4. Neoplasia Stom Eng 2011

8/3/2019 4. Neoplasia Stom Eng 2011

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Pathophysiology department, faculty of

Stomatology, 29.09.2011

Pathophysiological pathways of Tumor Growth


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Design of lecture

1. Typical forms of cell growth disturbance

2. Definition of Tumor Growth

3. Etiology

4. Risk factors5. Pathogenesis of Tumor growth

6. Major features of cellular growth regulation

7. Molecular mechanisms of cancer8. Neoplastic atipisms (Anaplasia)

9. Antineoplastic resistance


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Glossary

1. Neoplasianew growth

2. Tumor are named according to the tissue of origin with the

suffix oma added

3. Cancer refers to a malignant tumor

4. Tumor cell markersare substances that are produced by cancer

cell and found on tumor plasma membranes or in the bloodspinal fluid, urine (they include hormones, enzymes, genes,

antigens, antibodies)

5. Oncogenes are genes that can transform a normal cell into acancerous

6. Proto-oncogenes are normal genes, that regulate growth and

development by encoding for growth factors (GF) and GF

receptors


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Glossary

7. Heterozygosityloss of one gene copy

8. Transformationthe process by which a normal cell becomes

a cancer cell

9. Anchorage independentthey can continue to divide in a softagar gel

10. Autonomyrefers to the cancer cells indepence from normalcellular controls

11. Autocrine stimulatingthe ability to secrete GF that stimulatetheir own growth

12. Epigeneticsthat dont involve changes in DNA sequence


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NeoplasiaDefinition

1. A tumor is an abnormal mass of tissue, thegrowth of which is virtually autonomous and

exceeds that of normal tissues (by Robbins)

2. A tumor is abnormal mass of tissue, the growthof which exceeds and is uncoordinated with that of

the normal tissue and persists in the same excessive

manner after the cessation of the stimuli, which

avoke the change (by Willis)

3.Cancer is a disease of abnormal cell growth,

division and cell proliferation (by McCance,

S. Huether)


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Memory check !

Cell cycle

1) The reproduction or division of somatic

cells involves two sequential phases: mitosis (nuclear division) and interphase

cytokinesis (cytoplasmic division)

Beginning toward the end of mitosis


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Memory check !

2) Before a cell can divide, it must double its massand duplicate all of its contents. Most of thepreparation for division occurs during the

growth phase (interphase)


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Memory check !

3) There are four designated phases of the cell cycle:I. The S phase (synthesis)in which DNA is synthesized

in the cell nucleus

II. The G2 phase, in which RNA and protein synthesis

occurIII.The M phase (mitosis) which includes both nuclear

and cytoplasmic division

IV. G1 I phase, which is the period between the M phase

and the start of DNA synthesis Interphase, which consists of the G1, S and G2

phases, is the longest phase of the cell cycle.


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Memory check !

4) Gene and protein growth factors govern the proliferation

of different cell types Cells require highly specific proteins to stimulate cell

division. These growth factors are present in the serum invery low concentration (for example platelet-derivedgrowth factor stimulates the production of connective

tissue cells, or interleukin which stimulates theproliferation of T-cells)

Cells have specific receptors for the specific growth factorin their plasma membrane. Some growth factors are also

regulators of cell differentiation. It is likely that some genes code for growth factors, some

for receptors, some for intracellular regulatory proteins,some for proteins that help relay signals for cell divisionto the cell nucleus


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Epidemiology

General facts Cancer is the second leading cause of

death in the United States and other

countries Estimated number of new cancers in

2005 (1.372.910)

Estimated number of deaths from cancerin 2005 (570.280)


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EtiologyCarcinogenic Agents

1. Chemical carcinogenes

2. Radiation (physical)

3. Oncogenic viruses, bacterial cause

4. Role of inflammation, immunity in cancer

5. Loss of immune regulation and chronicinflammationn (parainflammation)


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1. Clinically important chemical carcinogenic

a. Polycyclic Aromatic hydrocarbons: present in cigarette smokeb. Azo dyes: -naphtylamine, aniline

c. Nitrosamines and amides (synthesized from nitrites in GIT)

d. Naturally occurring carcinogens (aflatoxin produced by the fungus

aspergillus flavus on moldy grains, peantus)

