scholarly journals Tumor cross-talk networks promote growth and support immune evasion in pancreatic cancer

2018 ◽  
Vol 315 (1) ◽  
pp. G27-G35 ◽  
Author(s):  
Christopher J. Halbrook ◽  
Marina Pasca di Magliano ◽  
Costas A. Lyssiotis
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Immune Evasion ◽  
Cross Talk ◽  
Tissue Repair ◽  
Ductal Adenocarcinoma ◽  
Normal Tissues ◽  
Pancreatic Cancer Cells ◽  
Key Driver ◽  
Tumor Maintenance

In the event of an injury, normal tissues exit quiescent homeostasis and rapidly engage a complex stromal and immune program. These tissue repair responses are hijacked and become dysregulated in carcinogenesis to form a growth-supportive tumor microenvironment. In pancreatic ductal adenocarcinoma (PDA), which remains one of the deadliest major cancers, the microenvironment is a key driver of tumor maintenance that impedes many avenues of therapy. In this review, we outline recent efforts made to uncover the microenvironmental cross-talk mechanisms that support pancreatic cancer cells, and we detail the strategies that have been undertaken to help overcome these barriers.

scholarly journals Resveratrol Ameliorates the Malignant Progression of Pancreatic Cancer by Inhibiting Hypoxia-induced Pancreatic Stellate Cell Activation

2020 ◽  
Vol 29 ◽  
pp. 096368972092998
Author(s):  
Ying Xiao ◽  
Tao Qin ◽  
Liankang Sun ◽  
Weikun Qian ◽  
Jie Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Formation ◽  
Malignant Progression ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic cancer is characterized by a hypoxic tumor microenvironment, which is primarily caused by massive fibrosis with pancreatic stellate cells (PSCs) as a main component. Our previous studies have shown that resveratrol can significantly inhibit pancreatic cancer. However, whether resveratrol can inhibit hypoxia-induced cancer development remains unclear. The objective of this study was to explore whether PSCs and hypoxia synergistically mediate aggressiveness in pancreatic cancer and detect the potential pleiotropic protective effects of resveratrol on hypoxia-induced pancreatic cancer progression. Human PSCs were treated with vehicle or resveratrol under normoxic or hypoxic conditions (3% O2), and PSC activation was assessed by immunofluorescence staining. SiRNA was used to silence hypoxia-inducible factor 1 (HIF-1) expression. The invasive capacity of Panc-1 and Mia Paca-2 cells cocultured with conditioned medium from PSCs was assessed by Transwell assays. To examine tumor formation kinetics, KPC (LSL-KrasG12D/+, Trp53fl/+, and Pdx1-Cre) mice were sacrificed at different time points. To investigate the antitumor effects of resveratrol in vivo, 8-wk-old KPC mice were divided into two groups and treated daily with or without 50 mg/kg resveratrol. Our data indicate that hypoxia induces PSC activation via HIF-1 and that the interleukin 6, vascular endothelial growth factor A, and stromal cell-derived factor 1 derived from activated PSCs promote both invasion and the epithelial–mesenchymal transition and inhibit apoptosis in pancreatic cancer cells. However, resveratrol inhibits hypoxia-induced PSC activation, blocks the interplay between PSCs and pancreatic cancer cells, and suppresses the malignant progression of pancreatic cancer and stromal desmoplasia in a KPC mouse model. Our data highlight that activated PSCs and intratumoral hypoxia are essential targets for novel strategies to prevent tumor–microenvironment interactions. Furthermore, the polyphenolic compound resveratrol effectively ameliorates the malignant progression of pancreatic ductal adenocarcinoma.

