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INTRODUCTION TO CANCER METASTASIS

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INTRODUCTION TO CANCER METASTASIS

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Contents

List of Contributors

Preface

I - CANCER METASTASIS FROM PRIMARY ORGANS

1 - Cancer Metastasis: An Introduction

1. INTRODUCTION

2. DISRUPTION OF CELL ADHESION: INITIATION OF METASTASIS

2.1 Adherens Junctions

2.2 Tight Junctions

3. MATRIX METALLOPROTEINASES IN CANCER METASTASIS

4. EMT IN CANCER METASTASIS

5. ORGAN-SPECIFIC METASTASIS

6. MICRORNAS AND CANCER STEM CELLS IN CANCER METASTASIS

7. CONCLUSIONS AND PERSPECTIVES

References

2 - Breast Cancer Metastasis

1. INTRODUCTION

2. BIOLOGY

2.1 Breast Cancer Proliferation Signals

2.2 Breast Cancer Microenvironment

2.3 Disseminated Tumor Cells and Circulating Tumor Cells

2.4 Breast Cancer Dormancy

2.5 Cancer Stem Cells

2.6 Intrinsic Subtypes

3. METASTATIC DISSEMINATION

3.1 Clinical Symptoms

3.2 Locoregional Recurrence

3.3 Bone Metastasis

3.4 Lung Metastasis, Pleural Metastasis

3.5 Liver Metastasis

3.6 Brain Metastasis

3.7 Peritoneal Dissemination

4. PROGNOSTIC FACTORS AFTER RECURRENCE

5. TREATMENT FOR METASTATIC BREAST CANCER

5.1 Endocrine Therapy

5.1.1 Selective Estrogen Receptor Modulators

5.1.2 Aromatase Inhibitors

5.1.3 Selective Estrogen Receptor Downregulators

5.2 Chemotherapy

5.2.1 Anthracyclines

5.2.2 Taxanes

5.2.3 Vinorelbine

5.2.4 Capecitabine

5.2.5 Eribulin

5.2.6 Platinum Salts

5.3 Metronomic Chemotherapy

5.4 Molecular Targeted Therapy

5.4.1 Trastuzumab

5.4.2 Lapatinib

5.4.3 T-DM1

5.4.4 Pertuzumab

5.4.5 Bevacizumab

5.4.6 Everolimus

5.5 Bisphosphonate

5.6 RANK-Ligand (RANKL)

5.7 Radiotherapy

5.8 Surgery

5.9 Palliative Care

6. CONCLUSIONS

References

3 - Prostate Cancer Metastasis

1. EPIDEMIOLOGY AND OVERVIEW OF METASTATIC PROSTATE CANCER

2. CELLULAR BIOLOGY OF PROSTATE CANCER METASTASES

2.1 The Androgen Receptor Signaling Pathway

2.2 The Phosphatidyl Inositol 3-Kinase/Akt-Signaling Pathway

2.3 Cell Cycle Pathways

2.4 DNA Repair Pathways

2.5 Wnt Pathways

2.6 Coregulator Factors

3. THE METASTATIC CASCADE

3.1 Bone Metastases

3.2 Lymph Node Metastases

3.3 Visceral Metastases

3.4 Clinical Considerations in Prostate Cancer Metastasis

3.4.1 Disease Recurrence and Risk Assessment

3.5 Overview of Treatment for Prostate Cancer Metastases

3.6 Treatment of Symptomatic Metastatic Disease

3.7 Future Areas of Development

3.8 Liquid Biopsy and Precision Medicine

3.9 Imaging Modalities

3.10 Investigational Therapies

4. CONCLUSIONS

References

4 - Lung Cancer Metastasis

1. GENERAL INFORMATION

2. MECHANISM OF METASTASIS

3. MOLECULAR MECHANISM IN THE REGULATION OF LUNG CANCER METASTASIS

4. EPITHELIAL TO MESENCHYMAL TRANSITION IN LUNG CANCER

5. CANCER STEM CELLS

6. CONCLUDING REMARKS

Acknowledgments

References

5 - Cervical Cancer Metastasis

1. INTRODUCTION

2. RISK FACTORS

3. PATHOGENESIS

4. HISTOPATHOLOGY

5. ROUTES OF DISSEMINATION

6. MAJOR MOLECULAR FACTORS

7. CONCLUSION

References

6 - Colorectal Cancer Metastasis

1. INTRODUCTION

