Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

Gzil, Arkadiusz; Zarębska, Izabela; Bursiewicz, Wiktor; Antosik, Paulina; Grzanka, Dariusz; Szylberg, Łukasz

doi:10.1007/s11033-019-05058-1

Cited by 80 publications

(53 citation statements)

References 177 publications

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“…While the field has unraveled many important signaling nodes and aberrant crosstalk pathways that are important for PaCSC biology [ 26 ], we are still far from understanding the biological intricacies of these cells. For example, the proto-oncogene nonreceptor tyrosine-protein kinase SRC is overexpressed in PDAC and has been linked to tumor development, progression, and metastasis [ 27 , 28 , 29 , 30 , 31 , 32 ]; however, the role of SRC kinases in PaCSCs has been understudied [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

Alcalá

Mayoral-Varo

Ruiz-Cañas

et al. 2020

IJMS

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The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed.

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Section: Introductionmentioning

confidence: 99%

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

Alcalá

Mayoral-Varo

Ruiz-Cañas

et al. 2020

IJMS

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“…As CD44 is widely accepted as one of the most reliable cancer stem cell markers in various kinds of cancer [ 42 , 43 ], and because BSH-polyR directly binds to the CD44 cell-surface protein as shown above, we thought that BSH-polyR could be a promising cancer stem cell-directed 10 B agent. To test this possibility, we prepared several cell populations with cellular heterogeneity by transforming NMuMG cells (normal murine mammary gland epithelial cells) with oncogenic lentivirus and YAP1-overexpressing lentivirus ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

In Vitro Studies to Define the Cell-Surface and Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a Potential Delivery Agent for Boron Neutron Capture Therapy

Fujimura

Yasui

Igawa

et al. 2020

Cells

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Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44High cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44High cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.

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“…CD133 (human prominin-1, PROM1) is a glycoprotein with five transmembrane domains and two larger extracellular glycosylation chains that serves as an important surface marker, showing abundant expression in both cytoplasm and nucleus of various tumor tissues, including hepatocellular carcinoma (HCC), brain tumor, pancreatic cancer, prostate cancer, and colon cancer [ 74 , 75 , 76 , 77 , 78 ]. The CD133 + subpopulation was initially isolated from Huh7, one of the benign HCC cell lines, and was shown to play potential roles in proliferation and tumorigenesis [ 34 ] in both SMMC7721 and PLC8024 cells [ 35 , 79 ].…”

Section: Identification and Plasticity Of Lcscsmentioning

confidence: 99%

Cancer Stem Cell Functions in Hepatocellular Carcinoma and Comprehensive Therapeutic Strategies

Liu

Yeh

Lin

2020

Cells

157

109

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Hepatocellular carcinoma (HCC) is a significant cause of cancer-related mortality owing to resistance to traditional treatments and tumor recurrence after therapy, which leads to poor therapeutic outcomes. Cancer stem cells (CSC) are a small subset of tumor cells with the capability to influence self-renewal, differentiation, and tumorigenesis. A number of surface markers for liver cancer stem cell (LCSC) subpopulations (EpCAM, CD133, CD44, CD13, CD90, OV-6, CD47, and side populations) in HCC have been identified. LCSCs play critical roles in regulating HCC stemness, self-renewal, tumorigenicity, metastasis, recurrence, and therapeutic resistance via genetic mutations, epigenetic disruption, signaling pathway dysregulation, or alterations microenvironment. Accumulating studies have shown that biomarkers for LCSCs contribute to diagnosis and prognosis prediction of HCC, supporting their utility in clinical management and development of therapeutic strategies. Preclinical and clinical analyses of therapeutic approaches for HCC using small molecule inhibitors, oncolytic measles viruses, and anti-surface marker antibodies have demonstrated selective, efficient, and safe targeting of LCSC populations. The current review focuses on recent reports on the influence of LCSCs on HCC stemness, tumorigenesis, and multiple drug resistance (MDR), along with LCSC-targeted therapeutic strategies for HCC.

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Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

Cited by 80 publications

References 177 publications

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

In Vitro Studies to Define the Cell-Surface and Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a Potential Delivery Agent for Boron Neutron Capture Therapy

Cancer Stem Cell Functions in Hepatocellular Carcinoma and Comprehensive Therapeutic Strategies

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