Cancer Biology: How Science Works [1st ed.] 303075698X, 9783030756987, 9783030756994

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Carsten Carlberg Eunike Velleuer

Cancer Biology: How Science Works

Cancer Biology: How Science Works

Carsten Carlberg · Eunike Velleuer

Cancer Biology: How Science Works

Carsten Carlberg Institute of Biomedicine University of Eastern Finland Kuopio, Finland

Eunike Velleuer Department for Pediatric Hemato-Oncology Children’s Hospital Krefeld, Nordrhein-Westfalen, Germany

ISBN 978-3-030-75698-7 ISBN 978-3-030-75699-4 (eBook) https://doi.org/10.1007/978-3-030-75699-4 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

This book starts with bad news: one in two of us will face during our lifespan the diagnosis of cancer, i.e., the detection of a malignant tumor. However, the good news are that less than half of all cancer patients die from the disease and that every second cancer death is preventable. Cancer is a collection of diseases that can affect basically every organ of our body, all of which have in common uncontrolled cellular growth. Behind every newly diagnosed malignant tumor in adulthood there is an individual history of probably 20 or more years of tumorigenesis. Cancer is typically considered as a disease of our genome caused by the accumulation of DNA point mutations as well as translocations, deletions and amplifications of larger genomic regions. However, tumorigenesis also comes along with abnormalities in cellular identity, different responsiveness to internal and external stimuli and major changes in the transcriptome, all of which are based on changes of our epigenome. In fact, most types of cancer carry mutations both in the genome and epigenome. The cells forming our body have the potential to grow in the context of wound healing or for the constant replacement of cells in our blood, skin or intestine. Malignant tumor formation often takes time making cancer in most cases to an age-related disease that we seem not to be able to evade. However, tumorigenesis is dependent on multiple environmental influences, including the surveillance of the immune system for cancer cells. Many pro- and anti-cancer effects of the environment we have under control by lifestyle decisions, such as retaining from smoking, selecting healthy food and being physically active. Thus, cancer preventive interventions are the most effective way to fight against cancer. We should try to understand ourselves in detail as well as in a global setting. Basic biology explains cellular mechanisms, such as growth, differentiation and cell death, which make life as a whole possible. Every (human) organism represents a complex interplay between hundreds of different cell types forming distinctive tissues and organs with specialized tasks. These processes need to be highly orchestrated especially during embryogenesis and later on in maintaining homeostasis of the adult body. Studying the cellular and molecular basis of these mechanisms is one of the most fascinating areas but also a great challenge. Nevertheless, research made the biggest steps in elucidating biological processes via studying malfunctions of normal mechanisms leading to different diseases. Therefore, this textbook wants not v

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Preface

only to describe basic mechanism leading to cancer but also to provide the readers with a more holistic view and placing these insights in the context of the personal consequences of everyone’s lifestyle decisions. The content of the book is linked to the lecture course in “Cancer Biology”, which is part of a series together with courses in “Molecular Medicine and Genetics”, “Molecular Immunology” and “Nutrigenomics”, that is given by one of us (C. Carlberg) in different forms since 2005 at the University of Eastern Finland in Kuopio. Moreover, biological processes explained in this book will be set into a clinical context using the experience of the daily care in oncology. This book also relates to the textbooks “Mechanisms of Gene Regulation: How Science Works” (ISBN 978-3-030-52321-3), “Human Epigenetics: How Science Works” (ISBN 978-3-03022907-8) and “Nutrigenomics: How Science Works” (ISBN 978-3-030-36948-4), the studying of which may be interesting to readers who like to get more detailed information. The clinical impact of the book is based on personal experience in detecting, treating and preventing cancer by one of us (E. Velleuer). Chapter 1 of this book will provide a general overview on cancer. Chapters 2–6 focus on the molecular basis of the disease, while Chaps. 7–9 will discuss the cellular aspects of cancer. Finally, Chaps. 10 and 11 will explain the concepts of an efficient therapy against cancer. By combining basic understanding of cellular mechanism of cancer with clinical examples, we hope to make this textbook a personal experience. A glossary in the appendix will explain the major specialist’s terms. We hope that readers will enjoy this rather visual book and get as enthusiastic as the authors about life and its malfunction counterpart reflected in cancer biology. Kuopio, Finland Düsseldorf, Germany March 2021

Carsten Carlberg Eunike Velleuer

Acknowledgements

The authors would like to dedicate this book to all victims of cancer, whom they know in person. Some managed to survive and enrich the world with their presence. Others are not anymore with us but will never be forgotten.

