Extracellular Targeting of Cell Signaling in Cancer

Strategies Directed at MET and RON Receptor Tyrosine Kinase Pathways
Standards Information Network (Verlag)
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  • erschienen am 10. Mai 2018
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International experts present innovative therapeutic strategies to treat cancer patients and prevent disease progression

Extracellular Targeting of Cell Signaling in Cancer highlights innovative therapeutic strategies to treat cancer metastasis and prevent tumor progression. Currently, there are no drugs available to treat or prevent metastatic cancer other than non-selective, toxic chemotherapy. With contributions from an international panel of experts in the field, the book integrates diverse aspects of biochemistry, molecular biology, protein engineering, proteomics, cell biology, pharmacology, biophysics, structural biology, medicinal chemistry and drug development.

A large class of proteins called kinases are enzymes required by cancer cells to grow, proliferate, and survive apoptosis (death) by the immune system. Two important kinases are MET and RON which are receptor tyrosine kinases (RTKs) that initiate cell signaling pathways outside the cell surface in response to extracellular ligands (growth factors.) Both kinases are oncogenes which are required by cancer cells to migrate away from the primary tumor, invade surrounding tissue and metastasize. MET and RON reside on both cancer cells and the support cells surrounding the tumor, called the microenvironment. MET and RON are activated by their particular ligands, the growth factors HGF and MSP, respectively. Blocking MET and RON kinase activation and downstream signaling is a promising therapeutic strategy for preventing tumor progression and metastasis. Written for cancer physicians and biologists as well as drug discovery and development teams in both industry and academia, this is the first book of its kind which explores novel approaches to inhibit MET and RON kinases other than traditional small molecule kinase inhibitors. These new strategies target key tumorigenic processes on the outside of the cell, such as growth factor activation by proteases. These unique strategies have promising potential as an improved alternative to kinase inhibitors, chemotherapy, or radiation treatment.
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978-1-119-30021-2 (9781119300212)

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Dr. James W. Janetka is an Associate Professor at Washington University School of Medicine, and has over 20 years of medicinal chemistry and drug discovery experience within both industry and academia. He has published 50 peer-reviewed manuscripts and holds 20 US patents in oncology and infectious disease.

Roseann Benson is a chemical engineer turned scientific writer and editor. As a consultant for Harvard and Washington University Medical Schools, she has edited and contributed to manuscripts and books that have been published by Wiley, CUP, Nature, and Science.
List of Contributors xiii

Preface xvii

1 Discovery and Function of the HGF/MET and the MSP/RON Kinase Signaling Pathways in Cancer 1
Silvia Benvenuti, Melissa Milan and Paolo M. Comoglio

1.1 Introduction 1

1.2 MET Tyrosine Kinase Receptor and its Ligand HGF: Structure 1

1.2.1 The Invasive growth Program 2

1.2.2 MET Mediated Signaling 4 MET Down-regulation 7

1.2.3 Cross-talk between MET and Other Receptors 7

1.2.4 MET Activation in Human Cancers 9 MET, Hypoxia and Ionizing Radiations 10 MET Expression in Cancer Stem Cells: a Paradigm of Inherence 11 Oncogene Addiction and Oncogene Expedience 11

1.2.5 Targeting HGF/MET as a Therapeutic Approach in Human Cancer 12 HGF Antagonists 13 Tyrosine Kinase Inhibitors 15 Anti-MET Monoclonal Antibodies 17 Alternative MET Blocking Strategies 18

1.2.6 Primary and Secondary Resistance 18 MET Role in Resistance to Anticancer Agents 19 Mechanism of Resistance to MET Inhibitors 19 Combinatorial Therapeutic Strategies 20

1.3 RON Tyrosine Kinase Receptor and its Ligand MSP 21

1.3.1 Discovery and Structural Biology 21

1.3.2 RON Mediated Signaling 25

1.3.3 Cross-talk between RON and other Receptors 26

1.3.4 RON Activation in Human Cancers 26

1.4 Targeting MSP/RON as a Therapeutic Approach in Human Cancer 27

1.5 Concluding Remarks 28

2 The Role of HGF/MET and MSP/RON Signaling in Tumor Progression and Resistance to Anticancer Therapy 45
Lidija Klampfer and Benjamin Yaw Owusu

