Lecture 3 virology Carcinogenesis - PowerPoint Presentation

Slide1

Lecture 3 virology

Carcinogenesis

Slide2

Carcinogenesis

Carcinogenesis or

Oncogenesis

=

creation of cancer= normal cells are transformed into cancer cells= characterized by

a progression of changes on cellular and genetic level

that ultimately reprogram a cell to undergo uncontrolled cell division, thus forming a malignant mass.

Many causes of cancer:

*There are

about 200 different types of cancer.

They can start in any type of body tissue.

What affects one body tissue may not affect another.

For example, tobacco smoke that you breathe in may help to cause lung cancer. Overexposing your skin to the sun could cause a melanoma on your leg. But the sun won't give you lung cancer and smoking won't give you melanoma.

**Apart from infectious diseases,

most illnesses are '

multifactorial

'. Cancer is no exception. In other words, there is no single cause for any one type of cancer.

Slide3

Causes of Cancers

There are many

different kinds of cancers

.

Cancer can develop in almost

any organ or tissue

, such as the lung, colon, breast, skin, bones, or nerve tissue.

There are

many causes

of cancers, including:

1..Benzene

and other chemicals

2..

Certain

poisonous mushrooms

and a type of poison that can grow on

peanut plants

(

aflatoxins

)

3..

Certain

viruses

4..Radiation

5..Sunlight

6..Tobacco

However,

the cause of many cancers remains

unknown.

Slide4

@

In general, if we are exposed to chronic infection, injury, pollution, unhealthy food, water air, tobacco and drug abuse, etc… over many years,

our risk

of developing cancer

increases markedly.

@@

We are all actually

swimming in the sea of germs

all through our life::::::::::::::::::

Only few of us

get the disease,,,,,,,

while

others resist

the germs successfully.

Slide5

Multistep carcinogenesis

Multiple genetic changes

must occur to convert a normal cell into a malignant one .

Intermediate stages

= transformation / immortalization / Hyperplasia and preneoplasia .

Cancer =

multistep process of cellular evolution

, probably involving

repeated selection of rare cells

with

some selection of growth advantage .

Cancer development requires

several ‘assaults

’

on an individual cell; The number (range )of mutations underlying this

process=3-8 .

To transform into a cancer cell =a series of changes which

slowly release the cell from the multiple checks and balances which control its normal growth.===

involves

both genetic changes and environmental factors,,,,,,,

Explains why cancer may take many years to develop

after exposure to a single risk factor

Therefore generally

a disease of middle and old age.

Slide6

Multistep Carcinogenesis

Tumor viruses=

usually acts as a

cofactor

providing only some of the steps required to generate malignant cells .

Tumor viruses=

necessary but not sufficient

for tumor with viral etiology .

Tumor viruses=

initiators

of neoplastic process .

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HUMAN CANCER VIRUSES

Slide8

HUMAN CANCER VIRUSES

It is generally agreed that viruses are involved

in 10–20% of all cancers .

Viruses are etiologic factors in the development of several types of human tumors , including 2 of great significance world wide :-

1- Cervical cancer by human Papiloma virus .

2- Liver cancer by Hepatitis B & c virus .

A limited amount of genetic information ( one or a few viral genes ) of a tumor virus can profoundly alter the growth behavior of cell into a neoplastic one .

Slide9

e

Tumor viruses

NO characteristic

Size ,shape , chemical composition

Cause benign & malignant tumors

Many species & Families

Common Occurrence In Animal Tumors but only few viruses Associated with human tumors

More :-

1- Rapid ,2-Reliable ,3-Efficient (tumor producer )

4- Readily analyzed role of cancer

Most recognized tumor viruses have RNA genome from which a DNA provirus is formed after infection of cells

( HCV is an exception)

1

5

4

3

2

6

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DNA TUMOR viruses



(

encode viral

oncoproteins

)

1..Affect cellular growth control pathways

2… important for viral replication .

RNA Tumor viruses (( Retrovirus ))

carry reverse transcriptase

 DNA copy  integrate

1- Highly

oncogenic

( direct – transforming ) v.

= cellular

oncogenes

.

2- Weakly

oncogenic

( slowly – Transforming ) v. .

3- Indirect CANCER Inducers

= HC V .

