Hyaluronan in cancer biology

Cover Page......Page 1
Copyright Page......Page 2
Dedication......Page 3
Preface......Page 4
Foreword......Page 7
List of Contributors......Page 9
CHAPTER 1 - Association Between Cancer and ‘‘Acid Mucopolysaccharides’’: An Old Concept Comes of Age, Finally......Page 12
Historical Perspective......Page 13
Overview......Page 14
Hyaluronan Can Influence Cell Fate: Studies from Embryology......Page 15
Extracellular Matrix of Normal Cells......Page 16
Mechanisms for Peritumor Stromal Abnormalities......Page 17
Malignancies Have Increased Hyaluronan......Page 18
Cancers Are Resilient in Utilizing Hyaluronan Metabolism fornbspTheir Own Promotion......Page 19
ABNORMALITIES IN OTHER GLYCOSAMINOGLYCANS
OCCUR IN MALIGNANCY......Page 20
References......Page 21
INTRODUCTION......Page 26
HYALURONAN, CD44, AND DRUG RESISTANCE......Page 27
CELL-AUTONOMOUS REGULATION OF CELL SURVIVAL SIGNALING PATHWAYS BY HYALURONAN AND CD44......Page 28
HYALURONAN, CD44, AND DRUG TRANSPORTERS......Page 30
HYALURONAN, EMMPRIN, AND THE GLYCOLYTIC PHENOTYPE......Page 32
HYALURONAN, CANCER STEM CELLS, AND DRUG RESISTANCE......Page 33
CONCLUSIONS......Page 35
ACKNOWLEDGMENTS......Page 36
References......Page 37
INTRODUCTION......Page 43
EXPRESSION OF HYALURONAN SYNTHASES AND HYALURONIDASES......Page 45
HYALURONAN SIGNALING PROMOTES THE MALIGNANT PHENOTYPE OF TUMOR CELLS......Page 46
REGULATION OF HYALURONAN LEVELS PRODUCED BY TUMOR CELLS......Page 49
REGULATION OF HYALURONAN SYNTHESIS BY PERITUMORAL STROMA CELLS......Page 50
ACKNOWLEDGMENTS......Page 52
References......Page 53
CHAPTER 4 - Hyaluronan Binding Protein 1 (HABP1/p32/gC1qR): A New Perspective in Tumor Development......Page 57
Purification, Cloning and Characterization......Page 59
HA Binding Motif in HABP1/p32/gC1qR......Page 60
Three-Dimensional Structure of HABP1/p32/gC1qR......Page 61
Chromosomal Localization and Genomic Organization of HABP1......Page 62
Subcellular Localization......Page 63
HABP1 as an Adhesive Protein......Page 64
Signal Transduction......Page 65
Upregulation of HABP1 in Apoptosis Induction......Page 66
ECTOPIC EXPRESSION OF HABP1 INDUCES APOPTOSIS,
AUTOPHAGIC VACUOLES, AND MITOCHONDRIAL
DYSFUNCTION......Page 67
Differential Expression of Hyaluronic Acid Binding Protein 1 (HABP1)/P32/C1QBP During Progression of Epidermal Carcinoma......Page 68
ASSOCIATION OF ALLELIC LOSS AT 17P13.3
CHROMOSOME WITH CANCER INITIATION
AND PROMOTION......Page 70
CONCLUSION......Page 71
References......Page 72
CHAPTER 5 - CD44 Meets Merlin and Ezrin: Their Interplay Mediates the Pro-Tumor Activity of CD44 and Tumor-Suppressing Effect of Merlin......Page 75
CD44 PROMOTES TUMOR INVASION AND METASTASIS......Page 76
CD44-MEDIATED SIGNALS AND THE DOWNSTREAM EFFECTORS OF CD44......Page 78
THE FUNCTION OF MERLIN IS REGULATED BY ITS POSTTRANSLATIONAL MODIFICATIONS......Page 80
MERLIN COUNTERACTS THE EFFECT OF EZRIN AND INHIBITS THE CD44–HA INTERACTION AND CD44 FUNCTION......Page 81
MERLIN IS INVOLVED IN SEVERAL IMPORTANT SIGNAL TRANSDUCTION PATHWAYS......Page 82
MERLIN ACTS UPSTREAM OF THE HIPPO SIGNALING PATHWAY IN DROSOPHILA......Page 83
A MODEL FOR CD44 SIGNALING THROUGH MERLIN AND THE ERM PROTEINS......Page 85
References......Page 86
HYALURONAN (HA) METABOLISM IN CANCER PROGRESSION......Page 92
CD44 (AN HA RECEPTOR) IN TUMOR PROGRESSION......Page 94
HA-Mediated CD44 Interaction with ErbB2 (p185HER2) Kinase......Page 95
HA-Mediated CD44 Interaction with EGFR......Page 96
HA-Mediated CD44 Interaction with TGFb Receptor Signaling......Page 99
HA-Mediated CD44 Interaction with c-Src Signaling......Page 100
HA-Mediated CD44 Interaction with RhoA-ROK Signaling and Cytoskeleton Function......Page 102
