CURRENT ADVANCES IN THE SCIENCE OF OSTEOSARCOMA : research.

Preface
	Osteosarcoma: The State of Affairs Dictates a Change in Clinical Practice and Clinical Trial Design
Contents
Contributors
1: Genomic Complexity of Osteosarcoma and Its Implication for Preclinical and Clinical Targeted Therapies
	General Introduction
		Genomics of Human Osteosarcoma
		Cell Line Genomics
		Cell Line Models of Metastatic Disease
		PDX Models
		Preclinical Models for Drug Testing
		Other PDX Studies
	References Cited
2: Genomics and the Immune Landscape of Osteosarcoma
	Introduction
	Genomic Landscape of Osteosarcoma
		Key Altered Genes and Pathways Associated with OS Genome Instability and Oncogenesis
			TP53
			RB1 and Other DNA Damage Repair Pathways
			Telomere Lengthening Pathways
			IGF Signaling/PI3K-mTOR
		Other Genomic Events Associated with OS Genome Instability
			Genome Doubling
			Chromothripsis
			Kataegis
	The Osteosarcoma Immune Landscape and Immunogenomic Interplay
		OS Immune Landscape
		OS Genomic Features Associated with the Immune Response
			Neoantigens
			Aneuploidy
			Genetic Alterations and Pathways
	Translational Applications
	Conclusion
	References
3: RECQ DNA Helicases and Osteosarcoma
	Introduction
	RECQ Family of DNA Helicases and Cancer Predisposition
	Structure and Functions of the RECQL4 DNA Helicase
	Rothmund-Thomson Syndrome (RTS): Nature’s Model of Osteosarcoma
	Understanding the Role of RECQL4 in Osteosarcoma Development Using Mouse Models
		Recql4 Global Knockout Mouse Models
		Recql4 Conditional (Bone-Specific) Mouse Models
	Clinical Implications for Understanding RECQ Gene Defects and Potentially Targeting RECQ-Related Pathways for Cancer Therapy
	References
4: Targeting the Cancer Epigenome with Histone Deacetylase Inhibitors in Osteosarcoma
	Introduction
	Targeting the Cancer Epigenome
		Broad Reprogrammers
		Targeted Reprogrammers
	Histone Acetylation in Cancer
		Histone Acetyltransferases
		Histone Deacetylases
	Nonhistone Protein Acetylation in Cancer
	Histone Deacetylase Inhibitors in Cancer
	Safety and Tolerance of Histone Deacetylase Inhibitors
	Preclinical Evidence for Histone Deacetylase Inhibitors in Osteosarcoma
		Emergence of HDACi in Drug Screening Studies for Osteosarcoma
		Mechanisms of HDACi Efficacy in Osteosarcoma
	Clinical Evidence for Histone Deacetylase Inhibitors in Osteosarcoma
		HDACs as Biomarkers in Osteosarcoma
		HDACi in Clinical Trials for Osteosarcoma
	Combination Therapy with Histone Deacetylase Inhibitors in Osteosarcoma
	Challenges in the Development of Histone Deacetylase Inhibitor Therapy for Osteosarcoma
	Conclusions
	References
5: Oncolytic Viruses and Their Potential as a Therapeutic Opportunity in Osteosarcoma
	Introduction
	Tumor Microenvironment
		Immunologic Landscape and Immunoediting
	Osteosarcoma TME
		Tumor Mutational Burden
		Immunoevasion
	Oncolytic Virotherapy in Osteosarcoma
	Oncolytic DNA Viruses
		Adenovirus
		Herpes Simplex Virus
		Vaccinia Virus
		Protoparvovirus
	Oncolytic RNA Viruses
		Reovirus
		Semliki Forest Virus
		Vesicular Stomatitis Virus
		Measles Virus
		Poliovirus
		Newcastle Disease Virus
		Maraba Virus
	Combination Therapy
	Challenges to Oncolytic Virotherapy
	Future Directions
	References
6: Applying Osteosarcoma Immunology to Understand Disease Progression and Assess Immunotherapeutic Response
	Introduction
	Assessing Osteosarcoma Disease Progression
		Osteosarcoma Immunology: Innate Immune System
			Myeloid Lineage
				Granulocytes
				Mononuclear Phagocytic System: Monocytes, Macrophages, and Dendritic Cells
					Monocytes
					Macrophages
					Dendritic Cells
					Myeloid-Derived Suppressor Cells
		Osteosarcoma Immunology: Adaptive Immune System
			Lymphoid Lineage
				T Lymphocytes
					Helper T Cells
					Cytotoxic T Cells
					Regulatory T Cells
				Lymphocytes
				Natural Killer Cells
	Assessing Immunotherapeutic Response in Osteosarcoma
		Checkpoint Blockade
		Other Immunotherapeutics
			Cytokine Stimulation
			Dendritic Cell Vaccines
			Genetically Modified T Cells
			Macrophage Activation
			Peptide Vaccines
	Future Perspectives
	References
7: Targetable Intercellular Signaling Pathways Facilitate Lung Colonization in Osteosarcoma
