Simpson / Heldin Hyaluronan Signaling and Turnover

1. Auflage 2014
ISBN: 978-0-12-800393-0
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 123, 418 Seiten

Reihe: Advances in Cancer Research

Advances in Cancer Research provides invaluable information on the exciting and fast-moving field of cancer research. Here, once again, outstanding and original reviews are presented on a variety of topics. This volume covers hyaluronan signaling and turnover. - Provides information on cancer research - Outstanding and original reviews - Suitable for researchers and students

Paraskevi Heldin, Ph.D., received her B.Sci. exam (Chemistry/Biochemistry Mathematics), Uppsala University in 1979 and her Ph.D., in Medical and Physiological Chemistry for studies on regulatory phosphorylation of proteins, Faculty of Medicine, Uppsala University, in 1987. After dissertation she changed research area and focused on the biology of hyaluronan under the supervision of Professor T.C. Laurent, Uppsala University. She worked at Department of Medical and Physiological Chemistry during 1987- 2000, and was awarded Docent appointment in Medical and Physiological Chemistry and Scientist Position from The Göran Gustafsson Foundation. Since 2001, she is Adjunct Associate Professor at the Department of Medical Biochemistry and Microbiology, and Associate Investigator and Head of the Matrix Biology Group in Ludwig Institute for Cancer Research, Uppsala, Sweden. Year 2013, she has appointed Adjunct Professor at the Department of Medical Biochemistry and Microbiology, Uppsala Unversity, Sweden. Dr Heldin's interests are focused on understanding the mechanisms of how hyaluronan-CD44 complexes interact with the receptors for the growth factors PDGF and TGFß for modulation of the proliferative and invasive behavior of malignant cells.

Autoren/Hrsg.

