scholarly journals Telomeres are shortened in acinar-to-ductal metaplasia lesions associated with pancreatic intraepithelial neoplasia but not in isolated acinar-to-ductal metaplasias

2010 ◽  
Vol 24 (2) ◽  
pp. 256-266 ◽  
Author(s):  
Seung-Mo Hong ◽  
Christopher M Heaphy ◽  
Chanjuan Shi ◽  
Soo-Heang Eo ◽  
HyungJun Cho ◽  
...  
Keyword(s):  
Intraepithelial Neoplasia ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Acinar To Ductal Metaplasia

scholarly journals Acinar transformed ductal cells exhibit differential mucin expression in a tamoxifen-induced pancreatic ductal adenocarcinoma mouse model

Biology Open ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. bio052878
Author(s):  
Kavita Mallya ◽  
Dhanya Haridas ◽  
Parthasarathy Seshacharyulu ◽  
Ramesh Pothuraju ◽  
Wade M. Junker ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Ductal Cells ◽  
Mucin Expression ◽  
Acinar To Ductal Metaplasia

ABSTRACTPancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible KrasG12D; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of KrasG12D in multiple PC cell lines resulted in downregulation of MUC1, MUC4, MUC5AC and MUC16. In addition, iKC mice exhibited ADM and transdifferentiation. Our results show that the iKC mouse more closely mimics human PC development and can be used to investigate pancreatic ductal adenocarcinoma (PDAC) biomarkers, early onset of PDAC, and ADM. The iKC model can also be used for preclinical strategies such as targeting mucin axis alone or in combination with neo-adjuvant, immunotherapeutic approaches and to monitor chemotherapy response.

scholarly journals The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Nathan M Krah ◽  
Jean-Paul De La O ◽  
Galvin H Swift ◽  
Chinh Q Hoang ◽  
Spencer G Willet ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Acinar Cells ◽  
Intraepithelial Neoplasia ◽  
Therapeutic Strategies ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Acinar To Ductal Metaplasia ◽  
Deadly Disease ◽  
Surprising Finding ◽  
Suppressive Mechanism

Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

scholarly journals Macrophages-induced IL-18–mediated eosinophilia promotes characteristics of pancreatic malignancy

2021 ◽  
Vol 4 (8) ◽  
pp. e202000979
Author(s):  
Hemanth Kumar Kandikattu ◽  
Murli Manohar ◽  
Alok Kumar Verma ◽  
Sandeep Kumar ◽  
Chandra Sekhar Yadavalli ◽  
...  
Keyword(s):  
Murine Model ◽  
Intraepithelial Neoplasia ◽  
Eosinophilic Inflammation ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Mucinous Neoplasm ◽  
Mechanistic Pathway ◽  
Ductal Cell ◽  
Pancreatic Malignancy ◽  
Acinar To Ductal Metaplasia

Reports indicate that accumulated macrophages in the pancreas are responsible for promoting the pathogenesis of chronic pancreatitis (CP). Recently, macrophage-secreted cytokines have been implicated in promoting pancreatic acinar-to-ductal metaplasia (ADM). This study aims to establish the role of accumulated macrophage-activated NLRP3-IL-18-eosinophil mechanistic pathway in promoting several characteristics of pancreatic malignancy in CP. We report that in a murine model of pancreatic cancer (PC), accumulated macrophages are the source of NLRP3-regulated IL-18, which promotes eosinophilic inflammation-mediated accumulation to periductal mucin and collagen, including the formation of ADM, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasm. Most importantly, we show improved malignant characteristics with reduced levels of oncogenes in an anti–IL-18 neutralized and IL-18 gene deficient murine model of CP. Last, human biopsies validated that NLRP3-IL-18–induced eosinophils accumulate near the ducts, showing PanINs formation in PC. Taken together, we present the evidence on the role of IL-18–induced eosinophilia in the development of PC phenotype like ADM, PanINs, and ductal cell differentiation in inflammation-induced CP.

Intestinal Heterotopic Pancreas Involved by Simultaneous PanIN-2 Lesion and Endocrine Microadenoma: a Unique Case

2017 ◽  
Vol 26 (2) ◽  
pp. 199-202
Author(s):  
Remus Cornea ◽  
Sorina Taban ◽  
Cristian Suciu ◽  
Codruta Lazureanu ◽  
Alis Dema
Keyword(s):  
Histopathological Examination ◽  
Intraepithelial Neoplasia ◽  
Heterotopic Pancreas ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Unique Case ◽  
Intraductal Papillary Mucinous Neoplasms ◽  
Pancreatic Endocrine Neoplasm ◽  
First Case ◽  
Mucinous Neoplasms

We hereby present the case of a 58-year-old male who underwent a total gastrectomy for gastric neoplasm. During the surgery, a tumor mass in the jejunum was identified, considered as metastasis, and resected. The histopathological examination of the jejunal lesion showed ectopic pancreas. In this area, two pathological distinct lesions were identified, one histologically compatible with pancreatic intraepithelial neoplasia (PanIN) type 2 lesion and the other with morphologic criteria for endocrine microadenoma. To our knowledge, this is the first case that evidences the presence of a concomitant premalignant exocrine lesion and benign endocrine lesion in a heterotopic pancreas (HP).Abbreviations: HP: heterotopic pancreas; IPMN: Intraductal Papillary Mucinous Neoplasms; PanIN: Pancreatic Intraepithelial Neoplasia; PEN: pancreatic endocrine neoplasm.

BRCA2 Dysfunction Promotes Malignant Transformation of Pancreatic Intraepithelial Neoplasia

2013 ◽  
Vol 13 (2) ◽  
pp. 261-269 ◽  
Author(s):  
Qi Wang ◽  
Hongrui Liu ◽  
Tingting liu ◽  
Shizhen Shu ◽  
He Jiang ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Intraepithelial Neoplasia ◽  
Pancreatic Intraepithelial Neoplasia

Pancreatic Intraepithelial Neoplasia

2001 ◽  
Vol 25 (5) ◽  
pp. 579-586 ◽  
Author(s):  
Ralph H. Hruban ◽  
N. Volkan Adsay ◽  
Jorge Albores–Saavedra ◽  
Carolyn Compton ◽  
Elizabeth S. Garrett ◽  
...  
Keyword(s):  
Intraepithelial Neoplasia ◽  
Pancreatic Intraepithelial Neoplasia

scholarly journals Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions

Gut ◽  
2021 ◽  
pp. gutjnl-2020-321112
Author(s):  
Dror Kolodkin-Gal ◽  
Lior Roitman ◽  
Yossi Ovadya ◽  
Narmen Azazmeh ◽  
Benjamin Assouline ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Precancerous Lesions ◽  
Intraepithelial Neoplasia ◽  
Preventive Therapy ◽  
Ductal Adenocarcinoma ◽  
Potential Contribution ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Promoting Effect ◽  
Paracrine Effects ◽  
Bcl2 Family

ObjectiveCellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development.DesignTo uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment.ResultsWe found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma.ConclusionsThese findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.

Association of aging and ARHGAP17 variation with pancreatic intraepithelial neoplasia

Pancreatology ◽  
2016 ◽  
Vol 16 (1) ◽  
pp. S14
Author(s):  
Y. Matsuda ◽  
M. Tanaka ◽  
A. Suzuki ◽  
A. Seki ◽  
K. Nonaka ◽  
...  
Keyword(s):  
Intraepithelial Neoplasia ◽  
Pancreatic Intraepithelial Neoplasia
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