Neoplasia LEC 3 DR.Eaman suud - PowerPoint Presentation

Slide1

Neoplasia

LEC 3

DR.Eaman suud

khalifa

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Etiology of cancer

Many factors may play a role in etiology of cancer:

 

I. Geographical & environmental factors:

These factors

form about 65% of all cancer etiology, while genetic factor form about 26%- 42% of cancer etiology

.

There is

geographical difference in the death from specific forms of cancer,

e.g. death from carcinoma of breast is about 4 - 5 times higher in U.S.A than Japan.

e.g. death from carcinoma of stomach in man & women is about 7 times higher in Japan than in U.S.A.

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All these geographical differences are due to environmental rather than genetic causes.

These

environmental factors

can present in workplace (occupational factors), in the

food,………etc.

Examples on occupation factors & associated cancer are:

Arsenic …………… Carcinoma of lung, carcinoma of skin

.

Asbestos ……………….. Carcinoma of lung, mesothelioma

.

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Benzene ………………… Leukemia, lymphoma.

Cadmium ………………… carcinoma of prostate

.

Chromium ………………… carcinoma of lung.

Nickle

…………………….. tumors of Nose, lung.

Vinyl chloride …………….. liver malignancy.

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Other environmental factors that have role in development of cancer:

1. Alcohol consumption.

2. Smoking.

 

II. Age:

Frequency of cancer increase with Age

(most

death of cancer between 55- 75 years), this is could be due to accumulation of Somatic mutations & change in immunity with increase age.

Cancer cause 10% of all death among children (below 15 years)

Major lethal Cancer in children is leukemia, CNS tumors, lymphoma & soft tissue sarcoma.

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III. Hereditary factor:

Hereditary forms of cancers can be divided into:-

Inherited cancer syndromes:

These syndromes characterized by:

There is inheritance of a

single mutant gene

(increase the risk of cancer).

Mode of inheritance is

Autosomal dominant

.

e.g

. Familial retinoblastoma.

Multiple endocrine neoplasia.

Neurofibromatosis type I & type II.

Autosomal

recessive syndromes of defective DNA repair.

A small group of

autosomal recessive disorders is collectively characterized by DNA instability.

e.g. Xeroderma pigmentosa, Ataxia telangiectasia.

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2. Familial cancer:

Virtually all sporadic cancer can be occur in familial pattern:

e.g.

Carcinoma of colon, carcinoma of breast, CNS tumors

.

Characteristics of Familial cancer:

1.

Early age of onset

.

2. Tumors

arising in two or more close relatives of patient

.

3.

Multiple or bilateral cancer

.

4.

Mode of transmission is not clear.

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Acquired pre neoplastic disorders:

1.Chronic skin fistula or long stand unhealed skin woun

d

(e.g. chronic osteomyelitis predisposing to develop

squamous cell carcinoma of skin

).

2.Hyperplasia, Metaplasia & dysplasia:

Like

carcinoma of lung,

develop in dysplastic bronchial tissue of habitual smoker.

3.Chronic atrophic gastritis

can predispose to

carcinoma of stomach

.

4.Chronic ulcerative colitis

, predispose to

carcinoma of colon

.

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5.Leukoplakia of oral cavity

,

vulva

(

squamous cell carcinoma

).

6.Villous adenoma of colon

, increase risk of

carcinoma of colon

.

 

 

Important note

:

Some of

benign tumors

can predispose to

malignant tumors

, like

adenoma of

colon, when enlarge can undergo malignant transformation.

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Molecular basis of Cancer (Carcinogenesis):

Principles of genetic basis of cancer:

1. Nonlethal genetic damage lies at the heart of carcinogenesis.

This damage

may be acquired

by the action of environmental agents like (chemicals, radiation, viruses), or may be due to genetic cause.

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2.

Four classes of normal regulatory genes (control the growth of cancers):

I.

Growth promoting

protooncogenes,

dominant genes, can transform cells into malignant cells, with single allele is damaged.

II.

Growth inhibiting

cancer suppressor genes (antioncogenes)

(recessive genes, can

transform

cells into malignant cells only if both alleles of gene are damaged).

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III.

Genes that regulate the apoptosis.

These genes

are targets of non-lethal genetic damage

.

IV. DNA

repair gene

, disability of DNA repair genes can predispose to widespread mutation & neoplastic transformation.

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Carcinogenesis:

is a multistep process at both

phenotypic & genetic levels.

Phenotypic level

includes:

I. Excessive growth.

II. Local invasion.

III. Metastasis.

These three criteria are called collectively

Tumor Progression

.