Simpson, Melanie

Heldin, Paraskevi

Inhaltsverzeichnis

1;Front Cover;1
2;Hyaluronan Signaling and Turnover;4
3;Copyright;5
4;Contents;6
5;Contributors;12
6;Preface;16
7;Chapter One: Emerging Roles for Hyaluronidase in Cancer Metastasis and Therapy;18
7.1;1. Introduction;19
7.2;2. Of Mole Rats and Men: Insights About HA and Cancer;20
7.2.1;2.1. HA and hyaluronidase accelerate human cancers;20
7.2.2;2.2. Naked mole rats resist cancer;22
7.3;3. Hyaluronidase Expression in Cancer;23
7.3.1;3.1. Hyal1;23
7.3.2;3.2. Hyal2;25
7.3.3;3.3. Hyal3, Hyal4, and PH-20;27
7.4;4. Hyaluronidase Function and the Metastatic Process;28
7.4.1;4.1. Vesicle trafficking and cell motility;28
7.4.2;4.2. Vesicle shedding;31
7.4.3;4.3. Products of hyaluronidase: Fragments versus oligos;33
7.4.4;4.4. Products of hyaluronidase: Beyond HA;34
7.5;5. Hyaluronidase Targeting in Cancer Therapy and Imaging;35
7.5.1;5.1. Structural and functional features of human Hyals;35
7.5.2;5.2. Targeting of hyaluronidase for cancer therapy;39
7.5.3;5.3. Hyaluronidase-targeting agents for tumor imaging;42
7.6;6. Conclusions and Future Perspective;43
7.7;Acknowledgments;44
7.8;References;44
8;Chapter Two: Targeting Hyaluronic Acid Family for Cancer Chemoprevention and Therapy;52
8.1;1. Introduction;53
8.2;2. Targeting HA Production;55
8.2.1;2.1. Targeting HA synthases;55
8.2.2;2.2. Chemical inhibitors of HA synthesis;56
8.2.2.1;2.2.1. 4-Methylumbelliferone;56
8.2.2.2;2.2.2. Other HA synthesis inhibitors;60
8.3;3. Targeting HA Signaling;60
8.3.1;3.1. HA oligosaccharides;60
8.4;4. HA as a Carrier for Drug Delivery;62
8.5;5. Targeting HA Receptors;65
8.5.1;5.1. CD44;65
8.5.1.1;5.1.1. CD44 vaccines;65
8.5.1.2;5.1.2. CD44 siRNA delivery;66
8.5.1.3;5.1.3. Targeting CD44 for delivering antitumor therapies;67
8.5.1.4;5.1.4. Targeting of CD44 protein;67
8.5.2;5.2. RHAMM;68
8.6;6. Targeting HAase;70
8.7;7. Conclusion;71
8.8;Acknowledgments;72
8.9;References;72
9;Chapter Three: Aberrant Posttranscriptional Processing of Hyaluronan Synthase 1 in Malignant Transformation and Tumor Prog ...;84
9.1;1. Splicing and Cancer;85
9.1.1;1.1. Splicing in the human genome;85
9.2;2. Control of Pre-mRNA Splicing;86
9.2.1;2.1. Splicing mutations;87
9.3;3. Impact on Cancer of Alterations in Splicing Machinery;88
9.4;4. Aberrant Splicing of Hyaluronan Synthase 1;89
9.4.1;4.1. B lineage malignancies;89
9.4.1.1;4.1.1. Multiple myeloma;89
9.4.1.2;4.1.2. Waldenstrom macroglobulinemia;90
9.4.2;4.2. Aberrant splice variants in hyaluronan synthase 1;90
9.5;5. Clinical Impact of Aberrant HAS1 Splicing;92
9.6;6. Genetic Variations in HAS1;93
9.7;7. Functional Impact of HAS1Vs;93
9.7.1;7.1. Synthesis of HA;93
9.7.2;7.2. Functional outcomes of HA synthesis in patients;94
9.7.2.1;7.2.1. Motility and malignant spread;94
9.7.2.2;7.2.2. HAS1Vs and oncogenic events;96
9.7.2.3;7.2.3. Intermolecular interactions of HAS1Vs;96
9.7.2.4;7.2.4. HAS1Vs and genetic instability;97
9.8;8. Functional Outcomes of HAS1Vs in Transfectants;97
9.8.1;8.1. HAS1Vs synthesize intracellular HA;97
9.8.2;8.2. HAS1FL and HAS1Vs form heteromultimers with HAS1Vs as the dominant partners;98
9.8.3;8.3. Multimers with HAS1Vs stabilize HAS1FL and maintain intracellular HA;99
9.9;9. HAS1Vs and Mitotic Catastrophe;100
9.9.1;9.1. A potential mechanism underlying the oncogenic properties of aberrant HAS1 splice variants: HAS1V-mediated rescue fro ...;100
9.9.1.1;9.1.1. Receptor for hyaluronan-mediated motility (RHAMM);100
9.9.1.2;9.1.2. Impact of RHAMM overexpression and isoform imbalance;101
9.9.1.3;9.1.3. Interaction between HAS1Vs, intracellular HA, and RHAMM: The Goldilocks hypothesis;102
9.10;10. Conclusion;105
9.11;Acknowledgments;105
9.12;References;105
10;Chapter Four: Hyaluronan Synthases Posttranslational Regulation in Cancer;112
10.1;1. Introduction;113
10.2;2. HA Synthesis;115
10.3;3. HA Catabolism;118