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Contents

1

Introduction to Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 The Global Burden of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Categorization and Diagnosis of Tumors . . . . . . . . . . . . . . . . . . . . . 1.3 Crucial Transitions in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Causes of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5 Cancer Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 1 4 7 10 12 16

2

Oncogenes and Signal Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Cellular Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Activating Oncogenes in Signal Transduction Pathways . . . . . . . . 2.3 Oncogenic Translocations and Amplifications . . . . . . . . . . . . . . . . 2.4 The Hallmarks of Cancer Concept . . . . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17 17 19 23 26 28

3

Tumor Suppressor Genes and Cell Fate Control . . . . . . . . . . . . . . . . . . 3.1 p53 - A Master Example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Tumor Suppressors and Oncogenes in Cell Cycle Control . . . . . . 3.3 Tumor Suppressor Inhibition and Cancer Onset . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29 29 33 35 40

4

Multi-step Tumorigenesis and Genome Instability . . . . . . . . . . . . . . . . 4.1 Characteristics of Tumor Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Multi-step Tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Genome Instability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Cancer Driver Mutations and Genes . . . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41 41 44 47 50 53

5

Cancer Genomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Human Genetic Variation and Cancer Susceptibility . . . . . . . . . . . 5.2 The Cancer Genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Cancer Genome Projects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55 55 59 62 66 ix

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6

Cancer Epigenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Epigenetic Mechanisms of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 DNA Methylation and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Chromatin Changes and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4 Epigenetic Reprogramming in Cancer . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67 67 72 76 81 85

7

Aging and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1 Central Role of Aging During Chronic Diseases . . . . . . . . . . . . . . 7.2 The Hallmarks of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3 Epigenetics of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4 Telomeres and Replicative Immortality . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87 87 89 93 96 98

8

Tumor Microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1 The Impact of the Wound Healing Program for Cancer . . . . . . . . 8.2 Cell Types of the Tumor Microenvironment . . . . . . . . . . . . . . . . . . 8.3 Inducing Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4 Tumor-Promoting Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5 Deregulating Cellular Energetics . . . . . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

101 101 104 108 110 111 114

9

Metastasis and Cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1 The Metastatic Cascade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 Epithelial-Mesenchymal Transition . . . . . . . . . . . . . . . . . . . . . . . . . 9.3 Metastatic Colonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4 Cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

115 115 118 121 123 128

10 Cancer Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1 Outline of Cancer Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2 Recognition of Tumor Antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3 Monoclonal Antibodies in Cancer Immunotherapy . . . . . . . . . . . . 10.4 Immune Cell Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

129 129 135 138 141 145

11 Architecture of Cancer Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 Classical Cancer Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Targeted Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3 Precision Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

147 147 152 156 160

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Abbreviations

3C 3D 5hmC 5hmU 5mC A ABL1 ADAMTS13 AIDS AKT ALK ALL AML AMPK AP-1 APC APAF1 APOBEC APR ARID AR ASNS ATAC-seq ATM ATR ATRX BAX BCL2 BCL2L BCR BER BID

Chromosome conformation capture 3-dimensional 5-hydroxymethylcytosine 5-hydroxyuracil 5-methylcytosine Adenine ABL proto-oncogene 1, non-receptor tyrosine kinase ADAM metallopeptidase with thrombospondin type 1 motif 13 Acquired immune deficiency syndrome Akt murine thymoma viral oncogene homolog Anaplastic lymphoma kinase Acute lymphoid leukemia Acute myeloid leukemia AMP-activated protein kinase Activating protein 1 APC regulator of WNT signaling pathway Apoptotic peptidase activating factor 1 Apolipoprotein B mRNA editing catalytic subunit Acute protein response AT-rich interaction domain Androgen receptor Asparagine synthetase (glutamine-hydrolyzing) Assay for transposase-accessible chromatin using sequencing ATM serine/threonine kinase ATR serine/threonine kinase ATRX chromatin remodeler BCL2 associated X, apoptosis regulator BCL2 apoptosis regulator BCL2 like B cell receptor Base excision repair BH3 interacting domain death agonist xi