e. Alkalating agents

f. Miscellaneous agents: Asbestos, vinyl chloride, metals (nickel),

arsenic, benzene, beryllium, cadmium, chromium component,

ethylene oxide

g. Hormones (estrogen)

h. Free radicals

Chemical agents


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Chemical carcinogenesis

Carcinogenesis is multistep process involving asequence of initiation (mutation) followed by

promotion (proliferation) and progression

Initiators: direct acting, non-direct acting

chemicals

Promotors - cause cellular proliferation of mutated

(initiated) cells. Proliferation may lead to

accumulation of additional mutations

Tumor progression appearance of subpopulation

which differ with respect to several phenotypic

attributes


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Human viruses associated with cancer

Virus family Types

1. Hepatitis viruses Hepatitis B

2. Herpesviruses Epstein-BarrKSHV/HHV-8 is linked toimmunodeficiency

3. Papillomaviruses HPH-16, HPV-18,31-other

4. Retroviruses HTLV-1

Hepatitis C

d


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Viral and microbial carcinogenesisDNA-viruses

HPV (human papilloma virus)

Epstein-Barr viruses (EBV) Hepatitis B virus(HBV) HPV cause benignsquamous (warts)in human, supporting

role in human cancers (cervical cancers) anogenital

Epstein-Barr viruses(EBV-member of the herpes virusfamily) is associated with four human cancers:a. Burkitt lymphoma,b. Nasopharingeal cancer,

c. B-cell lymphoma in immunosuppressive patients (AIDS),d. Some forms of Hodgkin disease.Kaposi sarcoma- associated withherpesvirus (HHV8)Hepatitis B virus (HBV)-hepatic cancer, hepatocellular

carcinoma


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C virusRNA viruses

human oncegenic retrovirus is

Human T-cell lymphotropic virus type 1

(HTLV-1)

Linked to the T-cell Leukemia/lymphoma

Hepatitis C virus

Bacterial cause cancer (microbial factors)

It is also associated with gastric lymphomas

Mechanism: H. pylori infection induces methylation of

specific genes in the gastric mucosa.

HP helicobacter pylori induced

Gastric ulcer and carcinoma


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Radiation(Carcinogenesis)

Ultraviolet Rays (sunlight) Ionizing

radiation X- rays, - rays, -, - particles,

protons, neutronsEffects: transcriptional errors and mutations

Physical factors


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Risk factors

Gender: In man cancer of lung, colon and prostate are theleading causes of cancer death; in woman- breast, colon,

lung are most common forms Geographic and Environmental factors:Japan-the death

rate from cancer of the stomach 7 times that in England,USA

Cancer of the breast in England, USA rate increases, but inJapan decreases Carcinoma of colon is much less common as a cause of

death in Japan

Increased risk of certain cancers with exposure to asbestos,alcohol vinyl chloride, 2-naphtylamine Association of carcinoma of the or pharynx, larynx, and

lung with cigarette smoking


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Risk factors

Age:Cancer is most common in those older than 55

years of age, certain cancers are particularity commonyounger than 15 years of age:

Leukemia and lymphomas Tumor of the hematopoietic system

Neuroblastoma

Wilms tumor Retinoblastomas

Sarcomas of bone and skeletal muscle

Ri k f


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Risk factorsI. Heredity:

1. Inherited cancer syndrome (inheritance by single mutant genes,autosomal-dominant trait):

a. familial retinoblastoma,

b. familial adenomatous polyposis

c. multiple endocrine neoplasia

2. Autosomal recessive syndromes of defective DNA repairChromosome DNA instability Increased by environmental carcinogens.

II. Acquired preneoplastic disorder; (clinical conditions which areassociated with an increased risk of developing cancers)

Cirrosis of liver-hepatocellular carcinoma

Atrophic gastritis or pernicious anemia - stomach cancer

Chronic ulcerative colitis - carcinoma of the colon

Leukoplakia of the oral and genital mucouse - squamous cell cancers

Certain benign tumor (e.q. village adenomas of the colon )


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NOTE!

(inflammation, immunity, and cancer)

1. Chronic inflammation (and more specifically

parainflammation) has been recognized as being an

important factor in the developments of cancer (ex.

sialedenits salivary gland carcinoma)

2. Although the immune system is indeed important in

protecting us against cancers caused by specific viral

infections, it does not effectively protect us against

most common cancers (breast or prostate lung, colon

cancer).


