scholarly journals The Role of S100A9 in the Interaction Between Pancreatic Ductal Adenocarcinoma Cells and Stromal Cells

2020 ◽  
Author(s):  
Pin-Jui Kung ◽  
Ting-Yu Lai ◽  
Jerry Cao ◽  
Li-Chung Hsu ◽  
Tsai-Chen Chiang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Clinical Outcomes ◽  
High Expression ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cancer Tissue ◽  
Poor Survival ◽  
Programmed Death Ligand 1 ◽  
Pancreatic Cancer Cells ◽  
Programmed Death

Abstract Background: A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. Methods: We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found that the expression of S100 calcium binding protein A9 (S100A9) was increased in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas.Results: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. Conclusions: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC.

scholarly journals The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells

2021 ◽  
Author(s):  
Pin-Jui Kung ◽  
Ting-Yu Lai ◽  
Jerry Cao ◽  
Li-Chung Hsu ◽  
Tsai-Chen Chiang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Survival Data ◽  
Metastatic Potential ◽  
Gene Expression Omnibus ◽  
High Expression ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cancer Tissue ◽  
Pancreatic Cancer Cells

Abstract Background A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. Methods We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas. Results We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. Conclusions PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.

scholarly journals DNA-Methylation-Caused Downregulation of miR-30 Contributes to the High Expression of XPO1 and the Aggressive Growth of Tumors in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1101 ◽  
Author(s):  
Asfar S. Azmi ◽  
Yiwei Li ◽  
Amro Aboukameel ◽  
Irfana Muqbil ◽  
Philip A. Philip ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Nuclear Export ◽  
The United States ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Multiple Tumor ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with high mortality in the United States. One of the important signal transduction proteins involved in the regulation of pancreatic cancer’s aggressive progression is the nuclear export protein (XPO1). High expression of XPO1 has been found in pancreatic, lung, breast and other cancers and lymphomas with a poor prognosis of patients with tumors and high proliferative activity of cancer cells. Because XPO1 exports multiple tumor suppressor proteins simultaneously from the nucleus, the inhibition of XPO1 may retain multiple tumor suppressors in the nucleus, resulting in the suppression of cell proliferation and the induction of apoptosis in tumors. In this study, we found that the high expression of XPO1 in pancreatic cancer cells could be, in part, due to the methylation of the miR-30 gene, leading to the low expression level of the miR-30 family. By co-transfection of the XPO1 3′-UTR-Luc target vector with miR-30 mimic, we found that XPO1 is a direct target of the miR-30 family. We also observed that the enforced expression of the miR-30 family inhibited the expression of XPO1, resulting in the suppression of pancreatic cancer growth both in vitro and in vivo. These findings could help to design a novel therapeutic strategy for the treatment of pancreatic cancer by introducing miR-30 into cancer cells.

scholarly journals The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

2021 ◽  
Vol 10 ◽  
Author(s):  
Yang Wu ◽  
Chun Zhang ◽  
Kuirong Jiang ◽  
Jens Werner ◽  
Alexandr V. Bazhin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Gastrointestinal Malignancy ◽  
Desmoplastic Reaction ◽  
Pancreatic Cancer Cells ◽  
Promising Strategy

Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.

Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 290-290 ◽  
Author(s):  
Thomas B Brunner ◽  
Serena Lunardi ◽  
Nigel B Jamieson ◽  
Su Yin Lim ◽  
Kristin L Griffiths ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Patients ◽  
Mononuclear Cells ◽  
Pancreatic Stellate Cells ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

scholarly journals Comparison of programmed death ligand 1 immunostaining for pancreatic ductal adenocarcinoma between paired cytological and surgical samples

CytoJournal ◽  
2021 ◽  
Vol 18 ◽  
pp. 28
Author(s):  
Michael Muggilli ◽  
Donna Russell ◽  
Zhongren Zhou
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Inflammatory Cells ◽  
Ductal Adenocarcinoma ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Positive Score ◽  
Well Differentiated ◽  
Combined Positive Score ◽  
Fixed Cell ◽  
Formalin Fixed

Objectives: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with surgery or chemotherapy. Programmed death ligand 1 expression (PD-L1) immunotherapy has been successful for treating lung and other cancers with PD-L1 expression. However, in many unresectable PDAC cases, cytological samples are the only available tissues for PD-L1 testing. The aim of this study is to retrospectively compare the expression of PD-L1 using cytological and surgical samples. Material and Methods: Paired formalin-fixed cell blocks and surgical samples from the same patients with confirmed diagnoses of PDAC (n = 28) were sectioned for PD-L1 immunohistochemistry. Using tumor proportion score (TPS) and combined positive score (CPS) to evaluate paired cell blocks and surgical samples, we counted and analyzed the data. Results: With TPS, the PD-L1 was expressed in 9/28 (32%) of PDAC surgical samples and in 9/28 (32%) of paired cytological samples. Overall, the PD-L1 expression had a correlation of 26/28 (93%). With CPS, the PD-L1 was expressed in 20/28 (71%) of PDAC surgical samples and in 16/28 (57%) of paired cytological samples. The PD-L1 expression had a correlation of 20/28 (71%) and a discrepancy of 8/28 (29%). The PD-L1 expression was significantly higher in moderately-differentiated PDAC than in well-differentiated with TPS. Conclusion: Cytological samples are useful for evaluating PD-L1 expression with TPS because the concordant rate was 93%. With CPS, cytological samples are limited due to the scant inflammatory cells with the concordant rate of 71%. Extensive sampling of the pancreatic tumor may improve the detection of immune cells expressing PD-L1 in cytological samples. With TPS, PD-L1 expression was significantly higher in moderate-differentiation of PDAC than in poor- and well-differentiation.