xii

bp BRAF BRCA1 BRD BRIP1 C C1QBP CAD CAR CCL CCN CCR CD CDC7 CDH CDK CDKI CDKN2A CDR CDT1 CEBPA CHEK ChIP CIMP CIN CIS CLEC12A CLL CML CNV COVID-19 CREBBP CSF CSNK2A1 CT CTCF CTLA4 CTNNB1 CXCL CYP19A1 DAMP DAXX DBD DCIS DDR

Abbreviations

Base pair B-Raf proto-oncogene, serine/threonine kinase BRCA1 DNA repair associated Bromodomain containing BRCA1 interacting protein C-terminal helicase 1 Cytosine Complement C1q binding protein Carbamoyl-phosphate synthetase Chimeric antigen receptor Chemokine (C-C motif) ligand Cyclin C-C chemokine receptor Cluster of differentiation Cell division cycle 7 Cadherin Cyclin-dependent kinase Cyclin-dependent kinase inhibitor Cyclin-dependent kinase inhibitor 2A Complementarity-determining region Chromatin licensing and DNA replication factor 1 CCAAT enhancer binding protein alpha Checkpoint kinase 2 Chromatin immunoprecipitation CpG island methylator phenotype Cervical intraepithelial neoplasia Carcinoma in situ C-type lectin domain family 12 member A Chronic lymphoid leukemia Chronic myeloid leukemia Copy number variation Coronavirus disease 2019 CREB binding protein, also called KAT3A Colony stimulating factor Casein kinase 2 alpha 1 Computed tomography CCCTC binding factor Cytotoxic T lymphocyte associated protein 4 Catenin beta 1 Chemokine (C-X-C motif) ligand Cytochrome P450 family 19 subfamily A member 1 Damage-associated molecular pattern Death domain associated protein DNA-binding domain Ductal carcinoma in situ DNA damage response

Abbreviations

DLBCL DNase-seq DNMT DOT1L EBV EGF EGFL EGFR EHMT2 EIF ELK1 EMA EMT ENCODE EP300 ERBB2 ERCC3 eRNA ES ESR1 EV EZH FACS FAD FAP FASN FBXO32 FDA FGF FLT FOS FOXO1 G GART GDF GDP GLS GR GRB2 GSH GTF2H4 GTP GWAS HAT HBV

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Diffuse large B cell lymphoma DNase I hypersensitivity followed by sequencing DNAMethyltransferase DOT1 like histone lysine methyltransferase Epstein-Barr virus Epidermal growth factor EGF like Epidermal growth factor receptor Euchromatic histone lysine methyltransferase 2 Eukaryotic translation initiation factor ETS transcription factor ELK1 European Medicines Agency Epithelial-mesenchymal transition Encyclopedia of DNA elements E1A binding protein p300, also called KAT3B Erb-B2 receptor tyrosine kinase 2, also called HER2 ERCC excision repair 3, TFIIH core complex helicase subunit Enhancer RNA Embryonic stem Estrogen receptor Extracellular vesicle Enhancer of zeste homolog Fluorescence-activated cell sorting Flavin adenine dinucleotide Familial adenomatous polyposis Fatty acid synthase F-box protein 32 US Food & Drug Administration Fibroblast growth factor Fms related receptor tyrosine kinase Fos proto-oncogene, AP-1 transcription factor subunit Forkhead box O1 Guanine Phosphoribosylglycinamide formyltransferase Growth differentiation factor Guanosine diphosphate Glutaminase Glucocorticoid receptor Growth factor receptor bound protein 2 Glutathione General transcription factor IIH subunit 4 Guanosine triphosphate Genome-wide association study Histone acetyltransferase Hepatitis B virus

