Basis of viral oncogenesis and the most common viruses causing cancer and their mechanism of causing cancer. Helpful for undergraduate and postgraduate teaching.
Call Girl Bangalore Nandini 7001305949 Independent Escort Service Bangalore
Oncogenic viruses
1.
2. Virus family Human cancer
Papovaviridae
Human papilloma virus • Cervical ca
• Other genital tract ca
• Esophageal ca
• Laryngeal ca
• Oropharyngeal ca
Merkel cell virus Merkel cell ca of skin
Herpesviridae
Epstein Barr virus • Burkitt’s lymphoma
• Hodgkins’s disease
• Nasopharyngeal ca
Human Herpesvirus -8 • Kaposi’s sarcoma
• Primary effusion lymphoma
Hepadnaviride
Hepatitis B virus Hepatocellular carcinoma
Retroviridae
HTLV -1 Adult T-cell leukemia/lymphoma
HIV AIDS related malignancies
Flaviviridae
Hepatitis C Hepatocellular carcinoma
DNAVirusesRNAViruses
3. Basic concepts
• Proto-oncogenes –
• Oncogenes –
• Tumour suppressor genes – supress any abnormal proliferation of cells(eg. p53, Retinoblastoma)
• Apoptosis regulatory genes – eg. bcl-2 (anti-apoptotic) and bax (pro-apoptotic genes)
• DNA repair genes
• Normal cellular genes whose products promote cell proliferation.
• Over-activation can lead to transformation of host cells
• Mutant or overexpressed versions of proto-oncogenes that function autonomously
without a requirement for normal growth-promoting signals
• When present in viral genome they are designated as V-onc
• Oncoproteins cause continuous stimulation of nuclear transcription factors that
cause increased expression of growth-promoting genes.
4. • Cell cycle is controlled by checkpoints at
different stages
• Any stress or damaged DNA is detected
at any checkpoint results in increased
protein p53 production.
• p53 is a tumour suppressor gene that
stops the progression of the cell cycle
(G1 arrest) and starts repair
mechanisms for the damaged DNA by inducing the expression of DNA repair genes
• If this DNA cannot be repaired, then it ensures the cell undergoes apoptosis and can
no longer replicate.
• The p53-encoding tumor suppressor gene is the most commonly mutated gene in
human cancer.
5. • Cell cycle is also closely regulated by Cyclins
which by activating cyclin-dependent kinase (CDK)
enzymes control cell progression
• Rb restricts the ability of a cell to progress from G1
to S phase in the cell cycle. CDK phosphorylates
Rb to pRb, making it unable to restrict cell
proliferation. This allows cells to divide normally in
the cell cycle.
• p16-INK4A a cell-cycle regulatory protein that
interacts with CDK4 and CDK6, inhibiting their
ability to interact with cyclins D.
6. Telomere and Telomerase
• Eukaryotic telomeres are usually identified as the
“capping function”
• They protect chromosome ends from DNA degradation
and fusion with other chromosomal ends
• Their length serves as an intrinsic biological clock that regulates the life span of the cell, i.e.
they provide limits on the number of replications a cell can go through.
• Telomere repeats are lost with each round of cell replication.
• Enzyme “Telomerase” causes elongation of telomeres, but not completely
• It is a ribonucleoprotein with reverse transcriptase activity, is composed of two main parts –
a telomere RNA component and a telomere reverse transcriptase
• Most somatic cells express insufficient telomerase, reactivation in malignant conditions
7. • Selective tropism for epithelium of skin (squamous epithelium) and mucus membrane
• Benign warts to malignant condition
• Non-enveloped, Icosahedral symmetry, ds-circular DNA
Papillomavirus
• Viral genome
• Early region (E1 –E7) Non-structural proteins
• E6 protein degrades p53 gene product
• E7 protein binds to RB gene product
• Late region (L1, L2) structural proteins
• L1 – Major capsid proteins
• L2 – Minor capsid proteins
8. Human papillomaviruses • Cervical carcinoma
• Other genital tract carcinoma
-- Anal, Vulval/Vaginal, Penile
• Esophageal carcinoma
• Laryngeal carcinoma
• Oropharyngeal carcinoma
• Types 1, 2, 4, and 7 cause benign squamous papillomas (warts) in humans
• Genital warts → low malignant potential and are a/w low-risk HPVs (HPV type-6 & -11).
• Squamous cell carcinoma of the cervix and anogenital region are a/w high-risk HPVs
(types-16 & -18)
9. E6
E7
p53 Bax
p21
Apoptosis
RB-E2F
CyclinD/
CDK4
Growth
arrest
Increased
telomerase
activity
• E6 enhances p53 degradation
• E6 also stimulates the expression of
TERT, the catalytic subunit of
telomerase
• E6 from high-risk HPV types has a
higher affinity for p53
• p21 tumour suppressor gene stop
signal for mitosis in mutated cell
• E7 inhibits the tumor suppression gene
– RB gene (retinoblastoma gene)
• Displaces the E2F transcription factor
that are normally sequestered by RB
10. • In benign warts, the HPV genome is maintained in a non-integrated
episomal form
• In cancers, the HPV genome is randomly integrated into the host genome,
which interrupts a negative regulatory region in the viral DNA, resulting in
overexpression of the E6 and E7 oncoproteins.