10.4;4. HAS2 Phosphorylation, AMPK, and Its Dual Effects on Tumors;120
10.5;5. O-GlcNAcylation and Cancer;125
10.5.1;5.1. HAS2 O-GlcNAcylation;129
10.6;6. Conclusions;130
10.7;Acknowledgment;130
10.8;References;130
11;Chapter Five: Hyaluronan-Coated Extracellular Vesicles-A Novel Link Between Hyaluronan and Cancer;138
11.1;1. Introduction;139
11.2;2. Extracellular Vesicles as Novel Communicators Between Cells;141
11.2.1;2.1. EVs-A quickly expanding field of research;141
11.2.2;2.2. Variable nomenclature of EVs;141
11.2.3;2.3. Origin and formation of EVs;142
11.2.4;2.4. Methods for the analysis of EVs;142
11.2.5;2.5. EVs as carriers of regulatory molecules into target cells;143
11.3;3. EVs Promote Tumor Progression;143
11.3.1;3.1. EVs associate with cancers;143
11.3.2;3.2. Promotion of invasion and metastasis by EVs;144
11.3.3;3.3. Thrombosis and EVs;145
11.3.4;3.4. Angiogenesis is promoted by EVs;145
11.3.5;3.5. EVs participate in antitumor immunity;145
11.4;4. HA Synthesis Enhances Shedding of Extracellular Vesicles;146
11.4.1;4.1. HA-EVs are common in cells with active HA secretion;146
11.4.2;4.2. HAS-induced protrusions as a platform for vesicle shedding;146
11.4.3;4.3. Regulation of HA synthesis and EV shedding by cellular glucose supply?;148
11.4.4;4.4. HA-EVs in tissue regeneration;150
11.4.5;4.5. Body fluids rich in HA are also rich in EVs;150
11.4.6;4.6. HA-EVs provide the missing link between HA and cancer?;151
11.5;5. HA-EVs as Predictors, Targets, and Carriers of Therapy;154
11.5.1;5.1. HA-EVs as potential biomarkers for HA-rich tumors;154
11.5.2;5.2. Utilization of HA-EVs as targets and carriers for therapy;155
11.6;6. Conclusions;156
11.7;Acknowledgments;156
11.8;References;157
12;Chapter Six: Hyaluronan in the Healthy and Malignant Hematopoietic Microenvironment;166
12.1;1. Introduction;168
12.1.1;1.1. Multipotent stem cells in bone marrow;168
12.1.2;1.2. The BM stem cell microenvironment;169
12.1.3;1.3. Basic aspects of HA biology;169
12.2;2. BM MSC, Their Derivatives, and HA;170
12.2.1;2.1. MSC and HA in BM;170
12.2.2;2.2. Fibroblasts and HA in BM;176
12.2.3;2.3. Osteoblasts and HA in BM;178
12.3;3. Macrophages and HA in the BM;180
12.3.1;3.1. Role of macrophages in BM;180
12.3.2;3.2. Effect of HA on macrophages;180
12.3.3;3.3. Effect of HA on osteoclasts;183
12.4;4. Endothelial Cells and HA in BM;183
12.4.1;4.1. Role of endothelial cells in BM;183
12.4.2;4.2. Expression of HA in EC;184
12.4.3;4.3. Functions of HA in BM EC: Cell recruitment;187
12.4.4;4.4. Functions of HA in BM EC: Angiogenesis;188
12.4.5;4.5. Functions of HA in BM EC: Vascular integrity;189
12.5;5. Nerve Cells and HA in BM;190
12.6;6. Role of HA in the BM Microenvironment in Hematological Malignancies;191
12.7;7. Conclusion;194
12.8;References;195
13;Chapter Seven: Hyaluronan Regulation of Endothelial Barrier Function in Cancer;208
13.1;1. Introduction;209
13.2;2. HA Regulation of Vascular Integrity;211
13.3;3. HA Regulation of Endothelial Barrier Function During Tumor Angiogenesis;214
13.4;4. HA Regulation of Endothelial Barrier Function During Cancer Metastasis;215
13.5;5. Potential Therapeutic Effects of HMW-HA in Inhibiting Endothelial Barrier Disruption During Cancer Progression;217
13.6;6. Conclusions;218
13.7;Acknowledgments;220
13.8;References;220
14;Chapter Eight: HAS2 and CD44 in Breast Tumorigenesis;228
14.1;1. Introduction;228
14.2;2. Molecular Classification of Breast Cancer;230
14.3;3. Role of Stromal HA in Tumor Progression;232
14.4;4. Expression of HAS Genes and Breast Cancer Malignancy;235
14.5;5. HA-CD44 Interactions: A Regulatory Network During TGFß-Mediated EMT;237
14.6;6. Conclusions;240
14.7;Acknowledgments;240
14.8;References;241
15;Chapter Nine: CD44 is a Multidomain Signaling Platform that Integrates Extracellular Matrix Cues with Growth Factor and Cy ...;248
