scholarly journals Expression of Hypoxia-Inducible Factors in Different Stages of Pancreatic Tumor Progression

Reports ◽  
2020 ◽  
Vol 3 (4) ◽  
pp. 30
Author(s):  
Jung Hwa Jung ◽  
Danuta Sosnowska ◽  
Jessica Weaver ◽  
Henri K. Parson ◽  
Carolina M. Casellini ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Pancreatic Tumor ◽  
Critical Role ◽  
Intraepithelial Neoplasia ◽  
Histochemical Staining ◽  
Ductal Adenocarcinoma ◽  
Novel Therapies ◽  
Hypoxia Inducible Factors ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Mucinous Neoplasm

Background: Early diagnosis in pancreatic cancer is key for improving prognosis. Hypoxia plays a critical role in tumor progression. Thus, an evaluation of associations between pancreatic tumor progression and markers of hypoxia is needed. Methods: We assessed the expression of hypoxia-inducible factors (HIF-1α and HIF-2α) by immuno-histochemical staining from 29 subjects with the following: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), and pancreatic ductal adenocarcinoma (PDAC) and compared it to the expression in non-tumor samples. Results: Expression of HIF-1α increased significantly from PanIN (3.01 ± 0.17) to IPMN (7.63 ± 0.18), NET (9.10 ± 0.23) and PDAC samples (11.06 ± 0.15, p < 0.0001). Similar findings were observed for HIF-2α (p < 0.0001)}. A strong correlation between HIF-1α and HIF-2α expression was demonstrated (R2 = 0.8408, p < 0.0001). Conclusions: This data suggest that HIF-1α and HIF-2α may play a role in the progression from PanIN through PDAC. Further studies are necessary to confirm these findings and determine the effect of HIFs abrogation on tumor progression that can lead to novel therapies.

scholarly journals Developmental Pathways Direct Pancreatic Cancer Initiation from Its Cellular Origin

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Maximilian Reichert ◽  
Karin Blume ◽  
Alexander Kleger ◽  
Daniel Hartmann ◽  
Guido von Figura
Keyword(s):  
Pancreatic Cancer ◽  
Poor Prognosis ◽  
Intraepithelial Neoplasia ◽  
Developmental Pathways ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Cellular Origin ◽  
Mucinous Neoplasm ◽  
Cancer Initiation ◽  
Advanced Stages

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis, since it is usually diagnosed at advanced stages. In order to employ tools for early detection, a better understanding of the early stages of PDA development from its main precursors, pancreatic intraepithelial neoplasia (PanIN), and intraductal papillary mucinous neoplasm (IPMN) is needed. Recent studies on murine PDA models have identified a different exocrine origin for PanINs and IPMNs. In both processes, developmental pathways direct the initiation of PDA precursors from their cellular ancestors. In this review, the current understanding of early PDA development is summarized.

scholarly journals Classification, Morphology, Molecular Pathogenesis, and Outcome of Premalignant Lesions of the Pancreas

2017 ◽  
Vol 141 (12) ◽  
pp. 1606-1614 ◽  
Author(s):  
Meredith E. Pittman ◽  
Rema Rao ◽  
Ralph H. Hruban
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Intraductal Papillary Mucinous Neoplasm ◽  
Intraepithelial Neoplasia ◽  
Mucinous Cystic Neoplasm ◽  
Premalignant Lesions ◽  
Ductal Adenocarcinoma ◽  
Cystic Neoplasm ◽  
Precursor Lesions ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Mucinous Neoplasm

Context.— Invasive pancreatic ductal adenocarcinoma has a greater than 90% mortality rate at 5 years. Understanding noninvasive, curable precursor lesions gives us the best hope for reducing mortality from pancreatic ductal adenocarcinoma. The 3 pancreatic precursor lesions that have been well studied include intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and pancreatic intraepithelial neoplasia. Objective.— To give an update on the latest clinical, molecular, and pathologic advances in intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and pancreatic intraepithelial neoplasia for the general surgical pathologist. Data Sources.— The current literature was analyzed and the authors' experiences with institutional and consult material were incorporated. Conclusions.— Our understanding of the molecular alterations that lead from pancreatic precursor lesion to invasive carcinoma continues to evolve. These advances aid clinicians in their treatment decisions and researchers in their search for actionable, druggable targets.

Pancreatic Intraepithelial Neoplasia and Pancreatic Tumorigenesis: Of Mice and Men

2009 ◽  
Vol 133 (3) ◽  
pp. 375-381 ◽  
Author(s):  
Niki A. Ottenhof ◽  
Anya N. A. Milne ◽  
Folkert H. M. Morsink ◽  
Paul Drillenburg ◽  
Fiebo J. W. ten Kate ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Progression ◽  
Mouse Models ◽  
Intraepithelial Neoplasia ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Pancreatic Carcinogenesis ◽  
Genetically Engineered Mouse Models

Abstract Context.—Pancreatic cancer has a poor prognosis with a 5-year survival of less than 5%. Early detection is at present the only way to improve this outlook. This review focuses on the recent advances in our understanding of pancreatic carcinogenesis, the scientific evidence for a multistaged tumor progression, and the role genetically engineered mouse models can play in recapitulating the natural course and biology of human disease. Objectives.—To illustrate the stepwise tumor progression of pancreatic cancer and genetic alterations within the different stages of progression and to review the findings made with genetically engineered mouse models concerning pancreatic carcinogenesis. Data Sources.—A review of recent literature on pancreatic tumorigenesis and genetically engineered mouse models. Conclusions.—Pancreatic cancer develops through stepwise tumor progression in which preinvasive stages, called pancreatic intraepithelial neoplasia, precede invasive pancreatic cancer. Genetic alterations in oncogenes and tumor suppressor genes underlying pancreatic cancer are also found in pancreatic intraepithelial neoplasia. These mutations accumulate during progression through the consecutive stages of pancreatic intraepithelial neoplasia lesions. Also in genetically engineered mouse models of pancreatic ductal adenocarcinoma, tumorigenesis occurs through stepwise progression via consecutive mouse pancreatic intraepithelial neoplasia, and these models provide important tools for clinical applications. Nevertheless differences between mice and men still remain.

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.

Abstract B115: Eflornithine (DFMO) Prevents Progression of Pancreatic Intraepithelial Neoplasia to Ductal Adenocarcinoma in LSL-KrasG12D/+ Mice

2012 ◽  
Vol 5 (11 Supplement) ◽  
pp. B115-B115
Author(s):  
Altaf Mohammed ◽  
Naveena B. Janakiram ◽  
Misty Brewer ◽  
Rebekah L. Ritchie ◽  
Anuj Marya ◽  
...  
Keyword(s):  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Intraepithelial Neoplasia

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 c-Fos/ERK promotes the progression from pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma

2016 ◽  
Vol 36 (6) ◽  
pp. 3413-3420 ◽  
Author(s):  
Lei You ◽  
Xiaoxia Ren ◽  
Yongxing Du ◽  
Wenjing Zhao ◽  
Ming Cui ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Intraepithelial Neoplasia
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