2.1 Introduction 45

2.2 HGF/MET Signaling in Cancer 47

2.3 MSP/RON Signaling in Cancer 52

2.4 Cross-talk between MET and RON Signaling Pathways 53

2.5 HGF/MET and MSP/RON Signaling Elicit Resistance to Cancer Therapy 55

2.6 Conclusions and Perspectives 58

References 58

3 HGF Activator (HGFA) and its Inhibitors HAI-1 and HAI-2: Key Players in Tissue Repair and Cancer 69
Hiroaki Kataoka and Takeshi Shimomura

3.1 Introduction 69

3.2 Discovery of HGFA 70

3.2.1 Tissue Injury-induced Activation of HGF 70

3.2.2 Identification of HGFA as a Serum Activator of pro-HGF 71

3.3 Synthesis of HGFA Zymogen in vivo 71

3.4 Molecular Structure of HGFA 72

3.4.1 The Gene Encoding pro-HGFA: HGFAC 72

3.4.2 ProHGFA Protein and its Activation 72

3.4.3 Structure Biology of HGFA 74

3.5 Substrates of HGFA in vivo 75

3.6 Regulation of HGFA Activity by Endogenous Inhibitors 76

3.6.1 HGF Activator Inhibitor-1 (HAI-1): a Cell Surface Regulator of HGFA Activity 76

3.6.2 HGF Activator Inhibitor-2 (HAI-2) 78

3.6.3 Protein C Inhibitor (PCI; SERPINA5) 78

3.7 Proposed Biological Functions of HGFA in vivo 78

3.8 Roles of HGFA in Cancer 80

3.8.1 Enhanced Activation of pro-HGF and pro-MSP in Cancer Tissues 80

3.8.2 Possible Roles of HGFA in Cancer Progression 80

3.9 Conclusions and Future Perspectives of HGFA Research in Cancer 82

References 83

4 Physiological Functions and Role of Matriptase in Cancer 91
Fausto A. Varela, Thomas E. Hyland and Karin List

4.1 Introduction 91

4.2 Discovery of Matriptase 91

4.3 Biochemical and Functional Characteristics of Matriptase - Inhibitors, Substrates and Structure 92

4.3.1 Endogenous Polypeptide Matriptase Inhibitors 92

4.3.2 Matriptase Substrates 94

4.3.3 Matriptase Structure 95

4.4 Physiological and Pathophysiological Functions of Matriptase 96

4.4.1 Matriptase in Epidermal Development and Homeostasis 96

4.4.2 Matriptase in the Gastrointestinal Tract 97

4.4.3 Matriptase in Thymocytes and Salivary Glands 98

4.4.4 Matriptase in Placental/Embryonic Development 98

4.4.5 Matriptase in Neural Tube Closure 99

4.4.6 Pathways requiring Matriptase 99

4.4.7 Matriptase in Viral Infection 101

4.5 Role of Matriptase in Cancer 101

4.5.1 Studying Matriptase in Cultured Cancer Cells and Tumor Grafting Models 108

4.5.2 In vivo Cancer Studies using Genetic Models 111 Squamous Cell Carcinoma 111 Colitis-associated Colon Carcinogenesis 112 Breast Cancer 112

4.6 Conclusions 114

References 114

5 The Cell-Surface, Transmembrane Serine Protease Hepsin: Discovery, Function and Role in Cancer 125
Denis Belitskin, Shishir Mani Pant, Topi Tervonen and Juha Klefstroem

5.1 Biology of Hepsin 125

5.1.1 Discovery of Hepsin 125 Cloning of Hepsin, HPN Gene 125 Assigning Hepsin to Type II Transmembrane Serine Protease Family 126

5.1.2 Hepsin Gene and Protein 126 Expression, Regulation and Structure 126 Hepsin Activation and Activity 130

5.1.3 Physiological Functions of Hepsin 131 Growth Factor Activation 131 Serine Protease Cascades 132 Cell Proliferation and Motility 132 Epithelial Integrity 133 Organ Development 135

