Gemcitabine resistance in pancreatic ductal adenocarcinoma

Binenbaum, Yoav; Na’ara, Shorook; Gil, Ziv

doi:10.1016/j.drup.2015.10.002

Cited by 327 publications

(307 citation statements)

References 92 publications

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“…Both CAT and SOD2, shown to be partly implicated in acquired resistance of PC in our study, have been suggested to promote chemoresistance in cancer (Dalla et al , 2012; Xu et al , 2014). Similarly, in other studies a role of gemcitabine-metabolising enzymes has been reported to underlie chemoresistant nature of PC cells (Duxbury et al , 2004; Amit and Gil, 2013; Binenbaum et al , 2015). Specifically, human equilibrative nucleoside transporter-1 and DCK have been shown to induce gemcitabine resistance in cancer cells by limiting its uptake and conversion to active metabolite form, respectively (Ohhashi et al , 2008; Nordh et al , 2014).…”

Section: Discussionsupporting

confidence: 57%

“…However, this approach failed in clinical trial further underscoring the complexity of underlying molecular mechanisms of PC chemoresistance (Allison, 2012). Recently, we and others have focused on additional mechanisms that involve cell-to-cell and/or cell-to-matrix interactions through release of soluble growth factors, direct intercellular interactions and generation of growth favourable niches within tumour microenvironment (Singh et al , 2010, 2012; Castells et al , 2012; Binenbaum et al , 2015). We demonstrated that stromal-derived chemokine, CXCL12, conferred gemcitabine resistance in PC cells (Singh et al , 2010).…”

Section: Discussionmentioning

confidence: 99%

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Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK

et al. 2017

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Background:Chemoresistance is a significant clinical problem in pancreatic cancer (PC) and underlying molecular mechanisms still remain to be completely understood. Here we report a novel exosome-mediated mechanism of drug-induced acquired chemoresistance in PC cells.Methods:Differential ultracentrifugation was performed to isolate extracellular vesicles (EVs) based on their size from vehicle- or gemcitabine-treated PC cells. Extracellular vesicles size and subtypes were determined by dynamic light scattering and marker profiling, respectively. Gene expression was examined by qRT-PCR and/or immunoblot analyses, and direct targeting of DCK by miR-155 was confirmed by dual-luciferase 3′-UTR reporter assay. Flow cytometry was performed to examine the apoptosis indices and reactive oxygen species (ROS) levels in PC cells using specific dyes. Cell viability was determined using the WST-1 assay.Results:Conditioned media (CM) from gemcitabine-treated PC cells (Gem-CM) provided significant chemoprotection to subsequent gemcitabine toxicity and most of the chemoresistance conferred by Gem-CM resulted from its EVs fraction. Sub-fractionation grouped EVs into distinct subtypes based on size distribution and marker profiles, and exosome (Gem-Exo) was the only sub-fraction that imparted chemoresistance. Gene expression analyses demonstrated upregulation of SOD2 and CAT (ROS-detoxifying genes), and downregulation of DCK (gemcitabine-metabolising gene) in Gem-Exo-treated cells. SOD/CAT upregulation resulted, at least in part, from exosome-mediated transfer of their transcripts and they suppressed basal and gemcitabine-induced ROS production, and partly promoted chemoresistance. DCK downregulation occurred through exosome-delivered miR-155 and either the functional suppression of miR-155 or restoration of DCK led to marked abrogation of Gem-Exo-mediated chemoresistance.Conclusions:Together, these findings establish a novel role of exosomes in mediating the acquired chemoresistance of PC.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK

et al. 2017

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“…Strong fibrotic reactions are also reported, leading to a fibrotic hypo-vascular barrier that surrounds pancreatic tumors, resulting in poor blood perfusion in transplanted tumors in contrast to the normal pancreas (Olive, Jacobetz et al, 2009). Over the last two decades, gemcitabine has been the cornerstone of chemotherapy for all stages of pancreatic cancer and works by targeting during DNA synthesis (Binenbaum, Na'ara et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

HDGF supports anti-apoptosis and pro-fibrosis in pancreatic stellate cells of pancreatic cancer

Chen

Wang

Chang

et al. 2018

Preprint

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Pancreatic cancer is refractory and characterized by extensively surrounding-and intra-tumor fibrotic reactions that are contributed by activated pancreatic stellate cells (PSCs). Activation of PSCs plays a pivotal role for developing fibrotic reactions to affect themselves or pancreatic cancer cells (PCCs). In the current study, we demonstrated that hepatoma-derived growth factor (HDGF) was secreted from transforming growth factor-β1

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“…Once these symptoms present themselves however, patients generally have progressed to an advanced disease stage that is difficult to treat [5]. Given this issue, the delayed diagnosis of PanCA is one of the leading factors contributing to its high mortality rate [4, 6]. In the US, PanCA is currently the fourth leading cause of cancer related deaths with 43,090 estimated to occur in 2017 [3].…”

Section: Introductionmentioning

confidence: 99%

Pancreatic Cancer: Current Status and Challenges

Muñoz¹,

Chakravarthy²,

Gong

et al. 2017

Curr Pharmacol Rep

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Purpose of the review The 5-year survival rate of patients with pancreatic cancer (PanCA) has remained stagnant. Unfortunately, the incidence is almost equal to mortality rates. These facts underscore the importance of concerted efforts to understand the pathology of this disease. Deregulation of multiple signaling pathways involved in a wide variety of cellular processes including proliferation, apoptosis, invasion, and metastasis contribute not only to cancer development but also to therapeutic resistance. The purpose of this review is to summarize current understanding of etiological factors including emerging evidence on the role of infectious agents, factors associated with therapeutic resistance and therapeutic options. Recent findings The unique aspect of PanCA is “desmoplasia”, a process that involves proliferation of stromal fibroblasts and collagen deposition in and around the filtrating cancer. Recent studies have identified pancreatic stellate cells (PSCs) as a potential source of such desmoplasia. Biphasic interactions between PSCs and cancer cells, endothelial cells, and/or myeloid derived suppressor cells in the tumor microenvironment contribute to pancreatic carcinogenesis. Summary We summarize limitations of current therapeutic approaches and potential strategies to overcome these limitations using natural products including botanicals as adjuvant/neo-adjuvant for effective management of PanCA.

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Gemcitabine resistance in pancreatic ductal adenocarcinoma

Cited by 327 publications

References 92 publications

Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK

Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK

HDGF supports anti-apoptosis and pro-fibrosis in pancreatic stellate cells of pancreatic cancer

Pancreatic Cancer: Current Status and Challenges

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