Vande Woude / Klein Advances in Cancer Research

1. Auflage 2009
ISBN: 978-0-08-091226-4
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 103, 160 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, including nitric oxide-induced apoptosis in tumor cells, detection of minimal residual disease, immunity to oncogenetic human papillomavirus, and modeling prostate cancer in the mouse.

Autoren/Hrsg.

Vande Woude, George F.

Klein, George

Inhaltsverzeichnis

1;Front Cover;1
2;Advances in Cancer Research;4
3;Copyright;5
4;Contents;6
5;Contributors;8
6;Chapter 1: The Function, Proteolytic Processing, and Histopathology of Met in Cancer;10
6.1;I. Introduction;11
6.2;II. Oncogenic Properties of Met;12
6.3;III. Receptor Cross Talk;12
6.4;IV. Proteolytic Processing of Met;14
6.5;V. Nuclear Localization of Met;17
6.6;VI. Histopathology and Expression of Met in Cancer;18
6.7;VII. Met as a Therapeutic Target;23
6.8;VIII. Perspective;24
6.9;References;25
7;Chapter 2: Managing Tumor Angiogenesis: Lessons from VEGF-Resistant Tumors and Wounds;34
7.1;I. Angiogenesis;35
7.2;II. Vegf and Tumor Angiogenesis;36
7.3;III. Vegf and Recruitment of Epc in Tumor Angiogenesis;36
7.4;IV. Role of Bone Marrow-Derived Immune Cells in Angiogenesis and Tumor Progression;37
7.5;V. Limitations in Targeting Vegf;38
7.6;VI. Tumor Stage-Dependent Responses TVegf;39
7.7;VII. Multiple Angiogenic Factors Produced by the Tumor Microenvironment;40
7.8;VIII. Vegf Inhibition and Increased Tumor Aggressiveness;41
7.9;IX. Wound Angiogenesis;42
7.10;X. Vascular Regression;44
7.11;XI. Wound Fibroblasts;45
7.12;XII. Hox Genes in Wound and Tumor Angiogenesis;46
7.13;References;47
8;Chapter 3: The TRAIL to Targeted Therapy of Breast Cancer;52
8.1;I. Introduction;52
8.2;II. TRAIL and Its Receptors;54
8.3;III. TRAIL-Induced Apoptosis in Breast Cancer Cells;60
8.4;IV. Mechanisms Determining TRAIL Sensitivity in Breast Cancer Cells;64
8.5;V. Overcoming TRAIL Resistance;67
8.6;VI. Future Directions;73
8.7;Acknowledgments;73
8.8;References;73
9;Chapter 4: Hepatitis B Virus X Protein: Molecular Functions and Its Role in Virus Life Cycle and Pathogenesis;84
9.1;I. Introduction;84
9.2;II. Is HBx an Essential or Accessory Regulatory Protein for Virus Replication?;86
9.3;III. HBx: A Potential Candidate in HCC Development;88
9.4;IV. HBx: Structural and Biochemical Features;89
9.5;V. HBx Activities;92
9.6;VI. Conclusion;103
9.7;References;104
10;Chapter 5: Drosophila Myc;120
10.1;I. Introduction: The Myc/Max/Mxd network in vertebrates;120
10.2;II. The Myc/Max/Mnt network in flies;122
10.3;Acknowledgments;147
10.4;References;147
11;Index;154
12;Color Plate;158