• Cells in which the viral genome has integrated show significantly more
genomic instability → pro-oncogenic mutations in host genome.
11. Vaccines
Sub-unit vaccine composed of HPV L1 proteins (viral capsid)
produced in vectors by DNA recombinant technology
• Cervarix – L1 proteins of HPV 16, 18 expressed in Baculovirus.
Schedule – 0, 2 and 6 months
• Gardasil – L1 proteins of HPV 6, 11, 16, 18 expressed in Saccharomyces cerevisiae.
Schedule – 0, 1 and 6 months
• 9–26 yrs of females and males recommended in US
• Gardasil 9 (2014) – against HPV 6, 11, 16, 18, 31, 33, 45, 52, 58.
12. • Non-enveloped ds-DNA virus causing subclinical infection in childhood
• JCV infects 40% to 86% of the general population worldwide.
• BK virus has more prevalence than JC virus and affects children <10yrs of age
• Possible route of transmission – respiratory route
• 5HT2A receptor (glial cells, astrocytes, B lymphocytes, platelets & kidney epithelial cells)
• Viral genome gets integrated to host genome and persists for life (kidney, BM & brain).
• JCV is detected in urine of one third of healthy individuals.
Polyomavirus
13. • Reactivation occurs during pregnancy – asymptomatic
shedding
• Severe immunosuppression – AIDS, Organ transplant
recipients, advanced lymphoid malignancy
demonstrable shedding in urine
• Reactivation leads to lytic productive infection of
oligodendrocytes and astrocytes leading to multiple foci
of demyelination in brain
• JC virus – Progressive Multifocal Leukoencephalopathy
• BK virus causes
Haemorrhagic cystitis in BM transplant patients
Polyoma associated nephropathy in renal transplant
recipients
Atypical
astrocytes
Intra-
nuclear
inclusion
bodies
14. • Enveloped ds-DNA virus with icosahedral
symmetry
• In the oropharynx, EBV infects epithelial cells,
where it actively replicates and cause lysis,
infected epithelial cells infect B cells.
Epstein barr virus
• It binds to CR2 or CD21 (of B cells) through gp360 on its surface
• Small number of memory B cells retain the virus in form of episome and become
latently infected (1 to 50 B cells per million)
15. • EBV nuclear antigen (EBNA) 1 protein
binds to viral DNA at oriP site and
allows the EBV genome to be
maintained in the B cell through
generations, also it blocks its own
degradation by proteasomes
• EBNA-2 up-regulates the expression
of EBV latent membrane protein
(LMP) 1 and LMP-2
• LMP-2 prevents reactivation of EBV
from latently infected cells
16. LMP-1
Acts as an
oncogene
On surface of
infected cells
as CD 40-R
Activation of
NF-ĸβ & JAK-
STAT pathway
Upregulates
Bcl-2
Pro-
angiogenic
factors like
VEGF
Survival &
Proliferation of
B-cells
Anti-apoptotic
Neo-
vascularization
B-cell growth
18. • 70% to 85% of hepatocellular carcinomas (HCC) worldwide are caused by HBV or HCV.
• Do not encode any viral oncoproteins.
• HBV DNA randomly integrates with the host genome, HCV RNA remains unintegrated
• HCC has multifactorial causation but dominant effect seems to be immunologically
mediated chronic inflammation with hepatocyte death followed by compensatory
regenerative process
• In regenerative process a plethora of growth factors, cytokines, chemokines etc are
produced by activated immune cells that promote cell survival, tissue remodeling, and
angiogenesis.
• The activated immune cells also produce reactive oxygen species → mutagenic.
Hepatitis B & C viruses
19. • Mediators also cause activation of the nuclear factor-
κB (NF-κB) pathway in hepatocytes
• The HBx gene in HBV genome hepatocellular has
been shown to cause HCC in mice.
• HBx can directly or indirectly activate a variety of
transcription factors and several signal transduction
pathways
• May interfere with p53 function
• In addition, viral integration can cause secondary rearrangements of chromosomes,
including multiple deletions → loss of unknown tumor suppressor genes.
20. • Human T-cell leukemia virus type 1 (HTLV-1), is firmly implicated in the
pathogenesis of adult T-cell leukemia/lymphoma (ATLL)
• Retrovirideae – enveloped, spherical virus with 2 identical copies of ss-RNA
• MOT – Sexual intercourse, blood products.
• Leukemia develops in 3% to 5% of the infected individuals, after a long
latent period of 40 to 60 years.
• Preferentially affects the CD4+ TH cells
HTLV-1
21. • Integration in host chromosomes is random (the viral DNA is found at
different locations in different cancers), the site of integration is identical
within all cells of a given cancer.
• Transcription activator (tax) gene essential for viral replication
• tax gene product modulates host cell function
• Affected cells express large quantity of IL2-receptors
LTR LTRgag pol env tax
22. Tax
protein
Inactivates cell cycle inhibitors
p16/INK4a
Activates cell cycle
enhancer -CyclinD
Activates NF-ĸβ, transcription factor
regulating anti-apoptotic genes
Interferes with DNA
repair pathway