Cancer Cancer is one of the most common diseases in the
developed world: 1 in 4 deaths are due to cancer 1 in 17 deaths are
due to lung cancer Lung cancer is the most common cancer in men
Breast cancer is the most common cancer in women There are over 100
different forms of cancer
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Cancer The division of normal cells is precisely controlled.
New cells are only formed for growth or to replace dead ones.
Cancerous cells divide repeatedly out of control even though they
are not needed, they crowd out other normal cells and function
abnormally. They can also destroy the correct functioning of major
organs.
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What causes cancer? Cancer arises from the mutation of a normal
gene. Mutated genes that cause cancer are called oncogenes. It is
thought that several mutations need to occur to give rise to cancer
Cells that are old or not functioning properly normally self
destruct and are replaced by new cells. However, cancerous cells do
not self destruct and continue to divide rapidly producing millions
of new cancerous cells.
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A factor which brings about a mutation is called a mutagen. A
mutagen is mutagenic. Any agent that causes cancer is called a
carcinogen and is described as carcinogenic. So some mutagens are
carcinogenic.
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Carcinogens Ionising radiation X Rays, UV light Chemicals tar
from cigarettes Virus infection papilloma virus can be responsible
for cervical cancer. Hereditary predisposition Some families are
more susceptible to getting certain cancers. Remember you cant
inherit cancer its just that you maybe more susceptible to getting
it.
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7 Viruses cause cancer Why has the study of viruses and cancer
been important?
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8 Viruses cause cancer Why has the study of viruses and cancer
been important? - We learn about the basic mechanisms of specific
types of tumors.
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9 Viruses cause cancer Why has the study of viruses and cancer
been important? - We learn about the basic mechanisms of specific
types of tumors. - We identify fundamental pathways important for
oncogenesis - viruses are lower complexity - We can identify
potential unique therapeutic targets for viral associated
tumors
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10 Viruses cause cancer 30-40% of cancers are known to have
viral etiology -But as more research is done, this percentage is
likely to be found to be higher
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11 Major human Oncogenic Viruses DNA Viruses Small DNA tumor
viruses - Adenovirus - SV40 - Human Papilloma virus (HPV)
Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposis Sarcoma
Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human
T-cell Leukemia Virus 1 (HTLV1) Hepatitis virus C
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12 Changes in cell that are at the roots of cancer
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13 Changes in cell that are at the roots of cancer Genetic and
epigenetic alterations:
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14 Changes in cell that are at the roots of cancer Genetic and
epigenetic alterations: Mutations Deletions Recombinations
Transpositions Epigenetic alterations (DNA methylation, imprinting)
Acquisition of viral genetic material
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15 Changes in cell that are at the roots of cancer Genetic and
epigenetic alterations: Mutations Deletions Recombinations
Transpositions Epigenetic alterations (DNA methylation, imprinting)
Acquisition of viral genetic material Various combinations of these
lead to the development of cancers - some viruses contribute single
hits while others contribute multiple hits.
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16 Inherited Somatic - Random - Transposition - Exposure to
deleterious environmental agents - Radiation - carcinogenic
chemicals - Viruses - Other persistent infections Source of genetic
alterations
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Viruses and Cancer 17
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21 Integrations that cause activation or inactivation of
oncogenes or tumor suppressors (e.g. RNA viruses) Expression of
genes that alter key signal transduction pathways - this is our
focus Chronic activation of inflammatory responses How do Viruses
contribute to cancer?
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22 Why do viruses cause cancer?
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23 Viruses and cancer cells have similar needs Proliferation
control Cell death control Modulation of immune response Induction
of vascularization Metastasis (tumor)/cell migration (viruses) Why
do viruses cause cancer?
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24 If youre infected, does this mean that you will get
cancer?
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25 No Viruses did not specifically evolve with the need to
cause cancer - they simply have similar (but distinct) needs If
youre infected, does this mean that you will get cancer?
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26 No Viruses did not specifically evolve with the need to
cause cancer - they simply have similar (but distinct) needs
Development of tumors almost always requires: Additional genetic
alterations and/or Compromised host (e.g. immuno-suppression) If
youre infected, does this mean that you will get cancer?
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27 Major human Oncogenic Viruses DNA Viruses Small DNA tumor
viruses - Adenovirus - SV40 - Human Papilloma virus (HPV)
Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposis Sarcoma
Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human
T-cell Leukemia Virus 1 (HTLV1) Hepatitis virus C
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28 Adenovirus Human virus but only causes cancer in non-human
cells SV40 Mesothelioma HPV Cervical Cancer Squamous cell anal
carcinoma Penile cancer Oral cancers Small DNA tumor viruses
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29 HPV SV40 Adenovirus Normally replicate episomally but almost
always found integrated in associated tumors - why? Small DNA tumor
viruses
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30 HPV SV40 Adenovirus Normally replicate episomally but almost
always found integrated in associated tumors - why? Replication
must be abortive HPV, viral encoded negative regulatory factor must
be deleted Small DNA tumor viruses
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31 DNA Tumor Viruses In Human Cancer Papilloma Viruses
urogenital cancer wart malignant squamous cell carcinoma Papilloma
viruses are found in 91% of women with cervical cancer 10% of human
cancers may be HPV-linked 16% of all female cancers linked to
HPV
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32 DNA Tumor Viruses In Human Cancer Papilloma Viruses >100
types identified - most common are types 6 and 11 Most cervical,
vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70%
of penile cancers) Effective Vaccine (quadrivalent recombinant HPV
6, 11, 16 and 18 proteins made in yeast - Gardasil)
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33 Papilloma Viruses The important transforming genes in
papilloma viruses are the non-structural regulatory genes, E6 and
E7 HPV is normally episomal but is always integrated in tumors
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35 Adenoviruses Highly oncogenic in animals Only part of virus
integrated Always the same part Early (regulatory) genes E1A and
E1B = Oncogenes
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36 SV40 The important transforming gene is T Ag - provides
similar functions as E1A + E1B (Adenovirus) and E6 and E7
(HPV)
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37 Abortive replication is key to oncogenesis by these small
viruses Expression of early (regulatory) genes in absence of
structural genes and virus production Can occur by infection of
non-permissive host Can occur by integrations that delete regions
of viral genome required for replication but leave early genes
intact.
