Extracellular Targeting of Cell Signaling in Cancer

Name: Extracellular Targeting of Cell Signaling in Cancer | Strategies Directed at MET and RON Receptor Tyrosine Kinase Pathways
Brand: Wiley
Price: 156.99 EUR
Availability: OnlineOnly

Strategies Directed at MET and RON Receptor Tyrosine Kinase Pathways

James W. Janetka Roseann Benson(Herausgeber*in)

Wiley (Verlag)

1. Auflage

Erschienen am 10. Mai 2018

488 Seiten

E-Book

ePUB mit Adobe-DRM

Systemvoraussetzungen

978-1-119-30021-2 (ISBN)

156,99 €inkl. 7% MwSt.

Systemvoraussetzungen

für ePUB mit Adobe-DRM

E-Book Einzellizenz

Als Download verfügbar

Beschreibung

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.

Weitere Details

Weitere Ausgaben

Inhalt

Cover
Title Page
Copyright
Contents
List of Contributors
Preface
Chapter 1 Discovery and Function of the HGF/MET and the MSP/RON Kinase Signaling Pathways in Cancer
1.1 Introduction
1.2 MET Tyrosine Kinase Receptor and its Ligand HGF: Structure
1.2.1 The Invasive growth Program
1.2.2 MET Mediated Signaling
1.2.2.1 MET Down-regulation
1.2.3 Cross-talk between MET and Other Receptors
1.2.4 MET Activation in Human Cancers
1.2.4.1 MET, Hypoxia and Ionizing Radiations
1.2.4.2 MET Expression in Cancer Stem Cells: a Paradigm of Inherence
1.2.4.3 Oncogene Addiction and Oncogene Expedience
1.2.5 Targeting HGF/MET as a Therapeutic Approach in Human Cancer
1.2.5.1 HGF Antagonists
1.2.5.2 Tyrosine Kinase Inhibitors
1.2.5.3 Anti-MET Monoclonal Antibodies
1.2.5.4 Alternative MET Blocking Strategies
1.2.6 Primary and Secondary Resistance
1.2.6.1 MET Role in Resistance to Anticancer Agents
1.2.6.2 Mechanism of Resistance to MET Inhibitors
1.2.6.3 Combinatorial Therapeutic Strategies
1.3 RON Tyrosine Kinase Receptor and its Ligand MSP
1.3.1 Discovery and Structural Biology
1.3.2 RON Mediated Signaling
1.3.3 Cross-talk between RON and other Receptors
1.3.4 RON Activation in Human Cancers
1.4 Targeting MSP/RON as a Therapeutic Approach in Human Cancer
1.5 Concluding Remarks
Acknowledgements
References
Chapter 2 The Role of HGF/MET and MSP/RON Signaling in Tumor Progression and Resistance to Anticancer Therapy
2.1 Introduction
2.2 HGF/MET Signaling in Cancer
2.3 MSP/RON Signaling in Cancer
2.4 Cross-talk between MET and RON Signaling Pathways
2.5 HGF/MET and MSP/RON Signaling Elicit Resistance to Cancer Therapy
2.6 Conclusions and Perspectives
References
Chapter 3 HGF Activator (HGFA) and its Inhibitors HAI1 and HAI2: Key Players in Tissue Repair and Cancer
3.1 Introduction
3.2 Discovery of HGFA
3.2.1 Tissue Injury-induced Activation of HGF
3.2.2 Identification of HGFA as a Serum Activator of pro-HGF
3.3 Synthesis of HGFA Zymogen in vivo
3.4 Molecular Structure of HGFA
3.4.1 The Gene Encoding pro-HGFA: HGFAC
3.4.2 ProHGFA Protein and its Activation
3.4.3 Structure Biology of HGFA
3.5 Substratesof HGFA in vivo
3.6 Regulation of HGFA Activity by Endogenous Inhibitors
3.6.1 HGF Activator Inhibitor-1 (HAI-1): a Cell Surface Regulator of HGFA Activity
3.6.2 HGF Activator Inhibitor-2 (HAI-2)
3.6.3 Protein C Inhibitor (PCI
SERPINA5)
3.7 Proposed Biological Functions of HGFA in vivo
3.8 Roles of HGFA in Cancer
3.8.1 Enhanced Activation of pro-HGF and pro-MSP in Cancer Tissues
3.8.2 Possible Roles of HGFA in Cancer Progression
3.9 Conclusions and Future Perspectives of HGFA Research in Cancer
References
