Cancer is a complex group of diseases with multiple eventual causes.

1. INFECTION AND CANCER
Amer Ali Khaleel
M.SC in Medical Immunology
Hawler Medical University

2. CANCER
 Cancer is a complex group of diseases with
multiple eventual causes.
 The impacts of cancer are multiple and far
reaching, affecting people of both gender,
and all ages.

4. Approximately 20% of all cancers are
associated with infectious agents , and
15% of all cancers are caused by
oncoviruses .

7.  "Infections are one of the biggest
and preventable causes of cancer
worldwide,”

8. CHARACTERISTICS OF ONCOGENIC VIRUSES:
1. The oncogenic viruses doesn't obey Koch's
postulates
2. These viruses cause little or no symptoms after
infection
3. Oncoviruses can either be DNA virus or RNA virus

9. THESE CRITERIA CAME TO BE KNOWN AS
KOCH’S POSTULATES:
1. The organism must be regularly associated with
the disease and its characteristic lesions.
2. The organism must be isolated from the diseased
host and grown in culture.
3. The disease must be reproduced when a pure
culture of the organism is introduced into a
healthy, susceptible host.
4. The same organism must be reisolated from the
experimentally infected host.

10. CANCERS AND INFECTIOUS AGENTS
 The most important advance in oncology ever is the
understanding that most cancers have specific causes,
and that these causes may be identified, leading
potentially to control.
 The causes of some cancers are infectious agents. The
proposal that cancers are caused by infectious agents has
had a very up and down history: today we can be certain
that many cancers have aetiologies with infectious agents
as necessary factors.

11. AETIOLOGY
 The etiology of cancer is multifactorial, with
genetic, environmental, medical, and lifestyle
factors interacting to produce a given malignancy.

12. CARCINOGENESIS
 Carcinogenesis, also called oncogenesis or
tumorigenesis, is the formation of a cancer ,
whereby normal cells are transformed into cancer
cells. The process is characterized by changes at
the cellular, genetics , epigenetic levels and
abnormal cell division.

13. INFECTION
Infection is one of the most important
causes of cancer.

14. INFECTIOUS AGENTS
 Such as hepatitis B (HBV) and C viruses (HCV), Epstein-
Barr virus (EBV), human papillomavirus (HPV), human
immunodeficiency virus type 1 (HIV-1), Helicobacter pylori
(H. pylori),Streptococcus bovis (S. bovis) and
Schistosoma haematobium contribute to the pathogenesis
of different cancers.

15. ONCOGENIC VIRUSES

16. ONCOVIRUS
An oncovirus is a virus that can
cause cancer and which induce
malignant transformation of cells.

17. Carcinogenesis is a multistep process i.e;
multiple genetic changes must occur to
convert normal cells to malignant one.
ONCOGENESIS

18.  Proto-oncogenes - normal (pre-mutation) (pre-
diseased) genes
 - present in normal cells
 - conserved in their genomes
 - code for proteins which regulate cell growth
& differentiation
 Oncogenes - mutated versions of proto-oncogenes
PROTO-ONCOGENES & ONCOGENES

19. Cause Uncontrolled
Or excessive cell growth

20. TUMOR SUPPRESSOR GENE
The normal functions is….
1. Slow down cell division.
2. Repair DNA mistakes.
3. Communicate apoptosis (if necessary).
 Once inactivated (turnoff) by mutation: cause cancer.

21. TUMOR SUPPRESSOR GENE
 In general, all oncoviruses promote
tumorigenesis via common pathways. Tumor
suppressor pathways, such as
 P53
 pRb

27. ONCOVIRUS ABILITY
1- produce oncoproteins.
2- inhibited the infected cells not killed
(cytotoxic).
3-has ability to be latency (sleeping in the
body).
4-has ability to cause chronic not acute.

28. WHAT ARE COMMON FEATURES AMONG
ONCOGENIC VIRUSES
Most oncogenic viruses often contribute to cancer
development in similar ways
•These viruses have the ability to infect, but not kill their host
cells.
•They establish persistent and long-term infections.
•They have evolved strategies that enable them to evade
mechanisms of viral clearance by the host immune system.

29. Why not all virally infected
individuals develop cancer?
“There is no single mechanism by
which viruses cause tumors”

30.  Viral disease may represent an easier target
than bacterial disease, but there are many
biological properties of viruses that stand in
the way of eradication using current
technology and current ways of thinking.