Galectin-3 is modulated in pancreatic cancer cells under hypoxia and nutrient deprivation

2020 ◽  
Vol 401 (10) ◽  
pp. 1153-1165 ◽  
Author(s):  
Antônio F. da Silva Filho ◽  
Lucas B. Tavares ◽  
Maira G. R. Pitta ◽  
Eduardo I. C. Beltrão ◽  
Moacyr J. B. M. Rêgo
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Ductal Adenocarcinoma ◽  
Reverse Transcription Pcr ◽  
Pancreatic Cancer Cells ◽  
Through Flow ◽  
Galectin 3

AbstractPancreatic ductal adenocarcinoma is one of the most aggressive tumors with a microenvironment marked by hypoxia and starvation. Galectin-3 has been evaluated in solid tumors and seems to present both pro/anti-tumor effects. So, this study aims to characterize the expression of Galectin-3 from pancreatic tumor cells and analyze its influence for cell survive and motility in mimetic microenvironment. For this, cell cycle and cell death were accessed through flow cytometry. Characterization of inside and outside Galectin-3 was performed through Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), immunofluorescence, Western blot, and ELISA. Consequences of Galectin-3 extracellular inhibition were investigated using cell death and scratch assays. PANC-1 showed increased Galectin-3 mRNA expression when cultivated in hypoxia for 24 and 48 h. After 24 h in simultaneously hypoxic/deprived incubation, PANC-1 shows increased Galectin-3 protein and secreted levels. For Mia PaCa-2, cultivation in deprivation was determinant for the increasing in Galectin-3 mRNA expression. When cultivated in simultaneously hypoxic/deprived condition, Mia PaCa-2 also presented increasing for the Galectin-3 secreted levels. Treatment of PANC-1 cells with lactose increased the death rate when cells were incubated simultaneously hypoxic/deprived condition. Therefore, it is possible to conclude that the microenvironmental conditions modulate the Galectin-3 expression on the transcriptional and translational levels for pancreatic cancer cells.

scholarly journals NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Feng Guo ◽  
Yingke Zhou ◽  
Hui Guo ◽  
Dianyun Ren ◽  
Xin Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Gene Sets ◽  
And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 21 ◽  
Author(s):  
Huiming Chen ◽  
Junfeng Zhao ◽  
Ningning Jiang ◽  
Zheng Wang ◽  
Chang Liu
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Precancerous Lesions ◽  
Clinical Specimen ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells ◽  
Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

scholarly journals Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer

2021 ◽  
Vol 118 (21) ◽  
pp. e2016904118
Author(s):  
Derek K. Cheng ◽  
Tobiloba E. Oni ◽  
Jennifer S. Thalappillil ◽  
Youngkyu Park ◽  
Hsiu-Chi Ting ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Success ◽  
Treatment Options ◽  
Mass Spectrometry Analysis ◽  
Ductal Adenocarcinoma ◽  
Ras Signaling ◽  
Wild Type ◽  
Feedback Mechanisms ◽  
Spectrometry Analysis ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRASG12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC.

scholarly journals CircRHOT1 Mediated Cell Proliferation, Apoptosis and Invasion of Pancreatic Cancer Cells by Sponging miR-125a-3p

2020 ◽  
Author(s):  
Sunkai Ling ◽  
Yanru He ◽  
Xiaoxue Li ◽  
Mingyue Hu ◽  
Yu Ma ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Biological Function ◽  
Diagnostic Marker ◽  
Biological Functions ◽  
Normal Tissues ◽  
Qrt Pcr ◽  
Pancreatic Cancer Cells ◽  
Cancer Tissues

Abstract Background: The present study aimed to investigate the mechanistic biological function of circRHOT1 in pancreatic cancer cells.Methods: The expression of circRHOT1 and miR-125a-3p in pancreatic cancer tissues and their paired adjacent normal tissues was quantified by qRT-PCR. By knocking down or overexpressing circRHOT1 and miR-125a-3p in pancreatic cancer cells, their functions and potential mechanisms were explored.Results: circRHOT1 was overexpressed in pancreatic cancer tissues and cell lines, and it was found to directly bind to miR-125a-3p, acting as an endogenous sponge to inhibit its activity. Knockdown of circRHOT1 expression significantly inhibited proliferation as well as invasion, and it promoted apoptosis of pancreatic cancer cells via the regulation of E2F3 through the targeting of miR-125a-3p.Conclusion: Taken together, our results demonstrated that circRHOT1 plays critical roles in regulating the biological functions of pancreatic cancer cells, suggesting that circRHOT1 may serve as a potential diagnostic marker and therapeutic target for patients with pancreatic cancer.