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Genetic level

includes

:

Cancer display

eight

changes in cell physiology,regarded as

hallmarks of cancer

These changes are included:

1. Autonomous growth:

This pattern of growth of cancer is under the control of

Oncogenes

(genes

derived from

Protoncogenes

).

These oncogenes produced

oncoproteins

(growth factors), which result in autonomous growth of cancer

.

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Mechanisms of action of

oncoproteins

:

By following steps:-

Step-I;

The

binding of growth factor

(

Oncoproteins

) to

specific receptors

on cell membrane.

Malignant cells acquire autonomous growth by followings:-

1. Acquiring the ability to synthesize the same growth factors to which they responsive (gene overexpression).

2. Pathological overexpression of normal growth factor receptors,

Her2 receptors

are overexpressed in 25- 30% of breast, lung carcinoma.

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Step- II; Growth factor & receptor complex activate several proteins on inner side of cell membrane

(transient activation under normal state while persistent activation under neoplastic conditions).

 

Step- III;

Transmission of signals from these proteins

along inner side of cell membrane along the cytoplasm

to the nucleus via secondary messenger.

Step- II & III: this is called (singling pathway)

.

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Two important genes that control this pathway (

Ras

….increase cells proliferation &

ABL…

……inhibit cell proliferation).

Cancer cells acquire autonomous growth is by

mutation in these genes that control the signaling pathway

(

transfer of signal from inner side of cell membrane to nucleus).

So

mutant

Ras

is the most common oncogene abnormalities in human tumors

Mutant

Ras

gene are present in 35% of human cancers (carcinoma of colon, carcinoma of pancreas……

etc

)

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Step- IV;

Activation of transcription inside the nucleus

.

Mutations affect the genes that regulate transcription of DNA may result in autonomous growth of cancers.

e.g.

Myc

gene

is commonly involved in human tumors like in carcinoma of colon, breast, lung)..

Step- V;

Entry of cell into the cell cycle

& result in cell division.

Normal cell cycle is consists of five phases (G

0

,G

1

, S, G

2

, M).

All these phases are under control of proteins (

Cyclins

&

Cyclins

dependent Kinase).

Cyclin

D overexpression is seen in many cancers (breast, esophagus & liver).

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2. Insensitivity to inhibitory signals

(

disruption of tumor suppressor genes):

 

Disruptions of

tumor suppressor genes

make the

cells resistant to inhibition of growth & increase their proliferation.

All tumor suppressor genes are caused inhibition of cell growth by two pathways:

I. stimulate antigrowth signal, causing cells to enter G

0

phase.

II. Prevent the cell to pass from phase G

1

to S phase.

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Examples of tumor suppressor genes:

1. RB gene:

This is the

first discovered suppressor gene

,

loss of normal RB gene was discovered initially in Retinoblastoma, but recently proved it lost in many tumors (breast cancer, bladder & lung cancer, osteosarcoma).

Both alleles of RB gene must be mutant

in order to regard this gene is mutant.

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2. Adenomatous Polyposis coli (APC) gene:

Loss of this gene can be seen in 70- 85% of sporadic carcinoma of colon.

Individuals born with loss or mutant of one of alleles of APC gene, they develop hundreds to thousands of adenomatous polyps in the colon which on second decade of life one or more of these polyps will undergo malignant transformation.

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3. TP53:

It is one of most commonly mutated in human cancers, it exert its

antiproliferative

effects by

:-

I. Arrest cell cycle at late G

1

phase & remain the cells in the G

0

phase (cell cycle pause) to allow a time for DNA repair.

II. Stimulate Apoptosis.

III. Helping in repair of DNA.

 

More than 70% of malignant human tumor show defect in functions of TP53

 

Most of mutations in TP53 are acquired & less commonly they are inherited mutations like

Li-

fraumeni

syndrome

(patient have many cancers like sarcomas, breast cancer, leukemia, brain tumors, adrenal tumors).

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3. Evasion of apoptosis:

Normally,

the mechanism of

apoptosis is mediated by many genes, & achieve by two phases

Initiation phase

, which is mediated by

TNF- Fas receptor

& inhibited by FLIP protein.

Or initiation phase (

caspases

activation) is mediated by

BAX, BAD genes & inhibited by bcl2 gene.

 

Execution phase

,

which is result in cellular degradation by

caspases

.

