International Review of Cell and Molecular Biology

1. Auflage 2015
ISBN: 978-0-12-802481-2
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 314, 298 Seiten

Reihe: International Review of Cell and Molecular Biology

International Review of Cell and Molecular Biology presents comprehensive reviews and current advances in cell and molecular biology. Articles address structure and control of gene expression, nucleocytoplasmic interactions, control of cell development and differentiation, and cell transformation and growth. The series has a world-wide readership, maintaining a high standard by publishing invited articles on important and timely topics authored by prominent cell and molecular biologists. Impact factor for 2013: 4.522. - Authored by some of the foremost scientists in the field - Provides comprehensive reviews and current advances - Wide range of perspectives on specific subjects - Valuable reference material for advanced undergraduates, graduate students and professional scientists

Autoren/Hrsg.

Inhaltsverzeichnis

1;Front Cover;1
2;International Review of Cell and Molecular Biology;2
3;International Review of Cell and Molecular Biology;3
4;International Review of Cell and Molecular Biology
;4
5;Copyrights
;5
6;Contents;6
7;Contributors;10
8;Epidermal Growth Factor Signaling in Transformed Cells;12
8.1;1. Introduction;13
8.2;2. Hallmarks of Transformation;14
8.2.1;2.1 Epithelial–Mesenchymal Transition;15
8.2.2;2.2 Role of EGFR in EMT;18
8.3;3. The ErbB/HER Receptor Family in Normal and Transformed Cells;19
8.3.1;3.1 Overview of EGFR Receptors, Ligands, and Signaling;19
8.3.2;3.2 ErbB/HER Family Members in Transformed Cells;21
8.3.3;3.3 EGFR Mutations;21
8.3.4;3.4 EGFR Polymorphism;22
8.3.5;3.5 EGFR Ligands;23
8.4;4. EGFR Signaling in Normal and Transformed Cells;24
8.4.1;4.1 Loss of Cell Adhesion and EGFR Signaling;25
8.4.2;4.2 Tumor Microenvironment and EGFR Signaling;26
8.4.3;4.3 Posttranslational Modifications and EGFR Signaling;28
8.4.4;4.4 Epigenetic Influences on EGFR Signaling;28
8.4.5;4.5 MicroRNAs and EGFR;29
8.4.6;4.6 Compartmentalization and Trafficking of EGFR;30
8.4.7;4.7 EGFR Transactivation;31
8.5;5. Cross Talk between EGFR Signaling and Other Major Signaling Pathways in Transformed Cells;32
8.5.1;5.1 Mesenchymal Epithelial Transition Factor;32
8.5.2;5.2 Transforming Growth Factor-Beta;33
8.5.3;5.3 Insulin-like Growth Factor;34
8.5.4;5.4 Sonic Hedgehog;34
8.5.5;5.5 Wnt;35
8.5.6;5.6 Notch;35
8.6;6. Therapy;36
8.6.1;6.1 EGFR as Target for Cancer Therapy;37
8.6.2;6.2 Anti-EGFR Therapy Approaches;37
8.6.3;6.3 Resistance to EGFR Therapy;39
8.7;7. Concluding Remarks;40
8.8;Acknowledgments;40
8.9;References;40
9;New Insights into Antimetastatic and Antiangiogenic Effects of Cannabinoids;54
9.1;1. Introduction;57
9.2;2. Cannabinoids as Systemic Anticancer Drugs;59
9.2.1;2.1 Range of Antitumorigenic Mechanisms of Cannabinoids;59
9.2.2;2.2 Cannabinoids: Clinical Implication as Systemic Anticancer Drugs;60
9.2.2.1;2.2.1 Case–control studies with Cannabis smokers;60
9.2.2.2;2.2.2 The endocannabinoid system as tumor-defense mechanism;62
9.2.2.3;2.2.3 Combinational cancer therapies with cannabinoids;64
9.2.2.4;2.2.4 Cannabinoids' impact on tumor-immune surveillance;67
9.2.3;2.3 Cannabinoids as Potential Clinical Option to Counteract Tumor Metastasis and Angiogenesis;70
9.3;3. Cannabinoids and Tumor Angiogenesis;72
9.3.1;3.1 Angiogenesis in Physiological and Pathophysiological Tissue Development;72
9.3.2;3.2 Cannabinoids' Effects on Tumor Angiogenesis In vivo;86
9.3.3;3.3 Direct Effects of Cannabinoids on Vascular Endothelial Cells;88
9.3.4;3.4 Impact of Cannabinoids on the Release of Angiogenic Factors from Tumor Cells;93
9.3.5;3.5 Cannabinoids and Angiogenesis: A Critical Outlook;95
9.4;4. Effects of Cannabinoids on Tumor Cell Metastasis;95
9.4.1;4.1 Impact of Cannabinoids on Tumor Cell Migration;96
9.4.2;4.2 Impact of Cannabinoids on Tumor Cell Invasion;97
9.4.2.1;4.2.1 Contribution of the endocannabinoid system to tumor cell invasion;101
9.4.3;4.3 Effects of Cannabinoids on Metastasis In vivo;104
9.4.4;4.4 Cannabinoids and Metastasis: A Critical Outlook;107
