Dissecting the role of hyaluronan synthases in the tumor microenvironment

Passi, Alberto; Vigetti, Davide; Buraschi, Simone; Iozzo, Renato V.

doi:10.1111/febs.14847

Cited by 78 publications

(57 citation statements)

References 119 publications

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“…150 Hyaluronic acid (HA) is a glycosaminoglycan that is a principal constituent of the tumor stroma and cancer cell surfaces. It is an important EMT mediator and metastatic cancers express increased levels of HA, its CD44 receptor, and its synthase in the tumor cell microenvironment, 151 particularly in breast, oral, prostate, and ovarian cancers. 152,153 HA-mediated EMT enhancement is driven by the expression of zinc finger E-box-binding homeobox 1 (ZEB1) and its interaction with CD44, which in turn activates HA synthase 2 (HAS2) expression.…”

Section: Epithelial-mesenchymal Transition: What Is New?mentioning

confidence: 99%

Molecular principles of metastasis: a hallmark of cancer revisited

Fares

Khachfe

et al. 2020

Sig Transduct Target Ther

1,429

935

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Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

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Section: Epithelial-mesenchymal Transition: What Is New?mentioning

confidence: 99%

Molecular principles of metastasis: a hallmark of cancer revisited

Fares

Khachfe

et al. 2020

Sig Transduct Target Ther

1,429

935

View full text Add to dashboard Cite

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“…Hyaluronic acid (HA) is a GAG that is not conjugated to peptides, and in contrast to the three others, it is not synthesized in the Golgi apparatus. Synthesis is performed by a family of three transmembrane glycosyltransferases, hyaluronan synthetase 1-3 (HAS1-3), which alternately conjugate gluconic acid and Nacetylglucosamine (reviewed in Weigel and DeAngelis, 2007;Passi et al, 2019). HASs are plasma-membrane-bound proteins, which probably are not only responsible for the synthesis but also for the extracellular export of the synthesized HA macromolecule via direct extrusion through an enzymatic pore.…”

Section: Hyaluronic Acidmentioning

confidence: 99%

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Henke

Nandigama

Ergün

2020

Front. Mol. Biosci.

725

613

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Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

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“…Although HC-HA has an essential physiological role during mammalian oocyte maturation (14), in pathological conditions monocytes interact with HC-HA matrices via cell surface CD44, thereby contributing to immune cells recruitment to the site of inflammation (15). As HA regulates a variety of cellular phenomena, it is not surprising that it has critical roles in several pathologies, including cancers (16,17), vascular diseases (18), diabetes (19) and respiratory diseases (20) that are the first causes of death in western countries.…”

Section: Hyaluronanmentioning

confidence: 99%

Sirtuin 1 reduces hyaluronan synthase 2 expression by inhibiting nuclear translocation of NF-κB and expression of the long-noncoding RNA HAS2–AS1

Caon

Bartolini

Moretto

et al. 2020

Journal of Biological Chemistry

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Hyaluronan (HA) is one of the most prevalent glycosaminoglycans of the vascular extracellular matrix (ECM). Abnormal HA accumulation within blood vessel walls is associated with tissue inflammation and is prominent in most vascular pathological conditions such as atherosclerosis and restenosis. Hyaluronan synthase 2 (HAS2) is the main hyaluronan synthase enzyme involved in HA synthesis and uses cytosolic UDP-glucuronic acid and UDP-GlcNAc as substrates. The synthesis of UDP-glucuronic acid can alter the NAD+/NADH ratio via the enzyme UDP-glucose dehydrogenase, which oxidizes the alcohol group at C6 to the COO− group. Here, we show that HAS2 expression can be modulated by sirtuin 1 (SIRT1), the master metabolic sensor of the cell, belonging to the class of NAD+-dependent deacetylases. Our results revealed the following. 1) Treatments of human aortic smooth muscle cells (AoSMCs) with SIRT1 activators (SRT1720 and resveratrol) inhibit both HAS2 expression and accumulation of pericellular HA coats. 2) Tumor necrosis factor α (TNFα) induced HA-mediated monocyte adhesion and AoSMC migration, whereas SIRT1 activation prevented immune cell recruitment and cell motility by reducing the expression levels of the receptor for HA-mediated motility, RHAMM, and the HA-binding protein TNF-stimulated gene 6 protein (TSG6). 3) SIRT1 activation prevented nuclear translocation of NF-κB (p65), which, in turn, reduced the levels of HAS2–AS1, a long-noncoding RNA that epigenetically controls HAS2 mRNA expression. In conclusion, we demonstrate that both HAS2 expression and HA accumulation by AoSMCs are down-regulated by the metabolic sensor SIRT1.

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Dissecting the role of hyaluronan synthases in the tumor microenvironment

Cited by 78 publications

References 119 publications

Molecular principles of metastasis: a hallmark of cancer revisited

Molecular principles of metastasis: a hallmark of cancer revisited

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Sirtuin 1 reduces hyaluronan synthase 2 expression by inhibiting nuclear translocation of NF-κB and expression of the long-noncoding RNA HAS2–AS1

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