Leseproben

Chapter 1 The Function, Proteolytic Processing, and Histopathology of Met in Cancer
Jason A. Hanna, Jennifer Bordeaux, David L. Rimm and Seema Agarwal Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA Abstract The hepatocyte growth factor (HGF) and its receptor, the Met receptor tyrosine kinase, form a signaling network promoting cell proliferation, invasion, and survival in normal and cancer cells. Improper regulation of this pathway is attributed to many cancer types through overexpression, activating mutations, or autocrine loop formation. Many studies describe the localization of Met as membranous/cytoplasmic, but some studies using antibodies targeted to the C-terminal domain of Met report nuclear localization. This chapter seeks to highlight the histopathology and expression of Met in cancer and its association with clinicopathological characteristics. We also discuss recent studies of the proteolytic processing of Met and effects of the processing on the subcellular localization of Met. Finally, we comment on Met as a therapeutic target for cancer treatment. I. Introduction The hepatocyte growth factor receptor (Met) is a transmembrane receptor tyrosine kinase (RTK) primarily expressed in both epithelial and endothelial cells. Met is produced as a single-chain 170 kDa precursor, which is then proteolytically cleaved at a furin site to produce its ? (45 kDa) and ? (150 kDa) subunits linked by a disulfide bond. The ? subunit is highly glycosylated and entirely extracellular. The ? subunit has a large extracellular domain, the transmembrane domain, and the intracellular domain. The extracellular portion of the Met receptor, including the entire ? subunit, shares homology to semaphorins and is therefore termed the Sema domain. It is this Sema domain that is responsible for ligand binding. The intracellular domain of Met contains three functionally important regions, the juxtamembrane domain, the tyrosine kinase domain, and the multisubstrate docking site at the C-terminal tail. The juxtamembrane region contains a serine (985) that can be phosphorylated by PKC to downregulate the kinase activity of the receptor as well as a tyrosine (1003) where the ubiquitin ligase Cbl can bind and lead to Met polyubiquitination and subsequent degradation (Birchmeier et al., 2003 and Gentile et al., 2008). Met is activated by the binding of its ligand, hepatocyte growth factor/scatter factor (HGF/SF), which then leads to the dimerization and autophosphorylation of the tyrosine residues (1230, 1234, 1235) within the activation loop of the tyrosine kinase domain. Subsequent phosphorylation of the C-terminal docking sites (tyrosines 1349 and 1356) of Met allows binding of downstream signaling molecules (many of which contain SH2 domains), including Grb2, Shc, Src, p85 subunit of PI3K, and Gab1. This leads to signal transduction through a number of pathways essential for an invasive growth program. In epithelial cells in vivo, this invasive growth program orchestrates cell spreading, cell–cell dissociation and an increase in motility. These processes together are known as cell “scattering,” and are morphologically similar to features of cells undergoing an epithelial–mesenchymal transition (Birchmeier et al., 2003). In addition the cells then migrate and settle in a new environment where they proliferate and generate new tubular structures (Gentile et al., 2008). All of these features of Met activation in vivo can be simulated in vitro by stimulating MDCK cells with HGF. Classical Met/HGF signaling promotes this invasive growth phenotype of cell survival and proliferation; however, a recent study has also demonstrated that caspase cleavage leads to the formation of a 40 kDa intracellular fragment of Met that was also proapoptotic through an unknown mechanism (Tulasne and Foveau, 2008). II. Oncogenic Properties of Met Under physiological conditions HGF secreted by mesenchymal cells acts on epithelial cells expressing the Met receptor. Both HGF and Met are essential for controlling processes during mammalian embryogenesis and as a result transgenic mice lacking either HGF or Met die by embryonic day 16.5 with defects in liver, tongue, and diaphragm, failure of skeletal muscle progenitor cells to migrate to limbs, as well as defects in branching morphogenesis of the lungs and kidneys (Birchmeier et al., 2003 and Schmidt et al., 1995). In the adult, upregulated HGF and Met is observed after injury to liver, kidney, or heart and is important in wound healing of the skin as well as liver