| Preface | xi |
| Abbreviations | xiii |
1. | VEGF and Its Receptors | 1 |
| Activities of VEGF | 1 |
| VEGF Isoforms | 2 |
| Regulation of VEGF Gene Expression | 2 |
| The VEGF Receptors | 3 |
| Role of VEGF in Physiological Angiogenesis | 5 |
| Role of VEGF in Pathologic Conditions | 6 |
| Therapeutic Implications and Perspectives | 7 |
2. | Hypoxic Regulation of VEGF | 12 |
| Transcriptional Regulation of VEGF | 12 |
| Post Transcriptional Regulation of VEGF | 13 |
| Abnormalities in the Hypoxic Regulation of VEGF | 16 |
3. | Molecular Mechanisms of VEGF-Induced Angiogenesis | 19 |
| Angiogenesis | 19 |
| The Role of Vascular Endothelial Growth Factor in Angiogenesis | 19 |
| The VEGF Signal Cascade in Angiogenesis | 21 |
4. | Crosstalk between VEGF and Bcl-2 in Tumor Progression and Angiogenesis | 26 |
| Angiogenic Potential of Tumor Cells Overexpressing Bcl-2 | 26 |
| Role of Bcl-2 in VEGF-Promoted Survival of Tumor Cells | 29 |
| Role of Bcl-2 in Endothelial Cells | 29 |
| Clinical Relevance of VEGF and Bcl-2 Expression | 31 |
5. | Vascular Endothelial Growth Factor in Breast Cancer | 40 |
| VEGF and Tumor Growth | 41 |
| Serum VEGF and Breast Cancer | 42 |
| VEGF and Clinical Consequences | 43 |
| Future Strategies in Breast Cancer | 44 |
6. | VEGF and Tumor Progression in Human Melanoma | 48 |
| VEGF in Tumor Angiogenesis | 48 |
| Angiogenesis and Human Melanoma | 49 |
| VEGF in Human Melanoma | 50 |
7. | VEGF in Esophageal Cancer | 54 |
| VEGF in Squamous Cell Carcinoma of the Esophagus | 54 |
| VEGF in Barrett's Disease and Adenocarcinoma of the Esophagus | 55 |
| Circulating VEGF Levels in Esophageal Carcinoma | 56 |
| VEGF and MVD during Neoadjuvant Treatment of Esophageal Carcinoma | 57 |
| VEGF-C and Lymphangiogenesis in Esophageal Carcinoma | 59 |
| Anti-VEGF Treatment of Esophageal Carcinoma | 60 |
8. | VEGF in Colorectal Cancer | 64 |
| Colon Cancer | 64 |
| VEGF in Colorectal Cancer Progression | 64 |
| Prognostic Value of VEGF in Colorectal Cancer Patients | 66 |
| The Role of VEGF in Metastasis of Colorectal Cancer | 66 |
| Anti-Angiogenic Therapy by Interference with the VEGF Pathway in Colorectal Cancer | 68 |
9. | Vascular Endothelial Growth Factor in Malignant Disease of the Central Nervous System | 72 |
| VEGF in the Normal Brain | 72 |
| VEGF Is Upregulated in Malignant Disease of the CNS | 72 |
| Angiogenesis in Glioma | 74 |
| Factors Influencing VEGF Production | 76 |
| C6 Glioma Is an Excellent Model for the Study of High Grade Human Glioma with Regard to VEGF | 76 |
| VEGF Is Responsible for the Virulent Nature of High Grade Gliomas | 77 |
| Interrupting VEGF-Receptor Signaling Inhibits Glioma Growth in Preclinical Models | 77 |
| Current Therapy of Glioma: VEGF Contributes to Treatment Failure | 78 |
10. | VEGF in Hematopoietic Malignancy | 83 |
| The VEGF/VEGF Receptor Pathway | 84 |
| Hematopoietic and Endothelial Cells Share a Common Hematopoietic/Endothelial Progenitor Cell | 84 |
| VEGF Bone Marrow Interactions in Hematological Malignancy | 85 |
| VEGF and Angiogenesis in Acute Leukemia and Myelodysplasia | 88 |
| VEGF and Angiogenesis in Myeloproliferative Disorders | 90 |
| VEGF and Angiogenesis in B-Cell Chronic Lymphocytic Leukemia | 92 |
| VEGF and Angiogenesis in Lymphomas | 93 |
| VEGF and Angiogenesis in Myeloma | 94 |
| VEGF Signalling Pathways As a Therapeutic Target in Hematological Malignancies | 95 |
11. | Targeting VEGF in Pancreatic Cancer | 107 |
| Cancer Metastasis | 107 |
| Tumor Angiogenesis | 107 |
| Regulation of Angiogenesis by the Microenvironment | 109 |
| VEGF/VPF: A Pro-Angiogenic Molecule | 109 |
| Regulation of VEGF/VPF Expression in Tumors | 110 |
| Development of a Human Pancreatic Adenocarcinoma Model | 110 |
| Anti-VEGF Therapy in Pancreatic Cancer | 111 |
| Anti-Angiogenic Therapy: Clinical Implications | 112 |
12. | Effects of Fibrinogen and Associated Peptide Fragments on the Activation of Human Endothelial Cells by VEGF in Vitro | 117 |
| Fibrinogen and Fibrin Formation | 118 |
| Fibrinolysis | 118 |
| Effects of Fibrinogen on Endothelial Cell Activation | 118 |
| Fibrin, VEGF and Angiogenic Mechanisms | 124 |
| Stimulation of VEGF Induced Angiogenesis by Fibrin E-Fragment | 126 |
| Fibrinogen E-Fragment Inhibits VEGF Activation of Endothelial Cells | 129 |
| The Effects of Other Fibrinogen/Fibrin Related Fragment on VEGF-Activation of Endothelial Cells | 130 |
13. | Vascular Endothelial Growth Factor (VEGF) and Its Role in Non-Endothelial Cells: Autocrine Signalling by VEGF | 133 |
| VEGF in the Cardiovascular System | 133 |
| VEGF and the Central Nervous System (CNS) | 134 |
| VEGF and Its Role in Bone | 135 |
| VEGF in Hematopoietic Cells and Hematological Malignancies | 135 |
| VEGF Signalling in Hematopoietic Cells | 136 |
| Evidence for VEGF Autocrine Signalling in Solid Tumors | 136 |
| Autocrine VEGF Signalling in Breast Cancer | 137 |
| VEGF Stimulates Breast Cancer Invasion | 137 |
| VEGF Signalling in Tumor Cells | 138 |
| Anti-Angiogenic Therapy | 139 |
14. | Vascular Endothelial Growth Factor C and Vascular Endothelial Growth Factor D: Biology, Functions and Role in Cancer | 145 |
| Molecular Biology of VEGF-C and VEGF-D | 145 |
| VEGF-C and VEGF-D Signalling and Function | 149 |
| VEGF-C and VEGF-D in Human Malignancy | 152 |
| Potential Therapeutic Roles | 156 |
| Index | 163 |