4. neoplasia stom eng 2011
TRANSCRIPT
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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
Pathogenesis of Tumor
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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
Pathogenesis of Tumor
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II. Inactivation of tumor suppressor genes (TSG)
Pathogenesis of Tumor
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
Pathogenesis of Tumor
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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Biological properties of benign and malignant tumors
(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)
Biological properties of benign and malignant tumors
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Biological properties of benign and malignant tumors
(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