Glycometabolic rearrangements–aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC): Roles, regulatory networks, and therapeutic potential

2021 ◽  
Author(s):  
Zhong Zhang ◽  
Hai-jun Zhang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Regulatory Networks ◽  
Therapeutic Potential ◽  
Aerobic Glycolysis ◽  
Ductal Adenocarcinoma

scholarly journals Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. I. Alexander ◽  
D. B. Vendramini-Costa ◽  
R. Francescone ◽  
T. Luong ◽  
J. Franco-Barraza ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Ductal Adenocarcinoma ◽  
Transforming Growth Factor Beta1 ◽  
Cancer Associated Fibroblast ◽  
Specific Tumor ◽  
Immunosuppressive Microenvironment ◽  
Anti Tumor Activity ◽  
Immunosuppressive Cytokines

AbstractPancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

scholarly journals The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3219 ◽  
Author(s):  
Balbina García-Reyes ◽  
Anna-Laura Kretz ◽  
Jan-Philipp Ruff ◽  
Silvia von Karstedt ◽  
Andreas Hillenbrand ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Transcriptional Elongation ◽  
Cyclin Dependent Kinases ◽  
Dismal Prognosis ◽  
The Family ◽  
Cycle Regulation

The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.

scholarly journals Carbohydrate 3′-sialyllactose as a novel target for theranostics in pancreatic ductal adenocarcinoma

Tumor Biology ◽  
2020 ◽  
Vol 42 (10) ◽  
pp. 101042832096527
Author(s):  
Kiyoshi Higashi ◽  
Keiko Maeda ◽  
Kaori Miyata ◽  
Saori Yoshimura ◽  
Keita Yamada ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Ductal Adenocarcinoma ◽  
Significant Activity ◽  
Gastric Cancer Cells ◽  
Complement Dependent Cytotoxicity ◽  
Elevated Expression ◽  
Novel Target

We previously demonstrated that the carbohydrate 3′-sialyllactose is overexpressed in cancer stem-like cells such as metastatic pancreatic and poorly differentiated gastric cancer cells, and undifferentiated human embryonic stem cells. In this study, we investigated the possibility of 3′-sialyllactose as a target for theranostics in cancers using a recombinant mouse monoclonal antibody r3B1E2 that binds to 3′-sialyllactose. Immunohistochemistry analysis confirmed an elevated expression of 3′-sialyllactose in tumors of pancreas, stomach, and testis, while no expression of 3′-sialyllactose was observed in corresponding normal controls. In addition, a stage-independent expression of 3′-sialyllactose was observed, especially in pancreatic ductal adenocarcinoma (PDAC). The level of serum 3′-sialyllactose in PDAC subjects was significantly higher than that in healthy controls, providing excellent AUC of 0.88. We next explored the therapeutic potential of r3B1E2 for PDAC in vitro. Treatment of r3B1E2 with 3′-sialyllactose-bearing human PDAC cells exhibited a complement-dependent cytotoxicity, whereas no significant activity of r3B1E2 against 3′-sialyllactose-negative cells was observed. Collectively, these findings raise the possibility of 3′-sialyllactose as a novel target for theranostics in PDAC.

scholarly journals Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential

2018 ◽  
Vol 9 (3-4) ◽  
pp. 78-86 ◽  
Author(s):  
Andrew Cannon ◽  
Christopher Thompson ◽  
Bradley R. Hall ◽  
Maneesh Jain ◽  
Sushil Kumar ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Ductal Adenocarcinoma ◽  
Insight Into

scholarly journals Glycometabolic rearrangements--aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Lidong Cao ◽  
Jiacheng Wu ◽  
Xianzhi Qu ◽  
Jiyao Sheng ◽  
Mengying Cui ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Biochemical Parameters ◽  
Malignant Tumors ◽  
Aerobic Glycolysis ◽  
Clinical Applications ◽  
Common Type ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Biomarkers

AbstractPancreatic cancer is one of the most malignant tumors worldwide, and pancreatic ductal adenocarcinoma is the most common type. In pancreatic cancer, glycolysis is the primary way energy is produced to maintain the proliferation, invasion, migration, and metastasis of cancer cells, even under normoxia. However, the potential molecular mechanism is still unknown. From this perspective, this review mainly aimed to summarize the current reasonable interpretation of aerobic glycolysis in pancreatic cancer and some of the newest methods for the detection and treatment of pancreatic cancer. More specifically, we reported some biochemical parameters, such as newly developed enzymes and transporters, and further explored their potential as diagnostic biomarkers and therapeutic targets.

