How cancer shapes evolution, and how

evolution shapes cancer

Evolution (N Y). 2011 December ; 4(4): 624634

1. Why understanding cancer from an evolutionary perspective is

important

Importance
i.
Understand cancer development at the level of the species as well as the level of
the cells and tissues
ii.
New insights to cancer prevent and treatment

2. Life history, lifespan and cancer

Older humans less likely to reproduce and contribute to the gene pool
Hence, less selective pressure to maintain tissues and suppress cancers in old age
Result general decline in tissue structure and function and increase cancer rates as
human ages
Antagonistic pleiotropy some processes which are important in organismal fitness in
youth may actually contribute to tissue decline and increased cancer in old age
Evolution has in effect weighed the costs and benefits of somatic tissue maintenance and
tumor suppression, favoring a strategy that maximizes reproductive success.

3. Evolved Tumour Supression

Multicellular organisms need to evolve potent tumour suppressive mechanisms

Somatic cell mutation can result in tissue disrupting rogue cells
These rogue cells can prevent the development of significant organization or
complexity
Two mechanisms
Intrinsic cells avoid becoming cancer cells
Integral cancer avoidance at the level of tissues and the whole organism
Intrinsic Tumour Suppression
i. Mechanisms to penalize disobedient cells
Cell senescence
Apoptosis
ii. Effective DNA repair
iii.
Telomeres

Restrict each somatic cells lifespan prevents immortalization

Integral Tumour Suppression
i.
Vertebrates have longer lives and bigger bodies bigger pool of cells over
longer period for oncogenic mutations
ii.
Evolution of additional mechanisms for tumour suppression
Immune systems
Antigen specific immunity
Tissue organization
Normal tissue can suppress rogue cell expansion peer pressure
Stem cells
Targets of cancer initiation
Do not divide often; protected niche
Integral Tumour Suppression by maintaining tissue fitness
Stem cells are competition with each other in their niche
So needs to consider the fitness of the stem cells and their niche
o Highly fit stem cells should oppose somatic mutation when there is
little room for improvement, the chance of a mutation improving fitness
will be much less and non-conformist cells are suppressed
o With reduced general cellular fitness, certain oncogenic mutations can be
adaptive (restoring fitness)
o Damage to the niche can also increase selection for adaptive mutations
Hence, cancer evolution driven by both oncogenic mutations and alterations
in selective pressure both can result from aging and carcinogen exposures
Cannot simply focus on the cancer but needs to consider its environment

4. Evolutionary perspectives on multistage carcinogenesis and

metastasis
Cells mutational changes conferring fitness advantage relative to normal cells in the same
niche clonal expansion alteration in local environment barriers to continued cancer
evolution (oxygen and nutrient limitations) further mutation to overcome these selection
barriers biological properties/ hallmarks of cancer (next lecture)
Metastasis multistage process where the cancer cells face numerous hurdles (invasion of
organ, escape into blood vessel or lymphatics, survival in blood or lymphatics, colonization of
distant tissue, successful growth of metastatic tumour)
needs appropriate combination of genetic changes and luck = hence rare
Metastatic cells can be considered an aggressive invasive species
Migratory ability provide a selective advantage by allowing the cancer cell clone to experience
more favourable environment

5. Carcinogens as promoters of somatic cell evolution

Carcinogens increase genetic mutations (genetic diversity) and also alters the
environment (selective pressures)
Modern humans encounter many new chemical and physical agents to which we have not
evolve effective protective mechanisms

6. Viewing cancer therapies through an evolutionary lens

Advanced cancers have higher mutation rates, multiple selective hurdles, variable
microenvironments and increased numbers of cell generations (NB: Cancers consist of
from a billion to a 1000 billion (1012) cells, resulting from 100s to 1000s of cell
generations , which is on the scale of the number of generations spanning the entire
evolutionary history of Homo sapiens).
Great genetic variability
o Ample opportunities to adapt to change and evolution of diverse types
Chemotherapy and radiation are selective pressures selecting for clones that can best
survive resistance
Postulated a fitness cost to chemotherapy
o Chemotherapy sensitive cells are often more fit and actually suppress the growth
of less fit chemotherapy resistant clones
o Hence, try to treat and debulk the tumour with chemotherapy but still maintain a
chemo-sensitive population to oppose the growth of chemo-resistant clones =
sinusoid growth curve

Targeted therapy
o Problem with development of resistance due mutation activating alternate
oncogene

o Develop combination therapies up front that target both the driving oncogene and
anticipated escape mechanisms
Prevent metastatic events
o Rapidly dividing mass of cells result in acidic and low oxygen environment
o This promotes evolution of clones with ability to migrate to greener pastures
o Theoretically, re-oxygenating tumours can remove this selective pressure,
prevent the evolution of clones with a more motile phenotype and decrease the
possibility of metastasis.

7. Conclusion
a) The evolution of multi-cellular animals necessitated the acquisition of potent tumour
suppressive mechanisms, which operate at levels of individual cells, tissue organization
and the whole body to limit cancers.
b) Cancer follows an evolutionary trajectory, with acquisition of mutations that allow the
cancer cells to adapt and succeed in the face of selective barriers.
c) Carcinogenic contexts, from chemicals to radiation to aging, can promote cancer
evolution both by increasing mutation frequency and by promoting selection for adaptive
mutations
d) Cancers respond to insults with selection for the clones that are most fit under that
context, such as during chemotherapy.
e) By understanding cancer from an evolutionary and ecological perspective, we should be
able to design more rational therapeutic approaches that manipulate cancer's evolutionary
trajectories for patient benefit.

7. So What About Cancer in Children?

Childhood cancers would be expected to be highly selected against during evolution

given that until the last half century, these cancers almost inevitably led to death before
reproduction.
Proposed evolutionary rationales
a) Recent evolution has substantially altered the human brain, bones and immune
system. A risk of childhood cancers affecting these tissues may have been a
tradeoff against the advantages of a more developed brain, faster bone
development in adolescence and a better immune system.
b) Maladaptation of our ancestral genome with modern environments, life-styles
and diets has contributed to recent increase in cancers our immune system
evolved to deal with more pathogen exposures early in life, not with modern
hygienic conditions.
c) Rapid growth of tissues during fetal development and early childhood is
important. The low rate of childhood cancer has not sufficiently impacted human
fitness as to necessitate the development of tumour suppressive innovations.