9.5;5. Conclusion;108
9.6;References;108
10;Insight into the Role of Wnt5a-Induced Signaling in Normal and Cancer Cells;128
10.1;1. Introduction;129
10.2;2. Wnt5a–Ror2 Axis in Developmental Morphogenesis;130
10.2.1;2.1 Planar Cell Polarity;131
10.2.2;2.2 CE Movements;132
10.2.3;2.3 Epithelial–Mesenchymal Interaction;134
10.3;3. Roles of Wnt5a–Ror2 Axis in Normal Cell Functions;135
10.3.1;3.1 Cell Polarity;136
10.3.2;3.2 Cell Migration;137
10.3.3;3.3 Gene Expression;139
10.3.4;3.4 Maintenance of Stemness;140
10.4;4. Wnt5a–Ror2 and Ror1 Axes in Cancer Cells;142
10.4.1;4.1 Tumor-Progressive Functions;142
10.4.1.1;4.1.1 Epithelial-to-mesenchymal transition and Wnt5a-Ror2 axis;142
10.4.1.2;4.1.2 Wnt5a–Ror2 axis in high motility and invasion;143
10.4.1.3;4.1.3 Wnt5a–Ror2 axis in metastasis;144
10.4.1.4;4.1.4 Ror1 axis in survival and proliferation of cancer cells;145
10.4.1.5;4.1.5 Cross talk with different signaling axes;147
10.4.1.6;4.1.6 Ror1 axis in drug resistance;148
10.4.2;4.2 Tumor-Suppressive Functions of Wnt5a;149
10.5;5. Concluding Remarks;149
10.6;Acknowledgments;151
10.7;References;151
11;New Insight into Cancer Aneuploidy in Zebrafish;160
11.1;1. Introduction;161
11.2;2. The Cause of Aneuploidy;162
11.3;3. Biological Effects of Aneuploidy;163
11.3.1;3.1 Gene Expression and Dosage Compensation;163
11.3.2;3.2 Impacts on Organism Fitness;164
11.3.3;3.3 Cellular Impacts on Noncancerous Cells;165
11.3.4;3.4 Aneuploidy in Cancer;165
11.4;4. Zebrafish as a Cancer Model for Human Cancers;166
11.4.1;4.1 Polyploid Zebrafish;167
11.4.2;4.2 Zebrafish Aneuploid Mutants;168
11.4.3;4.3 Aneuploid Nature of Zebrafish Cancers;169
11.5;5. Cancer Driver Genes on Aneuploid Chromosomes;170
11.5.1;5.1 Finding Cancer Driver Genes by Cross-Species Comparisons;170
11.5.2;5.2 Functional Validations of Cancer Driver Genes;173
11.6;6. Future Directions;173
11.7;Acknowledgments;175
11.8;References;175
12;The Amazing Ubiquitin-Proteasome System: Structural Components and Implication in Aging;182
12.1;1. Introduction;184
12.2;2. Aging;186
12.3;3. The Ubiquitin System;190
12.3.1;3.1 Ub-Conjugating Enzymes;191
12.3.2;3.2 The Fate of the Ubiquitinated Protein;193
12.3.3;3.3 Recycling of Ub;194
12.4;4. The Proteasome;195
12.4.1;4.1 20S CP: Structure, Function, and Assembly;195
12.4.2;4.2 19S RP: Structure, Function, and Assembly;198
12.4.3;4.3 Alternative Proteasome Forms;200
12.4.4;4.4 Subcellular Localization and Regulation of the Proteasome;200
12.4.5;4.5 The Endoplasmic Reticulum-Associated Degradation;205
12.4.6;4.6 The Outer Mitochondrial Membrane-Associated Degradation;208
12.4.7;4.7 Cross Talk between the UPS and the other Components of the Cellular Proteostasis Network;209
12.4.7.1;4.7.1 UPS and the other proteolytic pathways;209
12.4.7.2;4.7.2 UPS and the network of molecular chaperones;210
12.4.7.3;4.7.3 UPS and cellular antioxidant responses;211
12.5;5. Regulation of the Ub System during Cellular Senescence and In vivo Aging;213
12.6;6. Implication of ERAD and OMMAD in Cellular Senescence and In vivo Aging;214
12.7;7. Alterations of the Proteasome Functionality during Cellular Senescence and In vivo Aging;215
12.8;8. Modulation of the UPS as an Antiaging Approach;219
12.9;9. Conclusive Remarks and Perspectives;222
12.10;Acknowledgments;223
12.11;References;223
13;Biogenesis and Function of the NGF/TrkA Signaling Endosome;250
13.1;1. Introduction;251
13.2;2. NGF;253
13.2.1;2.1 Biogenesis;253
13.2.2;2.2 Physiological Importance;254
13.3;3. TrkA;254
13.3.1;3.1 Biogenesis and Localization;255
13.3.2;3.2 Signaling;256
13.4;4. The Signaling Endosome;257
13.4.1;4.1 Biogenesis;259
13.4.2;4.2 Trafficking;261
13.4.3;4.3 Rab Function;261
13.5;5. Concluding Remarks;263
13.6;Acknowledgments;264
13.7;References;264
14;Multiple Myeloma as a Model for the Role of Bone Marrow Niches in the Control of Angiogenesis;270
14.1;1. Introduction;270
14.2;2. EPCs and MSCs;272
14.3;3. Vascular Niche;273
14.4;4. Osteoblastic Niche;274
14.5;5. MM Niche and Angiogenesis;276
14.6;6. Targeting Angiogenesis in the MM Niche;280
14.7;7. Concluding Remarks;284
14.8;Acknowledgments;285
14.9;References;285
15;Index;294