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HDAC HGF Hi-C HIF1A HIV HK2 HLA HP1 HPV HR HSP ICAM ICGC IDH IDO1 Ig IGF IGH IL IL3RA IL6R indel INFγ iPS ITAM JAK JUN kb KDM KDR KIT KLF4 KMT LAD LDHA LIN28A LINE LOCK LPS LSD1 LTR MAF MAP2K MAPK MAX

Abbreviations

H istone deacetylase Hepatocyte growth factor High-throughput chromosome capture Hypoxia inducible factor 1 subunit alpha Human immunodeficiency virus Hexokinase 2 Human leukocyte antigen Heterochromatin protein 1, official name CBX5 Human papilloma virus Homologous recombination Heat shock protein Intercellular adhesion molecule International Cancer Genome Consortium Isocitrate dehydrogenase Indoleamine 2,3-dioxygenase 1 Immunoglobin Insulin-like growth factor Immunoglobulin heavy locus Interleukin Interleukin 3 receptor subunit alpha IL6 receptor Short insertion or deletion Interferon γ Induced pluripotent stem Immunoreceptor tyrosine-based activation motif Janus kinase Jun proto-oncogene, AP-1 transcription factor subunit Kilo base pairs (1000 bp) Lysine demethylase Kinase insert domain receptor, also called VEGFR2) KIT proto-oncogene, receptor tyrosine kinase Kr¨uppel-like factor 4 Lysine methyltransferase Lamin-associated domain Lactate dehydrogenase A Lin-28 homolog A Long interspersed element Large organized chromatin K9-modification Lipopolysaccharide Lysine specific demethylase 1, also called KDM1A Long terminal repeat Minor allele frequency Mitogen-activated protein kinase kinase Mitogen-activated protein kinase MYC associated factor X

Abbreviations

Mb MBD MCM MDM2 MDSC MECP2 MET MGMT MHC miRNA MIS-C MLH1 MMP MMR MNT MRI mRNA MS MSI MSS mTOR MYC NAD NADPH NANOG ncRNA NELFE NER NF-κB NHEJ NK NLS NO NPM1 NSD nt OCT4 PALB2 PAMP PCAWG PDCD1 PDGF PDGFRA PET PGE2

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Mega base pairs (1,000,000 bp) Methyl-DNA binding domain Minichromosome maintenance complex component MDM2 proto-oncogene, E3 ubiquitin protein ligase Myeloid-derived suppressor cell Methyl-CpG binding protein 2 Mesenchymal-epithelial transition O-6-methylguanine-DNA methyltransferase Major histocompatibility complex Micro RNA Multisystem inflammatory syndrome in children MutL homolog 1 Matrix metalloproteinase Mismatch repair MAX network transcriptional repressor Magnetic resonance imaging Messenger RNA Myeloid sarcoma Microsatellite instability Microsatellite stable Mammalian target of rapamycin MYC proto-oncogene, BHLH transcription factor Nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide phosphate Nanog homeobox Non-coding RNA Negative elongation factor complex member E Nucleotide excision repair Nuclear factor κB Non-homologous end-joining Natural killer Nuclear localization sequence Nitric oxide Nucleophosmin 1 Nuclear receptor binding SET domain protein Nucleotides Octamer-binding transcription factor 4 Partner and localizer of BRCA2 Pathogen-associated molecular pattern PanCancer Analysis of Whole Genomes programmed cell death 1, also called PD1 Platelet-derived growth factor Platelet-derived growth factor receptor α Positron emission tomography Prostaglandin E2

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PI3K PICS PIK3CA PIN PIP3 PMAIP1 PML Pol II PPARGC1B PPAT PRC PRKDC PRMT5 PTEN PTHrP RAF1 RARA RAS RB1 ROS RRM2 rRNA RSV RTK SAM SARS-CoV 2 SCD scFv SERPINE1 SETD2 SETDB1 SHC1 SHMT SINE SIRT SLAMF7 SLC SMARC SNAI snoRNA SNP SNV SOS1

