Transcript More Human Than Human

More Human Than Human
The Evolution of Cancer
By Chris Engdahl
The Facts (Light)
• Over 200 known types
• 13% of all deaths (7.6
million in 2007)
• ~ 1 in 6 will get it
• Found in all plants
• Found in all animals
Are we looking at this from the
wrong perspective?
Traditional Perspectives
Why is cancer so prevalent?
Why can’t we always treat it?
Why can’t we seem to win the war?
Evolutionary Perspectives
How does evolutionary theory pertain
to cancer?
How can we use evolution to plan and
model our treatments?
Proximate Causation
Lifestyle
Pathogens
Carcinogens
Genetic Abnormalities
Proximate Causation
1. Self Sufficient Growth
2. Evades Apoptosis
3. Antigrowth Signal Failure
4. Angiogenesis
5. Limitless Reproduction
6. Metastasis
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70.
Proximate Causation
This is not necessarily a
linear process
Most of us have already
had precancerous
growths and survived
(why?)
Hanahan, et al (2000)
Ultimate Causation
• Occurs in all
animals
• Children/youth
have extremely
low rates
• Rarely occurs
during
reproductive ages
• Cancer is a
disease of aging
Could this be an example of…
Antagonistic Pleiotropy
“Can I get an AMEN?”
Antagonistic Pleiotropy
“Natural selection will
frequently maximize
vigor in youth at the
expense of vigor later
on and thereby
produce a declining
vigor (senescence)
during adult life.”
George C. Williams
Williams, G.C. 1957. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411.
Antagonistic Pleiotropy
Natural selection favors strong
anticancer defenses through our
reproductive ages
This protects our bodies and genomes
just enough for us to maximize our
reproductive potential
As our “vigor” ends, we have no need to
maintain our systems (Disposable
Soma Hypothesis)
A universal trait (So those without it
quickly were selected against)
And to a lesser degree…
Gene-environment
mismatch (Diet)
Cellular level
reproductive
advantage
Pathogen virulence
(XMRV vs HPV)
Demographic effects
(Occupations,
cultural practices,
geography)
Cancer = Evolution
• Heritable changes in the
genome
• Cancer cells have an
adaptive advantage
• Unequal reproduction
(Cancers outcompete
normal cells)
• Natural selection
• Evolution of population
(good for them, bad for us)
Treating Cancer = Evolution
• Chemotherapy
• Targeted therapy
• Surgery
• Gene therapy
• Radiation Therapy
…are examples of selective pressures we apply to
cancer
Complications = Evolution
• Metastasis - Neoplasm
outcompetes and invades our
normal cells
• Drug resistance - Tumors stop
responding to treatments (i.e.
ABCB1 proteins pump
chemotherapy out of cells)
…are examples of selective pressures cancer applies
to us!
Is There Hope?
If cancer is an evolutionary process, why not
use evolutionary theory to fight it?
Evolution Based Treatments
Vaccinations
(+) Highly effective in some models (i.e.
HPV/Gardasil) if inoculated preexposure
(-) Useless against novel pathogens or the nonpathogenically derived cancers
Multi-drug Chemotherapy
(+) Prevents emergence of resistant strains
(-) Expensive, lack of comparable drugs in arsenal
Evolution Based Treatments
• Oncolytic viruses (Viral antagonists)
(+) Highly selective, outcompetes even cancer cells
(-) May elicit immune response. Pathogenicity potential
• Anaerobic bacteria (Clostridium novyi)
(+) Targets and kills anaerobic nuclei of tumors
(-) Ineffective against aerobic cancers (But useful in “boosting”
chemotherapy)
• Environmental manipulation (e.g. Focused
hyperthermia, antiangiogenic therapies)
(+) Tumors are more susceptible to change than normal cells
(-) Doesn’t often kill cells (may only weakens them)
The Take Home
Cancer is an evolutionary
process
Cancer is a disease of
senescence
Postreproductively,
antagonistic pleiotropy
makes our soma
“expendable”
Treatments should reflect
this understanding
Citations
•
Fan H. (2007) A new human retrovirus associated with prostate cancer. Proc Natl Acad Sci U S A; 104:1449–50.
•
Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell. Jan 7;100(1):57-70.
•
Jain RK, Forbes NS (2001). "Can engineered bacteria help control cancer?". Proc. Natl. Acad. Sci. U.S.A. 98 (26): 14748–50.
•
Kanerva A, Lavilla-Alonso S, Raki M, et al. (2008). "Systemic therapy for cervical cancer with potentially regulatable oncolytic
adenoviruses". PLoS ONE 3 (8): e2917.
•
Mengesha et al. (2009). "Clostridia in Anti-tumor Therapy". Clostridia: Molecular Biology in the Post-genomic Era. Caister Academic
Press
•
Pepper JW, Findlay CS, Kassen R, Spencer SL, Maley CC (2009). "Cancer research meets evolutionary biology". Evol. Appl. 2: 62–70.
•
Rein DT, Breidenbach M, Curiel DT (February 2006). "Current developments in adenovirus-based cancer gene therapy". Future Oncol 2
(1): 137–43
•
Ring A, Dowsett M (December 2004). "Mechanisms of tamoxifen resistance". Endocr. Relat. Cancer 11 (4): 643–58.
•
Rodier F, Campisi J, Bhaumik D (2007). "Two faces of p53: aging and tumor suppression". Nucleic Acids Res 35: 7475.
•
Urisman, R.J. Molinaro, N. Fischer, S.J. Plummer, G. Casey and E.A. Klein et al., (2006) Identification of a novel Gammaretrovirus in
prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog 2 (3)
•
Williams, G.C. (1957). Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411.