Chapter from harsh mohan

2. VIRAL ONCOGENESIS
• Many DNA and RNA viruses proven to be
oncogenic in animals & birds
• ONLY a few viruses have been linked
with human cancer.

3. Viral Oncology –historical perspective
• First tumour viruses described at start of
20th Century
• Retroviruses
– Avian leukaemia virus - Ellerman & Bang
– Avian sarcoma virus –Rous
• Ludwig Goss 1950s - retroviruses cause
tumours in mice
• William Jarrett – feline leukaemia virus

4. Viruses and human tumours
• Cervical cancer and the genital wart virus,
HPV
• Primary liver cancer and the Hepatitis B ,
C viruses
• T cell leukaemia in adults and the Human
T cell leukaemia virus
• Kaposis sarcoma HHV8

5. Mechanisms of viral oncogenesis:
• Impairment of signal transduction
– Growth factor expression
– Growth factor activation
– Cytoplasmic or membrane-bound kinases
– Transcription factors
• Inactivation of tumour suppressor genes
– Uncontrolled proliferation (Rb gene & p53)
– Inhibition of apoptosis (p53)

6. RNA TUMOUR VIRUSES
Divided into:
• Acute transforming viruses
• Slow transforming viruses

7. Acute Transforming viruses:
• Have acquired, by transduction, portions
of cellular genes.
• Their expression in cells leads to rapid
development of tumours.
• Such transduced viral genes are termed
viral oncogenes (v-oncs)

8. • The cellular genes from which the v-oncs
are derived are known as cellular
oncogenes (c-oncs) or proto-oncogenes.
• Infection with acute transforming retrovirus
leads to incorporation of viral oncogene
into host DNA, where it is expressed as a
transforming factor.
• They cause tumours in animals within a
few weeks.

9. Slow transforming viruses
• Do not possess viral oncogenes
• Produce tumours by integrating the
provirus (the DNA copy of the viral RNA
genome) at critical sites in cell genome.

10. • Result is deregulation of a neighbouring
cellular oncogene.
• Integration of provirus into host DNA and
activation of cellular genes are termed
“insertional mutagenesis”

11. HTLV1
• Human T-cell leukemia virus-1 (HTLV-1) is
a retrovirus , causing cancer in humans.
• HTLV-1 is associated with T-cell
leukemia/lymphoma ,endemic in certain
parts of Japan and the Caribbean basin
• But found sporadically elsewhere..

12. • Similar to the human immunodeficiency
virus (HIV), HTLV-1 has tropism for CD4+
T cells, the major target for neoplastic
transformation.

13. • Human infection requires transmission of
infected T cells via ;
– Sexual intercourse
– Blood products
– Breast - feeding.
• Leukemia develops only in about 3% to
5% of infected individuals after a long
latent period of 20 to 50 years

14. • HTLV-1 infection of T lymphocytes is
necessary for leukemogenesis, but the
molecular mechanisms of transformation
not clear.!!!!
– It does not contain a viral oncogene
– No consistent integration site next to a
cellular oncogene has been discovered.

15. • The long latency period between
initial infection and development of
disease suggests a multistep
process, during which many
oncogenic mutations are
accumulated.

16. • The genome of HTLV-1 contains, in
addition to the usual retroviral genes, a
unique region called pX.
• This region encodes several genes,
including one called TAX.
• The TAX protein has been shown to be
necessary and sufficient for cellular
transformation.

17. • By interacting with several transcription
factors, such as NF-κB, the TAX protein
can transactivate the expression of genes
that encode :
– Cytokines
– Cytokine receptors
– Costimulatory molecules.

18. • This leads to
– Autocrine signaling loops
– Increased activation of pro-mitogenic
signaling cascades.

19. • Furthermore, TAX can drive progression
through the cell cycle by directly binding to
and activating cyclins.

20. • TAX can also repress the function of
several tumor suppressor genes that
control the cell cycle, including
CDKN2A/p16 and p53.