scholarly journals Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

2019 ◽  
Author(s):  
Shixiang Guo ◽  
Andrew Fesler ◽  
Wenjie Huang ◽  
Yunchao Wang ◽  
Jiali Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Ectopic Expression ◽  
Metastatic Tumor ◽  
Ductal Adenocarcinoma ◽  
Cycle Arrest ◽  
Patient Prognosis ◽  
Improve Patient

AbstractTreatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. There is an urgent need to develop novel strategies to enhance survival and improve patient prognosis. microRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. In this study, we demonstrate that low expression of miR-15a is associated with poor prognosis of PDAC patients. miR-15a expression is reduced in PDAC while closely related miR-16 expression remains relatively unchanged. miR-15a suppresses several important targets such as Wee1, Chk1, Yap-1, and BMI-1 causing cell cycle arrest and inhibiting cell proliferation. Ectopic expression of miR-15a sensitizes PDAC cells to gemcitabine reducing the IC50over 6.5-fold. To investigate the therapeutic potential of miR-15a, we used a modified miR-15a (5-FU-miR-15a) with uracil (U) residues in the guide strand replaced with 5-fluorouracil (5-FU). We demonstrated enhanced inhibition of PDAC cell proliferation by 5-FU-miR-15a compared to native miR-15a.In vivowe showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth. These results support the future development of 5-FU-miR-15a as a novel therapeutic agent as well as a prognostic biomarker in the clinical management of PDAC.

scholarly journals Pancreatic Ductal Adenocarcinoma: The Dawn of the Era of Nuclear Medicine?

2021 ◽  
Vol 22 (12) ◽  
pp. 6413
Author(s):  
Christopher Montemagno ◽  
Shamir Cassim ◽  
Nicolas De Leiris ◽  
Jérôme Durivault ◽  
Marc Faraggi ◽  
...  
Keyword(s):  
Nuclear Medicine ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Single Photon ◽  
Current Knowledge ◽  
Photon Emission ◽  
Diagnostic Value ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Emission Computed Tomography

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90–95% of all pancreatic tumors, is a highly devastating disease associated with poor prognosis. The lack of accurate diagnostic tests and failure of conventional therapies contribute to this pejorative issue. Over the last decade, the advent of theranostics in nuclear medicine has opened great opportunities for the diagnosis and treatment of several solid tumors. Several radiotracers dedicated to PDAC imaging or internal vectorized radiotherapy have been developed and some of them are currently under clinical consideration. The functional information provided by Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) could indeed provide an additive diagnostic value and thus help in the selection of patients for targeted therapies. Moreover, the therapeutic potential of β-- and α-emitter-radiolabeled agents could also overcome the resistance to conventional therapies. This review summarizes the current knowledge concerning the recent developments in the nuclear medicine field for the management of PDAC patients.

Insulin-like growth factor 2 mRNA binding protein 2 promotes aerobic glycolysis and cell proliferation in pancreatic ductal adenocarcinoma via stabilizing GLUT1 mRNA

2019 ◽  
Vol 51 (7) ◽  
pp. 743-752 ◽  
Author(s):  
Shan Huang ◽  
Zheng Wu ◽  
Yunyun Cheng ◽  
Wenzhen Wei ◽  
Linlin Hao
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Binding Protein ◽  
Aerobic Glycolysis ◽  
Ductal Adenocarcinoma ◽  
Insulin Like Growth Factor ◽  
Mrna Binding Protein ◽  
Mrna Binding ◽  
Glut1 Mrna

Abstract Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) is a member of the IGF2BP protein family consisting of IGF2BP1~3 with the capacity of binding to many transcripts and regulating RNA stability, localization, and translation. In this study, we discovered that expression of IGF2BP2 was upregulated and led to a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). IGF2BP2 protein was gradually elevated from normal pancreas, pancreatic intraepithelial neoplasia to PDAC in an LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx1-Cre mouse model. Furthermore, we demonstrated that IGF2BP2 promoted aerobic glycolysis and PDAC cell proliferation through directly binding to and stabilizing GLUT1 mRNA. In summary, our study unveiled an important role of IGF2BP2 in PDAC development by modulating aerobic glycolysis and as a potential therapeutic target for PDAC treatment.

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