More Human Than HumanMore Human Than HumanThe Evolution of CancerThe Evolution of Cancer

By Chris EngdahlBy Chris Engdahl

The Facts (Light)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 Are we looking at this from the wrong perspective?wrong perspective?

Traditional PerspectivesTraditional PerspectivesWhy is cancer so prevalent?Why is cancer so prevalent?

Why can’t we always treat it?Why can’t we always treat it?

Why can’t we seem to win the war?Why can’t we seem to win the war?

Evolutionary Perspectives Evolutionary Perspectives How does evolutionary theory pertain How does evolutionary theory pertain

to cancer?to cancer?

How can we use evolution to plan and How can we use evolution to plan and model our treatments?model our treatments?

Proximate CausationProximate Causation

LifestyleLifestylePathogensPathogens

CarcinogensCarcinogensGenetic AbnormalitiesGenetic Abnormalities

Proximate CausationProximate Causation

1.1. Self Sufficient GrowthSelf Sufficient Growth

2.2. Evades ApoptosisEvades Apoptosis

3.3. Antigrowth Signal FailureAntigrowth Signal Failure

4.4. AngiogenesisAngiogenesis

5.5. Limitless ReproductionLimitless Reproduction

6.6. MetastasisMetastasisHanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70.Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70.

Proximate CausationProximate Causation

This is not necessarily a This is not necessarily a linear processlinear process

Most of us have already Most of us have already had precancerous had precancerous

growths and survived growths and survived (why?)(why?)

Hanahan, Hanahan, et alet al (2000) (2000)

Ultimate CausationUltimate Causation• Occurs in all Occurs in all

animalsanimals

• Children/youth Children/youth have extremely have extremely low rateslow rates

• Rarely occurs Rarely occurs during during reproductive agesreproductive ages

• Cancer is a Cancer is a disease of agingdisease of aging

Could this be an example of…Could this be an example of…

Antagonistic PleiotropyAntagonistic Pleiotropy

““Can I get an AMEN?”Can I get an AMEN?”

Antagonistic PleiotropyAntagonistic Pleiotropy

““Natural selection will Natural selection will frequently maximize frequently maximize vigor in youth at the vigor in youth at the

expense of vigor later expense of vigor later on and thereby on and thereby

produce a declining produce a declining vigor (senescence) vigor (senescence) during adult life.”during adult life.”

George C. WilliamsGeorge C. Williams

Williams, G.C. 1957. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411. Williams, G.C. 1957. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411.

Antagonistic PleiotropyAntagonistic Pleiotropy

Natural selection favors strong Natural selection favors strong anticancer defenses through our anticancer defenses through our

reproductive agesreproductive ages

This protects our bodies and genomes This protects our bodies and genomes just enough for us to maximize our just enough for us to maximize our

reproductive potential reproductive potential

As our “vigor” ends, we have no need to As our “vigor” ends, we have no need to maintain our systems (Disposable Soma maintain our systems (Disposable Soma

Hypothesis)Hypothesis)

A universal trait (So those without it A universal trait (So those without it quickly were selected against)quickly were selected against)

And to a lesser degree…And to a lesser degree…

Gene-environment Gene-environment mismatch (Diet)mismatch (Diet)

Cellular level Cellular level reproductive reproductive advantage advantage

Pathogen virulence Pathogen virulence (XMRV vs HPV) (XMRV vs HPV)

Demographic effects Demographic effects (Occupations, (Occupations,

cultural practices, cultural practices, geography)geography)

Cancer = EvolutionCancer = Evolution

• Heritable changes in the Heritable changes in the genomegenome

• Cancer cells have an Cancer cells have an adaptive advantageadaptive advantage

• Unequal reproduction Unequal reproduction (Cancers outcompete (Cancers outcompete normal cells)normal cells)

• Natural selectionNatural selection

• Evolution of population Evolution of population (good for them, bad for us)(good for them, bad for us)

Treating Cancer = EvolutionTreating Cancer = Evolution

• ChemotherapyChemotherapy

• Targeted therapyTargeted therapy

• SurgerySurgery

• Gene therapyGene therapy

• Radiation TherapyRadiation Therapy

……are examples of selective pressures we apply to are examples of selective pressures we apply to cancercancer

Complications = EvolutionComplications = Evolution

• Metastasis - Neoplasm Metastasis - Neoplasm outcompetes and invades our outcompetes and invades our normal cellsnormal cells

• Drug resistance - Tumors stop Drug resistance - Tumors stop responding to treatments (i.e. responding to treatments (i.e. ABCB1 proteins pump ABCB1 proteins pump chemotherapy out of cells) chemotherapy out of cells)

……are examples of selective pressures cancer applies are examples of selective pressures cancer applies to us!to us!

Is There Hope?Is There Hope?

If cancer is an evolutionary process, why not If cancer is an evolutionary process, why not use evolutionary theory to fight it?use evolutionary theory to fight it?

Evolution Based TreatmentsEvolution Based Treatments

VaccinationsVaccinations(+) Highly effective in some models (i.e. (+) Highly effective in some models (i.e.

HPV/Gardasil) if inoculated preexposureHPV/Gardasil) if inoculated preexposure

(-) Useless against novel pathogens or the non-(-) Useless against novel pathogens or the non-pathogenically derived cancerspathogenically derived cancers

Multi-drug ChemotherapyMulti-drug Chemotherapy(+) Prevents emergence of resistant strains(+) Prevents emergence of resistant strains

(-) Expensive, lack of comparable drugs in arsenal (-) Expensive, lack of comparable drugs in arsenal

Evolution Based TreatmentsEvolution Based Treatments

• Oncolytic viruses (Viral antagonists)Oncolytic viruses (Viral antagonists)(+) Highly selective, outcompetes even cancer cells(+) Highly selective, outcompetes even cancer cells

(-) May elicit immune response. Pathogenicity potential (-) May elicit immune response. Pathogenicity potential

• Anaerobic bacteria (Anaerobic bacteria (Clostridium novyi)Clostridium novyi)(+) Targets and kills anaerobic nuclei of tumors(+) Targets and kills anaerobic nuclei of tumors

(-) Ineffective against aerobic cancers (But useful in “boosting” (-) Ineffective against aerobic cancers (But useful in “boosting” chemotherapy)chemotherapy)

• Environmental manipulation (e.g. Focused Environmental manipulation (e.g. Focused hyperthermia, antiangiogenic therapies)hyperthermia, antiangiogenic therapies)

(+) Tumors are more susceptible to change than normal cells(+) Tumors are more susceptible to change than normal cells

(-) Doesn’t often kill cells (may only weakens them)(-) Doesn’t often kill cells (may only weakens them)

The Take HomeThe Take Home

Cancer is an evolutionary Cancer is an evolutionary processprocess

Cancer is a disease of Cancer is a disease of senescencesenescence

Postreproductively,Postreproductively,antagonistic pleiotropy antagonistic pleiotropy

makes our soma makes our soma “expendable”“expendable”

Treatments should reflect Treatments should reflect this understandingthis understanding

CitationsCitations• Fan H. (2007) A new human retrovirus associated with prostate cancer. Proc Natl Acad Sci U S A; 104:1449–50.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.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.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 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. 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 PressMengesha 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.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 Rein DT, Breidenbach M, Curiel DT (February 2006). "Current developments in adenovirus-based cancer gene therapy". Future Oncol 2 (1): 137–43(1): 137–43

• Ring A, Dowsett M (December 2004). "Mechanisms of tamoxifen resistance". Endocr. Relat. Cancer 11 (4): 643–58.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.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 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)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. Williams, G.C. (1957). Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411.