21. • The TAX gene therefore
– Turns on several cytokine genes and their
receptors (IL-2 and IL-2R, IL-15, and IL-15R)
– Thereby setting up an autocrine system that
drives T-cell proliferation.
• Of these cytokines, IL-15 seems to be
more important.

22. • Initially the T-cell proliferation is polyclonal
because the virus infects many cells.
• With TAX-based inactivation of tumor
suppressor genes , the proliferating T cells
are at increased risk of mutations, which
lead ultimately to the outgrowth of a
monoclonal neoplastic T-cell population

23. ONCOGENIC DNA VIRUSES
• As with RNA viruses, several oncogenic
DNA viruses that cause tumors in animals
have been identified.
• Four human oncogenic DNA viruses:
• Human papillomavirus (HPV)
• Hepatitis B virus (HBV)
• Epstein-Barr virus (EBV)
• Kaposi sarcoma herpesvirus (KSHV, also called
HHV8)

24. Human Papillomavirus
• Genetically distinct types of HPV have
been identified.
• Some types (e.g., 1, 2, 4, 6 and 7, 11)
cause benign squamous papillomas
(warts) in humans .

27. • High-risk HPVs (e.g., 16 and 18) have
been implicated in the genesis of several
cancers;
• Squamous cell carcinoma of the cervix
• Penile squamous cell carcinoma
• Anogenital squamous cell carcinomas.
• 20% of oropharyngeal cancers are
associated with HPV.
• Laryngeal cancer

29. Cancer of cervix

30. • In contrast to cervical cancers, genital
warts have low malignant potential and are
associated with low-risk HPVs
predominantly HPV-6 and HPV-11

31. • The oncogenic potential of HPV is related
to products of two early viral genes, E6
and E7.
• Together, they interact with a variety of
growth-regulating proteins encoded by
proto-oncogenes and tumor suppressor
genes.

32. • The E7 protein binds to the RB protein and
displaces the E2F transcription factors that
are normally sequestered by RB,
promoting progression through the cell
cycle.
• E7 protein from high-risk HPV types has a
higher affinity for RB than does E7 from
low-risk HPV types.

33. • E7 also inactivates the CDKIs-
CDKN1A/p21 and CDNK1B/p27.
• E7 proteins from high-risk HPV types
(types 16, 18, and 31) also bind and
activate cyclins E and A.

34. • The E6 protein has complementary
effects.
– It binds to and mediates the degradation of
p53 and BAX, a pro-apoptotic member of the
BCL2 family,
– It also activates telomerase.

35. • Integration interrupts the viral DNA,
resulting in overexpression of the
oncoproteins E6 and E7.
• Furthermore, cells in which the viral
genome has integrated show significantly
more genomic instability

36. Epstein-Barr Virus
• EBV, also called Human herpesvirus 4
(HHV-4), is a virus of the herpes family (
including Herpes simplex virus and
Cytomegalovirus)
• One of the most common viruses in
humans.

37. • Most people become infected with EBV,
–Often asymptomatic
–In others causes infectious
mononucleosis.
• It is named after Michael Epstein and
Yvonne Barr, who together with Bert
Achong discovered the virus in 1964.

38. • On infecting B-lymphocyte, the virus
genome becomes integrated and persists
within the cell as an episome.
• The virus can carry several distinct
programmes of virally-encoded gene
expression :
–lytic cycle or latent cycle.

39. The lytic cycle or productive infection
results in expression of viral proteins
with the ultimate objective of producing
infectious virions.
 This phase of infection does not
inevitably lead to lysis of the host cell
as EBV virions are produced by
budding from the infected cell.

40. • The latent cycle programmes are those
that do not result in production of virions.