Abbreviations

Phosphoinositide 3-kinase PTEN loss-induced cellular senescence Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Prostatic intraepithelial neoplasia Phosphatidylinositol-3,4,5-triphosphate Phorbol-12-myristate-13-acetate-induced protein 1 PML nuclear body scaffold RNA polymerase II PPARG coactivator 1 beta Phosphoribosyl pyrophosphate amidotransferase Polycomb repressive complex Protein kinase, DNA-activated, catalytic subunit Protein arginine methyltransferase 5 Phosphatase and tensin homolog Parathyroid hormone-related protein Raf-1 proto-oncogene, serine/threonine kinase Retinoic acid receptor alpha Rat sarcoma RB transcriptional corepressor 1 Reactive oxygen species Ribonucleotide reductase regulatory subunit M2 Ribosomal RNA Rous sarcoma virus Receptor tyrosine kinase S-adenosyl-L-methionine severe acute respiratory syndrome coronavirus 2 Stearoyl-CoA desaturase Single-chain variable fragment Serpin peptidase inhibitor, clade E SET domain containing 2 SET domain bifurcated histone lysine methyltransferase 1 SHC adaptor protein 1 Serine hydroxymethyltransferase Short interspersed element Sirtuin SLAM family member 7 Solute carrier family SWI/SNF-related matrix-associated actin-dependent regulators of chromatin Snail family transcriptional repressor Small nucleolar RNA Single nucleotide polymorphism Single nucleotide variant SOS Ras/Rac guanine nucleotide exchange factor 1

Abbreviations

SOX2 SP1 SRC SRF STAB1 STAT SUV39H1 SV40 SWI/SNF T TAM TCGA TCR TDG TERT TET TFAM TGFβ TGFBR TH THBS1 TIL Tis TLR4 TNF TNFRSF TP53 Treg TRIM tRNA TSS TWIST1 U UBTF UGDH UICC VEGF VHL WAT WHO WNT ZEB

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SRY-box 2 Specificity protein 1 SRC proto-oncogene, non-receptor tyrosine kinase Serum response factor Stabilin Signal transducer and activator of transcription Suppressor of variegation 3-9 homolog 1, also called KMT1A Simian virus 40 Switching/sucrose non-fermenting Thymine Tumor-associated macrophage The Cancer Genome Atlas T cell receptor Thymine-DNA glycosylase Telomerase reverse transcriptase Ten-eleven translocation Transcription factor A, mitochondrial Transforming growth factor β TGFβ receptor T helper Thrombospondin 1 Tumor infiltrating lymphocyte Carcinoma in situ Toll-like receptor 4 Tumor necrosis factor TNF receptor superfamily member Tumor protein p53 T regulatory Tripartite motif containing Transfer RNA Transcription start site Twist family BHLH transcription factor 1 Uracil Upstream binding transcription factor UDP-glucose 6-dehydrogenase Union for International Cancer Control Vascular endothelial growth factor Von Hippel-Lindau tumor suppressor White adipose tissue World Health Organization Wingless-type MMTV integration site family member Zinc finger E-box binding homeobox

Chapter 1

Introduction to Cancer

Abstract Cancer is the second leading cause of death that globally kills nearly 10 million people every year. One in two of us will be diagnosed with cancer at some point of his/her life. Malignant tumors can arise from different tissues and organs, thus there are many different types of cancer. In all of them the normal control of cell division and differentiation is lost, so that an individual cell multiplies inappropriately forming a primary malignant tumor. The cancer cells may eventually spread through the body and form potentially deadly metastases. The most promising strategy for reducing both the number of cancer cases as well as their mortality are preventive interventions like eliminating exposure to carcinogens, such as tobacco smoke. Keywords Non-communicable diseases · Mortality rates · Cancer driver genes · Tumorigenesis · Cancer prevention

1.1 The Global Burden of Cancer Non-communicable diseases contribute to more than 73% of deaths worldwide and even to a higher percentage in industrialized countries. In contrast, infectious (communicable), maternal, neonatal and nutritional diseases account only for less than 19% of worldwide deaths and injuries for 8%. In 2017 worldwide 17.8 million persons were dying from cardiovascular diseases, while neoplasms killed 9.6 million humans representing 17.1% of worldwide deaths (Fig. 1.1, top left). For comparison, in an industrialized country, such as Finland, the rate of cancer death was even 24.4% (Fig. 1.1, bottom left). In the past, cancer was seldomly the cause of death, since the average human life expectancy was far shorter and people died from other causes than cancer. However, medical care significantly changed during the last 100 years leading to drastic improvements in life expectancy. Unfortunately, this caused an increase in the overall burden of cancer and accordingly to a far higher number of cancer cases. In