15.1;1. Introduction;249
15.2;2. Ligation of ECM Components by CD44;251
15.2.1;2.1. Hyaluronic acid;251
15.2.2;2.2. Other ECM components that are CD44 ligands;254
15.3;3. CD44: Coreceptor for Cell-Surface Receptors;255
15.3.1;3.1. The role of CD44 in regulating HGF-induced Met activation;255
15.3.2;3.2. CD44-regulated activation of other RTKs: VEGRF, PDGFRß, FGFR, and EGFR;258
15.3.3;3.3. Involvement of CD44 in the signaling of TGF family members;259
15.3.4;3.4. CD44 and GPCRs;260
15.3.5;3.5. Other receptors;261
15.4;4. CD44 as a Multidomain Signal Integration Platform;261
15.4.1;4.1. HA cross-regulation of the CD44 coreceptor function;262
15.4.2;4.2. Integration of other ECM signals with the activation of RTKs;263
15.4.3;4.3. Signal integration through cytoplasmic partners;264
15.5;5. Concluding Remarks;265
15.6;References;266
16;Chapter Ten: Hyaluronan-CD44 Interaction Promotes Oncogenic Signaling, microRNA Functions, Chemoresistance, and Radiation ...;272
16.1;1. Introduction;273
16.1.1;1.1. Hyaluronan in tumor progression;273
16.1.2;1.2. CD44 in tumor progression;273
16.2;2. Regulation of Tumor Progression by HA/CD44;275
16.2.1;2.1. Ankyrin function;275
16.2.2;2.2. RhoGTPase signaling;276
16.2.3;2.3. Matrix metalloproteinases activities;277
16.3;3. Activation of CSCs by HA/CD44;278
16.3.1;3.1. CD44v3, a newly identified CSC marker;280
16.3.2;3.2. Nanog/Oct4/Sox2 and miR-302-regulated CSC functions;282
16.3.3;3.3. Nanog & miR-21-regulated CSC functions;284
16.3.4;3.4. ErbB2, p53, and CD44 signaling in CSCs;285
16.4;4. Conclusion;286
16.5;Acknowledgments;286
16.6;References;287
17;Chapter Eleven: Advances and Advantages of Nanomedicine in the Pharmacological Targeting of Hyaluronan-CD44 Interactions a ...;294
17.1;1. Introduction;295
17.2;2. Importance of Targeting Hyaluronan-CD44 in Tumors;296
17.3;3. Therapeutic Interventions/Strategies That Target Hyaluronan and/or CD44 to Perturb Hyaluronan-CD44 Interactions in Tumors;301
17.4;4. Advances in Nanomedicine Related with Hyaluronan-CD44 Targeting;312
17.4.1;4.1. Targeted drug delivery;312
17.4.2;4.2. Advantages of nanomedicine;312
17.4.3;4.3. Nanoparticle properties;313
17.4.4;4.4. Tissue-specific deletion of CD44 signaling;314
17.4.5;4.5. Targeting chemotherapeutics to CD44 with hyaluronan conjugates as drug carriers;316
17.4.6;4.6. Application of polysaccharides (hyaluronan) in nanomedicine;317
17.5;5. Concluding Remarks/Conclusions;321
17.6;Acknowledgments;321
17.7;References;322
18;Chapter Twelve: Hyaluronan/RHAMM Interactions in Mesenchymal Tumor Pathogenesis: Role of Growth Factors;336
18.1;1. Introduction;337
18.2;2. The Role of Hyaluronan and Its Receptors in Fibrosarcoma;340
18.2.1;2.1. HA production in mesenchymal tumors;341
18.2.2;2.2. RHAMM in fibrosarcoma development and progression;344
18.3;3. GF Signaling and ECM Organization in Fibrosarcoma Pathogenesis;349
18.3.1;3.1. Transforming growth factor-ß;350
18.3.2;3.2. Fibroblast growth factor;351
18.3.3;3.3. Platelet-derived growth factor;352
18.3.4;3.4. Insulin-like growth factor and epidermal growth factor;353
18.4;4. Concluding Remarks;354
18.5;References;355
19;Chapter Thirteen: CD147: Regulator of Hyaluronan Signaling in Invasiveness and Chemoresistance;368
19.1;1. Introduction;369
19.2;2. Structure and Pleiotropic Functions of CD147;370
19.3;3. CD147-Induced HA Synthesis and Signaling;373
19.4;4. CD147-HA Axis in Cellular Invasion;373
19.4.1;4.1. Epithelial-mesenchymal transitions;374
19.4.2;4.2. Regulation of invadopodia formation and activity by CD147;375
19.4.3;4.3. Regulation of invadopodia activity and invasiveness by CD147-induced HA-CD44 and EGFR signaling;376
19.5;5. CD147-HA Axis in Chemoresistance;378
19.6;6. Induction of the CD147-HA Axis by Kaposi´s Sarcoma-Associated Herpesvirus;380
19.7;7. Conclusions;381
19.8;References;383
20;Index;392
21;Color Plate;403

