in 12 of 20 human high-grade PanIN tissues and 124 of 172 human PDAC tissues post-operation. The expression of PPP2R2A appears to be correlated with clinical survival. Taken together, Kras(G12D)-driven PanIN showed the tumorigenic ability, however, did not undergo a malignant transformation, and decreased expression of PPP2R2A in PDACs may provided a new target for pancreatic carcinoma intervention.
    Cancer letters 07/2013; 339(1). DOI:10.1016/j.canlet.2013.07.010 · 5.62 Impact Factor
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