The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

Patil, Kalyani; Khan, Faraz Idris; Akhtar, Sabah; Ahmad, Aamir; Uddin, Shahab

doi:10.1007/s10555-021-09979-x

Cited by 44 publications

(33 citation statements)

References 333 publications

(501 reference statements)

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“…The low survival rate of PC was reported by the 2018 GLOBOCAN study based on data from 185 countries, demonstrating the closeness between the number of new cases of PC and the total number of deaths (2). The poor therapeutic outcome of PC patients not only results from late diagnosis, the degree of malignancy of the cancer, and its early metastasis, but is also attributable to the presence of a specific cell population in PC, namely cancer stem cells (CSCs), which are critical for the maintenance of tumor growth, survival, and migration, as well as distal tumor formation (3,4). Many surface markers for CSCs have been proposed in past studies, while CD133 (prominin-1) and CD44 are the most recognized and well-known CSC markers for PC (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

GFAT1 is highly expressed in cancer stem cells of pancreatic cancer

Wang¹,

Kuang²,

Wu³

et al. 2022

Ann Transl Med

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Background: Cancer stem cells (CSCs) play pivotal roles in the growth, invasion, metastasis, and chemoresistance of pancreatic cancer (PC). The current characterization of CSCs in PC is not complete.Glutamine-fructose-6-phosphate transaminase 1 (GFAT1) is a key enzyme that regulates the hexosamine pathway (HP), in which it not only controls glucose influx but also catalyzes the reaction to form glucosamine 6-phosphate. Recently, it was reported that GFAT1 is highly expressed in PC. However, the relevance of this high expression of GFAT1, especially its association with cancer stemness, has not been well defined and is thus addressed in the current study.Methods: GFAT1 levels were determined in PC from a public database and assessed by bioinformatics tools. GFAT1 expression in CD133 + and CD44 + CSCs in PC was analyzed by reverse transcriptionquantitative polymerase chain reaction (RT-qPCR) and immunostaining on cytospun cells after flow cytometry-based cell sorting. GFAT1 + cells were separated from GFAT1 − cells by transfection of PC cell lines with a designed plasmid that expressed red fluorescent protein (RFP) under a GFAT1 promoter. Tumor sphere formation, tumor growth, tumor cell invasion, cell migration, and the resistance to gemcitabineinduced apoptosis were determined in GFAT1 + vs. GFAT1 − PC cells.Results: GFAT1 levels were significantly upregulated in PC compared to the adjacent non-PC tissue.There were significantly more GFAT1 + cells in the CD133 + population than in the CD133 − population, and similarly, there were significantly more GFAT1 + cells in the CD44 + population than in the CD44 − population.Compared to GFAT1 − PC cells, GFAT1 + PC cells generated significantly more tumor spheres in culture, appeared to be more invasive and migratory, and were significantly more resistant to gemcitabine-induced cell apoptosis.Conclusions: GFAT1 is highly expressed in CSCs among PC cells and may be crucial for PC growth, metastasis, and chemoresistance.

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Section: Introductionmentioning

confidence: 99%

GFAT1 is highly expressed in cancer stem cells of pancreatic cancer

Wang¹,

Kuang²,

Wu³

et al. 2022

Ann Transl Med

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“…As expected under such circumstances, PC patients frequently suffer from poor prognosis ( 1 ). For most PC patients, surgery is not possible because of end-stage disease and, therefore, conventional chemotherapy remains the major treatment option ( 4 ). However, conventional chemotherapy has its own limitations.…”

Section: Introductionmentioning

confidence: 99%

β-Hydroxyisovaleryl-Shikonin Exerts an Antitumor Effect on Pancreatic Cancer Through the PI3K/AKT Signaling Pathway

et al. 2022

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Pancreatic cancer (PC) is marked with a low survival rate and lack of recognized effective treatment strategy. We investigated the antitumor effect of β-hydroxyisovaleryl-shikonin (β-HIVS) on PC and the associated working mechanism. Cell toxicity was determined using Cell Counting Kit-8 (CCK-8) assay. Acridine Orange/Ethidium Bromide (AO/EB) double-fluorescent staining assay accompanied by flow cytometry was utilized to estimate cell apoptosis. Cell cycle, reactive oxygen species (ROS), and mitochondrial membrane potential were all evaluated using flow cytometry. Transwell and wound healing assays were performed to evaluate cell migration and invasion. Protein expression was analyzed by Western blots. A xenograft mouse model was employed to determine the antitumor effect of β-HIVS in vivo. PC cell viability gradually decreased with increasing β-HIVS while apoptosis was enhanced together with cell-cycle blockage in the G0–G1 phases. β-HIVS induced mitochondrial dysfunction, ROS production, and DNA damage and inhibited the invasive and migratory ability of PC cells. We further confirmed the suppression of EMT and PI3K/AKT pathways as underlying mechanisms. The mouse model treated with the increasing dose of β-HIVS displayed decreased tumor growth rate, along with increased apoptosis. Thus, β-HIVS exerts antitumor effects on PC through inducing apoptosis, ROS production, decreasing mitochondrial membrane potential, and suppressing signal pathways, such as PI3K/AKT. In summary, β-HIVS might be a promising strategy for PC treatment.

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“…The drug-tolerant cancer cells harbor features of stemness, which largely overlap with CSCs traits, such as slow proliferation rate, plasticity, self-renewal ability, and tumor-initiating capacity. Indeed, CSCs identified in various tumor subtypes, including PDAC, have been found intrinsically more resistant to conventional chemotherapy than their non-CSCs counterparts [ 35 , 189 , 190 , 191 , 192 ] ( Figure 3 ). It is therefore plausible to speculate that the fundamental role of EMT in drug resistance is at least partly interceded by induction of a stem-like identity in tumor cells.…”

Section: Epithelial-to-mesenchymal Transition and Chemoresistance In Pancreatic Ductal Adenocarcinomamentioning

confidence: 99%

Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance

Palamaris

Felekouras

Sakellariou

2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogramming converts cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. EMT occurrence in pre-invasive pancreatic lesions has been implicated in early PDAC dissemination. Moreover, cancer cell phenotypic plasticity driven by EMT contributes to intratumoral heterogeneity and drug tolerance and is mechanistically associated with the emergence of cells exhibiting cancer stem cells (CSCs) phenotype. In this review we summarize the available data on the signaling cascades regulating EMT and the molecular isnteractions between pancreatic cancer and stromal cells that activate them. In addition, we provide a link between EMT, tumor progression, and chemoresistance in PDAC.

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The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

Cited by 44 publications

References 333 publications

GFAT1 is highly expressed in cancer stem cells of pancreatic cancer

GFAT1 is highly expressed in cancer stem cells of pancreatic cancer

β-Hydroxyisovaleryl-Shikonin Exerts an Antitumor Effect on Pancreatic Cancer Through the PI3K/AKT Signaling Pathway

Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance

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