5.2 Hepsin in Cancer 137

5.2.1 Gain of Oncogenic Function 137 Genetic Alterations 137 Altered Subcellular Localization 138 Oncogenic Hepsin Function in vivo 140 How HPN Promotes Cancer 141

5.2.2 Targeting Hepsin in Cancer 143

5.3 Future Prospects 144

5.3.1 Hepsin's Role as Guardian of Epithelial Integrity 144

5.3.2 Cancer Disease Progression and Metastasis 145 Uncontrolled Proteolysis 145

6 Targeting HGF with Antibodies as an Anti-Cancer Therapeutic Strategy 155
Dinuka M. De Silva, Arpita Roy and Donald P. Bottaro

6.1 Introduction 155

6.2 HGF Biology 156

6.2.1 HGF Gene Organization and mRNA Transcripts 156

6.2.2 HGF Protein Isoforms and Proteolytic Processing 156 HGF Isoforms 156 HGF Activation by Proteolytic Processing 159

6.2.3 Key HGF Interactions: Heparan Sulfate Proteoglycans and Met 160 Heparan Sulfate Proteoglycans 160 Met and Key Intracellular Effectors 161

6.2.4 Major Sites of HGF Expression: Tissues and Organs 162

6.2.5 HGF Function in Development and Adulthood 162 hgf or met altered Mice: Embryogenesis 163 hgf or met altered Mice: Late Development and Adulthood 163

6.3 HGF in Cancer 164

6.3.1 Lung Cancer 165

6.3.2 Hepatocellular Carcinoma 165

6.3.3 Genitourinary Malignancies 166

6.3.4 Breast Cancer 167

6.3.5 Colorectal and Gastric Carcinomas 167

6.3.6 Papillary Thyroid Carcinoma 168

6.3.7 Brain Tumors 168

6.3.8 Melanoma 169

6.3.9 Head and Neck Squamous Cell Carcinoma 169

6.3.10 Other Malignancies 169

6.4 Anti-HGF Monoclonal Antibodies as Anti-Cancer Therapeutic

Candidates 170

6.4.1 Rilotumumab 170

6.4.2 Ficlatuzumab 174

6.4.3 TAK-701 175

6.5 Conclusions and Future Directions 176

Acknowledgements 177

References 177

7 MET and RON Receptor Tyrosine Kinases as Therapeutic Antibody Targets for Cancer 199
Mark Wortinger, Jonathan Tetreault, Nick Loizos, and Ling Liu

7.1 MET as a Therapeutic Antibody Target for Cancer 199

7.2 Challenges in Developing MET Therapeutic Antibodies 200

7.3 Anti-MET Antibody Clinical Diagnostics 203

7.4 Anti-MET Antibodies in the Clinic 204

7.4.1 Onartuzumab - Roche 204

7.4.2 Emibetuzumab - Eli Lilly 206

7.4.3 ABT-700 - AbbVie 208

7.4.4 SAIT301 - Samsung 208

7.4.5 ARGX-111 - Argenx 209

7.4.6 Sym-015 - Symphogen 210

7.5 Additional anti-MET Antibodies 210

7.5.1 DN-30 - University of Turin Medical School 210

7.5.2 Other Preclinical Stage anti-MET Antibodies 210

7.6 Summary- anti-MET Antibodies 211

7.7 RON as a Therapeutic Antibody Target for Cancer 211

7.8 Conclusions and Future Outlook 216

References 216

8 Inhibitory Antibodies of the Proteases HGFA, Matriptase and Hepsin 229
Daniel Kirchhofer, Charles Eigenbrot, and Robert A. Lazarus

