scholarly journals Ganglioside GM2, highly expressed in the MIA PaCa-2 pancreatic ductal adenocarcinoma cell line, is correlated with growth, invasion, and advanced stage

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Norihiko Sasaki ◽  
Kenichi Hirabayashi ◽  
Masaki Michishita ◽  
Kimimasa Takahashi ◽  
Fumio Hasegawa ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Histological Grade ◽  
Ductal Adenocarcinoma ◽  
Advanced Stage ◽  
Synthesis Inhibitor ◽  
Younger Age ◽  
Glycolipid Synthesis ◽  
Functional Factors ◽  
Almost All ◽  
Tgf Β1

AbstractGangliosides, a group of glycosphingolipids, are known to be cell surface markers and functional factors in several cancers. However, the association between gangliosides and pancreatic ductal adenocarcinoma (PDAC) has not been well elucidated. In this study, we examined the expression and roles of ganglioside GM2 in PDAC. GM2+ cells showed a higher growth rate than GM2− cells in the adherent condition. When GM2– and GM2+ cells were cultured three-dimensionally, almost all cells in the spheres expressed GM2, including cancer stem cell (CSC)-like cells. A glycolipid synthesis inhibitor reduced GM2 expression and TGF-β1 signaling in these CSC-like cells, presumably by inhibiting the interaction between GM2 and TGFβ RII and suppressing invasion. Furthermore, suppression of GM2 expression by MAPK inhibition also reduced TGF-β1 signaling and suppressed invasion. GM2+ cells formed larger subcutaneous tumors at a high incidence in nude mice than did GM2– cells. In PDAC cases, GM2 expression was significantly associated with younger age, larger tumor size, advanced stage and higher histological grade. These findings suggest that GM2 could be used as a novel diagnostic and therapeutic target for PDAC.

scholarly journals KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2429
Author(s):  
Meichen Gu ◽  
Yanli Gao ◽  
Pengyu Chang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Kras Mutation ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Genomic Alteration ◽  
Pancreatic Carcinogenesis ◽  
Novel Method ◽  
Almost All ◽  
Lung Adenocarcinomas

Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

scholarly journals Tumor -Associated MUC1 Regulates TGF-β Signaling and Function in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Author(s):  
Priyanka Grover ◽  
Sritama Nath ◽  
Mukulika Bose ◽  
Alexa J. Sanders ◽  
Cory Brouwer ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Tumor Promoter ◽  
Ductal Adenocarcinoma ◽  
Potential Biomarker ◽  
Tgf Β1

AbstractPancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-β) is a cytokine that switches from a tumor-suppressor to a tumor promoter throughout tumor development, by a yet unknown mechanism. Tumor associated MUC1 (tMUC1) is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) interacts with other oncogenic proteins promoting tumor progression and metastasis. We hypothesize that tMUC1 levels regulate TGF-β functions in PDA in vitro and in vivo. We report that high-tMUC1 expression positively correlates to TGF-βRII and negatively to TGF-βRI receptors. In response to TGF-β1, high tMUC1 expressing PDA cells undergo c-Src phosphorylation, and activation of the Erk/MAPK pathway; while low tMUC1 expressing cells activate the Smad2/3 pathway, enhancing cell death. Correspondingly, mice bearing tMUC1-high tumors responded to TGF-β1 neutralizing antibody in vivo showing significantly retarded tumor growth. Analysis of clinical data from TCGA revealed significant alterations in gene-gene correlations in the TGF-β pathway in tMUC1 high versus tMUC1 low samples. This study deepens our understanding of tMUC1-regulated TGF-β’s paradoxical function in PDA and establishes tMUC1 as a potential biomarker to predict response to TGF-β-targeted therapies.

scholarly journals Liquid Biopsy as a Prognostic and Theranostic Tool for the Management of Pancreatic Ductal Adenocarcinoma

2022 ◽  
Vol 8 ◽  
Author(s):  
Daniel C. Osei-Bordom ◽  
Gagandeep Sachdeva ◽  
Niki Christou
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Liquid Biopsy ◽  
Ductal Adenocarcinoma ◽  
Advanced Stage ◽  
Resistance To Treatment

Pancreatic ductal adenocarcinomas (PDAC) represent one of the deadliest cancers worldwide. Survival is still low due to diagnosis at an advanced stage and resistance to treatment. Herein, we review the main types of liquid biopsy able to help in both prognosis and adaptation of treatments.