Chapter 4 Physiological Functions and Role of Matriptase in Cancer
4.1 Introduction
4.2 Discovery of Matriptase
4.3 Biochemical and Functional Characteristics of Matriptase - Inhibitors, Substrates and Structure
4.3.1 Endogenous Polypeptide Matriptase Inhibitors
4.3.2 Matriptase Substrates
4.3.3 Matriptase Structure
4.4 Physiological and Pathophysiological Functions of Matriptase
4.4.1 Matriptase in Epidermal Development and Homeostasis
4.4.2 Matriptase in the Gastrointestinal Tract
4.4.3 Matriptase in Thymocytes and Salivary Glands
4.4.4 Matriptase in Placental/Embryonic Development
4.4.5 Matriptase in Neural Tube Closure
4.4.6 Pathways requiring Matriptase
4.4.7 Matriptase in Viral Infection
4.5 Role of Matriptase in Cancer
4.5.1 Studying Matriptase in Cultured Cancer Cells and Tumor Grafting Models
4.5.2 In vivo Cancer Studies using Genetic Models
4.5.2.1 Squamous Cell Carcinoma
4.5.2.2 Colitis-associated Colon Carcinogenesis
4.5.2.3 Breast Cancer
4.6 Conclusions
References
Chapter 5 The Cell-Surface, Transmembrane Serine Protease Hepsin: Discovery, Function and Role in Cancer
5.1 Biology of Hepsin
5.1.1 Discovery of Hepsin
5.1.1.1 Cloning of Hepsin, HPN Gene
5.1.1.2 Assigning Hepsin to Type II Transmembrane Serine Protease Family
5.1.2 Hepsin Gene and Protein
5.1.2.1 Expression, Regulation and Structure
5.1.2.2 Hepsin Activation and Activity
5.1.3 Physiological Functions of Hepsin
5.1.3.1 Growth Factor Activation
5.1.3.2 Serine Protease Cascades
5.1.3.3 Cell Proliferation and Motility
5.1.3.4 Epithelial Integrity
5.1.3.5 Organ Development
5.2 Hepsin in Cancer
5.2.1 Gain of Oncogenic Function
5.2.1.1 Genetic Alterations
5.2.1.2 Altered Subcellular Localization
5.2.1.3 Oncogenic Hepsin Function in vivo
5.2.1.4 How HPN Promotes Cancer
5.2.2 Targeting Hepsin in Cancer
5.3 Future Prospects
5.3.1 Hepsin's Role as Guardian of Epithelial Integrity
5.3.2 Cancer Disease Progression and Metastasis
5.3.2.1 Uncontrolled Proteolysis
Acknowledgements
References
Chapter 6 Targeting HGF with Antibodies as an Anti-Cancer Therapeutic Strategy
6.1 Introduction
6.2 HGF Biology
6.2.1 HGF Gene Organization and mRNA Transcripts
6.2.2 HGF Protein Isoforms and Proteolytic Processing
6.2.2.1 HGF Isoforms
6.2.2.2 HGF Activation by Proteolytic Processing
6.2.3 Key HGF Interactions: Heparan Sulfate Proteoglycans and Met
6.2.3.1 Heparan Sulfate Proteoglycans
6.2.3.2 Met and Key Intracellular Effectors
6.2.4 Major Sites of HGF Expression: Tissues and Organs
6.2.5 HGF Function in Development and Adulthood
6.2.5.1 hgf or met altered Mice: Embryogenesis
6.2.5.2 hgf or met altered Mice: Late Development and Adulthood
6.3 HGF in Cancer
6.3.1 Lung Cancer
6.3.2 Hepatocellular Carcinoma
6.3.3 Genitourinary Malignancies
6.3.4 Breast Cancer
6.3.5 Colorectal and Gastric Carcinomas
6.3.6 Papillary Thyroid Carcinoma
6.3.7 Brain Tumors
6.3.8 Melanoma
6.3.9 Head and Neck Squamous Cell Carcinoma
6.3.10 Other Malignancies
6.4 Anti-HGF Monoclonal Antibodies as Anti-Cancer Therapeutic Candidates
6.4.1 Rilotumumab
6.4.2 Ficlatuzumab
6.4.3 TAK-701
6.5 Conclusions and Future Directions
Acknowledgements
References
Chapter 7 MET and RON Receptor Tyrosine Kinases as Therapeutic Antibody Targets for Cancer
7.1 MET as a Therapeutic Antibody Target for Cancer
7.2 Challenges in Developing MET Therapeutic Antibodies
7.3 Anti-MET Antibody Clinical Diagnostics
7.4 Anti-MET Antibodies in the Clinic
