2. Evolution as a unifying principle
for medical sciences:
the case of cancer
Paul W. Ewald
Department of Biology
Program in Disease Evolution
University of Louisville

3. What causes cancer?

4. Cecil Textbook of Medicine 15th Edn. 1979. p. 1910
“To date, there is no unambiguous evidence that any class
of human cancers is regularly caused by a virus. Some
cancers have been shown to be associated with elevated
levels of antibody to certain viruses or viral components
. . . However, no direct evidence exists that the viruses
and the cancers are causally linked.”

5. Cancers accepted as caused by infection during the last 3 decades
Cancer Pathogen ~ year Affected
accepted populations
Burkitts Lymphoma Epstein Barr virus + 1980 New Guinea, tropical
Plasmodium Africa and South
falciparum America
adult T-cell Human T 1980 Africa, Japan,
leukemia Lymphotropic Virus I Caribbean, So.
America
cervical cancer Human Papilloma 1985 worldwide
virus (HPV)
nasopharyngeal Epstein Barr virus 1990 China, Inuit
cancer (EBV)
liver cancer Hepatitis B & C 1995 worldwide
viruses
Kaposi’s sarcoma human herpesvirus 8 2000 Africa, Mediterranean,
MSM
MALT stomach cancer Helicobacter pylori 2000 worldwide
oropharyngeal cancer HPV 2005 worldwide

6. How important are infectious causes of cancer?
“To date, there is no unambiguous evidence that any class
of human cancers is regularly caused by a virus. Some
cancers have been shown to be associated with elevated
levels of antibody to certain viruses or viral components
. . . However, no direct evidence exists that the viruses
and the cancers are causally linked.” Cecil Textbook of
Medicine 15th Edn. 1979. p. 1910
“One-fifth of cancers worldwide are due to chronic
infections.” W.H.O. Media Centre. February 2006

7. Categories of disease causation
genetic (inherited alleles)
noninfectious
environmental parasitic
(diet, lifestyle, chemicals, radiation)

8. Categories of disease causation:
lung cancer
genetic
environmental parasitic
smoking

9. Categories of disease causation:
retinoblastoma
genetic
Mutations in the
gene coding for the
retinoblastoma
protein (pRb)
environmental parasitic

10. Categories of disease causation:
cervical cancer
genetic
cervical
cancer
environmental infectious
Oncogenic
serotypes of human
papillomavirus

11. Alternative hypotheses for carcinogenesis
Conventional Infectious Infection as a
explanation exacerbation primary cause
genetic
genetic genetic predisposition
predisposition predisposition & infection
infection
mutation mutation mutation
(sometimes)
metastatic cancer metastatic cancer metastatic cancer

12. Disruption of cellular barriers to cancer
Pathogen Cancer Disruption
cell cycle Immortalization Apoptosis Cell
arrest adhesion
Epstein Barr Burkitt’s, yes
virus nasopharyn-
geal
Human cervical,
papilloma head & neck
virus
HTLV adult T-cell
leukemia/
lymphoma
Human herpes Kaposi's
virus 8 sarcoma
Hepatitis B liver
virus

13. Disruption of cellular barriers to cancer
Pathogen Cancer Disruption
cell cycle Immortalization Apoptosis Cell
arrest adhesion
Epstein Barr Burkitt’s, yes yes yes yes
virus nasopharyngeal
Human cervical,
papilloma head & neck
virus
HTLV adult T-cell
leukemia/
lymphoma
Human herpes Kaposi's
virus 8 sarcoma
Hepatitis B liver
virus

14. Disruption of cellular barriers to cancer
Pathogen Cancer Disruption
cell cycle Immortalization Apoptosis Cell
arrest adhesion
Epstein Barr Burkitt’s, yes yes yes yes
virus nasopharyngeal
Human cervical, yes yes yes yes
papilloma head & neck
virus
HTLV adult T-cell yes yes yes yes
leukemia/
lymphoma
Human herpes Kaposi's yes yes yes yes
virus 8 sarcoma
Hepatitis B liver yes yes yes yes
virus

15. Predictions from infectious causation hypothesis
genetic
predisposition
& infection
Prediction: oncogenic mutations will
mutation occur later than infection during
oncogenesis
metastatic cancer

16. Predictions from infectious causation hypothesis
genetic
predisposition
& infection
Prediction: oncogenic mutations will
mutation occur later than infection during
oncogenesis
Cervical cancer: yes
metastatic cancer
Breast cancer: ?