** Mechanisms:

Some commonality among viruses that cause tumors= tumor viruses change cells by integrating their genetic material with the host cell's DNA. This is a permanent insertion in that the genetic material is never "removed."The

insertion mechanism can differ= depending on whether the genetic material in the virus is DNA or RNA.

Slide11

Linkages:

The link between viruses and cancer

was one of the pivotal discoveries in

cancer research

Family

Virus

Tumor / cancer

Papillomaviridae

Polyomaviridae

1- Human Papiloma viruses

Genital tumors

and sequamous carcinoma .

Oropharyngeal carcinoma .

2- Simian

virus .40

*Brain tumors

*Mesothelioma .

* Bone Tumors

.

Herpes viridae

1-EBV

Nasopharyngeal

carcinoma

* African Burkett's lymphoma .B- cell lymphoma . HepadnaviridaeHBV Hepatocelluar carcinomaFlaviviridae

HCV

Hepatocelluar carcinomaRetroviridaeHTCLAdult T-Cell leukemia Pox viridae

Molluscum contagiosum virus . * Small Benign growth ( proliferative disease in humans )

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Many people can be infected with a cancer- causing virus, and never get cancer.

The virus only causes cancer in certain situations. Many women get a

high risk HPV infection

, but never develop cervical cancer. Another example is Epstein-Barr virus (EBV). Most people are infected with

EBV,,,But

who catch it late in life get glandular fever and have an increased risk of lymphoma

Cancer is not an infectious disease like tuberculosis, typhoid, cholera, pneumonia, etc. It does not spread by contact.

It is not caused by any germs coming from outside.

Viruses can help to cause some cancers. But this does not mean that these cancers can be caught like an infection.

What happens is that the virus can cause

genetic changes

in cells that make them more likely to become cancerous.

Slide14

Transmission of Tumor viruses

1- Vertical Transmission :

1# virus genetic material in the

sprem

or the egg .

2# VIRUS PASSED ACROSS PLACENTA .

3# Virus transmitted in the breast milk .

Expression to virus early in life can result in tolerance to viral Ags

 I.R not eliminate the virus  large amount of virus produced  high frequency of cancer occurs .

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2..Horizontal Transmission

Probably does not occur in humans .

Evidence = close contacts with cancer patients do not have increased

freguncy

of cancer .

Rare Random Event

 if occur .

Slide16

DNA Tumor Viruses

Slide17

Polyomaviridae

Slide18

Polyomaviridae

Slide19

Genome

Genomes divided into two regions, early and late

Early proteins

LT, MT and

sT

antigens expressed

from differentially spliced mRNAs

Late,

capsid

proteins

VP1, VP2 and VP3 (viral

capsid

)

BKV and JCV : 75%

(nucleotide sequence Homology)

70% with SV40

Slide20

P

otentially

oncogenic

(tumor-causing)

P

ersist

as

latent infections

without causing disease

They may produce tumors in a host of a different species, or a host with an ineffective

immune system

The name

polyoma

refers to the viruses' ability to produce multiple (poly-) tumors (-

oma

)

Slide21

Polyoma

viruses,Host,Cell

receptor,Tissue

tropism,Disease

Disease

Tissue tropism

Cell receptor

Host

Abbreviation

viruse

Sarcoma in new born

hamsters

Brain tumors

Mesotheliomas

Bone tumor

lymphoma

Kidney cell

Gangliosides

Rhesus

Monkey

HumanSV40Simian virus40HemorrhagicCystitis*

Nephropathy**Kidney cellα(2,6)-linked

sialic acidHumanBKVBK virusProgressive multifocal leukencephalopathy***

Kidney cell

α(2,6)-linked sialic acidHumanJCVJC virus

Not knownNot known

Not knownHumanKIV

KI virusNot known

Not knownNot knownHuman

WUVWU virus Merkel carcinoma (skin

cancer)

Not

known

Not

known

Human

MCPyV

Merkel cell virus

*seen in bone marrow transplant recipients.

** seen in renal transplant recipients.

***Primarily seen in AIDS patients

Slide22

Pathogenesis

Immunocompromised

Slide23

PML

Fatal

demyelinating

disease of the white matter and involves multiple areas of the brain.

The clinical picture includes visual field defects, mental status changes and weakness.

The disease rapidly progresses to blindness, dementia and coma, and most patients die within 6 months.

