evolutionary biology of cancer-1
TRANSCRIPT
Life is about Choices: Evolutionary Biology
of CancerChi-Ping Day, Ph.D.
Laboratory of Cancer Biology and GeneticsNational Cancer Institute
System dynamics model of evolution.
Resource(R)
ComplexStructure
(C)
DegradationK1
UptakeK2 K3
Resource directs the evolution of multicellular organisms
Availability
Diversity
Overall complexity
Low stressEasy extraction
High stressEasy extraction
High stressHard extraction
Low stressHard extraction
Aging and offspring: strategy of complexity maintenance under stress (segregation of damages)
xx xx
xx
xx
xxx xx
xx
xx
Imperfect process
Remove/dilute damage
Resource
xxx
Imperfect process
Resource
Aging
Continuous surviving
Strategy of multicellular organisms
xx
xx
x
x
Resource
Somatic
Germline
ResourceDevelopment
xx
xx
x
x
Resource
Somatic
x
x
x
x
x
Aging(e.g. human)
Continuous surviving(e.g. hydra)
xx
xx
x
xSomatic x
x
x
x
x
AgingTelomeraseTelomere
(Growth rate)
Replicative limit
Aging Cell (2011) 10, pp761–768
Growth rate
Germline
Control of growth rate and body size in multicellular organisms
Somatic cells are given a “warranty” and disposable
Nature Genet 2014, 15:531
Stem cell output over damage determines aging rate
Age
Stem
cel
l fitn
ess
Stem
cell
outp
ut ca
paci
tyPre-adolescent Reproductive Post-reproductive
Stem cell population
Accumulated damages
death
Strategies of continuous existence: Trade-off in rate and power
Maintenance
Regeneration
Energy-generating mechanism 1
Mechanism 2
Niche 2
Niche 1
Time
% F
uncti
onal
stem
cell
rese
rve
(sol
id li
ne)
Damage level (dash line)
Lifespan 1 Lifespan 2
High stressEasy resource
Low stressHard resource
J Am Coll Cardiol 1997;30:1104–6
Scaling law in biology is based on trade-off in rate and power
Biological Reviews 83 (2008) 259-294
Clonal expansion and dominance occur more frequently when functional stem cell pool size is smaller
x
x
x
xx x
xx x
xx
x
x
Big SC pool
Small SC pool
Exp Gerontol. 2007 May ; 42(5): 385–390
Clonal dominance and expansion during hematopoietic stem cell aging
Clonal dominance and expansion during stem cell depletion in aging
Age
Canc
er in
cide
nce
Stem
cell
outp
ut ca
paci
ty
Pre-adolescent Reproductive Post-reproductive
Stem cell population
Functional stem cell pool size
Inci
denc
e (p
er 1
00,0
00)
Age-specific cancer incidence reflects the change of functional SC pool over time
NATURE 2000, 408:248
Why the cancer spectrum is so different between human and mouse?
The switched weakest link in 110 years
Func
tiona
l ste
m ce
ll po
ol si
ze
Pre-adolescent Reproductive Post-reproductive
Age
Canc
er in
cide
nce
Func
tiona
l ste
m ce
ll po
ol si
ze
Pre-adolescent Reproductive Post-reproductive
AgeCa
ncer
inci
denc
e
Oesteosarcoma, leukemia
Lung and colon cancers
Oesteosarcoma, leukemia
Lung and colon cancers
The switch of “weakest link” in life styles changes the spectrum of cancers in human
death death
Pre-industrial era Modern era
Summary (I)
1. Aging and limited lifespan are caused by the cost of complexity maintenance.2. Lifespan is determined by the functional stem cell output to tissue damage.3. Cancer arises from expansion of mutant clones when the size functional stem cell pool is small,
which may take place in (1) the early life stage or (2) stem cell decline during aging.4. Change in life history may modify the stem cell aging rate, resulting in change in cancer spectrum. 5. Deceleration in tissue damaging and stem cell declining may delay cancer occurrence.
Immunity: a damage control system for somatic cells
Virus
Damaged DNA
“damage” signal
Interferons
NK cell lignads NK cell killing
DC activation
“Non-self” antigens
T-cell and B-cell responses
Adaptive immunity as a system to maintain multicellular integrity
Initiating event Tissue damage Adaptive immunityAntigen release
Molecular pattern
Innate immunity
Microbial infection, DNA damage, etc.
Initiating event Damage expanding Damage removal Tissue repair
Immunosuppressant drugs increase cancer risk in patients receiving transplanted organs
JAMA. 2011;306(17):1891-1901
Acute infection in earlier stage may reduce cancer incidence later in life
Cancer Causes Control. 2010 August ; 21(8): 1193–1201.
Correlation of tumor-associated antigen Ab with lower cancer risk in healthy individuals
Conditions include bone fracture/osteoporosis, mastitis, pelvic surgeries, IUD use, no genital talc use, OC use, and current smoking
Cancer Epidemiol Biomarkers Prev 2005;14(5). May 2005
Trends in Immunology, 2013, 34:471
The tissue aging accelerates when the immunity declines, resulting in chronic inflammation
Immunity
Reproduction Environmental stress
Resource
Vital function
Endocrine system
Autonomous nervous system
Autonomous nervous and endocrine systems are resource distributing controllers
Allocation of resource to stress responses results in immunosuppression
Exp: cat; control: rabbit
Journal of Zoology 268 (2006) 9–16
Circadian rhythm functions to optimize energy allocation for efficiency
Stress response
Repair & Regeneration
Th1 immunity
Energy metabolism
Th2 immunity
Summary (II)
1. Immunity maintains the integrity of somatic tissues.2. Tumors may continuously form during lifetime, but are kept asymptomatic by immunosurveillance.3. However, the decline or suppression of immunity may allow the outbreak of small tumors,
becoming symptomatic.4. The allocation of resource away from immune system by life style may cause immune suppression,
promoting cancer occurrence.
Func
tiona
l ste
m ce
ll po
ol si
ze
Pre-adolescent Reproductive Post-reproductive
Age
Canc
er
inci
denc
e
death
Canc
er
sym
ptom
Imm
unitySummary (II)
xx
Initiating tumor
Expanding tumor
Mutant clone
Stem cell pool
Peripheral tissue
Evolutionary trade-off:• Reproduction vs.
Somatic maintenance• Nutrition vs. prolonged
exposure to carcinogens
Life history trade-off:• Reduction of infection
vs. lack of “training” of immunity
• Stress vs. immunity• Prolonged active time
vs. circadian rythem
Stress response
Repair & Regeneration
Th1 immunity
Energy metablism
Th2 immunity
太陽
陽明
少陽
少陰 太陰厥陰