2. MOLECULAR ASPECTS OF COLORECTAL CANCER METASTASIS

2.1 Biomarkers for Colorectal Cancer Metastasis

3. MAIN SITES OF COLORECTAL CANCER METASTASIS

3.1 Liver

3.2 Peritoneum

3.3 Lung

4. THERAPEUTIC OPTIONS FOR METASTATIC COLORECTAL CANCER

4.1 Surgical Intervention

4.2 Chemotherapy

5. CHALLENGES AND PROBABLE SOLUTIONS

5.1 Personalized Medicine

5.2 Immunotherapy

6. CONCLUSIONS

References

7 - Metastatic Pancreatic Cancer: Current State and Future Directions

1. INTRODUCTION

1.1 Pancreatic Cancer Epidemiology, Demographics, and Etiology

1.2 Genetics and Biology of Pancreatic Ductal Adenocarcinoma

2. MANAGEMENT OF PANCREATIC DUCTAL ADENOCARCINOMA

2.1 Screening

2.2 Diagnosis

2.2.1 Presenting Symptoms

2.2.2 Laboratory Tests and Radiological Imaging

2.3 Staging

2.4 Treatment and Clinical Trials

2.5 Novel Treatment Opportunities in Pancreatic Ductal Adenocarcinoma

2.5.1 Next-Generation Sequencing

2.5.2 Drugs Targeting Tumor Metabolism

2.5.3 Drugs Targeting the Stromal Compartment

2.5.4 Immunotherapy and Cancer Vaccines

3. MOLECULAR MECHANISMS DRIVING METASTASIS

3.1 The Seed: Tumor Cell-Specific Events Promoting Metastasis

3.1.1 Genetic Events

3.1.2 Loss of Differentiation and Epithelial-to-Mesenchymal Transition

3.1.3 Cancer Stem Cells Concept

3.2 The Soil: Tumor Microenvironment

3.3 Tumor-Stroma Crosstalk

3.3.1 The TGF-β Pathway

3.3.2 Tumor-Derived Exosomes and the Metastatic Niche

4. IN VIVO EXPERIMENTAL MODELS

4.1 Patient-Derived Xenografts

4.2 Genetically Engineered Mouse Models

4.3 Organoid Models

5. OPEN QUESTION: ONSET AND DYNAMICS OF METASTASES

6. CONCLUSIONS

References

8 - Gastric Cancer Metastasis

1. EPIDEMIOLOGY AND SCREENING PROGRAMS

2. METASTATIC GC—CLINICAL ASPECTS

2.1 Symptoms

2.2 GC—Metastatic Patterns

2.3 Importance of Diagnostics

3. DIAGNOSIS OF METASTATIC GC WITH A PARTICULAR FOCUS ON 18-F-FDG PET/CT

3.1 Current Role of 18-F-FDG PET/CT Imaging in GC Diagnostics

3.2 Usefulness of PET/CT in the Preoperative Staging of GC Compared With Other Diagnostic Methods

3.3 Usefulness of PET/CT in the Assessment of Distant Metastasis (M1) and Its Prognostic Role

3.4 Limitations of 18-FDG-PET/CT in GC Diagnosis

3.5 Usefulness of Laparoscopy Alone and in Combination With PET/CT in the Assessment of GC Metastases

3.6 Follow-Up of Patients After Radical Treatment of GC

3.7 18F-FLT PET/CT in Metastatic GC Diagnosis

3.8 Usefulness of Magnetic Resonance Imaging in the Evaluation of GC Metastasis

3.9 Perspective Directions for Improvement and Development of PET Imaging

4. PROGNOSTIC AND PREDICTIVE FACTORS

5. BIOMARKERS

6. TREATMENT METHODS OF METASTATIC GC

7. CONCLUSION

References

9 - Hepatocellular Carcinoma: Metastatic Disease

1. INTRODUCTION

2. EPIDEMIOLOGY

2.1 Incidence

2.2 Underlying Disease/Risk Factors

2.3 Development of Metastatic Hepatocellular Carcinoma

3. DIAGNOSIS

3.1 Imaging

3.2 Biopsy

4. PROGNOSIS AND STAGING

5. TREATMENT

6. CONCLUSIONS

References

10 - Metastatic Bladder Cancer

1. INTRODUCTION

2. EPIDEMIOLOGY

3. STAGING

3.1 Carcinoma In Situ

4. GRADING

5. STAGING TOOLS

6. EMERGING BIOMARKERS

7. PROGNOSTIC FACTORS

