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Targeting the Wnt Pathway in Cancer

:	Katherine H. Goss
:	Kathleen H. Goss, Michael Kahn
:	Targeting the Wnt Pathway in Cancer
:	Springer-Verlag
:	9781441980236
:	1
:	CHF 133.00
:

:	Klinische Fächer
:	English

:	240
:	Wasserzeichen
:	PC/MAC/eReader/Tablet
:	PDF

Inappropriate activation of the Wnt signaling pathway is observed in many human cancers and is sufficient to drive tumor initiation and progression in numerous contexts. Multiple mechanisms, such as overexpression of Wnt ligands, inactivation of the APC and Axin tumor suppressors, and mutation of ?-catenin, are responsible for pathway activation in tumor cells. The development of potent Wnt pathway antagonists for therapeutic use has been a major effort for investigators in both academia and industry in recent years. This book will provide an overview of the Wnt pathway as a therapeutic target for cancer, and discuss the preclinical development of inhibitors specifically directed to upstream and downstream components of the pathway.

	Targeting the WntPathway in Cancer	3
	Preface	5
	Contents	7
	Contributors	9
	Chapter 1: An Introduction to Wnt Signaling	13
	1.1 The War on Wnt	13
	1.2 Wnt Signaling Regulates Genes	14
	1.3 Wnt Signaling Causes Human Cancer	15
	1.4 Downregulation of Wnt Signaling	19
	1.5 Interactions at the Cell Surface	21
	1.6 Interactions in the Nucleus	22
	1.7 Wnt and Stem Cells	23
	1.8 Structural Biology	23
	1.9 Conclusion	24
	References	24
	Chapter 2: Regulation of Wnt Secretion and Distribution	31
	2.1 Introduction	32
	2.2 Wnts Are Posttranslationally Modified in the ER	32
	2.3 Wls and the Retromer Complex Are Involved in the Intracellular Trafficking of Wnts	34
	2.4 Wnts Associate with Lipoproteins in the Dedicated Secretory Route	36
	2.5 HSPGs Regulate Extracellular Diffusion and Gradient Formation of Wnts	38
	2.6 Concluding Remarks	40
	References	41
	Chapter 3: Wnt Signaling in Stem Cells	46
	3.1 Introduction	47
	3.1.1 Stem Cells	47
	3.1.2 Human Embryonic Stem Cells	48
	3.1.3 Induced Pluripotent Stem Cells (iPSCs)	48
	3.1.4 Somatic Stem Cells	49
	3.1.5 Cancer Stem Cells	50
	3.1.6 Wnt Signaling	51
	3.1.7 Wnt Signaling in Stem Cells	51
	3.1.8 Wnt Signaling in Cancer Stem Cells	53
	3.1.9 Concluding Thoughts	57
	References	59
	Chapter 4: Crosstalk of the Wnt Signaling Pathway	62
	4.1 Growth Factor Signaling	62
	4.1.1 EGF	64
	4.1.2 HGF	66
	4.1.3 TGFb	67
	4.1.4 IGF	69
	4.1.5 VEGF	70
	4.1.6 FGF	70
	4.2 Developmental Pathways	71
	4.2.1 Notch Pathway	71
	4.2.2 Hedgehog Pathway	73
	4.3 Wnt and Other Networks	74
	4.3.1 Prostaglandin/Cox-2 Pathway	74
	4.3.2 PI3K/AKT Pathway	76
	4.3.3 mTOR	77
	4.3.4 Ras Pathway	79
	4.3.5 Miscellaneous Signaling Pathways	80
	4.4 Conclusion	80
	References	81
	Chapter 5: Dysregulation of the Wnt Pathway in Solid Tumors	92
	5.1 Introduction	93
	5.2 Colorectal Cancer	97
	5.2.1 Upregulation of Pathway Activators	97
	5.2.2 Loss of Pathway Inhibitors	97
	5.3 Breast Cancer	98
	5.3.1 Upregulation of Pathway Activators	98
	5.3.2 Loss of Pathway Inhibitors	99
	5.4 Lung Cancer	100
	5.4.1 Upregulation of Pathway Activators	100
	5.4.2 Loss of Pathway Inhibitors	101
	5.4.3 Mesothelioma	101
	5.5 Gastric Cancer	102
	5.5.1 Upregulation of Pathway Activators	102
	5.5.2 Loss of Pathway Inhibitors	102
	5.6 Head and Neck Cancer	103
	5.6.1 Upregulation of Pathway Activators	103
	5.6.2 Loss of Pathway Inhibitors	103
	5.7 Prostate Cancer	104
	5.7.1 Upregulation of Pathway Activators	104
	5.7.2 Loss of Pathway Inhibitors	104
	5.8 Pancreatic Cancer	105
	5.8.1 Upregulation of Pathway Activators	105
	5.8.2 Loss of Pathway Inhibitors	105
	5.9 Hepatocellular Carcinoma and Hepatoblastoma	106
	5.9.1 Upregulation of Pathway Activators	106
	5.9.2 Loss of Pathway Inhibitors	106
	5.10 Kidney Cancer	107
	5.10.1 Upregulation of Pathway Activators	107
	5.10.2 Loss of Pathway Inhibitors	107
	5.11 Bladder Cancer	107
	5.11.1 Upregulation of Pathway Activators	107
	5.11.2 Loss of Pathway Inhibitors	108
	5.12 Skin Cancer	108
	5.12.1 Upregulation of Pathway Activators	108
	5.12.2 Loss of Pathway Inhibitors	109
	5.13 Tumors of the Central Nervous System (CNS)	109
	5.13.1 Gliomas	109
	5.13.2 Medulloblastomas	110
	5.13.3 Other CNS Tumors	110
	5.14 Musculoskeletal Tumors	111
	5.14.1 Osteosarcoma	111
	5.14.2 Ewing’s Sarcoma	111
	5.14.3 Soft Tissue Tumors	111
	5.15 Gynecological Cancers	112
	5.15.1 Ovarian Cancer	112
	5.15.2 Endometrial Cancer	113
	5.15.3 Cervical Cancer	113
	5.16 Other Tumors	113
	5.16.1 Esophageal Cancer	113
	5.16.2 Adrenal Tumors	114
	5.16.3 Thyroid and Parathyroid Tumors	114
	5.16.4 Pituitary Tumors	115
	5.17 Conclusion	115
	References	117
	Chapter 6: WNT/b-Catenin Signaling in Leukemia	140
	6.1 WNT/b-Catenin Signaling in Normal Hematopoietic Stem Cells	141
	6.2 WNT/b-Catenin Signaling in Lymphopoiesis	142
	6.3 WNT Signaling in B-Cell Lineage Acute Lymphoblastic Leukemia	142
	6.4 Negative Regulation of WNT/b-Catenin Signaling Through BTK	144
	6.5 WNT/b-Catenin Signaling Promotes Leukemogenesis in the T-Cell Lineage	144
	6.6 WNT/b-Catenin Signaling is Required for Leukemia-Initiation in Acute Myeloid Leukemia	145
	6.7 Role of Prostaglandin E/b-Catenin Signaling in Leukemia Stem Cell Maintenance in AML	146
	6.8 WNT Signaling in Chronic Myeloid Leukemia	147
	6.9 Perspective	148
	References	149
	Chapter 7: Use of Genetically Engineered Mouse Models in Identification and Validation of Therapeutic Targets for Colon Cancer	154
	7.1 Introduction	154
	7.2 Genetically Engineered Mouse Models for Colonic Adenomas	155
	7.3 Therapeutic Ta