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Characteristics of neoplasma:

Differentiation (loss) and anaplasia

Pleomorphism (variation size)

Hyperchromasia

High N/C (nucleous/cytoplasma) ratio (normal 1:4-1:6)

Disturbed orientation

Displasialoss in uniformity of individual cells and less intheir architectural orientation

Anaplasia (hallmarks of cancer cell)

The loss of cell differentiation, irregularities of the size and

shape of the nucleus, and loss of normal tissue structure.


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Classification

Due to on the characteristic of their

parenchyma

Benign Malignant

Based on 4 criteria

1. Differentiation and anaplasia

2. Rate of growth3. Local invasion

4. Metastases

C i


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Rate of growth and local invasion

Benign: slow growing, cohesive, expansive

capsuleMalignant: Autonomy,Infiltration, Invasion,

destruction, and metastasis

Most reliable feature of malignancyis theMetastasis

2nd most reliable featureInvasiveness

Comparison

C ll d fi d b h i bl


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Cancer cells are defined by two heritable

properties: 1. autonomy and 2. anaplasia

(literally without form)

1. Cancer cells

independence fromnormal cellularcontrol

2. Is a loss of

differentiation

Cancer cells has lost its ability

1) to function normally

2) to control its growth and division

PATHOGENESIS OF NEOPLASIA


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The target molecules are:

Protooncogenes Oncogenes

Tumor suppressor genes

Telomeres/reactivation of telomeraseApoptosis prevention gene

Caretaker genes (DNA repair)

The Molecular Basis of Cancer is a

non lethal genetic damage!

PATHOGENESIS OF NEOPLASIA

Carcinogenesis


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Carcinogenesis

Carcinogenesis multistep process:

Four classes of genes are the targets of geneticdamage:I. Growth-promoting proto-oncogenes (oncogenes)

II. Growth-inhibiting tumor-supressor genes

III. Genes that regulate apoptosis

IV. Genes that regulate DNA repair

General : Activation of growth promoting

Inactivation of Tumor suppressor genes

Disregulation , Resistance to apoptosis


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Pathogenesis of Tumor

1. Carcinogenesis is a multistep process

2. Development of C. requires the accumulationof multiple genetic changes:Inherited germ line mutation

Acquired mutation1. Tumor is derived from monoclonal expansionof mutated cell

2. Host important mutations in:a. Growth promoting genes (protooncogenes)

b. Growth inhibiting tumor suppressor genes

c. The genes regulating apoptosis


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Cell cycle regulation


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The sequence of events that characterize


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The sequence of events that characterizenormal cell proliferation

Under physiologic conditions all proliferation can be readily

resolved into the following steps: The binding of a growth factor to its specific receptor on the

cell membrane

Transient and limited activation of the growth factor receptor,

which in turn activates several signal transduction proteins on the

inner half of the plasma membrane

Transmission of the transduced signal across the cytosol to the

nucleous via second messengers

Induction and activation of nuclear regulatory factors that

initiate DNA transcription

Entry and progression of the cell into the cell cycle resulting

ultimately in cell division

Gentetic disturbances of any of the above leads to transformation.


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Transformation due to genetic disturbance of:

Growth factors Growth factors receptors

Signal transducting

Regulation transcription

Normal Cell

Tumor Cell

Transformed proliferation

Abnormal and autonomy

regulation

of growth

Disturbance of replication

Pathogenesis of cancer


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Pathogenesis of cancer

Normal cell

DNA damage

Mutations in the genome of somatic cells

Genetic factors inherited

mutations in genes affecting

Cell growth or DNA repair

Acquired

environmental

factors: chemical,radiation, viruses

Activation of growthpromoting oncogens

Inactivation of cancersuppressor genes

Alteration of genesthat regulate apoptosis

Expression of altered

gene product and lossof regulatory gene products

Oncoproteins

Malignant Neoplasm

Clonal expansion

Additional mutation

(progression)

Heterogenity



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Pathogenesis of TumorI. Activation of protooncogen oncogens

Protooncogenes are normal cellular genes involved with growth and

cellular differentiation1. Oncogenes are derived from protooncogenes by either

a. A change in the gene sequence, resulting in a new gene product(oncoproteins)

b. Loss of gene regulation resulting in overexpression of the normalgene product

2. Mechanisms of oncogene activation

a. Point mutation

b. Chromosomal translocationc. Gene amplification(reduplication of oncoproteins)

d. Insertions, deletions

e. Gene silencing (DNA methilation, histone modification)

f. Exogenous sequences (tumor) viruses


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Turning off genes without mutation (epigeneticsilencing is caused by reversible chemical

modification methylation, acetylation of histones,DNA methylation ets.)