ACKNOWLEDGMENTS......Page 104
References......Page 105
INTRODUCTION: HA, CD44, THE TUMOR MICROENVIRONMENT, AND METASTASIS......Page 111
PENETRATION: CD44 PROMOTED INVASION AND INTRAVASATION......Page 113
CELL–CELL ADHESION: ROLE OF CD44 IN PROMOTING EXTRAVASATION......Page 119
THE ROLE OF CD44 IN PROMOTING TISSUE-SPECIFIC METASTASIS......Page 123
References......Page 124
 CHAPTER 8 - Involvement of CD44, a Molecule with a Thousand Faces, in Cancer Dissemination......Page 128
PROLOGUE......Page 129
CD44 Structure......Page 131
CD44 Ligands and the Mechanism of Ligand Binding......Page 132
THE INTERACTION BETWEEN THE CD44 OF LB CELLS AND HYALURONATE – IN VITRO STUDIES......Page 133
ELUCIDATION OF HA BINDING MECHANISM IN LB CELLS......Page 136
THERAPY OF THE MALIGNANT LYMPHOMA: BLOCKING THE INTERACTION BETWEEN CD44 AND ITS LIGAND BY TARGETING THE CD44 VARIANT WITH RELEVANT ANTIBODY......Page 139
GENE VACCINATION WITH CD44 VARIANT CONSTRUCT, RATHER THAN WITH STANDARD CD44 CONSTRUCT, GENERATES RESISTANCE TO TUMOR GROWTH......Page 141
EPILOGUE......Page 142
References......Page 144
INTRODUCTION......Page 148
RHAMM AND CANCER......Page 150
EXTRACELLULAR AND INTRACELLULAR RHAMM ONCOGENIC FUNCTIONS IN CULTURE......Page 153
Functions of RHAMM in Animal Models of Repair and Disease......Page 155
RHAMM PROTEIN FORMS CONTROL MULTIPLE SIGNALING NETWORKS......Page 158
ACKNOWLEDGMENTS......Page 166
INTRODUCTION......Page 170
HA BIOSYNTHESIS......Page 171
ALTERED HA SYNTHESIS IN CANCER......Page 172
TUMOR–STROMAL INTERACTION......Page 173
NOVEL FUNCTION OF HA IN STROMAL CELL RECRUITMENT......Page 175
EPITHELIAL–MESENCHYMAL TRANSITION CAUSED BY HA OVERPRODUCTION......Page 177
ROLES OF HA-RICH ECM IN TUMOR ANGIOGENESIS......Page 178
CONCLUSION AND PERSPECTIVES......Page 180
References......Page 181
INTRODUCTION......Page 185
HYALURONIDASES......Page 186
HAase EXPRESSION IN TUMOR CELLS......Page 188
HAase FUNCTIONS IN GENITO-URINARY TUMORS......Page 190
HAase as a Tumor Suppressor......Page 191
Regulation of HAase Activity......Page 192
REGULATION OF HAase GENE EXPRESSION......Page 193
HAase and Apoptosis......Page 194
HAase as a Diagnostic and Prognostic Indicator......Page 195
HAase and Cancer Therapeutics......Page 197
References......Page 198
INTRODUCTION......Page 203
HYALURONIDASES AND THEIR STRUCTURE......Page 205
THE WARBURG EFFECT......Page 206
HYALURONIDASE INHIBITORS......Page 208
HYALURONAN FRAGMENTATION......Page 209
HYALURONIDASES AS ANTI-CANCER CHEMOTHERAPEUTIC AGENTS......Page 211
THE CONUNDRUMS INVOLVING HYALURONIDASES IN MALIGNANCY......Page 212
References......Page 213
INTRODUCTION......Page 217
PRODUCTION OF HA FRAGMENTS......Page 218
CD44......Page 220
Receptor for HA-Mediated Motility (RHAMM)......Page 223
Toll-Like Receptor (TLR)......Page 225
DIFFERENT SIZES OF HA HAVE DIFFERENT BIOLOGICAL FUNCTIONS......Page 226
HA Fragments of 4–6-mers (z1.35 kDa)......Page 232
Angiogenesis......Page 236
Effects on Tumor Cells......Page 237
Immune Response and Inflammation......Page 239
HA Fragments of 100-mers or Larger (z20 kDa)......Page 240
CONCLUSIONS AND FUTURE PROSPECTS......Page 242
References......Page 245
CHAPTER 14 - Hyaluronan in Human Tumors: Importance of Stromal and Cancer Cell-Associated Hyaluronan......Page 251
Hyaluronan Accumulation in Malignant Tumors......Page 252
Hyaluronan in Tumor Cells Arising from Simple Epithelia......Page 253
Hyaluronan in Tumor Cells Arising from Stratified Epithelia......Page 259
Stromal Accumulation of Hyaluronan......Page 261
Enhanced Synthesis of Hyaluronan in Tumors......Page 264
Catabolism as a Determinant of Tumor Hyaluronan Content?......Page 266
Genomic Changes in the Tumor Stroma......Page 267