scholarly journals Tumor-associated macrophages promote PD-L1 expression in tumor cells by regulating PKM2 nuclear translocation in pancreatic ductal adenocarcinoma

Oncogene ◽  
2021 ◽  
Author(s):  
Qing Xia ◽  
Jing Jia ◽  
Chupeng Hu ◽  
Jinying Lu ◽  
Jiajin Li ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Cells ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Killer Cell ◽  
Ductal Adenocarcinoma ◽  
Tumor Associated Macrophages ◽  
Tgf Β1

AbstractIn many types of cancer, tumor cells prefer to use glycolysis as a major energy acquisition method. Here, we found that the 18fluoro-deoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-based markers were positively associated with the expression of programmed cell death ligand 1 (PD-L1), pyruvate kinase M2 (PKM2), both of which indicate poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. In this study, we confirmed that transforming growth factor-beta1 (TGF-β1) secreted by tumor-associated macrophages (TAMs) was a key factor contributing to the expression of PD-L1 in PDAC cells by inducing the nuclear translocation of PKM2. Using co-immunoprecipitation and chromatin immunoprecipitation assays, we demonstrated that the interaction between PKM2 and signal transducer and activator of transcription 1 (STAT1) was enhanced by TGF-β1 stimulation, which facilitated the transactivation of PD-L1 by the binding of PKM2 and STAT1 to its promoter. In vivo, PKM2 knockdown decreased PD-L1 expression in PDAC cells and inhibited tumor growth partly by promoting natural killer cell activation and function, and the combination of PD-1/PD-L1 blockade with PKM2 knockdown limited tumor growth. In conclusion, PKM2 significantly contributes to TAM-induced PD-L1 overexpression and immunosuppression, providing a novel target for immunotherapies for PDAC.

Clinicopathological significance of Necl-4 expression in pancreatic ductal adenocarcinoma

2016 ◽  
Vol 70 (7) ◽  
pp. 619-624 ◽  
Author(s):  
Aya Kawanishi ◽  
Kenichi Hirabayashi ◽  
Misuzu Yamada ◽  
Yumi Takanashi ◽  
Atsuko Hadano ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tissue Microarray ◽  
Histological Grade ◽  
Tumour Size ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Clinicopathological Significance ◽  
E Cadherin

AimsThe loss, or decreased expression, of nectin-like molecule 4 (Necl-4; an immunoglobulin-like cell adhesion molecule) is reported to be associated with the development and progression of certain types of cancer. We investigated the clinicopathological significance of Necl-4 expression in patients with pancreatic ductal adenocarcinoma (PDAC).MethodsImmunohistochemical analyses of Necl-4 (n=258) and E-cadherin (n=256) expression were performed using tissue microarray blocks of PDAC samples. Necl-4 expression of 38 pancreatic intraepithelial neoplasia (PanIN) lesions included in tissue microarray cores was also evaluated. Necl-4 and E-cadherin expression was considered positive if >30% of cells were stained, and negative if ≤30% of cells were stained.ResultsNecl-4 expression was positive in 45.7% (n=118) and negative in 54.3% (n=140) of PDAC cases. Necl-4 staining was positive in 96.7% (n=29) and negative in 3.3% (n=1) of low-grade PanIN cases, and positive in 62.5% (n=5) and negative in 37.5% (n=3) of high-grade PanIN cases. The number of cases with positive Necl-4 expression decreased in the order low-grade PanIN>high-grade PanIN>PDAC (p<0.001). Negative Necl-4 expression was significantly associated with a larger tumour size of >30 mm, perineural invasion, lymphatic involvement, lymph node metastasis (pN1), an advanced TNM (tumour, node, metastases) stage (stage IIB–IV), an advanced histological grade (G2/3), and shorter overall survival. E-cadherin staining was positive in 46.1% (n=118) and negative in 53.9% (n=138) of PDAC cases. Necl-4 expression correlated positively with E-cadherin expression (r=0.405, p<0.001).ConclusionsThe results suggest that Necl-4 is associated with carcinogenesis and aggressiveness of PDAC.

Simvastatin attenuates macrophage-mediated gemcitabine resistance of pancreatic ductal adenocarcinoma by regulating the TGF-β1/Gfi-1 axis

2017 ◽  
Vol 385 ◽  
pp. 65-74 ◽  
Author(s):  
Guozhe Xian ◽  
Juan Zhao ◽  
Chengkun Qin ◽  
Zhenhai Zhang ◽  
Yanliang Lin ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Gemcitabine Resistance ◽  
Tgf Β1
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