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What is cancer? Ula Hibner, IGMM HCV and Cancer Is cancer a disease of modern times? 1.7million years old osteosarcoma Odes et al. 2016 SAJS Homo erectus Cancer-like growth in different life forms Gall (tumour-like growth) on a brown algae Corals: calicoblastic epitheliomas Hydra Crested cactus (example of fasciation). Believed to be due to somatic mutations in Aktipis et al.(2015), Phil. Trans. R. Soc. B 20140219. stem cells. First written account of cancer: Edwin Smith papyrus (1600 BC) Hippocrates (ca. 460 BC – ca. 370 BC): oncos = swelling Cancer attributed to accumulation of black bile. Despite our immensely improved understanding of cancer, surgery is often still the most effective treatment Dutch engraving with two views of woman who had a tumor removed from her neck in 1689. The National Library of Medicine What is cancer? A disease of cells due to mutations (a disease of DNA) "All cells come from other cells... Where a cell originates it must have been preceded by another cell, just as animals are produced only by other animals and plants by other plants." Rudolf Virchow (1821 –1902) JD Watson & F. Crick: DNA structure (1952) First complete genome sequence (1977) : am3 φX174 bacteriphage 5386 base pairs 1 gagttttatc gcttccatga cgcagaagtt aacactttcg gatatttctg atgagtcgaa 61 aaattatctt gataaagcag gaattactac tgcttgttta cgaattaaat cgaagtggac 121 tgctggcgga aaatgagaaa attcgaccta tccttgcgca gctcgagaag ctcttacttt 181 gcgacctttc gccatcaact aacgattctg tcaaaaactg acgcgttgga tgaggagaag 241 tggcttaata tgcttggcac gttcgtcaag gactggttta gatatgagtc acattttgtt 301 catggtagag attctcttgt tgacatttta aaagagcgtg gattactatc tgagtccgat 361 gctgttcaac cactaatagg taagaaatca tgagtcaagt tactgaacaa tccgtacgtt 421 tccagaccgc tttggcctct attaagctca ttcaggcttc tgccgttttg gatttaaccg 481 aagatgattt cgattttctg acgagtaaca aagtttggat tgctactgac cgctctcgtg 541 ctcgtcgctg cgttgaggct tgcgtttatg gtacgctgga ctttgtggga taccctcgct 601 ttcctgctcc tgttgagttt attgctgccg tcattgctta ttatgttcat cccgtcaaca 661 ttcaaacggc ctgtctcatc atggaaggcg ctgaatttac ggaaaacatt….. Human genome sequencing Venter et al., 2001 Evolution of sequencing technology There is a massive data accumulation… Major consortia produce massive data on genomics of cancer Massive accumulation of post-genomic data: epigenomes, transcriptomes, proteomes, interactomes, metabolomes…. Systems biology or how to make sense of it all? "The goal is personalized therapy that takes into account the genetics of the cancer and the patient" John Mendelsohn (MD Anderson Cancer Center) Mutation rates The human body contains about 1013 cells of which ≈ 1% divide in an adult. Fidelity of DNA replication is estimated at ≈ 10-10, which gives on average 0.3 errors per cell cycle per cell and 3x1010 for per division of all dividing cells. In addition external sources give rise to DNA damage. In a young organism DNA repair is efficient. Less so in an aged organism. Moreover, tumours often have a mutator phenotype, mainly due to defective DNA repair (BRCA, mutL, mutant p53 …) ! vastly increased mutation rate How many have functional consequences? (L. Loeb, Nature Reviews Cancer, June 2011) Accumulation of mutations MR Stratton et al. Nature 458, 719-724 (2009) doi:10.1038/nature07943 Number of mutations in different tumour types is highly variable Range: ≈ 10 to > 105 mutations (exons only) Value of 10/Mb: 150 nonsynonymous mutations within expressed genes Schreiber and Schumacher, 2015 Epimutations have the same functional consequences as mutations (but are reversible...) Are all mutations equally important? Are all mutations equally important? Drivers versus passengers Drivers Colorectal cancer progression model (Fearon and Vogelstein, 1990) Are all mutations equally important? Drivers versus passengers To stop the car you need to target the driver(s) The drivers are either oncogenes or a loss of tumour suppressors An oncogene is a gene whose gain of function participates in the initiation or development of cancer. An oncogene is a gene whose gain of function participates in the initiation or development of cancer. Growth factor (e.g. c-sis) Receptor (e.g.EGFR) Signal transduction (e.g. src, Ras, RAF, AKT, cyclinD) Transcription factors (e.g. c-myc) DNA Cell proliferation Inhibitors of apoptosis (e.g.Bcl2) Oncogenes (gain of function associated with cancer) 1911: Rous sarcoma virus (Peyton Rous) 1970: RSV encodes an oncogene (src) (GS Martin) 1980: src sequence (Chernilofsky et al) 1976 : Healthy cells contain protooncogenes related to viral oncogenes Michael Bishop & Harold Varmus (Nobel Prize 1989) Inappropriate oncogene activation usually triggers intrinsic failsafe mechanisms Apopto(ccells Oncogeneac(va(on Senescence/apoptosis barrier Additional mutations, often a loss of a tumour suppressor, are needed to overcome these barriers A loss of function of a tumour suppressor participates in the initiation or development of cancer. Tumour suppressors (loss of function causally associated with cancer) 1971: Normal cells are dominant over the malignant ones when the two are fused. H. Harris 1971: two-hit hypothesis A. Knudson The first tumour suppressor discovered: pRb, a regulator of cell cycle The most studied: the p53 tumour suppressor (82 530 references in Pubmed since its discovery in 1980) Mutated in 50% of all human cancers