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38 Small DNA Tumor Viruses What are the needs of small DNA
tumor viruses that make them oncogenic and What are the key
mechanisms through which they attain their needs?
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39 Small DNA Tumor Viruses DNA viral genome Host RNA polymerase
Viral mRNA Viral protein Utilizes Host Cell DNA Replication
Machinery Need cells that are in S- phase to replicate viral genome
Host enzymes
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42 Inappropriate activation of cell cycle
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43 Inappropriate activation of cell cycle Apoptosis
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44 Inappropriate activation of cell cycle Apoptosis e.g.
-Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis -
Defense mechanism against rogue proliferating cells?
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45 Inappropriate activation of cell cycle Apoptosis e.g. -
Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis -
Same is true for over-expression of Adenovirus E1A or HPV E7
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46 Encode early genes that inhibit apoptosis Adenovirus E1B HPV
E6 SV40 T Ag
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47 SV40 and HPV
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48 Adenovirus E1B is Bcl2 family member - blocks function of
pro- apoptotic Bcl2 family members through dimerization
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49 Summary Small DNA tumor viruses usually replicate in
episomal form but are found integrated in viral associated tumors
Early genes promote cell cycle progression and prevent apoptosis
Adenovirus - E1A (cell cycle) and E1B (apoptosis) HPV - E7 (cell
cycle) and E6 (apoptosis) SV40 - T Ag (cell cycle and
apoptosis)
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50 Herpes viruses Oncogenic members: Epstein Barr virus (EBV)
Kaposis Sarcoma Herpes virus (KSHV) Oncogenic mechanisms are
distinct from small DNA tumor viruses - Dont need to integrate -
Cell cycle is not driven by lytic replication regulatory genes
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51 Herpes viruses Hallmark of herpesviruses:
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52 Herpes viruses Hallmark of herpesviruses: Existence of
latent stage (in addition to lytic/replicative stage)
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53 Herpes viruses Lytic replication phase for
herpesviruses:
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54 Herpes viruses Lytic replication phase for herpesviruses: -
Herpesviruses are large and encode 80-100 lytic associated genes -
Encode their own DNA polymerase and replication accessory enzymes -
Therefore, they dont require an S-phase environment for replication
- Encode early genes that induce cell cycle arrest
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55 Herpes viruses Latency: - Small subset of viral genes are
expressed that are not expressed during lytic replication. -
Latency is partly a way for virus to hide from immune system - In
cases of EBV and KSHV, latency genes can also induce cell
differentiation/activation programs that facilitate expansion of
infected cell population and induce trafficking to specific
lymphoid compartments that are suited to the life cycle of the
virus
57 Epstein Barr virus Pathologies in immuno-competent
individuals Infectious mononucleosis Burkitts Lymphoma Hodgkins
lymphoma Nasopharyngeal carcinoma Pathologies in immuno-compromised
individuals Post-transplant lymphoproliferative diseases (PTLD)
Hodgkins lymphoma A variety of non-Hodgkins lymphoblastoid
malignancies
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58 Epstein Barr virus Latency genes Non-antigenic - EBNA1
(Epstein Barr Nuclear Antigen 1) - episomal replication and
segregation function Antigenic - EBNA2 - EBNA3A, 3B, 3C - EBNA-LP -
LMP1 (Latent Membrane Protein 1) - LMP2A Those in Red are key
regulatory genes involved in B cell activation
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60 Epstein Barr virus 4 different types of latency True Latency
- no viral gene expression EBNA1 only - EBNA1 (non-antigenic)
Default - EBNA1, LMP1, and LMP2 (moderately antigenic) Growth -
EBNA1, LMP1, LMP2, EBNA2, EBNA- LP, EBNA3A, 3B, 3C (highly
antigenic) Growth program -Initial infection (prior to immune
response) - Immuno-compromised individuals - in vitro infection of
nave peripheral blood lymhocytes
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63 Epstein Barr virus Greater than 90% of US population are
carriers of EBV -Only small percentage of carriers develop tumors -
who? - Immuno-compromised - allows full set of oncongenic genes to
be expressed - Immuno-competent who have multiple additional
genetic hits EBV does not integrate - exists as an extrachromosomal
episome
65 Hepatitis B and C Long latency period to development of HCC
(Hepatocellular Carcinoma) 20-30 years Mechanism is probably due to
chronic inflammatory response
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66 Silver lining to viral associate cancers Offer unique
targets not common to normal uninfected cells Examples: HPV -
Gardasil EBV - In vitro production of EBV specific CTLs for PTLD -
Treatment with agents that induce lytic cycle (butyrate plus
Gancyclovir) KSHV - Anti-retroviral therapy