41. • EBV has been implicated in the
pathogenesis of several human tumors:
• Burkitt lymphoma,
• B-cell lymphomas in patients with
– acquired immunodeficiency syndrome
– other causes of immunosuppression,
• A subset of Hodgkin lymphoma
• Nasopharyngeal carcinoma.

42. • Except for nasopharyngeal carcinoma, all
others are B-cell tumors.
• A subset of T-cell lymphomas and the rare
NK-cell lymphomas may also be related to
EBV

43.  Burkitt lymphoma is endemic in certain
parts of Africa and is sporadic elsewhere.
• In endemic areas, tumor cells in virtually
all patients carry the EBV genome.

45. • The molecular basis of B-cell proliferations
induced by EBV is complex.
– EBV uses the complement receptor, CD21, to
attach to and infect B cells.
– In vitro such infection leads to polyclonal B-
cell proliferation and generation of B-
lymphoblastoid cell lines.

46. • One of the EBV-encoded genes, called
LMP-1, acts as an oncogene.
• Its expression in transgenic mice induces
B-cell lymphomas.
• LMP-1 promotes B-cell proliferation by
activating signaling pathways, such as NF-
κB and JAK/STAT, which mimic B-cell
activation via the B-cell surface molecule
CD40.

47. • Likewise LMP-1 prevents apoptosis by
activating BCL2.
• Thus, the virus "borrows" a normal B-cell
activation pathway to promote its own
replication by expanding the pool of cells
susceptible to infection.

48. • Another EBV-encoded gene, EBNA-2,
transactivates several host genes,
including cyclin D and the src family
genes.

49. • EBV genome contains also a viral
cytokine, vIL-10, that was pirated from the
host genome.
• This viral cytokine can prevent
macrophages and monocytes from
activating T cells , favouring EBV-
dependent transformation of B cells

50. • In immunologically normal individuals,
EBV-driven polyclonal B-cell proliferation
in vivo is readily controlled.
• The individual either remains
asymptomatic or develops a self-limited
episode of infectious mononucleosis.

51. • Therefore , evasion of the immune system
seems to be a key step in EBV-related
oncogenesis.
• In regions of the world where Burkitt
lymphoma is endemic;
– concomitant (endemic) malaria (or other
infections) impair immune competence,
allowing sustained B-cell proliferation.

52. Although LMP-1 is the primary
transforming oncogene in the EBV
genome, it is not expressed in EBV-
derived Burkitt lymphoma.
Reason - it is also one of the major viral
antigens recognized by the immune
system

53. Presumably, infected cells expressing viral
antigens such as LMP-1 are kept in check
by the immune system.
Lymphoma cells emerge only when
additional mutations, such as the t(8;14)
translocation, a consistent feature of this
tumor, activate the MYC oncogene.

54. • Alternatively MYC activation may
substitute for LMP-1 signaling, allowing
the tumor cells to down-regulate LMP-1
and evade the immune system.

55. • In non-endemic areas,
– 90% of tumors do not harbor the EBV
genome.
– But all tumors possess the specific t(8 ; 14)
translocation.

56. • This observation suggests that, although
non-endemic Burkitt lymphomas are
triggered by mechanisms other than EBV,
they develop cancer by similar pathways

57.  Nasopharyngeal carcinoma is endemic
in southern China and some other locales,
and the EBV genome is found in all
tumors.
• LMP-1 is expressed in epithelial cells as
well.
• In these cells, as in B cells, LMP-1
activates the NF-κB pathway.,

58. • Furthermore, LMP-1 induces the
expression of pro-angiogenic factors such
as VEGF, FGF-2, MMP-9, and COX2,
which may contribute to oncogenesis.
• As in Burkitt lymphoma, EBV acts in
concert with other, unidentified factors

60. Hepatitis B and C viruses
• The epidemiologic evidence linking
chronic HBV and hepatitis C virus (HCV)
infection with hepatocellular carcinoma is
strong .
• It is estimated that 70% to 85% of
hepatocellular carcinomas worldwide are
due to infection with HBV or HCV.