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 C. Carlberg and E. Velleuer, Cancer Biology: How Science Works, https://doi.org/10.1007/978-3-030-75699-4_1

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1 Introduction to Cancer

Cardiovascular diseases Cancers Respiratory diseases Lower respiratory infections Dementia Digestive diseases Neonatal disorders Diarrheal diseases Diabetes Liver diseases Road injuries Kidney disease Tuberculosis HIV/AIDS Suicide Malaria Homicide Parkinson disease Drowning Meningitis Protein-energy malnutrition Maternal disorders Alcohol use disorders Drug use disorders Hepatitis Fire Poisonings Heat (hot and cold exposure) Terrorism Natural disasters

Cardiovascular diseases Cancers Dementia Digestive diseases Respiratory diseases Liver diseases Suicide Lower respiratory infections Parkinson disease Alcohol use disorders Kidney disease Diabetes Road injuries Drug use disorders Drowning Heat (hot and cold exposure) Homicide Fire Tuberculosis Diarrheal diseases Neonatal disorders Meningitis Poisonings HIV/AIDS Protein-energy malnutrition Hepatitis Maternal disorders Terrorism Malaria Natural disasters

17.79 million 9.56 million 3.91 million 2.56 million 2.51 million 2.38 million 1.78 million 1.57 million 1.37 million 1.32 million 1.24 million 1.23 million 1.18 million 954,492 793,823 619,827 405,346 340,639 295,210 288,021 269,997 231,771 193,639 184,934 166,613 129,720 126,391 120,632 72,371 53,350 26,445 9603

Poor sanitation No access to handwashing facility Drug use Diet low in legumes Low bone mineral density Child stunting Diet low in calcium Non-exclusive breastfeeding

World: Number of deaths

21,359 13,089 8546 2416 1784 1178 868 713 682 598 569 390 289 289 116 104 87 73 57 48 46 19 18 12 6 4 2 2 2 0 0 0

High blood pressure Smoking High blood sugar Air pollution (outdoor & indoor) Obesity Outdoor air pollution Diet high in sodium Diet low in whole grains Alcohol use Diet low in fruits Diet low in nuts and seeds Indoor air pollution Diet low in vegetables Diet low in seafood omega-3 fatty acids Low physical activity Unsafe water source Secondhand smoke Low birth weight Child wasting Unsafe sex

Diet high in red meat Discontinued breastfeeding

High blood pressure High blood sugar Obesity Smoking Diet low in whole grains Diet low in nuts and seeds Alcohol use Diet low in vegetables Diet high in sodium Low physical activity Diet low in fruits Diet low in seafood omega-3 fatty acids Diet low in legumes Air pollution (outdoor & indoor) Outdoor air pollution Drug use Low bone mineral density Secondhand smoke Diet low in calcium Unsafe sex Diet high in red meat Low birth weight Indoor air pollution No access to handwashing facility Child wasting Unsafe water source Poor sanitation Non-exclusive breastfeeding

Finland: Number of deaths

Child stunting Discontinued breastfeeding

10.44 million 7.1 million 6.53 million 4.9 million 4.72 million 3.41 million 3.2 million 3.07 million 2.84 million 2.42 million 2.06 million 1.64 million 1.46 million 1.44 million 1.26 million 1.23 million 1.22 million 1.1 million 1.08 million 1.03 million 873,408 774,241 707,248 585,348 534,767 327,314 232,777 220,678 184,760 160,983 59,882 28,595 24,833 10,012

World: Risk factors for death

12,136 8901 6022 5639 2900 2577 2332 1930 1896 1882 1875 1505 1161 1130 1127 1118 659 613 325 136 118 32 31 18 5 4 1