7.1 Histologic Variants of Urothelial Bladder Cancer and Nonurothelial Bladder Cancer

8. CLINICAL PRESENTATION OF METASTATIC BLADDER DISEASE

9. MANAGEMENT OF CLINICALLY LOCALIZED BLADDER CANCER, POSITIVE PELVIC NODES AND METASTATIC DISEASE

9.1 Radical Cystectomy in Conjunction With Perioperative Chemotherapy

9.2 Postchemotherapy Lymphadenectomy

9.3 Trimodal Bladder-Sparing Therapy

10. CLINICAL PROGNOSTICATORS

10.1 Prechemotherapy Prognosticators

10.2 Postchemotherapy Prognosticators

11. MANAGEMENT OF METASTATIC BLADDER CANCER

11.1 Standard Chemotherapy Regimes

11.2 Methotrexate, Vinblastine, Doxorubicin, Cisplatin

11.3 Gemcitabine and Cisplatin

11.4 Neoadjuvant Chemotherapy

11.5 Radiosensitizing Chemotherapy

11.6 Alternative Chemotherapeutic Agents

12. NEW AGENTS

12.1 Tyrosine Kinase Receptor Inhibitors

12.2 Cell Cycle Regulators

13. IMMUNOTHERAPY

13.1 PD-L1 Inhibitors

13.2 Anticytotoxic T Lymphocyte Associated Antigen (Anti-CTLA-4)

14. ROLE OF SURGERY IN METASTATIC BLADDER CANCER

14.1 Extended Lymph Node Dissection

14.2 Palliative Treatment Options in Metastatic Bladder Cancer

14.2.1 Palliative Chemotherapy

14.2.2 Palliative Radiation

14.2.3 Palliative Surgery

14.3 Supportive Measures in Patients with Advanced and/or Metastatic Bladder Cancer

15. CONCLUSIONS

References

11 - Metastatic Cutaneous Squamous Cell Carcinomas

1. INTRODUCTION

2. DEFINING THE HIGH-RISK VARIANT

2.1 Clinical

2.1.1 Immunosuppression

2.1.1.1 HEMATOLOGIC MALIGNANCIES

2.1.1.2 SOLID ORGAN TRANSPLANT

2.1.1.3 HEMATOPOIETIC STEM CELL TRANSPLANT

2.1.1.4 HUMAN IMMUNODEFICIENCY VIRUS INFECTION

2.1.2 Genetic Disorders

2.1.3 Cutaneous Squamous Cell Carcinomas Arising at the Site of a Preexisting Lesion

2.1.4 Clinical Features of the Tumors

2.1.4.1 LESION SIZE

2.1.4.2 LESION SITE

2.1.4.3 RECURRENCE

2.1.5 Human Papillomavirus

2.2 Histologic Features of High RISK

2.2.1 Tumor Thickness

2.2.2 Perineural Invasion

2.2.3 Lymphovascular Invasion

2.2.4 Histologic Differentiation

2.2.5 Histologic Subtype

2.3 Molecular High-Risk Markers

2.3.1 Epidermal Growth Factor Receptor

2.3.2 Cytogenetic Alterations: CKS1B and Protein Tyrosine Phosphatase Receptor Type D

2.3.3 Epithelial–Mesenchymal Transition

2.3.4 IKKalpha

3. STAGING SYSTEMS

4. TREATING HIGH-RISK CUTANEOUS SQUAMOUS CELL CARCINOMA

5. SENTINEL NODE BIOPSY

6. TREATMENT OF LOCALLY ADVANCED OR METASTATIC CUTANEOUS SQUAMOUS CELL CARCINOMA

7. CONCLUDING REMARKS

References

12 - Osteosarcoma Metastasis—Prognostic Factors and Treatment Strategies

1. INTRODUCTION

2. CLINICAL FEATURES OF METASTASIS FROM OSTEOSARCOMA

2.1 Incidence

2.2 Detection

2.3 Prognostic Factors

3. TREATMENT FOR METASTASIS FROM OSTEOSARCOMA

3.1 Surgical Treatment

3.2 Radiotherapy

3.3 Emerging Treatment Options

4. CONCLUSION

References

II - CANCER METASTASIS TO DISTANT ORGANS

13 - Lymph Node Metastasis*

1. INTRODUCTION

2. HISTORY

3. MECHANISMS—HOW TUMORS METASTASIZE TO LYMPH NODES

3.1 Molecular Aspects

3.2. Mechanical (Anatomic) Aspects

3.2.1 Angiogenesis

3.2.2 Lymphangiogenesis

3.2.3 Lymphatic Pathways From Primary Tumor to Sentinel Lymph Node

3.2.4 Mechanobiology and Tumor Progression