Leseproben

2. Hallmarks of Transformation
Carcinogenesis is a process by which normal, otherwise healthy cells break free of normal control mechanisms to acquire sustained proliferation, growth suppressor evasion, resistance to cell death, indefinite replication, invasion of neighboring tissues, and undergo angiogenesis to provide nutrients to support rapidly dividing cells. As these processes are important to normal cell growth and differentiation, one can therefore view cancer as deregulated differentiation, often occurring from “differentiation blocks” whereby faster-growing, less-differentiated cell populations expand faster than neighboring differentiated cells (Greaves, 1982). Because transcription factors are at the heart of normal cellular development (Tenen et al., 1997; Shivdasani and Orkin, 1996), aberrant regulation or activation of physiologically important transcription factors often leads to tumor formation (Alcalay et al., 2001). In the last decade, two additional hallmarks have been added: reprogramming of energy metabolism and evading immune destruction (Hanahan and Weinberg, 2011). In carcinoma, the most prevalent form of all human cancers (80–90%), malignant transformation is associated with the loss of differentiated epithelial characteristics and a coinciding increase of less-mature mesenchymal traits, a process termed the epithelial-mesenchymal transition (EMT) (Figure 1). EMT occurs physiologically during embryonic development, but also plays a fundamental role later in life during pathological processes, including cancer and fibrosis. In cancer, EMT contributes to tumor progression by conferring properties such as invasiveness, the ability to metastasize, resistance to therapy, and possibly the generation of stem-like cancer cells (Mallini et al., 2014). Cells undergoing an EMT-like transition are believed to be more motile and invasive, thought to be a critical step in the progression toward metastasis (Garcia de Herreros and Moustakas, 2014). In addition to changes in adhesion, cancer cells also acquire the capability to sustain proliferative signaling in a number of alternative ways. Some tumor cells produce growth factor ligands themselves, to which they can respond via the expression of cognate receptors, resulting in autocrine proliferative stimulation. Alternatively, cancer cells may send signals to stimulate neighboring normal cells within the supporting tumor-associated stroma, which reciprocate by supplying the cancer cells with various growth factors. Receptor signaling can also be deregulated by elevating the levels of receptor proteins displayed at the cancer cell surface, rendering such cells hyperresponsive to otherwise limiting amounts of growth factor ligand; the same outcome can result from structural alterations in the receptor molecules that facilitate ligand-independent firing (Hanahan and Weinberg, 2011). Growth factor independence may also derive from the constitutive activation of components of signaling pathways operating downstream of these receptors.
Figure 1 Epidermal growth factor receptor (EGFR) and the hallmarks of epithelial-mesenchymal transition (EMT). Schematic highlighting the phenotypic changes cells undergo during EMT. Several of these phenotypic changes are directly regulated by EGFR. 2.1. Epithelial–Mesenchymal Transition
One of the earliest steps in tumor progression is when epithelial-like cells begin to take on the phenotypic traits of mesenchymal cells. EGFR and EGF signaling plays a critical role in the initiation of this process, termed EMT. Epithelia are sheets of tightly associated specialized epithelial cells that line surfaces throughout the body. These cellular sheets perform vital functions as a barrier while also regulating nutrient and fluid exchange. To carry out these functions, epithelial cells possess highly specialized cell architecture and are polarized. The apical–basal polarity present in epithelial cells requires structural integrity of intercellular junctions and extracellular interactions between epithelial cells and substrates or neighboring cells (Martin-Belmonte and Perez-Moreno, 2012). These junctional complexes include tight junctions that physically separate the apical and basolateral plasma membranes to maintain the polarized protein/lipid composition of the respective membrane domains, adherens junctions essential for cell–cell adhesion, desmosomes involved in intercellular adhesion, and gap junctions that facilitate intercellular communication. Together, these junctions restrict cell motility, preserve tissue integrity, and permit individual cells to function as cohesive units (Martin-Belmonte and Perez-Moreno, 2012). As such, tumors must find ways, including activation of the EGF signaling pathway, to disrupt