8.1 Anti-Serine Protease Antibodies for Therapeutic Applications 229

8.2 Antibodies can Inhibit Trypsin-Fold Serine Proteases in Diverse Ways 230

8.2.1 Orthosteric Inhibition (Active Site Binding) 231

8.2.2 Allosteric Inhibition 231

8.2.3 Exosite Inhibition 231

8.2.4 Inhibition of Zymogen Activation 231

8.2.5 Cofactor Inhibition 231

8.2.6 Inactivation of Oligomeric Serine Proteases 232

8.2.7 Comparison of Abs with Natural Occurring Protein Modes of Inhibition 232

8.3 Introduction to Antibodies against HGFA, Matriptase and Hepsin 233

8.4 Inhibitory HGFA Antibodies 234

8.5 Inhibitory Matriptase Antibodies 238

8.6 Inhibitory Hepsin Antibodies 239

8.7 Conclusion 240

References 240

9 Inhibitors of the Growth-Factor Activating Proteases Matriptase, Hepsin and HGFA: Strategies for Rational Drug Design and Optimization 247
James W. Janetka and Robert A. Galemmo, Jr

9.1 Introduction 247

9.1.1 Proteolytic Control of HGF/MET Oncogenic Signaling 247

9.1.2 Proteolytic Control of MSP/RON Kinase Signaling 248

9.1.3 The Identification of HGF and MSP Converting Enzyme Activity 249

9.2 Small Molecular Weight Inhibitors of HGFA, Matriptase and Hepsin 251

9.2.1 Mechanism-based Inhibitors derived from Substrate Sequences 251

9.2.2 Approved Drugs as Starting Points for Inhibitor Design 257

9.2.3 Retro-Engineering Inhibitors of Related Proteases 258

9.3 Improving Drug-like Properties of the Current Inhibitors: Lessons from the Oral Anti-Coagulants 264

9.4 Conclusion 269

References 270

10 Cyclic Peptide Serine Protease Inhibitors Based on the Natural Product SFTI-1 277
Blake T. Riley, Olga Ilyichova, Jonathan M. Harris, David E. Hoke and Ashley M. Buckle

10.1 Introduction: Naturally Occurring Polypeptide Serine Protease Inhibitors 277

10.1.1 Serpins 277

10.1.2 Standard Mechanism Inhibitors 278 Kunitz Type 278 Kazal Type 278 Bowman-Birk Inhibitor (BBI) Family 278

10.2 Selective Inhibitors of Serine Proteases using the Sunflower Trypsin Inhibitor (SFTI-1) as a Scaffold for Rational Drug Design 279

10.2.1 Trypsin 279

10.2.2 Chymotrypsin, Neutrophil Elastase and Cathepsin G 286

10.2.3 Proteasome 286

10.2.4 Matriptase and other Type II Transmembrane Serine Proteases (TTSPs) 286

10.2.5 MASP-1 and MASP-2 286

10.2.6 Other KLKs (KLK5, 7, 14) 287

10.2.7 KLK4 287

10.3 Normal and Pathophysiological Functions of the Human Tissue Kallikrein (KLK)-related Serine Protease Family 288

10.3.1 Physiological Role for KLKs 288

10.3.2 KLKs and their Role in Prostate Cancer Pathogenesis 289

10.3.3 Kallikrein-related Peptidase 4 as a Point of Therapeutic Intervention 290

10.4 Inhibitors of KLK4 Serine Protease 291

10.4.1 Molecular Basis of KLK4 Inhibition by SFTI-1 291

10.4.2 Use of SFTI-1 as a Scaffold in Ligand Design and Optimization 292

10.4.3 Identification of an Optimal Tetrapeptide Substrate 292

10.4.4 SFTI-1FCQR is a Potent Selective Inhibitor of KLK4 293 Structural Basis for Potency and Selectivity of SFTI-1FCQR Derivative 293

10.5 Potential Therapeutic Applications and Challenges 294

10.6 Conclusions/Future Directions 297

References 297

11 Screening Combinatorial Peptide Libraries in Protease Inhibitor Drug Discovery 307
Marcin Poreba, Paulina Kasperkiewicz, Wioletta Rut and Marcin Drag

