Cancer: From a Darwins Perspective

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Cancer From a Darwins Perspective

• Giri Ramsingh M.D
• 10.9.09

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Why study evolutionary biology?
No biological problem is solved until both the
proximate and evolutionary causation has been
elucidated Ernest Mayr
A recurring fault in a complex machinery or plant
would require evaluating not just the immediate
fault line but the entire system design
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• Cancer biologists How?
• Evolutionary biologists Why?

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Evolutionary steps
Inheritable genetic mutation
Unstable conditions (limited resources,
environmental challenges)
Competition
Positive selection of beneficial traits
Diversification of molecules, cells, tissues and
physiological processes
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Evolutionary process
CANCER SUSCEPTIBILITY
DEVELOPMENT OF CANCER CLONE
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Evolution aims towards perfection but is never
perfect
Changes in design of a product often results in
a transient decline in its quality. Subsequent
adjustment in a production line restores the
product to it original high quality James
Graham, Cancer Selection 1992
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Evolutionary feature Potential
consequences
Just selects from the best available options
Deletrious trade-off and malfuction under stress
Rapidly changing circumstances result in
genotype-environment mismatch
No eyes to future
The fitness test for natural selection is
survival and reproductive success
The post-reproductive life can reveal the
design limitations
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If cancer is detrimental why is it so common?
During Natural Selection all that matters is
reproductive success
As the clock tics on, the intrinsic design
limitations or trade offs of our bodies come into
play.
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Nature-Nurture mismatch
Our social behavior has rapidly changed since
stone age
Normal genes and gene variants selected then now
operate in a changed environment
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Skin cancer and human migration
Loss of melanin upon migration from Africa to
Europe
Fastest rising rate of cancer in Northern Europe
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Diet and Cancer

• Binge eating and little exercise
• High calorie intake associated with breast,
  colon, prostate and pancreatic cancer
• - Lower cancer rates in rodents under
  calorie restriction

• Excess intake and storage in times of plenty
  provides
• insurance against times of famine and long
  distance travel/migration.
• Dramatic increase in incidence of cancer in
  Arizona Pima Indians,
• Canadian Inuits, Australian Aborigines and
  polynasians.

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Breast and prostate cancer

• 1/11 men will develop prostate cancer
• 1/10 women will develop breast cancer

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• Humans have the largest breast size proportionate
  to the body
• And the largest prostate size proportionate to
  the body
• Breast cancer incidence extremely high in humans
  compared to other species, especially in the
  developed countries
• Spontaneous clinically diagnosed prostate cancer
  is uniquely human.

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Non-seasonal estrus with cyclic mammary gland
priming is uniquely human

• Normal constraints to breast cancer
• (hunter-gatherer society)
• -Late menarche
• Early, spaced, repetitive pregnancy
• Protracted breast feeding

Dr.Theodorico Borgognoni examining Breast in a
nunnery 1275
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Prostate Cancer

• Only function- lubrication of sperm passage
• High incidence in Europe and North America
• Increase in age-specific incidence last few
  decades (independent of screening)

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Keeping prostate active beyond reproductive age-
? Nature-Nurture mismatch
Hayes, Brit J of cancer 2000
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?genes

• 10 of breast and prostate cancer is familial
• 40 of prostate cancer and 30 of breast cancer
  is attributed to inherited susceptibility ( based
  on studies comparing monozygotic and dizygotic
  twins.

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Winners become losers

• Most of the alleles (SNPs) associated with
  increased risk of breast and prostate cancer is
  involved in increasing the sex hormone receptor
  signaling
• Women with these variants - enhanced fertility
  and a greater ability to pass on the genes
• Men with these variants- enhanced prostate
  priming, mate-attracting potency, hunting,
  survivability and enhanced ability of passing on
  the genes

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Large prostate Enhanced hormone receptor
signalling Diet Longer post reproductive
life ?others
Non seasonal estrous cycle Enhanced hormone
receptor signalling Early menarchy Late
pregnancy Fewer pregnancy Decreased breast
feeding Dietary- increased calories Longer post
reproductive life
Nature
mismatch
Nurture
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Childhood Cancer

• 3/1000 develop cancer in first 20 yrs of life
• Adult cancer- 83 arise from epithelia
• Pediatric cancer- Predominantly bone, brain and
  immune system

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• All these organs ( bone, brain and immune
  system) have undergone recent pronounced
  evolutionary change

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Osteosarcoma

• Typically occurs in the growth zones of the most
  rapidly growing bones in adolescents
• Most occur in the top 75th percentile for height
  for their age group
• Highest risk at pubertal growth spurt ( for each
  of the bones)
• Pubertal growth spurt is a recent evolutionary
  change unique to humans

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• Immune system- Leukemia/lymphoma
• Fastest evolving system in any species because of
  evolving pathogens ( leukemia/lymphoma common in
  most mammal)
• CNS tumors- Three fold increase in brain size
  compared to chimpanzees.

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• Promoting spermatogenesis Cancer testis
  associated (CTA) genes in malignant cells eg
  melanoma
• Tug-of war over resources during gestation
  Cadherins- adhesion and invasion of embryo, ANG
  gene in placental angiogeneis
• Signals for morphogeneis and apoptosis Notch,
  Hedgehog, Hox etc

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Clonal Evolution of Cancer Natural Selection

• Self sufficiency of cells in signals controlling
  growth
• Loss of sensitivity to anti-growth signals
• Evasion of apoptosis via mutation or loss of gate
  keeper genes
• Development of limitless replicative potential
• Sustained angiogenesis
• Tissue invasion and metastasis

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Clonal Selection
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Ecological theater of Carcinogenesis(Predation
and Competition)

• Escaping predation
• Immune system attack on early cancer cells
  (immunosurveillance)
• Escape mechanisms-
• alpha-defensins in some cancers (lung, renal
  etc),
• low oxygen tissue environment,
• Down regulating MHC complex in tumor cells
• Increased regulatory T-cells in the tumor
  microenvironment

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• Winning the competition
• competition between cancer and normal cell and
  among different clones of cancer cells.
  Competition for nutrients, waste disposal

Growth advantage Mutations in growth signal/
cell survival pathways Nutrients Glycolytic
phenotype ?local acidosis?extracellular matrix
degradation?invasion Oxygen/nutrients/waste
disposal Neovascularization Maintaining
diversity (diversity leads to faster
evolution) Genomic instability (aneuploidic and
polyploidic tumors are more aggressive) Migration
and distant colonization Invasion, cell-cell
interaction
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Tough environment promotes evolution

• Stable microenvironment relatively
  homogenous cells
• Unstable/disturbed microenvironment diversity
  of microenvironment diversity of clones
  faster evolution to cancer

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Reversing the competitive advantage

• Reducing the number of cancer cells that can be
  supported in the tissue
• Targetting the genomic instability of cancer
  cells
• Reducing the negative competitive effects of
  cancer cells on normal cells
• Increasing the negative competitive effect of
  normal cells on cancer cells

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Hunting for Cancer related genes

• Genes subject to rapid evolution along human
  lineage
• Special emphasis on genes expressed during
  gamete, embryonic and placental development
• Sequencing the genes in much wider range of
  primates and other mammals
• Identification of positively selected amino acid
  sites and linking adaptive molecular evolution to
  aspects of life history and mating system.

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Understand the Cancer Ecosystem
Somatic evolution
Ecology
Mutation
microenvironment
Tumor cell
Natural Selection
Tumor progression
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Minimize the Mismatch
Macro Evolution
Ecology
Mutation
Macro Environment
Human Species
Natural Selection
Cancer susceptibility