Diagnosis:

CT or MRI

lumbar puncture for JCV

PCR

Treatment

:

Cidofovir

may be beneficial.

highly active antiretroviral therapy( HAART) in AIDS patients

Slide24

BK nephropathy:

no evidence that BKV causes

disease in the immune competent

population

possible route of infection through

contaminated food or water or

respiratory spread

remains

latent in lymphocytes,

urogenital

tract,

and brain but may

be reactivated if the host becomes

immunocompromised

.

especially associated with disease in renal transplant patients;

thought to cause graft failure in 2-5% of this population

treatment is to decrease

immunosuppression

as much as possible without causing rejection

Cidofovir

appears to reduce BKV-associated nephropathy

viral inclusions and cellular changes

in BK nephropathy are seen in tubular

epithelium of a renal transplant case

Slide25

Human

Papilloma

Virus (HPV)

Slide26

Human

Papilloma

Virus (HPV)

How common is human

papillomavirus

(HPV) infection?

HPV is the most common sexually transmitted infection in the United States. Currently, more than

20 million

men and women in the United States are infected with HPV, and more than

6 million

are estimated to become infected each year. HPV is most common in young women and men in their

late teens and early 20s. By age 50, at least 80 percent

of sexually active women will have acquired HPV infection.

Slide27

How serious is disease caused by HPV?

HPV infection can lead to

cervical cancer in women as well as to other cancers that can affect males or females.

Cervical cancer

is diagnosed in more than

9,700 women each year

in the United States each year and causes

3,700 deaths======

Seventy percent of cervical cancers are caused by strains of HPV included in the newly licensed HPV vaccine.

HPV also causes

Genital warts

in men and women.

Slide28

HPV-INDUCED CANCERS

Slide29

Papillomaviridae

Papilloma

virus

can infect broad spectrum of vertebrates ( human , animals ,rabbits …..etc ).

HPV had been implicated in the pathogenesis of

HUMAN

oral , laryngeal nasopharyngeal and cervical warty

carcinomatous

lesions .

HOST

Vertebrate

CELL TROPISM :

Epithelial cells of skin & mucous membranes

Slide30

VIRION

Non-enveloped. Small,

icosahedral

, about 52-55 nm in size. A single molecule of circular

dsDNA

is contained within the

capsid

, which is composed of 72

pentamers

arranged on a T = 7 lattice.

GENOME

Circular

dsDNA

, about 8 kb in size, associated with cellular

histones

in a chromatin-like complex

.

Slide31

REPLICATION:

NUCLEAR

Replication is divided in two distinct steps that are linked to the

differentiation state

of the host epithelial cell:

The

plasmid

replication

The vegetative replication

Slide32

A) The plasmid replication

takes

place

in the

basal

squamous

epithelial cells.

It corresponds to viral DNA replication in synchrony with the host cell chromosome in order to ensure an average of one viral genome per basal cell.

1..Virus attaches

to host receptors and is

endocytosed

into vesicles in the basal

squamous

epithelial cell.

2..Transport

to the nucleus and

uncoating

of the viral DNA.

3..

Early-region transcription and translation of the early proteins.

4..Steady-state viral DNA nuclear replication. Requires the viral E1 and E2 proteins .

Slide33

B) The vegetative replication

 

Which occurs in

differentiated

keratinocytes

.

In these cells, which no longer undergo cellular DNA synthesis, there is a burst of viral DNA synthesis with active production of

virions

.

1..Vegetative viral DNA synthesis.

2..Transcription of the late region.

3..Capsid proteins L1 and L2 synthesis.

4..Assembly of the

virion

particles.

5..Nuclear breakdown and release of viruses.

Slide34

Basic virology of human

papilloma

virus

A- HPV structure

Small ( 55-60 nm )

Icosahedral ( cubic ) symmetry .

Capsid = 72 capsomere

DNA genome .

Non enveloped – stable / infectious .

Resistant to :

Heat .

Organic solvents .

Therapeutic agents

.

E6 + E 7= (

Onco

-proteins )

Slide35

Carcinogenic potential OF DIFFERENT HPV types

High risk types

( 15 types ) : HPV 16 , 18 , 31 , 33 ,35 , 39 , 45 , 51 , 52 ,56 ,58 ,68,73 , 82 .