11.1 Introduction 307

11.2 Proteases Involved in Cancer 309

11.2.1 Metalloproteases 309

11.2.2 Serine Proteases 310

11.2.3 Cysteine Proteases 311

11.2.4 Aspartic Proteases 311

11.2.5 Threonine Proteases 312

11.2.6 Target Protease Substrates and Inhibitors 312

11.3 Identification and Optimization of Preferred Substrates 313

11.3.1 Positional Scanning of Substrate Combinatorial Libraries (PS-SCL) 313

11.3.2 Peptide Microarrays 318

11.3.3 Hybrid Combinatorial Substrate Library (HyCoSuL) 318

11.3.4 Counter Selection Substrate Library (CoSeSuL) 320

11.3.5 Combinatorial Substrate Synthesis for Aminopeptidase Screening 320

11.3.6 Internally Quenched Fluorescent (IQF) Substrates 321

11.3.7 Phage Display 322

11.3.8 Protease Substrates - Summary 325

11.4 Design of Covalent Inhibitors Based on Substrates 326

11.4.1 Background and General Characteristics of Inhibitors 326

11.4.2 Substrate-based Inhibitor Design and Discovery 327

11.4.3 PS-SCL Applied to Inhibitors other than Substrates 328

11.4.4 Inhibitors from Phage Display Screening and Directed Evolution of Proteins 331

11.5 Anticancer Drugs - How much Information do We Need? 334

11.6 Conclusions 336

Acknowledgements 337

References 337

12 Chemical Probes Targeting Proteases for Imaging and Diagnostics in Cancer 351
Pedro Goncalves and Steven H. L. Verhelst

12.1 Introduction 351

12.2 Chemical Probes for Proteases 352

12.2.1 Substrate-based Probes 352

12.2.2 Activity-based Probes (ABPs) 356

12.2.3 Photo-crosslinking probes 356

12.2.4 Non-Covalent Probes 358

12.3 Molecular Imaging of Cancer 358

12.3.1 Imaging Tumors with Substrate-based Probes 359 Preclinical Model Systems 359 Clinical Trials 361

12.3.2 Imaging Tumors with ABPs 362 Conventional and multimodal ABPs 362 Quenched ABPs 364 Towards Clinical Applications 365

12.3.3 Imaging Tumors with Affinity-based Reagents 366 Preclinical Models 366 Clinical Trials 367

12.4 Conclusions 369

Acknowledgements 370

References 371

13 Cancer Diagnostics of Protease Activity and Metastasis 377
Timothy J. O'Brien and John Beard

13.1 Introduction 377

13.2 The Proteins Identified from Patient Tumor Profiling 386

13.2.1 Matriptase 386

13.2.2 Hepsin 387

13.2.3 KLK7 387

13.2.4 KLK6 388

13.2.5 KLK8 388

13.2.6 TMPRSS3 388

13.2.7 MMP-7 389

13.3 ELISA Assay Development 389

13.4 The Role of Markers for Cancer Surveillance and Tumor Monitoring (Early Detection) 390

13.5 Cell Signaling and the Cancer Cascade 399

13.6 Conclusions and Future Prospects 400

References 402

14 Roles of Pericellular Proteases in Tumor Angiogenesis: Therapeutic Implications 411
Janice M. Kraniak, Raymond R. Mattingly and Bonnie F. Sloane

14.1 Introduction 411

14.2 Initiation of Angiogenesis 412

14.3 Mechanisms of New Blood Vessel Formation 413

14.3.1 Sprouting Angiogenesis 414

14.3.2 Intussesceptive or Non-sprouting Angiogenesis 415

14.3.3 Neovasculogenesis 415

14.3.4 Vascular Mimicry 416

14.4 Pericellular Proteases and Angiogenesis 417

14.4.1 Metalloproteinases: MMPs, ADAMs and ADAM-TS 418 MMPs 418 ADAMs and ADAM-TS 422

14.4.2 Serine Proteases 424

14.4.3 Cysteine Cathepsins 425 Cysteine Cathepsins in Angiogenesis 426

14.5 Novel Approaches for Targeting Tumor Angiogenesis 428

14.6 Summary 432

Acknowledgements 433

References 433

Index 447

Discovery and Function of the HGF/MET and the MSP/RON Kinase Signaling Pathways in Cancer