Epigenetic mechanisms in the pathogenesis oftumor growth: gene silencing

Protein prod cts of oncogenes


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Protein products of oncogenes

1. Growth factors

2. Growth factors receptors3. Signal transducting proteins (guanosine GTP-

triphosphate binding proteins and non-receptorassociated tyrozine kinase)

4. Nuclear transcription proteins (mus,jun,fos)

5. Cyclins and cyclin - dependent kinases regulatethe progression of cells through the cell cycle

Note! Activated oncogenes lack regulatory control and

are over expressed, resulting in unregulated cellular

proliferation



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II. Inactivation of tumor suppressor genes (TSG)


Rb Retinoblastoma

WT-1, - 2 Wilms TUMOR

p53 Lung, breast, colon etc.

APC Adenomatous polyps andcolom cancer

BRCA -1 breast cancer

NF-1, -2 neurofibromas, neuromas


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TSG encode proteins that regulate andsuppress cell proliferation by inhibiting

progression of the cell through the cell cycle.

Mechanisms of action of some tumor

suppressor genes.

a. P53 prevents a cell with damaged DNA from

entering S-phase

b. Rb prevents the cell from S-phase until theappropriate growth signals are present


III Impairment of the regulation of Apoptosis


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III. Impairment of the regulation of Apoptosis

1. Over expression of Bcl-2 - prevent apoptosis (in

follicular lymphomas)2. Low expression, blocked genes promoting

apoptosis bax, bad, bcl-xs, bid

3. Mutation of p53 promotes apoptosis in mutatedcell by stimulation bax synthesis

4. c-myc promotes cellular proliferation

when associated with p53 leads to apoptosis

when associated with Bcl-2 inhibits apoptosis


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Role of telomerase

21

TumorSenescentpostmitotic

cell

IV Telomeres/telomerases


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IV. Telomeres/telomerases

ATTENTION! Other than germ cells, body cellscouldnt unlimited divided, because of regulation by

telomeres. There are control the activity of chromosome.Telomeres are protective ends or caps and becomesmaller with each cell division. Short telomeres normallysignal the cell to cease cell division. Cancer cells, when

they reach a critical age, activate telomerase, whichrestore and maintain telomeres resulting in to divideover and over again immortality of cancer cell.

Shortening of telomere take place after each division

of cell. In tumor cells due to specific enzymestelomerases telomeres are permanently recovered. So,there is unlimited division of cell.

V. Disorder of DNA repair Caretaker genes mutations

Growth of the tumor and its transformation


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Growth of the tumor and its transformation

Progression of the tumor


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Progression of the tumor

Main hallmarks of cancer


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Increase selfproductionin growth signalsautocrine regulation

Inactivation of antigrowthsignals

Resistance (evading) toapoptosis

Limitless replicativepotential

Sustained angiogenesis Tissue invasion and

metastatis + Warburg effects ?

Main hallmarks of cancer

Metastatic avenues/sequence


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Metastatic avenues/sequence

Neoplastic cell multiplication and local invasion

Lymphatic Blood vessels

Penetration

Cellulardeath

Cellulargrowth

Efferentlymphaticentrance

Noneoplasm

Extravasations

Organ tropism

New growth site

AngiogenesisMetastatic neoplasm


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Angiogenesis

Cancer needs blood/supply to deliver O2 and

nutrients. Cancer has ability to grow new blood

vessels. Cancer can secrete factors that stimulate

new blood vessel growth angiogenesis.

Example of angiogenic factor is vascular

endothelial growth factor (VEGF) (other factors).

