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.

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 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 Morphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs)

2008 ◽  
Vol 393 (4) ◽  
pp. 561-570 ◽  
Author(s):  
Jan-Bart M. Koorstra ◽  
Georg Feldmann ◽  
Nils Habbe ◽  
Anirban Maitra
Keyword(s):  
Pancreatic Cancer ◽  
Intraepithelial Neoplasia ◽  
Pancreatic Intraepithelial Neoplasia

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 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.

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