Silvia Benvenuti, Melissa Milan and Paolo M. Comoglio

Candiolo Cancer Institute, Italy

1.1 Introduction

MET and RON oncogenes encoding two related tyrosine kinase receptors are among the most important genes involved in the control of the invasive growth genetic program. Under physiological conditions, such as embryonic development and organ regeneration, the invasive growth program controls the normal tissue development by coordinating, in time and space, several biological events including cellular proliferation, disruption of intercellular junctions, migration through the extracellular matrix (ECM), and protection from programmed cell death (apoptosis). In transformed tissues, MET or RON deregulation results in cancer formation and metastatic dissemination. Upon either ligand stimulation or constitutive receptor activation, cancer cells are induced to leave the primary tumor, degrade the basal membrane, move towards different organs and generate metastasis (1,2). The two sibling receptors exert a dual role: they are necessary oncogenes for those tumors that rely on MET activity for growth and survival (oncogene addiction) and adjuvant, pro-metastatic genes for other tumors, where MET activation is a secondary event that exacerbates the malignant properties of already transformed cells (oncogene expedience). In this complex scenario, MET and RON become very attractive candidates for targeted therapeutic intervention.

1.2 MET Tyrosine Kinase Receptor and its Ligand HGF: Structure

MET oncogene, positioned on chromosome 7q21-31, is composed of 21 exons encoding a transmembrane tyrosine kinase receptor made of a disulphide-linked heterodimer (190 kDa), which originates from the proteolytic cleavage, in the post-Golgi compartment, of a single chain precursor. The heterodimer is formed by a single-pass transmembrane ß chain (145 kDa) and a completely extracellular a chain (45 kDa). The extracellular portion contains a SEMA (semaphorin) domain, an atypical motif made by over 500 amino acids, which has a low affinity binding activity for the ligand and is involved in receptor dimerization; a plexin, SEMA and integrin cysteine-rich (PSI) domain, which encompasses about 50 residues and contains 4 disulphide bonds; and 4 immunoglobulin-plexin-transcription structures (IPT domain), a characteristic protein-protein interaction region. A single pass hydrophobic membrane-spanning domain is followed by the intracellular portion made of a juxtamembrane section followed by a catalytic site and a C-terminal regulatory tail (Figure 1.1). The juxtamembrane segment is essential for receptor down-regulation (2). It contains a serine residue (Ser985) that, upon phosphorylation, is responsible for inhibition of receptor kinase activity, and a tyrosine (Tyr1003) capable of binding the E3-ubiquiting ligase CBL (cellular homologue of Cas NS-1 oncogene), that promotes receptor degradation (3,4). The catalytic site contains two tyrosines (Tyr1234 and Tyr1235) that regulate the enzymatic activity. Finally, the C-terminal tail encompasses two tyrosines (Tyr1349 and Tyr1356) that, when phosphorylated, generate a docking site able to recruit a vast cohort of intracellular molecules and adaptor proteins responsible for transducing the signaling triggered by the ligand-receptor interaction (5).The latter two tyrosines have shown to be essential and sufficient to execute MET physiological functions (5), and to elicit MET oncogenic potential (6).

Figure 1.1 MET tyrosine kinase receptor and its ligand HGF: structure.MET is a transmembrane tyrosine kinase receptor made of a disulphide-linked heterodimer formed by a single-pass transmembrane ß chain and a completely extracellular a chain. The extracellular portion contains a SEMA domain, involved in ligand binding and receptors dimerization; a PSI domain, encompassing four disulphide bonds; and four IPT domains, a protein-protein interaction region. A single pass transmembrane domain is followed by the intracellular portion made of a juxtamembrane section, a catalytic site and a C-terminal regulatory tail. The juxtamembrane segment contains a serine (serine 985) and a tyrosine (tyrosine 1003) responsible to inhibit receptor kinase activity and promote receptor down-regulation. The catalytic site contains the 'catalytic' tyrosines 1234 and 1235 that regulate the enzymatic activity, while the C-terminal tail encompasses the 'docking' tyrosines 1349 and 1356 that, upon phosphorylation, generate a docking site able to recruit a vast cohort of intracellular adaptors and molecules responsible of triggering the signal transduction cascade.HGF: hepatocyte growth factor; HL: hairpin loop; IPT: immunoglobulin-plexin transcription domain; K: kringle; PSI: plexin-semaphorin-integrin domain; SEMA: semaphorin domain; SPH: serine-protease domain.