Biological properties of benign and malignant tumors


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(Activisms)1. Abnormality of proliferation

a) unregularity of proliferation,b) Loss of proliferation limit,

2. Abnormality of differentiation

3. Abnormality of metabolism and energy production

a) Tendency to anaerobic glycolysis (Warburg effect)Increased production of oncoproteins,

b) Synthesis of embryonic proteins,

c) Change of resynthesis of energy,

d) Phenomenon of metabolic traps (glucose, aminoacids),

e) Decrease concentration of c-AMP and increase concentration of c-GMP,

4. Physico-chemical abnormality (K+, Ca2+)

5. Antigenic abnormality (iso, transplatatory, embryonic,

hetero)



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(Atipisms)

6. Morphologic abnormality

7. Abnormal functioning

a) Inhibition of functions,

b) Increase of functions,

c) Disturbance of functions

8. Abnormal tumor cell-to-host organism interaction

a) immunodepression,

b) Ectopic endocrine syndromes

c) Influence of stress,d) Cardiovascular insufficiency

e) Muscular dystrophy,

f) Amino acid, energetic, antioxidative, vitamine and

other deficits

Antineoplastic resistance of organism


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Antineoplastic resistance of organism

1. Anticarcinogenic (inactivation, elimination, pinocytosis,

interferon, antibodies, antioxidants)

2. Antitransformational (DNA repair enzymes, antioncogenic

mechanisms)

3. Anticelular (specific and non specific, immune protection,

TNF, IL-1, allogen inhibition by the normal cells, keilons:tissue

specific mitogen supressors 1lipoprotein cancerolysis,contact inhibiting, cAMP+, cGMP-, labrocytosis, increase ofhumoral protection)

Pathways of increase antineoplastic resistance

Activation of apoptosis

Immunotherapy

Photodynamic therapy

Biotechnology

Typical Test


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Typical Test1. Choose the correct definitions:

a) A tumor is an abnormal mass of tissue, the growth ofwhich is virtually autonomous and exceeds that of thenormal tissues

b) Cancer is a disease of abnormal cell growth, division andcell proliferation

c) Tumor is a increase of a number of cell

d) Tumor is a hyperplasia and hypertrophia of tissueI. a,c II. b,d, III. a,b IV. a,b,c,d

2. All the following are causes of tumor, EXCEPT:

a) Epstein-Barr virusesb) HTLV-1c) Megalovirused) Hepatitis B-Ve) Human herpes viruses


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3. All the following are the chemical causes of cancer, EXCEPT:

a)Asbestos

b)Vinyl chloride

c) PgE1

d)Arsenic

e) Benzene

4. All the followingare the cancer-induced DNA-viruses, EXCEPT:

a) HPV

b) EBV

c) HBVd) HTLV-1

e) HHV8


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5. Which are the endogenous carcinogenic chemicals:

a) Free radicals

b) Aflatoxinc) Vinyl chloride

d) Estrogen

I. a,b II. b,c III. c,d IV. a,d

6. Warburg effect is manifested by:

a) Activation of growth promoting protooncogenes

b) Activation of antioxidantsc) Increased oxygen consumption

d) Activation of anaerobic glycolusis


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7. Which of the following suppressor gene is related with apoptosis:

a) Rb

b) p53

c) APCd) NF-1

I. a,b II. b,c III. c,d IV. a,d

8. Choose the four classes of genes, which are the targets of tumor growth

a) Genes that regulate DNA repair

b) Genes that regulate adhesion molecules synthesis

c) Genes that regulate apoptosis

d) Inhibiting genese) Protooncogens

I. a,b,c,d,e II. a,b,c III a,c,d,e IV. c,d,e


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9. Which of the following about mechanisms of oncogene activation is false:

a) Point mutation

b) Chromosomal translocation

c) Amplification

d) Insertion of mutagens

e) DNA repair

10. False statement about tumor suppressor gene is:

a) TSG encode proteins that regulate and suppress cellproliferation

b) p53 prevents a cell with damaged DNA from entering S-phasec) Rb prevents the cell from S-phase until the growth signals are

present

d) TSG encode proteins of growth receptors


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11.Biological properties of tumors are following

a) Immunodepression

b) Antioxidants deficitc) Increase concentration of cAMP

d) Decrease concentration of cGAM

e) Phenomenon of metabolic traps.

I. a,b,c II. d,e III. a,b,c,e

12. All the following are antineoplastic resistance , EXCEPT:

a) Antioxidants

b) Decrease of cAMPc) Allogen inhibition

d) Labrocytosis

4. Neoplasia Stom Eng 2011

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