regeneration (Birchmeier et al., 2003, Borowiak et al., 2004 and Chmielowiec et al., 2007). In addition to Met's functions in these normal processes, its ability to induce proliferation, motility, and invasion can also contribute to the development of cancer. Some tumors express both HGF and Met leading to an autocrine loop where secreted HGF causes the constitutive activation of Met and as a consequence, enhances tumor cell growth and metastasis. Met can also be activated independent of HGF stimulation as a result of overexpression, abnormal processing, absence of negative regulators such as Cbl, expression of the TPR–MET gene fusion product formed due to chromosomal rearrangement, or a number of activating mutations in the juxtamembrane and kinase domains that have been identified in renal papillary carcinoma, lung cancer, hepatocellular carcinoma, and gastric cancer (Danilkovitch-Miagkova and Zbar, 2002, Gentile et al., 2008, Lee et al., 2000, Ma et al., 2003, Park et al., 1986 and Peschard et al., 2001). III. Receptor Cross Talk Met is known to interact and cross talk with several membrane proteins, including a number of RTKs (Fig. 1). One of the first RTKs identified to interact with Met was the recepteur d'origine nantais (Ron). Ron is a RTK with significant homology to Met and is activated by binding of its ligand macrophage stimulating protein (MSP) (Thomas et al., 2007). Met and Ron have been shown to interact before ligand induced dimerization and are able to transphosphorylate each other. In addition, the expression of an inactive Ron receptor was able to suppress the transforming capabilities of activating Met mutants suggestive of a dominant negative role (Follenzi et al., 2000). In a cohort of ovarian cancers, Ron and Met were found to be coexpressed in 42% of the specimens. In addition, coactivation of both receptors in ovarian cancer cell lines synergistically enhanced the motility and invasiveness of the cells (Maggiora et al., 2003). Ron and Met coexpression associate with shorter survival in cancer implying that the interaction and subsequent activation of both Ron and Met may be involved in promoting distant metastasis and recurrence in many tumor types (Cheng et al., 2005 and Lee et al., 2005). Fig. 1 Met cross talk with other membrane receptors. Met interacts with the cell adhesion receptors E-cadherin, CD44v6, ?6?4 integrin, members of the Plexin B family, the death receptor Fas, and other receptor tyrosine kinases such as Ron and ErbB family members.
Met and Ron also share many structural similarities in the extracellular domain with the Plexin B family of semaphorin receptors. They all contain the ?500 amino acid conserved Sema, the ?80 amino acid cysteine rich Met-related sequence, and four copies of an Ig domain (Gherardi et al., 2004). Giordano et al. first reported the ability of Plexins of the B family to transactivate Met and Ron in the absence of HGF/MSP when stimulated with their semaphorin ligands as a mechanism to activate the invasive growth program (Conrotto et al., 2004 and Giordano et al., 2002). This interaction was also found to have proangiogenic properties in endothelial cells (Conrotto et al., 2005). Met also interacts with the v6 splice variant of CD44 to associate Met with the actin cytoskeleton via the Ezrin, radixin and moesin (ERM) proteins, and for the proper assembly and activation of the downstream Ras/MAPK pathway (Orian-Rousseau et al., 2002 and Orian-Rousseau et al., 2007). Met interaction with the laminin receptor, ?6?4 integrin, leads to phosphorylation of ?6?4 integrin which then recruits and amplifies signaling of the Ras–Src signaling cascade (Bertotti et al., 2005, Bertotti et al., 2006 and Trusolino et al., 2001). Met interacts with the death receptor Fas in a ligand independent manner and prevents Fas ligand binding, thereby inhibiting Fas activation and induction of Fas promoted apoptosis (Wang et al., 2002). HGF binding to Met however displaces Met from Fas which can then induce downstream Met signaling promoting cell curvival. Alternatively, HGF-induced disassociation of Fas from Met may provide a proapoptotic effect allowing the FasL to bind the free Fas. In addition, Met is shown to play an additional proapoptotic role in a caspase dependent manner (Foveau et al., 2007). Finally, we and others have shown that E-cadherin interacts with Met at the plasma membrane to optimize the localization of the receptor for ligand stimulation (Hiscox and Jiang, 1999 and Reshetnikova et al., 2007). Met also interacts with...