31. It appears that a tumor viruses usually acts
a cofactor, providing only some of the
steps required to generate malignant cells.
Viruses are necessary - but not sufficient-
for development of tumors with viral
etiology. Viruses often acts as initiators of
neoplastic process and may do so by
different mechanisms

33. VIRUSES ASSOCIATED WITH HUMAN CANCERS
Infectious Agent Associated Cancers
Epstein-Barr virus (EBV) Burkitt lymphoma- Hodgkin lymphoma
Nasopharyngeal carcinoma
Hepatitis B virus (HBV) Hepatocellular carcinoma
Hepatitis C virus (HCV) Hepatocellular carcinoma
Human papillomavirus types (HPV)16, 18 Genital tumors
Oropharyngeal cancer
Human immunodeficiency virus 1 (HIV 1) AID-related malignancies
Human T-cell lymphotropic virus 1 (HTLV1) Adult T-cell leukemia
Kaposi sarcoma herpesvirus/ human
herpesvirus 8 (KSHV/HHV 8)
Kaposi sarcoma
Markel cell virus Markel cell carcinoma

34. EPSTEIN–BARR VIRUS (EBV)
 EBV is a double-stranded DNA virus
 During primary infection, EBV replicates in epithelial or B
cells of the oropharynx, and then, to escape immune
surveillance, turns off most of its genes and enters a state of
latency, with resting memory B cells as the primary
reservoir.

35.  EBV genes expressed during latent infection include six
nuclear antigens (EBNA-1, 2, 3A, 3B, 3C, and leader
protein (LP)).
 Three latent membrane proteins (LMP-1, 2A, and 2B).
 LMP-1 is generally considered as the main oncogenic
protein of EBV,

36.  These proteins are essential for the ability of EBV to
immortalise B cells and transform a variety of other cell
types.
 EBV can induce up regulation of c-myc through
translocation of c-myc protooncogene to one of the Ig
heavy chain gene , subsequently c-myc cooperates with
the transcriptional factor Sp1 leading to enhanced
telomerase reverse transcriptase (TERT) expression.

37.  LMP1 is shown to be essential for EBV transformation of
lymphocytes and is an important factor in rendering the
cells resistant to apoptosis, either through inhibition of the
proapoptotic gene BAX or by encoding a homologue of the
anti-apoptotic protein Bcl-2.

38.  LMP-1 constitutively activates members of the tumour
necrosis factor receptor (TNF-R) superfamily, through
which it induces several signaling pathways, including:
1-The nuclear factor kappa B (NF-κB)
2-Mitogen activated protein kinase (MAPK)
3-Janus-activated kinase/signal transducer and activator
of transcription (JAK/STAT) , which consequently lead to cell
growth and proliferation.

39.  The EBV genome also encodes viral IL-10, a homologue
to human IL- 10.
 EBV IL-10 can act to down regulate class I and II MHC
molecules and inhibit the expression of co-stimulatory
molecules required for proper cytotoxic T-cell (CTL)
activation. Thereby, EBV demonstrates strategies to evade
the immune response to protect virally infected cells from
immune clearance.

40. HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS
(HCV)
 HBV is a DNA virus and HCV is an RNA virus.
 Both are hepatotropic viruses that can cause acute and
chronic hepatic infections.
 The typical natural history of viral carcinogenesis in HCC
involves many years of chronic viral infection leading to
development of cirrhosis in about 20-30% of patients, which
subsequently leads to HCC.

41.  HBV may target genes involved in cellular signaling
pathways at sites of viral integration, such as the human
telomerase reverse transcriptase hTERT pathway.
 It may cause deletions in chromosomal regions carrying the
p53 gene, which might result in a loss of p53 gene.
 HBV may cause disruptions and translocations in the
cellular DNA, resulting in genetic instability.

42.  The HBV gene X (HBV-X) is the most commonly integrated
HBV gene. Through its function as a transcriptional
transctivator it seems to contribute indirectly to
carcinogenesis through activating several kinases and
signalling pathways, such as
 1- MAPK.
 2- c-jun N-terminal kinase (JNK).
 3- phosphatidylinositol 3-kinase (PI3K), and
 4- JAK/STAT signaling cascades.