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Changes in mechanism of apoptosis in malignant tumors are:

1. Decrease level of Fas protein (as in Hepatocellular carcinoma).

2. Loss of Tp53 (Tp53 is responsible for action of Fas protein).

3. Increase level of FLIP protein which inhibits apoptosis.

4. Increase level of Bcl2 gene which inhibit apoptosis (as in 85% of B-cell lymphoma).

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4. Limitless replicative potential

Most of normal human cells have capacity of 60 to 70 doublings, after this, the cells lose the capacity to divide (due to loss of Telomerase enzymes which is important in DNA replication).

In malignant tumors, there is increased level of Telomerase.

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5. Developed sustained Angiogenesis:

Angiogenesis has dual effects on tumor growth:

1. Supplies nutrients & oxygen.

2. Newly formed endothelial cells during angiogenesis, will stimulate the growth of adjacent tumor cells by secretion of polypeptides (like platelets growth factor).

Angiogenesis is also important for development of metastasis.

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Most of cancers cannot grow more than 1 to 2 mm in diameter or thickness unless they are vascularized, because after this size the tumors fail to enlarge without vascularization (because hypoxia increases apoptosis).

Cells of malignant tumor are the main inducer of angiogenesis by their production of growth factors (

Angiogenetic

factors).

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6. ABILITY TO INVADE & METASTASIZE

The Metastatic pathway of cancer can be divided into two phases:

1. Invasion of Extracellular matrix:

Include the following steps

I. Detachment of tumor cells from each other (by losing of E- cadherin & B- catenin molecules).

II. Attachment of tumor cells to matrix components.

III. Degradation of Extracellular Matrix (by Metalloproteinase).

IV. Migration of tumor cells to the vessels (mediated by Cytokines).

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2. Vascular dissemination& Homing of tumor cells;

In circulation

, Tumor cells are liable to destruct by immunity cells of host

.

To avoid such destruction, tumor cells are arranged themselves into small emboli (by adhesion to WBC

S

, PLATELETS).

Then

tumor cells leave circulation by adhesion to the endothelial cells & destruction of basement membrane of vessels, to enter the extracellular matrix of metastatic site.

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7. Altered cellular metabolism

.

Tumor

cells undergo a metabolic

switch to aerobic glycolysis (called the Warburg effect),

which enables the synthesis of the macromolecules and

organelles

that are needed for rapid

cell growth

8.Ability

to evade the host immune

response.

You will recall that the cells of the innate and adaptive immune system can recognize and eliminate cells displaying abnormal antigens (e.g., a mutated oncoprotein). Cancer cells exhibit a number of alterations that allow them to evade

the host

immune response

.

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The metastatic cascade. Schematic illustration of the sequential steps involved in the

hematogenous

spread of a tumor.

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Karyotype changes of Tumors

The genetic damage that activate Oncogenes & inactivate Tumor Suppressor genes is either

point mutation

(

not change the karyotype

), or

large mutation (change the karyotype).

 

The common structural abnormalities in the genome of tumor cells are:

1.

Balanced translocation: (commonest abnormality)

.

More common in

hemopoietic

tumors e.g.

chronic myeloid leukemia t(9,22).

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2

. Deletion:

More common in non

hemopoietic

solid tumor e.g. deletion in chromosome

13 in retinoblastoma

, deletion

in chromosome 5

in carcinoma of colon.

3

. Gene amplification:

e.g.

breast carcinoma associated with Amplification of

Myc

& HER2 genes.

Slide34

Carcinogenesis according to carcinogens:

Carcinogenesis can be divided

into three steps:-

A. initiation step:

in which there is

DNA damage

(

lies at the heart of tumor)

, usually

due to (CHEMICALS, VIRUSES & RADIATION)

, these are called

initiators.

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B. promotion step:

maintained the damage of DNA

(

HORMONES, DRUGS, PHENOL)

, these are called

promoters

which

augment replication of cells with DNA damage.

C. Tumor progression

:

local increase in the size of tumor, local invasion & metastasis.

 

Important notes on these steps of carcinogenesis:

1. Application of promoters before the initiators will not result in completion of carcinogenesis.

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2. Some of carcinogens can act as initiators, promoters, this is called complete carcinogens.

3. Not all carcinogens induced DNA damage & will not necessary result in initiation of cancer.

4. Initiators are mutagenic but are not induce cells proliferation, while promoters are non-mutagenic but can induce cells proliferation.

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The 3 phases in the development of

cancer cells(multistep theory)

Initiation – a single cell undergoes a mutation that causes it to divide repeatedly

Promotion – a tumor develops and cells within the tumor mutate

Progression – a cell mutates in such a way that allows it to invade surrounding tissue

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Thank you