17. Cancer mortality
US: ~ 540,000/year
Worldwide: 7.6 million/year (13% of all deaths)
Site of cancer Deaths/year
worldwide
Lung 1.3 million
Stomach 1 million
Liver 660,000
Colon 655,000
Breast 500,000

18. Infectious agents and breast cancer
Mouse Mammary Tumor Virus (MMTV)
-Causes mammary tumors in Mus domesticus
-In 30-40% of human breast cancer & < 5% normal tissue
within M. domesticus’s range (USA, Australia)
[Wang et al 1995, Liu et al 2001, Etkind et al. 2000, Ford et al 2003,
Lawson et al 2006]
-Breast cancer rates reduced by ~1/3 outside of M.
domesticus’s range (Japan, eastern Europe, northern &
eastern Asia) [Stewart et al. 2000]
-Effects on barriers to cancer
--disregulates cell cycle arrest
--inhibits apoptosis
--inhibits cell adhesion

19. Infectious agents and breast cancer
Epstein Barr Virus
-US: EBV in 51% of BC; < 10% of normal adjacent
tissue [Bonnet et al 1999]
-France, Denmark, the Netherlands, France, Algiers &
Tunisia: EBV in BC 30-40% > in adjacent tissues [Fina et
al. 2001]
-More strongly associated with breast cancer when florid
EBV infections occur during adolescence [Yasui et al 2001]

20. Infectious agents and breast cancer
Human papillomavirus
-Oncogenic HPV in 15.9% of 107 breast cancers [Kroupis et al 2006]
& 24.8% of 101 breast cancers [Damin et al 2004]
-HPV (serotype16) in breast cancer concurrent with cervical cancer
--46% of 41 cases of when cervical cancer started first
--0% of 9 cases when breast cancer started first [Hennig et al 1999]
-Transmission route to breast is uncertain
--self contamination from genital area?
--genital to oral to breast sexual contact?
--via blood or lymph?

21. Risk factors and disease causation:
breast cancer
genetic
BRCA alleles
?
breast
cancer
noninfectious
environmental infectious
Mutagens, hormonal Human Papillomavirus,
alteration Mouse Mammary Tumor Virus,
Epstein Barr Virus

22. Prediction: Mutations should occur later than infection
during oncogenesis: BRCA1 & PTEN
genetic
predisposition } BRCA1 (BReast CAncer 1): facilitates repair of
& infection double-strand breaks in DNA & restricts cell division
mutation
PTEN (Phosphatase and TENsin homolog):
restricts cell division & fosters apoptosis
metastatic cancer

25. Disruption of cellular barriers to breast cancer
Disruption
Pathogen Stimulation of Immortalization Apoptosis Cell adhesion
proliferation
Epstein yes yes yes yes
Barr virus EBNA3, EBNA2 ups telomerase BHRF1; LMP2 Inhibits nm23
&/or EBNA-LP ups Bcl-x
inhibits pRb
Human yes yes yes yes
papilloma E6 degrades p53 E6 ups telomerase E6 degrades p53 Inhibits CD44
virus E7 binds pRb
MMTV yes yes yes
?
due to Env protein due to Env Inhibits nm23
protein
Nm23: Non-Metastatic cell binding protein
CD44: glycoprotein involved in cell adhesion
ITAM: immunoreceptor tyrosine-based activation motif
EBNA: Epstein Barr Nuclear Antigen

26. Estrogen immune suppression/infection hypothesis
Finding Explanation
Excess cancer for postmenopausal, Nulliparous women more exposed
nulliparous women to sexually transmitted pathogens
Excess cancer during and just after Immune suppression by estrogen
pregnancy and progesterone during pregnancy
Excess cancer if menarche is early Early menarche means immune
suppression and more exposure to
sexually transmitted pathogens
Only early pregnancies protect late pregnancies associated with
increased exposure to sexually
transmitted pathogens
Estrogen receptor negative cancers Effect of estrogen on infection
need not be via estrogen receptors

27. Categories of disease causation:
cervical cancer
genetic
?
breast
cancer
environmental parasitic
HPV, MMTV, EBV
Mutagens, hormonal
alteration

28. Disruption of cellular barriers to cancer
Disruption
Pathogen Cancer Stimulation of Immortalization Apoptosis
proliferation
Epstein Burkitt’s, yes yes yes
Barr virus nasopharyn- EBNA3, EBNA2 &/or ups telomerase LMP2 ups Ras &
geal EBNA-LP inhibits pRb Bcl; BHRF1
Human cervical, yes yes yes
papilloma oropharyn- E6 degrades p53 E6 ups telomerase E6 degrades p53
virus geal E7 binds pRb
HTLV adult T-cell yes yes yes
leukemia/ Tax ups IL2 & IL2 Tax ups telomerase via Tax enhances
lymphom receptor; p30II via NFkappaB EGR3 &
CREB-BP suppresses p53 by
enhancing KLF4
Hepatitis B liver yes yes yes
virus Bx binds to PPARγ insertion blocks Bx binds to
repression of PPARγ
telomerase

29. Cancers that may be accepted as caused by
infection during the next 20 years
Cancer Candidate pathogens Year
accepted?
Hodgkin’s lymphoma EBV 2010?
nonHodgkin’s lymphomas EBV, SV40 2010?
breast cancer MMTV, EBV, HPV 2010-15?
skin cancers HPV 2010-15?
mesothelioma simian virus 40 2010-2015?
colon cancer JC Virus 2010-15?
merkel cell cancer merkel cell polyomavirus 2010-15?
prostrate mouse gamma retrovirus, BK 2010-25?
virus
ovarian cancer unknown retrovirus, EBV 2015-25?