these junctions in order for tumors to progress and metastasize. Continued expression and functional activity of junctional complexes are required for polarized cells to remain tightly associated within the epithelium and to coordinate signaling pathways that regulate proliferation. Loss of junctional complexes is associated with depolarization, loss of differentiated characteristics, enhanced epithelial cell proliferation, and acquisition of an invasive potential. For these reasons, these junctional complexes are often aberrantly regulated during tumor formation and progression. Intracellular effector molecules orchestrate the transcriptional downregulation of cell adhesion molecules, disassembly of junctional complexes, and changes in cytoskeletal organization during EMT that lead to the subsequent loss of intercellular junctions and cell polarity. These changes occur at multiple molecular levels, including gene regulation through promoter methylation/demethylation or histone acetylation/deacetylation, alternative splicing, protein translocation/sequestration, and transcriptional regulation of target genes. As epithelial cells lose intercellular adhesion, the cytoskeleton reorganizes and cells gain mesenchymal cell characteristics including increased motility and the expression of mesenchymal genes. Underscoring the important interrelationship between EMT and adhesion, several key transcription factors that promote EMT directly regulate the expression of both cell adhesion and cell polarity complexes. For example, the EGF signaling intermediates Snail (now known as SNAI1), Slug (SNAI2), Sip1 (Zeb2), E47 (E2a), Twist1, FoxC2, FoxC1, GSC, ß-catenin, and Zeb1 regulate E-cadherin gene repression and influence the gene-expression patterns that underlie EMT (Garcia de Herreros and Moustakas, 2014). Ultimately, the cellular changes resulting from EMT promote many hallmarks of cancer, including loss of contact inhibition, enhanced invasiveness, altered growth control, and increased resistance to apoptosis. EMT is typically initiated by extracellular activation resulting from an intricate network of interactions among several signaling pathways and eventually leads to increased stability of the mesenchymal phenotype (Lamouille et al., 2014). Many of these pathways have common end points, including E-cadherin downregulation and expression of EMT-associated genes. E-cadherin, a calcium-dependent adhesion molecule that mediates homophilic cell–cell adhesion, is a central regulator of the epithelial phenotype and its expression is lost in many tumors either through mutations in the CDH1 gene, which encodes E-cadherin, or through transcriptional repression of CDH1 during EMT. Downregulation of E-cadherin results in the loss of E-cadherin-dependent junctional complexes and E-cadherin-mediated sequestration of ß-catenin. Unsequestered ß-catenin activates transcriptional regulation through LEF/TCF4 (lymphoid-enhancer-binding factor/T-cell factor-4) and further drives the EMT process. Due to cross talk between integrin and E-cadherin signaling, downregulation of E-cadherin is also involved in the switch from cadherin-mediated adhesion in epithelial cells to integrin-mediated adhesion predominant in mesenchymal cells (Nagathihalli and Merchant, 2012). Loss of expression or functional activity of many cell adhesion molecules and cell polarity proteins (e.g., PAR, crumbs (CRB), and scribble (SCRIB) complexes) during EMT is intricately related to advanced stages of tumor progression and invasiveness. Indeed, many of the proteins that control epithelial polarity are tumor suppressors or proto-oncoproteins, and their contributions to the early stages of tumorigenesis have been described in an excellent review by Martin-Belmonte and Perez-Moreno (2012). The initiation of most important cellular processes is under tight transcriptional control, mediated by transcription factors that regulate the activation of a web of downstream targets and mediators. The cellular transition from an epithelial to mesenchymal phenotype is no exception. One of the best described transcription factors involved in EMT is SNAI1, which has been characterized as a critical central regulator of EMT. SNAI1 binds to E-box consensus sequences in the E-cadherin promoter and repressing genes involved in cell polarity genes found in the Crumbs, Par, and Scribble complexes (Whiteman et al., 2008). Binding of Snail to the E-cadherin promoter is facilitated by local modifications of the CDN1 chromatin structure by SIN3A, histone deacetylases (HDAC)-1 and -2, and Polycomb 2 complex proteins (Herranz et al., 2008) and posttranslational modifications of Snail such as phosphorylation (PAK, GSK3ß)/dephosphorylation (SCP) and lysine oxidation (LOXL2) (Peinado et al.,...