Leseproben

Chapter Two Targeting Hyaluronic Acid Family for Cancer Chemoprevention and Therapy
Vinata B. Lokeshwar*,†,‡,1; Summan Mirza*; Andre Jordan§    * Department of Urology, University of Miami-Miller School of Medicine, Miami, Florida, USA
† Department of Cell Biology, University of Miami-Miller School of Medicine, Miami, Florida, USA
‡ Miami Clinical Translational Institute, University of Miami-Miller School of Medicine, Miami, Florida, USA
§ Sheila and David Funte Program in Cancer Biology, University of Miami-Miller School of Medicine, Miami, Florida, USA
1 Corresponding author: email address: [e-mail] Abstract
Hyaluronic acid or hyaluronan (HA) is perhaps one of the most uncomplicated large polymers that regulates several normal physiological processes and, at the same time, contributes to the manifestation of a variety of chronic and acute diseases, including cancer. Members of the HA signaling pathway (HA synthases, HA receptors, and HYAL-1 hyaluronidase) have been experimentally shown to promote tumor growth, metastasis, and angiogenesis, and hence each of them is a potential target for cancer therapy. Furthermore, as these members are also overexpressed in a variety of carcinomas, targeting of the HA family is clinically relevant. A variety of targeted approaches have been developed to target various HA family members, including small-molecule inhibitors and antibody and vaccine therapies. These treatment approaches inhibit HA-mediated intracellular signaling that promotes tumor cell proliferation, motility, and invasion, as well as induction of endothelial cell functions. Being nontoxic, nonimmunogenic, and versatile for modifications, HA has been used in nanoparticle preparations for the targeted delivery of chemotherapy drugs and other anticancer compounds to tumor cells through interaction with cell-surface HA receptors. This review discusses basic and clinical translational aspects of targeting each HA family member and respective treatment approaches that have been described in the literature. Keywords Hyaluronic acid HA synthase CD44 RHAMM HYAL-1 Targeted cancer therapy Abbreviations 4-MU 4-methylumbelliferone HA hyaluronic acid HAase hyaluronidase HAS HA synthase oHA HA oligosaccharides sHA sulfated hyaluronic acid UGA UDP-glucuronic acid 1 Introduction
Several members of the hyaluronic acid (HA) family of molecules, HA synthases (i.e., HAS1, HAS2, HAS3), HA receptors (i.e., CD44 and RHAMM), and hyaluronidases (mainly HYAL-1), are critical determinants of tumor growth and progression (Adamia, Pilarski, Belch, & Pilarski, 2013; Ghosh, Kuppusamy, & Pilarski, 2009; Golshani et al., 2007; Karbownik & Nowak, 2013; Orian-Rousseau, 2010; Simpson & Lokeshwar, 2008; Sironen et al., 2011). HA family members promote malignant behavior of tumor cells in vitro, and tumor growth, metastasis, and angiogenesis in xenograft models (Bharadwaj et al., 2009; Chao, Muthukumar, & Herzberg, 2007; Gurski et al., 2012; Li, Li, Brown, & Heldin, 2007; Lokeshwar, Cerwinka, & Lokeshwar, 2005; Lokeshwar et al., 2006; Siiskonen, Poukka, Tyynela-Korhonen, Sironen, & Pasonen-Seppanen, 2013; Tan et al., 2011). HA family of molecules are also potential diagnostic and prognostic markers for a variety of carcinomas including breast, bladder, endometrial, ovarian, and prostate (Auvinen et al., 2014; Bouga et al., 2010; Chi et al., 2012; Franzmann et al., 2003; Golshani et al., 2007; Gomez et al., 2009; Kramer et al., 2011; Lokeshwar et al., 2000, 2002; Paiva et al., 2005; Yoshida, Matsuda, Naito, & Ishiwata, 2012; Zhang, Chang, & Liu, 2013). In tumor tissues, HA is contributed by both tumor stroma and tumor cells and induces intracellular signaling by binding to HA receptors. HYAL-1 is the major tumor-derived hyaluronidase (HAase) that is almost exclusively expressed by tumor cells. By degrading HA, HAase/HYAL-1 generates small HA fragments, some of which (~ 10–25 disaccharide units) are angiogenic (Lokeshwar et al., 2001, 1999; West, Hampson, Arnold, & Kumar, 1985). In experimental model systems such as breast, bladder, prostate, and colon, studies have been mainly focused on modulating the expression of individual HA family molecules and assessing