scholarly journals RGS16, a novel p53 and pRb cross-talk candidate inhibits migration and invasion of pancreatic cancer cells

2014 ◽  
Vol 5 (11-12) ◽  
pp. 420-435 ◽  
Author(s):  
Miranda B. Carper ◽  
James Denvir ◽  
Goran Boskovic ◽  
Donald A. Primerano ◽  
Pier Paolo Claudio
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cross Talk ◽  
Migration And Invasion ◽  
Pancreatic Cancer Cells

scholarly journals BRM270 Inhibits the Proliferation of CD44 Positive Pancreatic Ductal Adenocarcinoma Cells via Downregulation of Sonic Hedgehog Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Do Luong Huynh ◽  
Hyebin Koh ◽  
Nisansala Chandimali ◽  
Jiao Jiao Zhang ◽  
Nameun Kim ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Ductal Adenocarcinoma ◽  
Cell Phenotype ◽  
Sonic Hedgehog Signaling ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Adenocarcinoma Cells

Pancreatic cancer has a poor survival rate as compared to other types of cancer. Surface marker CD44 plays important role in epithelial-mesenchymal transition and cancer stem cell phenotype. Therefore, targeting CD44 positive pancreatic cancer cells might enhance therapies effectiveness. Our previous studies indicated the antitumorigenesis effect of BRM270 in osteosarcoma, lung cancer, and glioblastoma; however there is no evidence on BRM270 impacts on pancreatic cancer growth. In this study, we investigated the effect of BRM270 on the isolated CD44 positive pancreatic ductal adenocarcinoma cells (CD44+PDAC). Results showed that CD44 positive cells undergo apoptosis induced by BRM270. Moreover, BRM270 also inhibits stemness and metastasis traits in CD44+PDAC via Sonic hedgehog signaling pathway and SALL4 expression.In vivostudy indicated that tumor growth derived from CD44+PDAC was suppressed as daily uptake by BRM270 5 mg/kg. These data suggest the alternative approach in antipancreatic tumorigenesis via herbal plants extract and selectively targeting CD44+PDAC cells in tumor.

scholarly journals Differential Dependency of Human Pancreatic Cancer Cells on Targeting PTEN via PLK 1 Expression

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 277
Author(s):  
Jungwhoi Lee ◽  
Jungsul Lee ◽  
Woogwang Sim ◽  
Jae-Hoon Kim
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Intracellular Signaling ◽  
Biomarker Discovery ◽  
Human Pancreatic Cancer ◽  
Normal Tissues ◽  
Pancreatic Cancer Cells ◽  
Prognostic Implications ◽  
Plk1 Expression

Even though the tumour suppressive role of PTEN is well-known, its prognostic implications are ambiguous. The objective of this study was to further explore the function of PTEN expression in human pancreatic cancer. The expression of PTEN has been dominant in various human cancers including pancreatic cancer when compared with their matched normal tissues. The pancreatic cancer cells have been divided into PTEN blockade-susceptible and PTEN blockade-impassible groups dependent on targeting PTEN by altering intracellular signaling. The expression of PTEN has led to varying clinical outcomes of pancreatic cancer based on GEO Series (GSE) data analysis and Liptak’s z analysis. Differential dependency to PTEN blockade has been ascertained based on the expression of polo-like kinase1 PLK1 in pancreatic cancer cells. The prognostic value of PTEN also depends on PLK1 expression in pancreatic cancer. Collectively, the present study provides a rationale for targeting PTEN as a promising therapeutic strategy dependent on PLK1 expressions using a companion biomarker discovery platform.

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