scholarly journals Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma

2018 ◽  
Author(s):  
Christopher A. Natale ◽  
Jinyang Li ◽  
Tzvete Dentchev ◽  
Brian C. Capell ◽  
John T. Seykora ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
G Protein ◽  
Immune Therapy ◽  
Estrogen Signaling ◽  
Ductal Adenocarcinoma ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Cancer Types ◽  
G Protein Coupled

AbstractFemale sex is associated with lower incidence and improved clinical outcomes for many cancer types, including pancreatic ductal adenocarcinoma (PDAC). Although the mechanisms responsible for this sex difference are unknown, recent data suggests nonclassical estrogen signaling through the G Protein-coupled Estrogen Receptor (GPER) is likely involved. Here we used murine syngeneic tumor models and human xenografts to test whether GPER signaling inhibits pancreatic ductal adenocarcinoma (PDAC). Activation of GPER with the specific, small molecule agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically delivered G-1 was well tolerated in PDAC bearing mice, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors. These data, coupled with the wide tissue distribution of GPER, and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against many different cancer types.

scholarly journals Methionine Aminopeptidase 2 as a Potential Target in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Eliana Steinberg ◽  
Rawnaq Esa ◽  
Ouri Schwob ◽  
Tali Stern ◽  
Natalie Orehov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Metastatic Cancer ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Methionine Aminopeptidase ◽  
Inhibition Of Proliferation ◽  
Expression Levels ◽  
Potential Target ◽  
Pancreatic Cancer Cells

Abstract Pancreatic ductal adenocarcinoma (PDA) is an aggressive metastatic cancer with a very low survival rate. This tumor is hypovascularized and characterized by hypoxic regions, yet they are not impeded by the oxidative stress in their microenvironment. PDA’s high resilience raises the need to find new effective therapeutic targets. This study investigated methionine aminopeptidase 2 (MetAp2) — a metallopeptidase known to play an important role in tumor progression — as a potential target for treating PDA by blocking its activity. Immunohistology of patient-derived PDA tissue sections revealed high expression of MetAp2 in metastatic regions compared with primary sites. Pancreatic cancer cells (cell lines and patient derived) exhibited high expression levels of MetAp2 and significant inhibition of proliferation upon exposure to a selective MetAp2 inhibitor. The growth of Orthoptic pancreatic PancOH7 tumors in mice was significantly suppressed when MetAp2 inhibitor was administered orally. Our finding revealed that the inhibition of MetAp2 in cells was associated with a significant reduction in glutathione (GSH) levels, a substance known for its role in alleviating oxidative stress, which suggests a possible rationale for the anti-cancer activity in highly hypoxic tumors such as PDA. Taken together, our results indicate that MetAp2 can be a studied as a target in PDA and possibly in other tumors with high expression levels of MetAp2 which are not necessarily highly angiogenic tumors.

scholarly journals Ezrin and Radixin Differentially Modulate Cell Surface Expression of Programmed Death Ligand-1 in Human Pancreatic Ductal Adenocarcinoma KP-2 Cells

Immuno ◽  
2022 ◽  
Vol 2 (1) ◽  
pp. 68-84
Author(s):  
Takuro Kobori ◽  
Rina Doukuni ◽  
Honami Ishikawa ◽  
Yui Ito ◽  
Rie Okada ◽  
...  
Keyword(s):  
Cell Surface ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Checkpoint ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Ductal Adenocarcinoma ◽  
Mrna Levels ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

Immune checkpoint blockade (ICB) therapies, such as immune checkpoint inhibitors against programmed death ligand-1 (PD-L1), have not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Despite the critical role of PD-L1 in various types of cancers, the regulatory mechanism of PD-L1 expression on the cell surface of PDAC is poorly understood. Therefore, uncovering potential modulators of cell surface localisation of PD-L1 may provide a new strategy to improve ICB therapy in patients with PDAC. Here, we examined the role of ezrin/radixin/moesin (ERM) family scaffold proteins that crosslink transmembrane proteins with the actin cytoskeleton in the surface localisation of PD-L1 in KP-2 cells, a human PDAC cell line. Our results demonstrated the abundant protein expression of PD-L1, ezrin, and radixin, but not moesin, as well as their colocalisation in the plasma membrane. Interestingly, immunoprecipitation analysis detected the molecular interaction of PD-L1 with ezrin and radixin. Moreover, gene silencing of ezrin moderately decreased the mRNA and cell surface expression of PD-L1, while that of radixin greatly decreased the surface expression of PD-L1 without altering the mRNA levels. Thus, radixin and ezrin differentially modulate the cell surface localisation of PD-L1 in KP-2 cells, highlighting a potential therapeutic target to improve the current ICB therapy in PDAC.

scholarly journals Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2

Oncogene ◽  
2021 ◽  
Vol 40 (17) ◽  
pp. 3164-3179
Author(s):  
Yang Liu ◽  
Tianchi Tang ◽  
Xiaosheng Yang ◽  
Peng Qin ◽  
Pusen Wang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Noncoding Rna ◽  
Pancreatic Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Noncoding Rnas ◽  
Ductal Adenocarcinoma ◽  
Overall Survival Rate ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

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