scholarly journals “Open Sesame?”: Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3206
Author(s):  
Ornella Randazzo ◽  
Filippo Papini ◽  
Giulia Mantini ◽  
Alessandro Gregori ◽  
Barbara Parrino ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Rapid Progression ◽  
Nucleoside Transporter ◽  
Equilibrative Nucleoside Transporter ◽  
Multimodal Analysis ◽  
Predictive Role ◽  
Aggressive Tumor ◽  
Disease Free ◽  
Free Status

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.

scholarly journals HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

2005 ◽  
Vol 202 (11) ◽  
pp. 1493-1505 ◽  
Author(s):  
Holger K. Eltzschig ◽  
Parween Abdulla ◽  
Edgar Hoffman ◽  
Kathryn E. Hamilton ◽  
Dionne Daniels ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Nucleoside Transporter ◽  
In Vivo Models ◽  
Equilibrative Nucleoside Transporter ◽  
Hypoxia Inducible Factor 1 ◽  
And Function

Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)–dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1α mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.

Predictive and Prognostic Properties of Human Equilibrative Nucleoside Transporter 1 Expression in Gemcitabine-Treated Pancreatobiliary Cancer: A Meta-Analysis

2019 ◽  
pp. 1-22 ◽  
Author(s):  
Larissa J. Vos ◽  
Dimas Yusuf ◽  
Arthur Lui ◽  
Zainab Abdelaziz ◽  
Sunita Ghosh ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Nucleoside Transporter ◽  
Free Survival ◽  
Equilibrative Nucleoside Transporter ◽  
Antibody Assays ◽  
Tumor Expression ◽  
Disease Free ◽  
Primary Drug

Purpose Gemcitabine, the primary drug for the treatment of pancreatobiliary cancer (PBC), requires human equilibrative nucleoside transporter 1 (hENT1) to enter cells. High tumoral hENT1 expression has been linked with improved survival among patients with PBC treated with gemcitabine; however, this finding has been inconsistent, and studies used different expression assays. Methods Databases were reviewed for studies that examined hENT1 and clinical outcome in PBC. Of 307 publications, 34 studies were found that used immunohistochemistry (IHC) with one of eight anti–hENT1 antibody assays. Five studies were excluded for redundancy, and 29 studies underwent detailed review. Results On average, 51% of tumor samples had high hENT1 expression (range, 7% to 92%). Among studies that examined hENT1 expression and overall survival (OS), 58% (15 of 26 studies) showed an association between high tumoral hENT1 and improved OS for gemcitabine-treated patients. Among 10D7G2 antibody studies, 88% (seven of eight studies) demonstrated this association. Studies with other antibodies—in particular, SP120 (two of nine studies)—were less consistent. The ability to detect an association between improved OS and high hENT1 was antibody dependent (χ2 P = .0237). An association between high tumoral hENT1 expression and improved disease-free/progression-free survival (DFS/PFS) was demonstrated in 71% of studies (15 of 21 studies). Pooled hazard ratio (HR) analyses of all antibody studies demonstrated a link between high hENT1 tumor expression and improved OS (HR, 0.674; 95% CI, 0.509 to 0.893; P = .006) and DFS/PFS (HR, 0.740; 95% CI, 0.517 to 0.1.059; P = .10). This signal was stronger among studies that used the 10D7G2 antibody in comparison to those in which another antibody was used, with HRs of 0.488 (95% CI, 0.396 to 0.602; P < .001) and 0.410 (95% CI, 0.280 to 0.599; P < .001), respectively. Conclusion High tumoral hENT1 expression on IHC with 10D7G2 is a strong and reproducible prognostic marker for improved outcome among gemcitabine-treated patients with PBC.

scholarly journals ELK3 Mediated by ZEB1 Facilitates the Growth and Metastasis of Pancreatic Carcinoma by Activating the Wnt/β-Catenin Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiuyan Zhao ◽  
Yingchun Ren ◽  
Haoran Xie ◽  
Lanting Yu ◽  
Jiawei Lu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Rapid Progression ◽  
Normal Tissues ◽  
Online Databases ◽  
Ternary Complex Factor

Rapid progression and metastasis are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). ELK3, a member of the ternary complex factor (TCF), has been associated with the initiation and progression of various cancers. However, the role of ELK3 in PDAC is not yet fully understood. Online databases and immunohistochemistry were used to analyze the ELK3 levels in PDAC tissues. The function of ELK3 was confirmed by a series of in vivo and in vitro studies. Western blotting and immunofluorescence were used to detect the molecular mechanisms of PDAC. ChIP-qPCR was used to study the mechanism responsible for the elevation of ELK3 expression in PDAC. The ELK3 levels were higher in PDAC tissues than in adjacent normal tissues. Functionally, we demonstrated that ELK3 acted as an oncogene to promote PDAC tumorigenesis and metastasis. Further study suggested that ELK3 promoted PDAC cell migration and invasion by activating the Wnt/β-catenin pathway, and proved that ZEB1 could directly bind to the promoter of ELK3 to increase its transcription. Finally, both were associated with the patients’ clinicopathological features and worse overall survival. Conclusively, our findings enrich the role of ELK3 in PDAC, and provide potential avenues for exploring more effective biomarkers and therapeutic strategies for the treatment of PDAC.