7.4.1 Onartuzumab - Roche
7.4.2 Emibetuzumab - Eli Lilly
7.4.3 ABT-700 - AbbVie
7.4.4 SAIT301 - Samsung
7.4.5 ARGX-111 - Argenx
7.4.6 Sym-015 - Symphogen
7.5 Additional anti-MET Antibodies
7.5.1 DN-30 - University of Turin Medical School
7.5.2 Other Preclinical Stage anti-MET Antibodies
7.6 Summary-anti-MET Antibodies
7.7 RON as a Therapeutic Antibody Target for Cancer
7.8 Conclusions and Future Outlook
References
Chapter 8 Inhibitory Antibodies of the Proteases HGFA, Matriptase and Hepsin
8.1 Anti-Serine Protease Antibodies for Therapeutic Applications
8.2 Antibodies can Inhibit Trypsin-Fold Serine Proteases in Diverse Ways
8.2.1 Orthosteric Inhibition (Active Site Binding)
8.2.2 Allosteric Inhibition
8.2.3 Exosite Inhibition
8.2.4 Inhibition of Zymogen Activation
8.2.5 Cofactor Inhibition
8.2.6 Inactivation of Oligomeric Serine Proteases
8.2.7 Comparison of Abs with Natural Occurring Protein Modes of Inhibition
8.3 Introduction to Antibodies against HGFA, Matriptase and Hepsin
8.4 Inhibitory HGFA Antibodies
8.5 Inhibitory Matriptase Antibodies
8.6 Inhibitory Hepsin Antibodies
8.7 Conclusion
References
Chapter 9 Inhibitors of the Growth-Factor Activating Proteases Matriptase, Hepsin and HGFA: Strategies for Rational Drug Design and Optimization
9.1 Introduction
9.1.1 Proteolytic Control of HGF/MET Oncogenic Signaling
9.1.2 Proteolytic Control of MSP/RON Kinase Signaling
9.1.3 The Identification of HGF and MSP Converting Enzyme Activity
9.2 Small Molecular Weight Inhibitors of HGFA, Matriptase and Hepsin
9.2.1 Mechanism-based Inhibitors derived from Substrate Sequences
9.2.2 Approved Drugs as Starting Points for Inhibitor Design
9.2.3 Retro-Engineering Inhibitors of Related Proteases
9.3 Improving Drug-like Properties of the Current Inhibitors: Lessons from the Oral Anti-Coagulants
9.4 Conclusion
References
Chapter 10 Cyclic Peptide Serine Protease Inhibitors Based on the Natural Product SFTI-1
10.1 Introduction:Naturally Occurring Polypeptide Serine Protease Inhibitors
10.1.1 Serpins
10.1.2 Standard Mechanism Inhibitors
10.1.2.1 Kunitz Type
10.1.2.2 Kazal Type
10.1.2.3 Bowman-Birk Inhibitor (BBI) Family
10.2 Selective Inhibitors of Serine Proteases using the Sunflower Trypsin Inhibitor (SFTI-1) as a Scaffold for Rational Drug Design
10.2.1 Trypsin
10.2.2 Chymotrypsin, Neutrophil Elastase and Cathepsin G
10.2.3 Proteasome
10.2.4 Matriptase and other Type II Transmembrane Serine Proteases (TTSPs)
10.2.5 MASP-1 and MASP-2
10.2.6 Other KLKs (KLK5, 7, 14)
10.2.7 KLK4
10.3 Normal and Pathophysiological Functions of the Human Tissue Kallikrein (KLK)-related Serine Protease Family
10.3.1 Physiological Role for KLKs
10.3.2 KLKs and their Role in Prostate Cancer Pathogenesis
10.3.3 Kallikrein-related Peptidase 4 as a Point of Therapeutic Intervention
10.4 Inhibitors of KLK4 Serine Protease
10.4.1 Molecular Basis of KLK4 Inhibition by SFTI-1
10.4.2 Use of SFTI-1 as a Scaffold in Ligand Design and Optimization
10.4.3 Identification of an Optimal Tetrapeptide Substrate
10.4.4 SFTI-1FCQR is a Potent Selective Inhibitor of KLK4
10.4.4.1 Structural Basis for Potency and Selectivity of SFTI-1FCQR Derivative
10.5 Potential Therapeutic Applications and Challenges
10.6 Conclusions/Future Directions
References
Chapter 11 Screening Combinatorial Peptide Libraries in Protease Inhibitor Drug Discovery
11.1 Introduction