and probably inactivated in the majority of the remaining ones. Oncogenes and tumour suppressors have opposite effects on cancer initiation and progression. It should be easy to tell them apart. How about TGF-β? TGF-β has many different activities in different cell types inhibitory, cytotoxic activator cytostatic, cytotoxic, EMT inducer mitogen, activator Tumours are complex ecosystems constituted by many cell types Quail & Joyce, 2013, Nature Medicine 19, 1423-1437 TGF-β in cancer initiation and progression Tumour suppressing activity ! ! ! ! Tumour progressing activity Oncogenes and tumour suppressor regulate one or more of the essential features of cancer: the cancer hallmarks Hanahan and Weinberg (2000, 2011) Hallmarks Functional heterogeneity (Hanahan and Weinberg 2000; 2011) Hallmarks are quantitative traits which are not uniformly distributed in all tumour cells. There is an impressive acceleration in gaining knowledge about mechanisms of cancer. But do we get more cancer than we used to? In industralised countries about 30% of individuals will be diagnosed with cancer in their lifetime. - Ageing population - Better diagnosis - Unhealthy lifestyles Cancer incidence increases with age NCI data And we live longer than we used to: female life expectancy in Japan is 89 years (but 48 in Sierra Leone). Cancer incidence (US) Siegel et al., 2012. CA Cancer J Clin 2012; 62:10–29 Cancer incidence (US) Cancer mortality Siegel et al., 2012. CA Cancer J Clin 2012; 62:10–29 How far should we go in the early detection of cancer? normal epithelium adenoma carcinoma in situ invasive carcinoma > 30% of healthy men aged 40 have in situ prostate carcinoma > 30% of healthy women aged 40-50 have in situ breast cancer Virtually all individuals at 50-70 years have in situ thyroid carcinoma (less than 0.1% are diagnosed with cancer) Is the good prognosis associated with early detection due to the fact that we are treating lesions that would never have become a full blown cancer? Judah Folkman and Raghu Kalluri Cancer without disease, Nature 2004 Mina J Bissell & William C Hines Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression Nature Medicine 2011 We live in a polluted environment Adopt dangerous lifestyles and are exposed to chronic infections What proportion of cancers is avoidable by prevention? How much of cancer is due to « bad luck »? What exactly is the “bad luck” source of cancer? Let’s start with simple cells The sole ambition of a bacterium is to produce two bacteria. François Jacob,1973 Exponentially growing E. coli in a rich medium divides every 20 minutes E. coli All very similar…. (Functionally equivalent) Dictostelium discoideum: a simple differentiation Individual amoeba Scarce nutrients Aggregate into slugs and differentiate into fruiting bodiies Dictostelium discoideum: a simple differentiation The stalk is composed of dead cells. Only the cells composing the fruiting body have a chance of transmitting their DNA to the next generation. If the cells in the slug show any genetic diversity (which they do), there should be a strong selection pressure for any cell to be part of the fruiting body. This is a short-term perspective… A population of free living amoeba is composed of yellow (wt) and blue (cheater) individuals. The cheaters only differentiate into spores, they are selected for the transmission of their genomes. Everything works initially, how about in the next generation? West et al. Nature Reviews Microbiology 4, 597–607 (August 2006) | doi:10.1038/nrmicro1461 Cheaters? A concept of the game theory John Maynard Smith Why is this relevant to cancer? Cells of multicellular organisms specialize in different functions In a multicellular organism, rather than competing for space and nutrients, cells cooperate to achieve a coordinated multicellular organism They abandon their « sole ambition » of becoming two cells; they both exercise and are subject to social controls from other cells. Cells communicate Through direct contact Microvesicles and exosomes Belting M , and Wittrup A J Cell Biol 2008;183:1187-1191 through gap junctions altered composition of the ECM by soluble mediators EDNA CUKIERMAN, VISUALS UNLIMITED SCIENCE PHOTO LIBRARY Cancer cells are cheaters: they are defective either in signal reception or response Cheater mutations free cells that carry them from social controls. Georges de La Tour - Cheater with the Ace of Diamond Acquisition of a cheater phenotype is an all-encompassing hallmark of cancer Cheater mutations free cells that carry them from social controls. Georges de La Tour - Cheater with the Ace of Diamond What biological processes are concerned by “cheating” in cancer? Foundations of multicellularity Aktipis et al.(2015), Phil. Trans. R. Soc. B 20140219. Foundations of multicellularity: breakdown in cancer Aktipis et al.(2015), Phil. Trans. R. Soc. B 20140219. Foundations of multicellularity: breakdown in cancer Aktipis et al.(2015), Phil. Trans. R. Soc. B 20140219. Is cancer risk an unavoidable consequence of multicellular life? Aktipis et al.(2015), Phil. Trans. R. Soc. B 20140219. Because cancer hallmarks arise through deregulation of the very foundations of multicellularity….. …the “war on cancer” can never be definitely won. We need to concentrate on its prevention and its control (turning most cancers into a chronic rather than an acute disease).