Hyaluronan Support for Migration and Survival of Malignant Cells......Page 268
Hyaluronan and Inflammation......Page 270
References......Page 272
CHAPTER 15 - The Oncofetal Paradigm Revisited: MSF and HA as Contextual Drivers of Cancer Progression......Page 279
Introduction......Page 280
MSF: Its Molecular Characterization And Spectrum Of Bioactivities......Page 281
The Oncofetal Pattern Of Msf Expression: Contextual Control By Ecm And Soluble Factors......Page 286
Section Summary and Significance......Page 290
The Contextual Control Of Target Cell Response To Msf By Ecm And Soluble Factors......Page 291
Section Summary and Significance......Page 293
An Extended Oncofetal Paradigm Of Cancer Pathogenesis: The Inter Dependent Contribution Of Genetic And Epigenetic Mechanisms......Page 294
Acknowledgments......Page 297
References......Page 298
Overview of Prostate Cancer Progression......Page 301
HA Synthases And Hyaluronidases......Page 302
Inflammation Response And Hypoxia......Page 303
Tumorigenesis......Page 305
Angiogenesis And Lymphangiogenesis......Page 310
Metastasis And Bone Turnover......Page 311
References......Page 313
Hyaluronan and melanoma......Page 320
CD44 Influences MM Proliferation......Page 322
Hyaluronan Affects MM Migration via CD44......Page 324
Hyaluronan metabolism, melanoma, and UV-B......Page 325
Conclusion and perspectives......Page 327
References......Page 328
THE TUMOR MICROENVIRONMENT OF BREAST CANCER......Page 331
INTRATUMORAL HYALURONAN LOCALIZATION DURING BREAST CANCER TUMORIGENESIS AND PROLIFERATION......Page 332
METABOLISM OF HYALURONAN IN BREAST CANCER – DYSREGULATION OF A FINELY TUNED PROCESS......Page 333
Comparative Expression and Isoform Functionality of the Hyaluronan Synthases......Page 334
HAS-2 is a Prognostic Indicator of Breast Cancer Tumorigenesis and Metastasis......Page 335
Hyaluronan Degradation – An Essential Component of Breast Cancer Progression......Page 339
THE CO-ORDINATED FUNCTION AND IMPORTANCE OF HA METABOLISM IN BREAST CANCER......Page 343
References......Page 345
INTRODUCTION......Page 351
CLINICAL APPLICATIONS OF HYALURONIDASE IN MALIGNANT DISEASE......Page 353
HYALURONIDASE PREPARATIONS IN ADDITIONAL CLINICAL STUDIES IN VIENNA......Page 354
EXTENDED STUDIES OF THE USE OF HYALURONIDASE AS ADJUNCTS IN CANCER CHEMOTHERAPY......Page 355
SIDE EFFECTS OBSERVED DURING CLINICAL AND EXPERIMENTAL USES OF HYALURONIDASE......Page 358
APPLICATION OF HYALURONIDASE IN EXPERIMENTAL ANIMAL MODELS OF CANCER......Page 359
OVERVIEW AND ADDITIONAL OBSERVATIONS......Page 360
CONCLUDING REMARKS AND SUMMARY......Page 362
References......Page 364
CHAPTER 20 - Exploiting the Hyaluronan– CD44 Interaction for Cancer Therapy......Page 367
EXPLOITING THE HYALURONAN–CD44 INTERACTION FOR CANCER THERAPY......Page 368
Interference with CD44–HA Interactions by Soluble CD44......Page 369
Interference with CD44–HA Interactions by Antibodies......Page 377
Interference with CD44–HA Interactions by HA......Page 379
Targeting Chemotherapeutics to CD44 with HA......Page 380
Targeting Chemotherapeutics to CD44 with HA Drug Carriers......Page 381
Targeting Chemotherapeutics to CD44 with Antibodies......Page 382
CD44 MEDIATED CANCER IMMUNOTHERAPY......Page 383
GENE THERAPY BY DOWN REGULATION OF CD44 PRODUCTION......Page 384
GENE THERAPY BY PRODUCTION OF CYTOTOXIC GENES THROUGH CD44 REGULATION......Page 385
CONCLUSION......Page 386
References......Page 387
ONCOGENIC SHEEP RETROVIRUSES......Page 392
IDENTIFICATION OF HYAL-2 AS THE CELL-ENTRY RECEPTOR FOR JSRV AND ENTV......Page 394
HYAL-2 LOCATION AND ENZYMATIC ACTIVITY......Page 397
HYAL-2 ROLE IN SHEEP RETROVIRUS ONCOGENESIS?......Page 399
References......Page 401
Index......Page 404
Color Plate......Page 412