3.2.5 The Role of the Lymph Node Microenvironment in Progression of Metastatic Cancer

4. CLINICAL ASPECTS OF LYMPH NODE METASTASIS

4.1 Clinical Diagnosis

4.2 Radiological Imaging

4.2.1 Mammography

4.2.2 Ultrasound

4.2.3 Magnetic Resonance Imaging

4.2.4 Computed Tomography

4.2.5 Positron Emission Tomography With CT

4.2.6 Lymphoscintigraphy

4.3 Treatment of Lymph Node Metastases

4.3.1 Surgery

4.3.2 Other Treatments

5. PATHOLOGY

5.1 Gross Autopsy

5.2 Histopathologic Techniques for Identifying Lymph Node Metastasis

5.2.1 Lymph Node Microanatomy (Willard-Mack, 2006)

5.2.2 Pathologic Examination of Lymph Nodes

5.2.2.1 GROSS EVALUATION (LESTER ET AL., 2009; TANG ET AL., 2009)

5.2.2.2 MICROSCOPIC EXAMINATION

6. CONCLUSIONS & SUMMARY

References

14 - Molecular Involvement of the Bone Marrow Microenvironment in Bone Metastasis

1. INTRODUCTION

2. TYPES OF BONE METASTASIS

2.1 Osteolytic Bone Metastasis

2.2 Osteoblastic Bone Metastasis

3. PATHOPHYSIOLOGY OF BONE METASTASIS

3.1 Dissemination Process of Bone Metastatic Tumor Cells

3.2 Bone Metastatic Tumor Cell Targets the Osteoblastic Niche in the Bone Marrow

3.3 Molecular Mechanisms of Survival, Tumor Colonization, Tumor Dormancy, and Metastatic Outgrowth

4. TREATMENT OPTIONS FOR BONE METASTASIS

4.1 Antiresorptive Agents

4.2 Pain Management

5. DISCUSSION/CONCLUSION

Acknowledgments

References

15 - An Overview on Hepatic Metastasis

1. INTRODUCTION

2. HEPATIC PHYSIOLOGY AND CANCER BIOLOGY

3. HEPATIC FUNCTIONAL AND SURGICAL ANATOMY

4. CLINICAL PRESENTATION AND DIAGNOSIS

4.1 Clinical Presentation

4.2 Ultrasound

4.3 Computed Tomography Scan

4.4 Magnetic Resonance Imaging

4.5 Positron Emission Tomography

4.6 Fine Needle Aspiration Biopsy

5. TREATMENT OF HEPATIC METASTASES

5.1 Surgery

5.2 Liver Metastases From Colorectal Tumors

5.3 Hepatic Metastases from Neuroendocrine Tumors

5.4 Liver Metastases from Sarcoma

5.5 Hepatic Metastases From Other Primary Sites

5.6 Besides Surgery: Alternative Therapies and Adjuvants

5.7 Ablation: Radiofrequency and Chemical Ablation

5.8 Arterial Embolization

5.9 Portal Embolization

5.10 Chemotherapy: Neoadjuvant Preoperative and Adjuvant Postoperative

6. CONCLUSIONS

References

16 - Pulmonary Metastasis

1. DEVELOPMENT OF PULMONARY METASTASES

2. RATIONALE FOR LOCAL TREATMENT OF PULMONARY METASTASES

3. DIAGNOSIS OF PULMONARY METASTASES

4. PREOPERATIVE EXAMS

4.1 Control of the Primary Tumor

4.2 Exclusion of Extrathoracic Metastases

4.3 Complete Resection is Feasible

4.4 Can the Patient Tolerate Lung Resection?

5. SURGICAL RESECTION

5.1 Extent of Surgical Resection

5.2 Surgical Approach

6. RADIOLOGICAL ABLATION

7. RADIOTHERAPY

8. LYMPH NODE INVOLVEMENT

9. RESECTION OF RECURRENT METASTASES

10. LUNG METASTASIS IN GIVEN TUMOR TYPES

10.1 Colorectal Cancer

10.2 Soft Tissue Sarcoma

10.3 Osteosarcoma

10.4 Renal Cell Carcinoma

10.5 Melanoma

10.6 Nonseminomatous Testicular Germ Tumor

10.7 Breast Cancer

10.8 Head and Neck Tumor

10.9 Other Tumors

11. CONCLUSION

References

17 - Brain Metastasis: Basic Biology, Clinical Management, and Insight From Experimental Model Systems