Probable ( Moderate )

risk types (3 types) : HPV 26 , 53 ,66.

Low risk types

(12 types ):HPV 6, 11 , 40 , 42 , 43 ,44 ,54 , 61,70, 72 ,81 .

Location of lesion:

Mucosal types

( > 40 types ) : Genital and non genital areas like airways , conjunctiva .

Cutaneous types

.

Slide36

Papiloma viral replication cycle

Papova viruses undergo 2 types of interactions with the host cells : -

1- Permissive cells

 viral replication  synthesis of progeny of virus  cell death

( lysis) .

2- Non permissive cells  no replication

( = chronic and latent infections ) transformation  integration of viral genes with host genomes  altered cellular phenotype  no virus progeny produced .

Slide37

Pathogenesis

HPV infections ===

1- As a rule : Latent and persistent

( without clinical manifestation )

2- As an exception :

clinically expressed disease

:

A- Most

HPV infections :

 minor manifestations  resolved quickly .

B- minority

 HPV persistence  either:

Condylomas ( Benin lesions ) warts .

Cancer –precursor lesions .

Invasive cancers

.

Slide38

Transmission of HPV

Transmitted environmentally or by casual skin to skin contact ,and there are separate group of about 30 HPV are typically transmitted through sexual contact

Slide39

Transmission of HPV

A) As a rule

 Mechanical trauma

through :

1-Sexual transmission :

> 20 million American are infected by this way .

2-Extra genital transmission:

oral ,

oropharyngeal

, conjunctiva , nose ,laryngeal and esophagus .

3-

Fomite

transmission:

sex toys , examination tools , towels, and underwear .

B)Vertical transmission

: mother to infants during child

birth:Best

example : juvenile

Rec-Resp

- papillomata RRP by HPV 6 and 11 .

Slide40

Prevention & Control

Slide41

Vaccination

To prevent HPV infection

Antibody to one of the HPV types cross reactive with other HPV types .

Well preserved L1 gene

 target of vaccination production strategies

.

Slide42

Vaccination

Well preserved L1 gene

 target of vaccination production strategies

.

A variety of HPV vaccines may provide immunity (neutralizing antibodies) to a combination of high-risk or high- and low-risk HPV types’

In 2006, the FDA licensed a

quadrivalent

, prophylactic HPV vaccine

which is designed to reduce the incidence of cervical cancer caused by HPV 16 and 18 and vulvar

condylomas

by HPV6 and

11.

It offers protection for up to 5 years

after vaccination; However it does

not eliminate the risk of cervical cancer

due to presence of other oncogenic HPV types.

Slide43

Two HPV vaccines:

Cervarix

(GSK) and Gardasil (Merck):

Cervarix

is an inactivated

bivalent

vaccine that protects against HPV types 16 and 18.

Gardasil

is an inactivated

quadrivalent

vaccine that protects against HPV types 16 and 18, and also against types 6 and 11, which are human papillomaviruses that cause genital warts.

Slide44

`

Epstein Barr Virus (EBV)

Slide45

EBV is associated

with:

1-Burrkits

lymphoma:

cancer

of

th

lymphatic

system

(in particular,

B

lymphocytes

).

2-nasopharyngeal carcinoma.

3-B-cell lymphomas

.

4-

 Hodgkin's lymphoma

Slide46

Seven-year-old Nigerian boy with a several month history of jaw swellnig which had been treated with antibiotics. The tumor was ulcerated and draining.

Picture of a mouth of a patient with Burkitt's lymphoma showing disruption of teeth

Slide47

Cytomegalovirus (CMV)

Slide48

Mechanism

of

Cell transformation

Human CMV induced

oncomodulation

may result from the activity of virus

regulatory proteins

and

noncoding RNA

, which influence properties of tumor cells including cell proliferation, survival, invasion, production of

angiogenic

factors, and immunogenicity.

As

a result, HCMV infection may lead to a shift to a more malignant phenotype of tumor cells and tumor progression

Slide49

HCMV gene products have been reported to be involved

in:

cell

cycle dysfunction,

genome

instability,

cell

immortalization,

inhibition

of important cellular players involved in apoptosis and immune invasion 

Slide50

Other gene products with oncogenic potential are

immediate early (IE) 1 and IE2

.

