scholarly journals The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Cancers ◽  
2018 ◽  
Vol 10 (2) ◽  
pp. 33 ◽  
Author(s):  
Sandra Valle ◽  
Laura Martin-Hijano ◽  
Sonia Alcalá ◽  
Marta Alonso-Nocelo ◽  
Bruno Sainz Jr.
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Patient Survival ◽  
Biological Properties ◽  
Common Type ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Metastatic Capacity

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (<7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.

scholarly journals Progressively De-Differentiated Pancreatic Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a Quiescent Stem State

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1572 ◽  
Author(s):  
Giulia Ambrosini ◽  
Elisa Dalla Pozza ◽  
Giuseppina Fanelli ◽  
Claudia Di Carlo ◽  
Andrea Vettori ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Potential ◽  
Ductal Adenocarcinoma ◽  
Live Cells ◽  
Quiescent State ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively identify their peculiarities for an efficient therapeutic approach. In this study, CSCs have been obtained by culturing different PDAC cell lines with a specific growth medium. Cells were characterized for the typical stem/mesenchymal properties at short-, medium-, and long-term culture. Metabolomics, proteomics, analysis of oxygen consumption rate in live cells, and the effect of the inhibition of lactate transporter on cell proliferation have been performed to delineate the metabolism of CSCs. We show that gradually de-differentiated pancreatic cancer cells progressively increase the expression of both stem and epithelial-to-mesenchymal transition markers, shift their metabolism from a glycolytic to an oxidative one, and lastly gain a quiescent state. These quiescent stem cells are characterized by high chemo-resistance, clonogenic ability, and metastatic potential. Re-differentiation reverts these features, re-activating their proliferative capacity and glycolytic metabolism, which generally correlates with high aggressiveness. These observations add an important piece of knowledge to the comprehension of the biology of CSCs, whose metabolic plasticity could be exploited for the generation of promising and selective therapeutic approaches for PDAC patients.

scholarly journals The Anthrax Toxin Receptor 1 (ANTXR1) Is Enriched in Pancreatic Cancer Stem Cells Derived from Primary Tumor Cultures

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Sonia Alcalá ◽  
Paola Martinelli ◽  
Patrick C. Hermann ◽  
Christopher Heeschen ◽  
Bruno Sainz
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Primary Cultures ◽  
Anthrax Toxin ◽  
Ductal Adenocarcinoma ◽  
Tumor Type ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Toxin Receptor

Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related mortality. Cancer stem cells (CSCs) have been shown to be the drivers of pancreatic tumor growth, metastasis, and chemoresistance, but our understanding of these cells is still limited by our inability to efficiently identify and isolate them. While a number of markers capable of identifying pancreatic CSCs (PaCSCs) have been discovered since 2007, there is no doubt that more markers are still needed. The anthrax toxin receptor 1 (ANTXR1) was identified as a functional biomarker of triple-negative breast CSCs, and PDAC patients stratified based on ANTXR1 expression levels showed increased mortality and enrichment of pathways known to be necessary for CSC biology, including TGF-β, NOTCH, Wnt/β-catenin, and IL-6/JAK/STAT3 signaling and epithelial to mesenchymal transition, suggesting that ANTXR1 may represent a putative PaCSC marker. In this study, we show that ANTXR1+ cells are not only detectable across a panel of 7 PDAC patient-derived xenograft primary cultures but ANTXR1 expression significantly increased in CSC-enriched 3D sphere cultures. Importantly, ANTXR1+ cells also coexpressed other known PaCSC markers such as CD44, CD133, and autofluorescence, and ANTXR1+ cells displayed enhanced CSC functional and molecular properties, including increased self-renewal and expression of pluripotency-associated genes, compared to ANTXR1- cells. Thus, this study validates ANTXR1 as a new PaCSC marker and we propose its use in identifying CSCs in this tumor type and its exploitation in the development of CSC-targeted therapies for PDAC.

scholarly journals Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

2019 ◽  
Vol 20 (17) ◽  
pp. 4242 ◽  
Author(s):  
Monish Ram Makena ◽  
Himavanth Gatla ◽  
Dattesh Verlekar ◽  
Sahithi Sukhavasi ◽  
Manoj K. Pandey ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Cycle Progression ◽  
Patient Survival ◽  
Epithelial Mesenchymal Transition ◽  
Ductal Adenocarcinoma ◽  
Steady Increase ◽  
Mesenchymal Transition ◽  
Pancreatic Carcinogenesis ◽  
Tumor Immune Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

scholarly journals The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Sabrina Bimonte ◽  
Antonio Barbieri ◽  
Maddalena Leongito ◽  
Giuseppe Palma ◽  
Vitale del Vecchio ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Biological Activities ◽  
Biological Properties ◽  
Ductal Adenocarcinoma ◽  
Small Noncoding Rnas ◽  
Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.

scholarly journals Yap1-2 Isoform Is the Primary Mediator in TGF-β1 Induced EMT in Pancreatic Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Chao Gao ◽  
Mei-Yu Quan ◽  
Qian-Jie Chen ◽  
Ruo Yang ◽  
Yuanyuan Wu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Western Blot ◽  
Epithelial To Mesenchymal Transition ◽  
Hippo Pathway ◽  
Akt Signaling ◽  
Protein Isoforms ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Alternative Mrna Splicing

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive human malignancy and intrinsically resistant to conventional therapies. YAP1, as a key downstream effector of the Hippo pathway, plays an important role in tumorigenesis including PDAC. Alternative mRNA splicing of YAP1 results in at least 8 protein isoforms, which are divided into two subgroups (YAP1-1 and YAP1-2) based on the presence of either a single or double WW domains. We investigated the functions and regulatory mechanisms of YAP1-1 and YAP1-2 in PDAC cells induced by TGF-β to undergo epithelial-to-mesenchymal transition (EMT). CRISPR-Cas9 and shRNA were used to silence YAP1 expression in pancreatic cancer cells. Re-constituted lentivirus mediated overexpression of each single YAP1 isoform was generated in the parental knockout L3.6 cells. EMT was induced by treatment with TGF-β, EGF and bFGF in parental and the constructed stable cell lines. Western blot and qPCR were used to detect the expression of EMT markers. Scratch wound healing and transwell assays were used to detect cell migration. The stability and subcellular localization of YAP1 proteins were determined by Western blot analysis, immunofluorescence, as well as ubiquitination assays. We showed that TGF-β, EGF and bFGF all significantly promoted EMT in PDAC cells, which was inhibited by knockdown of YAP1 expression. Interestingly, YAP1-1 stable cells exhibited a stronger migratory ability than YAP1-2 cells under normal culture condition. However, upon TGF-β treatment, L3.6-YAP1-2 cells exhibited a stronger migratory ability than L3.6-YAP1-1 cells. Mechanistically, TGF-β treatment preferentially stabilizes YAP1-2 and enhances its nuclear localization. Furthermore, TGF-β-induced EMT and YAP1-2 activity were both blocked by inhibition of AKT signaling. Our results showed that both YAP1-1 and YAP1-2 isoforms are important mediators in the EMT process of pancreatic cancer. However, YAP1-2 is more important in mediating TGF-β-induced EMT, which requires AKT signaling.

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