1. INTRODUCTION

2. BIOLOGY

2.1 Brain Metastasis Formation

2.2 Brain Microenvironment

2.3 Alternative Vascularization Methods

2.4 Molecular Mechanisms of Brain Metastasis

3. CLINICAL MANAGEMENT

3.1 Diagnosis

3.2 Prognosis

3.2.1 Prognostic Scores

3.3 Treatment

3.3.1 Oligometastatic Disease (1–3 Metastases)

3.3.2 Multiple Metastatic Lesions (>3 Metastases)

3.3.3 Preventative Treatment

3.3.4 Recent Advances in Systemic Therapy

4. EXPERIMENTAL MODEL SYSTEMS

5. PRECLINICAL FINDINGS

5.1 Blood–Tumor Barrier Patency

5.2 Dormancy

6. CONCLUSION

References

III - EMERGING TARGETS FOR CANCER METASTASIS

18 - Developmental Pathways: Emerging Therapeutic Targets for Cancer Metastasis

1. INTRODUCTION

2. PROMETASTATIC CHANGES AND DEVELOPMENTAL PATHWAYS

2.1 Resistance to Anoikis

2.2 Epithelial-to-Mesenchymal Transition

2.3 Motility and Migration

2.4 Neoangiogenesis

3. NOTCH SIGNALING AND METASTASIS

3.1 Notch Family of Signaling Molecules

3.2 Notch in the Metastatic Cascade

3.3 Notch Targeting as Antimetastatic Strategy

3.3.1 Notch-Based Therapeutic Strategies

3.3.2 Targeting Notch Ligands and Receptors

4. ANTIMETASTATIC POTENTIAL OF WNT AND HEDGEHOG TARGETING

4.1 Wnt Targeting

4.1.1 Wnt Signaling and Cancer

4.1.2 Role of Wnt Signaling in Metastasis and Therapeutic Potential

4.2 Hedgehog, Metastatic Cascade and Emerging Therapies

4.2.1 Hedgehog Family

4.2.2 Hedgehog-Based Therapeutic Strategies

5. CONCLUDING REMARKS

References

19 - Emerging Therapeutic Targets for Cancer Metastasis: From the Perspective of Embryo Implantation

1. INTRODUCTION

2. THE SIMILARITY BETWEEN EMBRYO IMPLANTATION AND TUMOR METASTASIS

2.1 Angiogenesis

2.2 Migration and Invasion

2.3 Immune Escape

3. TROPHOBLAST INVASION INHIBITORY FACTORS DERIVED FROM THE MATERNAL ENDOMETRIUM DURING EMBRYO IMPLANTATION AND THEIR IMPLICATIO...

3.1 Inhibitors of the ECM-Degrading Enzymes

3.2 Cytokines

3.3 Metastasis Suppressor Genes

3.4 High-Temperature Requirement Factor A Family of Serine Proteases

3.5 Glycoproteins

4. CONCLUSIONS AND PERSPECTIVES

Acknowledgments

References

20 - Wnt Signaling as a Therapeutic Target in Cancer and Metastasis

1. INTRODUCTION

2. WNT SIGNALING AND CANCER

3. THE ROLE OF WNT SIGNALING IN EPITHELIAL–MESENCHYMAL TRANSITION AND CANCER STEM CELLS

4. THERAPEUTIC STRATEGIES TARGETING WNT SIGNALING

4.1 Nonsteroidal Anti-inflammatory Drugs

4.2 Vitamin A and D

4.3 Antibody-Based Strategies

4.4 Small-Molecule Inhibitors

5. PROTEIN KNOCKDOWN STRATEGIES

6. VIRAL-BASED THERAPIES

6.1 Genetic Strategies

7. CONCLUSION

References

Index

A

B

C

D

E

F

G

H

I

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

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