The

unconventional “hit and run” mechanism has been proposed to explain the transformation by

IE1/IE2.

Slide51

HEPATITIS B VIRUS

Hepatitis B virus a member of the

Hepadnaviridae

family.

42-nm spherical

virions

with

circular genome of double-stranded DNA (3.2

kbp

). One strand of the DNA is incomplete and variable in length.

Slide52

Hepatitis B Virus

DNA genome

RNA polymerase II

RNA Provirus

Reverse transcriptase

DNA genome

Host enzyme

Viral enzyme

Strong correlation between HBV and

hepatocellular

carcinoma

Slide53

In addition to causing hepatitis, hepatitis B virus is a risk factor in the development of

liver cancer

in humans.

Studies have proved

persistent infection

with hepatitis B virus to be an important cause of chronic liver disease and the development of

hepatocellular

carcinoma.

The hepatitis B virus

transactivator

protein,

X protein

, is a potential viral

oncoprotein

which interferes with p53 (tumor suppressor gene).

.

A dietary carcinogen,

aflatoxin

, may be a cofactor for

hepatocellular

carcinoma, especially in Africa and China.

Slide54

The advent of an effective

hepatitis B vaccine

for the prevention of primary infection raises the possibility of prevention of

hepatocellular

carcinoma.

Slide55

RNA Tumor Viruses

Include:

1.Retroviruses.

2.HCV.

Slide56

Slide57

RNA Genome - Retroviruses

RNA genome

Reverse transcriptase

DNA genome

(provirus)

Integrase

Integrates

Host RNA polymerase II

RNA genome

unusual mode of replication which gives them the potential to transform the cell

Slide58

Replication

Slide59

Genome structure

The gene order in all retroviruses is 5'-

gag-pro-pol-env-3'.

gag

, which

encodes the core proteins (group-specific antigens);

pro

, which encodes a protease enzyme;

pol

, which encodes the reverse

transcriptase enzyme (polymerase);

and

env

, which encodes the

glycoproteins

that form projections on the envelope of the

particle.

HTLV contains regulatory genes (tax

and rex) and accessory genes (p12, p13, p30 and HBZ), in addition to structural genes (

gag, pol and env).

Slide60

Human T-cell lymphoma virus

1979 –

HTLV-1

1981 –

HTLV-2

1983 –

HTLV-3:

this virus was classified in the HTLV genus; However, upon further research, it was reclassified into the

Lentivirus

genus and given the name

human immunodeficiency virus

(HIV).

2005 –

HTLV-4

Slide61

HTLV-1

adult T-cell lymphoma virus type 1

has been implicated in several kinds of diseases including

1- very aggressive

Cutaneous

adult T-cell lymphoma

(ATL),

2- Tropical Spastic

paraparesis

.

1–5%

of infected persons are thought to develop cancer.

HTLV-1 predominately infects

CD4+ T cells

 malignant transformation .

Seven

HTLV-1 genotypes are

recognised

.

RT-PCR not serologically distinguish them.

Slide62

Human T-

lymphotropic

virus 2 (HTLV-II)

HTLV-II

shares approximately 60% genomic homology with

HTLV-I

.

classified into

4

molecular subtypes.

several cases of

myelopathy

/tropical spastic

paraparesis

hairy cell leukemia

.

Slide63

Transmission

Slide64

Malignancies

Adult T cell leukemia/lymphoma:

group of

lymphoproliferative

disorders characterized by localization of

neoplastic

T lymphocytes to the skin.

In ATL, the main pathogenic protein

, Tax,

leads to

leukogenesis

and immortalization of T lymphocytes. This is achieved by stimulation of interleukin-15

(IL-15)

and interleukin-2

(IL-2),

in turn leading to T-cell growth and transformation.

Cutaneous

T-cell lymphoma.

Slide65

Diagnosis

Slide66

Slide67

Hepatitis C virus

member of the

Flaviviridae

family.

genome of single-stranded RNA 9.4 kb in size.

1–5% of infected individuals with HCV leads to

hepatocellular

carcinoma, which is the fifth most common cause of cancer worldwide.

Chronic infection

with hepatitis C virus with persistent degeneration and regeneration of cells is considered to be a causative factor in

hepatocellular

carcinoma.

HCV core protein interferes with p53 (tumor suppressor gene).