	Introduction
	The Metastatic Bottleneck
	Cell-Autonomous Mechanisms that Facilitate Metastatic Lung Colonization in Osteosarcoma
		Mechanisms that Resist Late Apoptosis Drive the Persistence of Disseminated Osteosarcoma Cells
		Increased Expression of HSAP5 Facilitates Management of ER Stress During Metastatic Progression
		Efficient Translation of Complex Transcripts Is Required for Osteosarcoma Metastatic Progression
		Epigenetic Changes Influence Gene Expression Programs to Promote Metastasis
	Tumor-Host Interactions that Mediate Osteosarcoma Lung Metastasis
		Elements of Both Host- and Tumor-Derived Extracellular Matrix Promote Osteosarcoma Survival and Stemness During Metastasis
		Interactions with Resident Immune Surveillance Mechanisms and Infiltrating Cells Facilitate Immune Evasion
		Tumor-Educated Mesenchymal Stem Cells Facilitate Growth of Disseminated Osteosarcoma Cells Through IL6 Production
		Bidirectional Cytokine Signaling Between Osteosarcoma Cells and Lung Parenchyma Regulates Metastatic Progression
	Conclusions
	References
8: Wnt Signaling in Osteosarcoma
	Introduction
	Overview of Wnt/β-Catenin Signaling Pathway
		The Canonical Wnt Pathway
		The Noncanonical Wnt Pathways
	Wnt Signaling in Osteosarcoma
	Wnt Antagonists in Osteosarcoma
		WIF1
		sFRP
		DKK-1: Tumor Suppressor or Pro-tumorigenic Factor?
		DKK-3
		SOST
		Naturally Occurring Small Molecules
		Other Small Molecules
		Other Drugs Recently Shown to Inhibit OS
	Therapy Against Wnt Target Genes in Osteosarcoma
	Wnt/B-catenin Signaling and Stem Cells
	Summary
	References
9: Receptor Tyrosine Kinases in Osteosarcoma: 2019 Update
	AXL
	EPHB2
	FGFR2
	IGF1R
	RET
	Multi-TKIs
	References
10: The Role of ALDH in the Metastatic Potential of Osteosarcoma Cells and Potential ALDH Targets
	Introduction
	ALDH in Other Molecular Pathways
		Notch
		mTOR
		ALDH Inhibition with Disulfiram
		In Vivo Studies
		Copper
		Retinal
	Conclusions
	References
11: Autophagy in Osteosarcoma
	Introduction
	Regulation of Autophagy in Osteosarcoma
	Autophagy and Tumorigenesis
		Cell Survival Versus Cell Death
	Dual Role of Autophagy in Osteosarcoma
	Heat Shock Proteins and Autophagy
	Autophagy Inhibition: From Drug Development to Challenges into Clinical Translation
	Summary
	References
12: The Fas/FasL Signaling Pathway: Its Role in the Metastatic Process and as a Target for Treating Osteosarcoma Lung Metastases
	Introduction
	Fas Pathway Is Involved in Development of OS Metastases in the Lungs
		Expression of Fas Receptor Correlates with OS Metastatic Potential in Animal Models and in Patient Specimens
		Functional Fas, FasL, and Downstream Fas Signaling Are Important for OS Lung Metastasis Progression
	Fas Signaling Plays an Important Role in Response of OS to Therapy
	Regulation of the Fas Signaling Pathway
		Epigenetic Regulation of Fas Expression
		Regulation of Fas Expression in OS Cells by miRNA
	Summary
	References
13: Exosomes: Dynamic Mediators of Extracellular Communication in the Tumor Microenvironment
	Introduction
	The Role of Exosomes in Cancer
	The Role of Exosomes in Drug Resistance
	The Role of Exosomes in Angiogenesis and Lymphogenesis
	The Role of Exosomes in Cancer Cell Proliferation and Survival
	The Role of Exosomes in Cancer Migration, Invasion, and Metastasis
	The Role of Exosomes in Cancer and Immune Cell Interactions
	The Emerging Role of Exosomes in Osteosarcoma
	Conclusions
	References
14: Comparative Immunology and Immunotherapy of Canine Osteosarcoma
	Introduction
	The Immunology of Canine OSA
		Mutational Burden
		Immune Landscape
			Monocytes/Macrophages
			Myeloid-Derived Suppressor Cells
			Regulatory T Cells
			T Cells
			Checkpoint Molecule Expression
			Metastatic Lesions
	Immunotherapy of Canine OSA
		Immune Modulatory Agents
			Coley’s Toxins
			BCG
			Muramyl Tripeptides
			Cytokines
			Losartan
			Bisphosphonates
		Active Vaccination
			Bacterial Vaccines
				Listeria monocytogenes
				Salmonella Typhimurium
			DNA Vaccines
			Oncolytic Viruses
			FasL-Mediated Inflammation
		Cell-Based Therapies
			Tall 104 Cells
			Polyclonal Activated T Cells
			NK Cell Therapies
			CAR T Cell Technology
			Additional Strategies for Induction of ICD
	References
Index