Hyaluronan-CD44 axis orchestrates cancer stem cell functions

Skandalis, Spyros S.; Karalis, Theodoros; Chatzopoulos, Athanasios; Karamanos, Nikos K.

doi:10.1016/j.cellsig.2019.109377

Cited by 100 publications

(85 citation statements)

References 127 publications

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“…Human breast cancer stem cells are molecularly defined as a population of CD24 Low /CD44 High cells [ 33 ]. CD44 is a cell-surface protein that interacts with hyaluronic acid and is involved in cell adhesion, migration, and metastasis [ 34 , 35 , 36 ]. Importantly, CD44 was reported to localize at lipid rafts on the cell surface [ 37 , 38 ] and exhibits several types of modifications including glycosylation [ 39 , 40 ].…”

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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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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“…HA plays pivotal roles in inflammation and cancer through its association with the transmembrane receptor CD44 (261), a 80-95-kDa type-I transmembrane glycoprotein that is the major cell-surface receptor for HA and that is implicated in a wide variety of biological processes, including cell adhesion and migration (262,263). CD44 plays a prominent role in tumor cell signaling (264) and is an important marker for various cancer stem cells (CSCs), including pancreatic (265)(266)(267) and gastric (268,269) CSCs. Cell surface adhesion receptor CD44 is a multifunctional receptor that controls many biological functions involved in cancer cell adhesion and migration (270), is highly expressed in many cancers and regulates metastasis, although the underlying mechanisms leading to cancer cell detachment from the tumor mass and invasion of the surrounding extracellular matrix (ECM) are not totally elucidated.…”

Section: Rafts and Metastasismentioning

confidence: 99%

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

Mollinedo

Gajate

2020

Journal of Lipid Research

187

206

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Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts. Many signal transduction processes involved in cancer development (insulin-like growth factor system and phosphatidylinositol 3-kinase-AKT) and metastasis [cluster of differentiation (CD)44] are dependent on or modulated by lipid rafts. Additional proteins playing an important role in several malignant cancers (e.g., transmembrane glycoprotein mucin 1) are also being detected in association with lipid rafts, suggesting a major role of lipid rafts in tumor progression. Conversely, lipid rafts also serve as scaffolds for the recruitment and clustering of Fas/CD95 death receptors and downstream signaling molecules leading to cell death-promoting raft platforms. The partition of death receptors and downstream signaling molecules in aggregated lipid rafts has led to the formation of the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER, which leads to apoptosis amplification and can be pharmacologically modulated. These death-promoting rafts can be viewed as a linchpin from which apoptotic signals are launched. In this review, we discuss the involvement of lipid rafts in major signaling processes in cancer cells, including cell survival, cell death, and metastasis, and we consider the potential of lipid raft modulation as a promising target in cancer therapy.

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“…HA serves as a primary ECM component of the stem cell niche and is often overexpressed in several cancer types. In fact, the HA-rich ECM provides a favorable microenvironment for self-renewal and maintenance of CSCs by influencing the behavior of stromal cells [ 43 ]. In a study by Okuda et al [ 44 ], HA in metastatic breast cancers stimulated the interactions of CSC and tumor-associated macrophages (TAMs) that, in turn, activated stromal fibroblasts to support self-renewal via fibroblast growth factor (FGF) activation.…”

Section: Extracellular Matrix As a Niche For Cancer Stem Cell Formmentioning

confidence: 99%

Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

Kesh

Gupta

Durden

et al. 2020

Cancers

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The extracellular matrix (ECM) has remained an enigmatic component of the tumor microenvironment. It drives metastasis via its interaction with the integrin signaling pathway, contributes to tumor progression and confers therapy resistance by providing a physical barrier around the tumor. The complexity of the ECM lies in its heterogeneous composition and complex glycosylation that can provide a support matrix as well as trigger oncogenic signaling pathways by interacting with the tumor cells. In this review, we attempt to dissect the role of the ECM in enriching for the treatment refractory cancer stem cell population and how it may be involved in regulating their metabolic needs. Additionally, we discuss how the ECM is instrumental in remodeling the tumor immune microenvironment and the potential ways to target this component in order to develop a viable therapy.

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Hyaluronan-CD44 axis orchestrates cancer stem cell functions

Cited by 100 publications

References 127 publications

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

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

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

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