61. • However, the mode of action of these
viruses in tumorigenesis is not fully
elucidated.
– HBV and HCV genomes do not encode any
viral oncoproteins.
– Though the HBV DNA is integrated within the
human genome, there is no consistent pattern
of integration in liver cells.

62. • Indeed, the oncogenic effects of HBV and
HCV are multifactorial.
• The dominant effect seems to be
immunologically mediated chronic
inflammation with hepatocyte death
leading to regeneration, and genomic
damage.

63. Chronic viral infection leads to
compensatory proliferation of hepatocytes.
This regenerative process is aided and
abetted by a plethora of;
Growth factors
Cytokines
Chemokines
“All promoting survival, tissue
remodeling, and angiogenesis”.

64. The activated immune cells also produce
other mediators, such as reactive oxygen
species, that are genotoxic and
mutagenic.

65. Possible outcomes.
• Activation of the NF-κB pathway in
hepatocytes caused by mediators derived
from the activated immune cells.
• Activation of the NF-κB blocks apoptosis,
allowing the dividing hepatocytes to incur
genotoxic stress and to accumulate
mutations

66. • Furthermore, both HBV and HCV also
contain proteins within their genomes that
may more directly promote the
development of cancer.
– HBV genome contains a gene known as HBx,
– Mice transgenic for this gene develop
hepatocellular cancers.
– HBx can directly or indirectly activate a variety
of transcription factors and several signal
transduction pathways.

68. Kaposi's sarcoma
• A form of skin cancer that can involve
internal organs.
• It is most often found in patients with
acquired immunodeficiency syndrome
(AIDS), and can be fatal.

69. • Kaposi's sarcoma (KS) was a very rare
form of cancer, primarily affecting elderly
men of Mediterranean and eastern
European background.
• It also existed as endemic disease in
Tropical regions
• Until the 1980s, it began to appear among
AIDS patients.

70. Kaposi Sarcoma and HHV8
• Studies in 2000 showed that HHV-8 was the
culprit behind.
• Mechanism
– Patient's altered response to cytokines
– HIV-1 transactivates Tat protein, promoting the
growth of endothelial cells.
– HHV-8 can then encode IL 6 viral proteins,
specific cytokines that stimulate cell growth in the
skin.
• This becomes KS.

72. Oral KS

73. Skin lesions

76. OTHER BIOLOGICAL CARCINOGENIC
AGENTS
Parasites.
• Schistosoma haematobium infection of the
urinary bladder - squamous cell carcinoma
of the urinary bladder.
• Clonorchis sinensis, the liver fluke, lives in
the hepatic duct and is implicated in
causation of cholangiocarcinoma.

77. • Fungus, Aspergillus flavus grows in stored
grains and liberates aflatoxin B1 ; -
hepatocellular carcinoma
• Bacteria- Helicobacter pylori, MALT gastric
lymphoma and gastric carcinoma,

78. Helicobacter pylori
• First incriminated as a cause of peptic
ulcers, H. pylori now has been the first
bacterium classified as a carcinogen.
• H. pylori infection is implicated in the
genesis of both gastric adenocarcinomas
and gastric lymphomas.

79. Pathogenesis
• Similar to that of HBV- and HCV-induced
liver cancer
• It involves increased epithelial cell
proliferation in a background of
chronic inflammation

80. • H. pylori genome also contains genes
directly implicated in oncogenesis.
• Strains associated with gastric
adenocarcinoma have been shown to
contain a cytotoxin-associated A (CagA)
gene.

81. • The gastric lymphomas associated with H.
pylori are of B-cell origin, called MALT
lymphomas (mucosl associated
associated lymphoid tumours).

82. • The molecular pathogenesis is
incompletely understood
– Strain-specific H. pylori factors !!
– Host factors in expression of inflammatory
cytokines such as IL-1β and tumor necrosis
factor (TNF).!!