MET high affinity ligand is known as the scatter factor (SF) or hepatocyte growth factor (HGF). SF is a factor capable of inducing scatter of epithelial cells, a complex phenomenon that consists of a first step in which cells dissociate one from another and a second phase in which the released cells begin to move (7,8). While HGF is a potent growth stimulator for primary hepatocytes kept in culture (9), the two molecules were later shown to be identical (10). SF/HGF belongs to the plasminogen family of peptidases; it contains an amino terminal hairpin loop (HL), followed by four Kringle domains, flanked by an activation portion and a serine-protease domain (SPH) devoid of proteolytic activity (Figure 1.1). This ligand, synthesized and secreted as a single chain inactive precursor (pro-HGF) by stromal cells (i.e. fibroblasts), is present in the extracellular environment of almost all tissues. Its activation occurs locally upon proteolytic cleavage by proteases that cleave the bond between Arg494 and Val495.

To date, several proteases (present either in the serum or within cells) have been proposed as HGF/SF activators, including HGF activator (HGFA) (11), plasma kallikrein and coagulation factors XIIa and XIa (12), matriptase and hepsin (13,14), TMPRSS2 (15), TMPRSS13 (16), urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA) (17). Among them, HGFA and matriptase, synthesized in turn as inactive precursors, show the most efficient pro-HGF/SF processing activity (18). Mature HGF is a heterodimer made of a 69 kDa a chain and a 34 kDa ß chain linked by a disulfide bond. HGF contains two binding sites with differential affinity for the MET receptor: a high-affinity site located within the a chain and a low affinity site in the ß chain. The low affinity site in the ß chain becomes accessible only after pro-HGF activation, which is essential for receptor dimerization and subsequent activation. Cells of mesenchymal origin are the primary producers and source of HGF in the pericellular environment, which acts on cells expressing the MET receptor (cells of epithelial origin) in a paracrine manner.

1.2.1 The Invasive growth Program

Cancer is a multistep process that results from the accumulation of somatic genetic alterations, which either inactivate tumor suppressor genes (i.e. p53, pRB or APC) or activate dominant proto-oncogenes (i.e. RAS or PI3K) (19,20). These aberrant events release cells from proliferative control and allow primary tumor formation. The initial tumor growth is followed by invasive dissemination and ultimately metastasis, which is the cause of almost all cancer-related deaths. The ability of neoplastic cells to invade the surrounding tissues, survive in foreign environments, and settle at distant sites, defines a genetic program known as invasive growth. The invasive growth program also occurs under physiological conditions. Throughout embryogenesis, invasive growth orchestrates complex events such as gastrulation (responsible of originating the mesoderm from the embryonic epithelium), morphogenesis of epithelia, angiogenesis, nervous system formation and myoblasts migration (21). In adult life, invasive growth is necessary in normal tissues during acute injury repair (23,24) when cells at the wound edge reprogram themselves and start rapidly dividing prior to migrating towards the cut edge to regenerate the lacking tissue.

The invasive growth program consists of several stages, each of them occurring in a specific time and place, all harmoniously orchestrated to allow germ layers in the embryo, and tissues in the adult, to re-organize. All these events require cells to proliferate, migrate, overcome apoptosis, invade the surrounding tissues and re-organize themselves into new three-dimensional structures. Epithelial-mesenchymal transition (EMT) is the mechanism behind the earlier phases of the invasive growth program. During EMT, cells release junctions that maintain the epithelial monolayer structure, change their polarity by means of cytoskeleton rearrangements and attain the ability to move within the extracellular environment. Ultimately, the cells lose their epithelial phenotype to acquire a mesenchymal one. All these events, necessary during embryogenesis for correct...

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