scholarly journals Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6188
Author(s):  
Friederike V. Opitz ◽  
Lena Haeberle ◽  
Alexandra Daum ◽  
Irene Esposito
Keyword(s):  
Tumor Microenvironment ◽  
Immune Surveillance ◽  
Early Time ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Cystic Neoplasms ◽  
Complex Interactions ◽  
Immunosuppressive Tumor Microenvironment ◽  
Desmoplastic Stroma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.

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

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.

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