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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).