43.  It also enhances cell cycle progression through
deregulation of p53 and retinoblastoma pRb
genes.
 Through these interactions the virus promotes
dysplasia and cancer after years of chronic
infection

44. HUMAN HERPESVIRUS 8 (HHV-8)
 KSHV is a double-stranded DNA
 Also referred to as kaposi's sarcoma-associated
herpesvirus (KSHV)
 KSHV establishes latent infection in its host.
 KSHV encodes the largest number of potential
oncogenes, is able to transform primary human
endothelial cells.

45.  The KSHV latency-associated nuclear antigen 1 (LANA-
1) is KSHV oncoprotein, which is expressed during latent
infection.
 LANA-1 can interfere with different cellular processes such
as the induction of telomerase activity through binding to
Sp1 and it can form a complex that trans-activates the
telomerase reverse transcriptase (TERT) promoter leading
to telomere elongation and cellular immortalization.

46.  KSHV also encodes oncoproteins with anti-apoptotic
functions including: viral b-cell lymphoma-2 oncoprotein
(vBcl-2) a homologue to the human anti-apoptotic protein ,
and viral FLICE inhibitory protein (v-FLIP), which exerts anti-
apoptotic function by either binding to Fas-associated death
domain and caspase 8 or via activation of the nuclear factor
kappa B (NF-κB) pathway.

47.  KSHV can also exert anti-apoptotic effects through different
mechanisms, such as the repression of p53 transcriptional
activity by LANA-1.
 Other viral encoded proteins such as modulator of immune
recognition-1 and 2 (MIR1 and MIR2) accelerate MHC-I
degradation and help infected cells evade cytotoxic killing.

48. HUMAN PAPILLOMAVIRUS (HPV)
 HBV is a double-stranded DNA virus.
 It is a common cause of sexually transmitted diseases
(STD).
 Oncogenic strains are HPV 16 and 18 associated with
cervical carcinoma.
 The oncogenic potential of the HPV lies in the
oncoproteins early (E6 and E7), which can bind to and
modulate a number of different gene products, in
particular, the tumor suppressors proteins (p53 and pRb).

49.  E6 binds to p53 tumor suppressor gene leading to
degradation pathways involved in cycle arrest and
apoptosis.
 E7 binds to retinoblastoma (RB) tumor suppressor
HPV E7 binds to pRb and activates genes that start
the cell cycle leading to tissue proliferation.

50.  The HPV genome integrates randomly into the host genome.
 The virus encodes six viral regulatory proteins (E1, E2, E4,
E5, E6 and E7). Two proteins, E6 and E7 are considered as
oncogenic proteins.
 HPV proteins can induce genomic instability in infected cells
through different mechanisms.

51.  HPV-16 E7 interacts with the pRb, disrupting its control
over E2F and leading to activation of proteins, such as
cyclin–CDK complexes, consequently resulting in
unrestricted cell progression through the G1 to S phases of
the cell cycle.
 HPV-16 E6 is also known to induce genetic instability
through inhibition of an important enzyme in the DNA
repair machinery called DNA methyltransferase , which
inhibits repair of critical genes including p53.

52. OTHER INFECTIOUS AGENTS

53. OTHER INFECTIOUS AGENTS ASSOCIATED WITH HUMAN
CANCERS
Infectious Agent Associated Cancers
Helicobacter pylori Gastric cancer
Streptococcus bovis Colorectal cancer
Liver flukes Cholangiocarcinoma
Schistosomes Bladder cancer

54. Multiple tools to fight infections, such as vaccination, safe
injection practices, screening of blood transfusion, safe sex
practices, antimicrobial treatments can have beneficial
effects on the future burden of cancer related-infections.
PREVENTION SOLUTION

55. SUMMARY
 Viruses are causative agent of several type of
human cancer .
 Tumor viruses established persistent infection in
hosts, with long latent period before tumor
appearance.
 Viral infections tend to be more chronic than
bacterial infections, thus viruses have a more
prominent role in the development of cancer.

56. REFERENCES
 Causal role of infectious agents in cancer: An overview
doi: 10.22088/cjim.8.3.153
 Human oncogenic viruses: nature and discovery
doi: 10.1098/rstb.2016.0264
 The role of human cytomegalovirus infection in cancer:
Taher, Chato
 Viral Oncology: Molecular Biology and Pathogenesis
doi:10.3390/jcm6120111
 WHO,2018.

57. THANK YOU