their effects on tumor cell phenotypes both in vitro and in vivo. Each HA synthase or HYAL-1, either alone or coexpressed, contributes to tumor cell proliferation, motility, and invasion, and to enhanced tumor growth, metastasis, and angiogenesis in xenografts; in contrast, knockdown of these genes inhibits tumor cell functions (Adamia et al., 2013; Bharadwaj et al., 2009; Chao et al., 2007; Ghosh et al., 2009; Golshani et al., 2007; Li et al., 2007). In the case of HYAL-1, promotion of tumor cell function is dose dependent. At levels detected in clinical specimens, HYAL-1 promotes tumor growth, invasion/metastasis, and angiogenesis; however, overexpression of HYAL-1 at levels exceeding those expressed in tumor tissues induces apoptosis and inhibits tumor formation (Lokeshwar, Cerwinka, Isoyama, & Lokeshwar, 2005; Lokeshwar & Selzer, 2008). Therefore, while a limited degradation of the pericellular HA matrix generates angiogenic HA fragments which induce intracellular signaling, complete degradation of the HA matrix, as a result of experimental overexpression of HYAL-1, will inhibit tumor growth and progression. Studies on HA-mediated signaling usually do not distinguish between HA and HA fragments present in the pericellular matrix. However, tumor-associated HA consists of both large HA polymers (mol. wt = 0.5 × 106 Da) and smaller angiogenic oligosaccharides, the latter correlating with HAase activity in tumor tissues (Franzmann et al., 2003; Lokeshwar et al., 2001). Angiogenic HA fragments have been detected in the urine of patients with bladder cancer and Wilm's tumor, in the saliva of patients with head and neck cancer, and in bladder and prostate tumor tissues (Franzmann et al., 2003; Kumar, West, Ponting, & Gattamaneni, 1989; Lokeshwar, Obek, Soloway, & Block, 1997; Lokeshwar et al., 2001). In contrast to the angiogenic HA fragments, HA oligosaccharides consisting of 2–3 disaccharide units have been shown to have antitumor activity, presumably because they inhibit HA-induced signaling (Ghatak, Misra, & Toole, 2002; Hosono et al., 2007; Toole, Ghatak, & Misra, 2008; Urakawa et al., 2012). Interaction between pericellular HA/angiogenic fragments and HA receptors induces multiple intracellular pathways. For example, CD44-HA and/or RHAMM-HA signaling promotes cell survival, cancer stemness, motility, and invasion by activating growth factor receptor signaling (e.g., ErbB2, c-Met), PI3/Akt and Erk pathways, small GTPase proteins (i.e., RhoA and Rac1), Ras, NFkB and src signaling, cytoskeleton reorganization, etc., and some of these pathways, in turn, may induce HA synthase and HA receptor expression (Benitez et al., 2011; Benitez, Yates, Shamaldevi, Bowen, & Lokeshwar, 2013; Bernert, Porsch, & Heldin, 2011; Bharadwaj et al., 2011; Bourguignon, Wong, Earle, Krueger, & Spevak, 2010; Dortet, Veiga, Bonazzi, & Cossart, 2010; Hatano et al., 2011; Kim, Park, Lee, & Jeoung, 2008; Lokeshwar et al., 2010; Misra, Toole, & Ghatak, 2006). CD44 and RHAMM also have compensatory roles and therefore, if HA receptors are to be targeted for cancer therapy, silencing of both receptors may be necessary to completely abrogate HA signaling (Benitez et al., 2011; Lokeshwar et al., 2010; Turley & Naor, 2012). HA-mediated signaling events also induce expression of a variety of cytokines and chemokines, COX2, and matrix metalloproteinases, which promote tumor angiogenesis and invasion/metastasis (Chow, Tauler, & Mulshine, 2010; Dunn et al., 2009; Lokeshwar et al., 2010; Misra et al., 2008, 2006; Porsch et al., 2013; Vincent, Jourdan, Sy, Klein, & Mechti, 2001; Voelcker et al., 2008). HA signaling studies reveal that targeting HA and other HA family members by small-molecule inhibitors, genetic manipulation, and vaccination could be exploited for cancer therapy. In this review, we discuss some of these approaches. 2 Targeting HA Production
2.1 Targeting HA synthases
Although targeting of HA synthases has not been exploited for therapeutic purposes, genetic knockdown studies shed light on the crucial roles that HA synthases play in different types of cancers. For example, HAS1 knockdown in bladder cancer cells induces cell cycle arrest in G2-M phase,...