scholarly journals ELK3 Mediated by ZEB1 Facilitates the Growth and Metastasis of Pancreatic Carcinoma by Activating the Wnt/Β-Catenin Pathway

2021 ◽  
Author(s):  
Qiuyan Zhao ◽  
Yingchun Ren ◽  
Haoran Xie ◽  
Lanting Yu ◽  
Jiawei Lu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Rapid Progression ◽  
Normal Tissues ◽  
Online Databases ◽  
Ternary Complex Factor

Abstract BackgroundRapid progression and metastasis are the major cause of death of pancreatic ductal adenocarcinoma (PDAC) patients. ELK3, a member of ternary complex factor (TCF), has been associated with the initiation and progression of various cancers. However, the role of ELK3 in PDAC need to be further elucidated.MethodsOnline databases and immunohistochemistry were used to analyze ELK3 level in PDAC tissues. The function of ELK3 was confirmed by a series of in vivo and in vitro studies. Western blot and immunofluorescence were used to detect the molecular mechanisms in PDAC. ChIP-qPCR was used to study the mechanism responsible for elevation of ELK3 in PDAC. ResultsELK3 level was higher in PDAC tissues than that in adjacent normal tissues. Functionally, we demonstrated that ELK3 acted as an oncogene to promote PDAC tumorigenesis and metastasis. Further investigations suggested that ELK3 could promote PDAC cells migration and invasion by activating Wnt/β-catenin pathway. Then we proved that ZEB1 could directly bind to the promoter of ELK3 to increase its transcription. Finally, both of them were associated with patients’ clinicopathological features and worse overall survival. ConclusionsOur findings enrich the role of ELK3 in PDAC, and provide potential avenues for exploring more effective biomarkers and therapeutic strategies in the treatment of PDAC.

Randomized multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a prospective evaluation of the of the association between tumor hENT1 expression and clinical outcome with gemcitabine treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4007-4007
Author(s):  
Elizabeth Poplin ◽  
Harpreet Wasan ◽  
Lindsey Rolfe ◽  
Mitch Raponi ◽  
Tone Ikdahl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Controlled Trial ◽  
Ductal Adenocarcinoma ◽  
Nucleoside Transporter ◽  
Adjuvant Trial ◽  
Equilibrative Nucleoside Transporter ◽  
Randomized Controlled ◽  
Hazard Ratios ◽  
Gemcitabine Treatment ◽  
Clinical Trial Information

4007 Background: Gemcitabine requires membrane transporter proteins to cross the cell membrane. Low expression of the human equilibrative nucleoside transporter-1 (hENT1) may play a role in gemcitabine resistance in PDAC. CO-101 (also known as CP-4126), a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1 and to circumvent transporter-mediated resistance. We conducted a randomized, controlled trial (LEAP) in patients with mPDAC to determine whether CO-101 improved survival vs gemcitabine in patients with low hENT1 tumors. The study also prospectively tested the hypothesis that gemcitabine is more active in patients with hENT1 high than hENT1 low tumors in metastatic disease. Methods: Patients were randomized to CO-101 or gemcitabine. An immunohistochemistry test measuring tumor hENT1 expression was developed in parallel with the recruitment phase of LEAP. To dichotomize the population, a hENT1 cut-off was defined using primary PDAC tumor samples from an adjuvant trial. LEAP participants provided a metastasis sample during screening for blinded hENT1 assessment, and the cut-off was applied to these samples. The primary endpoint of the study was overall survival in the low hENT1 subgroup. Results: 367 patients were enrolled, with metastasis hENT1 status available for 358/367 (97.5%). 232/357 (65%) were hENT1 low. There was no difference in overall survival between CO-101 and gemcitabine in the hENT1 low subgroup, or overall, with hazard ratios of 0.994 [95% CI 0.746, 1.326] and 1.072 [95% CI 0.856, 1.344] respectively. Within the gemcitabine arm, there was no difference in survival between the hENT1 high and low subgroups (HR 1.147 95% CI 0.809, 1.626). The observed side effect profile was typical of gemcitabine and was similar in both treatment arms, in the hENT1 low subgroups and overall. Conclusions: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1 expression. Metastasis hENT1 expression did not predict gemcitabine treatment outcome in patients with mPDAC. Clinical trial information: NCT01124786.

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