11.2 Proteases Involved in Cancer
11.2.1 Metalloproteases
11.2.2 Serine Proteases
11.2.3 Cysteine Proteases
11.2.4 Aspartic Proteases
11.2.5 Threonine Proteases
11.2.6 Target Protease Substrates and Inhibitors
11.3 Identification and Optimization of Preferred Substrates
11.3.1 Positional Scanning of Substrate Combinatorial Libraries (PS-SCL)
11.3.2 Peptide Microarrays
11.3.3 Hybrid Combinatorial Substrate Library (HyCoSuL)
11.3.4 Counter Selection Substrate Library (CoSeSuL)
11.3.5 Combinatorial Substrate Synthesis for Aminopeptidase Screening
11.3.6 Internally Quenched Fluorescent (IQF) Substrates
11.3.7 Phage Display
11.3.8 Protease Substrates - Summary
11.4 Design of Covalent Inhibitors Based on Substrates
11.4.1 Background and General Characteristics of Inhibitors
11.4.2 Substrate-based Inhibitor Design and Discovery
11.4.3 PS-SCL Applied to Inhibitors other than Substrates
11.4.4 Inhibitors from Phage Display Screening and Directed Evolution of Proteins
11.5 Anticancer Drugs - How much Information do We Need?
11.6 Conclusions
Acknowledgements
References
Chapter 12 Chemical Probes Targeting Proteases for Imaging and Diagnostics in Cancer
12.1 Introduction
12.2 Chemical Probes for Proteases
12.2.1 Substrate-based Probes
12.2.2 Activity-based Probes (ABPs)
12.2.3 Photo-crosslinking probes
12.2.4 Non-Covalent Probes
12.3 Molecular Imaging of Cancer
12.3.1 Imaging Tumors with Substrate-based Probes
12.3.1.1 Preclinical Model Systems
12.3.1.2 Clinical Tria
12.3.2 Imaging Tumors with ABPs
12.3.2.1 Conventional and multimodal ABPs
12.3.2.2 Quenched ABPs
12.3.2.3 Towards Clinical Applications
12.3.3 Imaging Tumors with Affinity-based Reagents
12.3.3.1 Preclinical Models
12.3.3.2 Clinical Trials
12.4 Conclusions
Acknowledgements
References
Chapter 13 Cancer Diagnostics of Protease Activity and Metastasis
13.1 Introduction
13.2 The Proteins Identified from Patient Tumor Profiling
13.2.1 Matriptase
13.2.2 Hepsin
13.2.3 KLK7
13.2.4 KLK6
13.2.5 KLK8
13.2.6 TMPRSS3
13.2.7 MMP-7
13.3 ELISA Assay Development
13.4 The Role of Markers for Cancer Surveillance and Tumor Monitoring (Early Detection)
13.5 Cell Signaling and the Cancer Cascade
13.6 Conclusions and Future Prospects
References
Chapter 14 Roles of Pericellular Proteases in Tumor Angiogenesis: Therapeutic Implications
14.1 Introduction
14.2 Initiation of Angiogenesis
14.3 Mechanisms of New Blood Vessel Formation
14.3.1 Sprouting Angiogenesis
14.3.2 Intussesceptive or Non-sprouting Angiogenesis
14.3.3 Neovasculogenesis
14.3.4 Vascular Mimicry
14.4 Pericellular Proteases and Angiogenesis
14.4.1 Metalloproteinases: MMPs, ADAMs and ADAM-TS
14.4.1.1 MMPs
14.4.1.2 ADAMs and ADAM-TS
14.4.2 Serine Proteases
14.4.3 Cysteine Cathepsins
14.4.3.1 Cysteine Cathepsins in Angiogenesis
14.5 Novel Approaches for Targeting Tumor Angiogenesis
14.6 Summary
Acknowledgements
References
Index
EULA

1
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...

Systemvoraussetzungen

Als PDF speichern Als Link merken

Extracellular Targeting of Cell Signaling in Cancer

Beschreibung

Weitere Details

Weitere Ausgaben

Inhalt

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

1.1 Introduction

1.2 MET Tyrosine Kinase Receptor and its Ligand HGF: Structure

1.2.1 The Invasive growth Program

Systemvoraussetzungen

1
Discovery and Function of the HGF/MET and the MSP/RON Kinase Signaling Pathways in Cancer