Oncopathology 2 Flashcards
growth-inhibitory signals is which type of cancer gene ?
Tumor suppressor Genes
What will happen if the Tumor Suppressor Genes are not active?
the cells become refractory to growth inhibition
How do these tumor suppressor genes work? How do they produce their effect on growth inhibition?
Or what are their mechanisms ?
1- Quiescence
2- (Senescence)
3-Checkpoint inhibition
4-Initiating apoptosis in the cell.
Explain the Quiescence mechanism?
Forcing the cell to enter the G0 phase of cell cycle
Explain the (Senescence) mechanism?
Permanent prevention of replication
Explain the Checkpoint inhibition mechanism?
And give example……
Inhibition of progress of the cell through the cell cycle
One example is : CDKI (cyclin dependent kinase inhibitors)
Inactivation of tumor suppressor genes requires inactivation of both / one
allele of the gene.
Both
Inactivation of both alleles is known as “……………….” (LOH)
Loss of Heterozygosity
Inactivation of both alleles is known as “Loss of Heterozygosity” (LOH)
and is the basis of ………….hypothesis of carcinogenesis
Knudson’s two hit
Inherited susceptibility (inherited cancer susceptibility) of cancer already have Homozygous /heterozygote state, one normal allele and one damaged allele, so he needs one/two hit to develop cancer ?
Heterozygote
One
in the sporadic ( not inherited) cases both alleles are normal So it is homozygote/ Heterozygous so he needs two/ one hits
homozygote
Two
Knudson’s two-hit hypothesis of carcinogenesis what we mean by hit ?
hit means inactivation
Knudson’stwo-hit hypothesis of carcinogenesis this hypothesis explains
why patient with inherited cancer develop cancer quicker/ slower than patient with no previous predisposition (Sporadic).
Quicker
However in the sporadic cases (one/ both) alleles are normal (homozygote) so he needs (one /two) hits, the first one (will/will not)develop cancer because tumour suppressor gene is (recessive/dominant) and this requires the two genes to be damaged. After the (first/second)hit he developed the heterozygous state. Once he have the second hit develop (heterozygote / homozygote) state
1-Both
2-two
3- will not
4-recessive
5-first
6-heterozygote
Give me 4 examples of tumor suppressor genes ?
- RB gene
- TP53 gene
- NF1 (Neurofibromin)
- NF2 (Merlin)
- APC (Adenomatous Polyposis Coli)
tumor suppressor gene,(one hit is /two hits are ) required?
Two
……………gene is the most commonly mutated gene in human cancers
TP53
The product of TP53 gene is known as…….
p53 protein.
…….Governor of the cell cycle
RB رؤى العنبري
Which gene is the Guardian of the Genome?
Tp53
p53 functions to protect the cell from neoplastic transformation by 3
main mechanisms:
- Activation of temporary cell cycle arrest (quiescence).
- Induction of permanent cell cycle arrest (senescence).
- Triggering programmed cell death (apoptosis)
When the p53 get activated?
Give me examples
p53 can be activated by various stressful stimuli that put the cell into danger of neoplastic transformation
includes DNA damage, excessive growth stimulating signals, and hypoxia.
P53 can initiate apoptosis or repair DNA by itself ( ✅ or ❌ )
❌
P53 (can not )initiate apoptosis or repair DNA by itself. However, it activates the transcription factors that are
necessary to do these functions
How do tumor cells invade the extracellular matrix?
What are the 3 steps
1-Loosening of intercellular connections between tumor cells
2-Degradation of the ECM through proteolytic enzymes
3- Locomotion (Movement and migration of the cells).
E-cadherins is………… molecule
adhesion
في ال junctions
What is the function of proteolytic enzymes?
Degradation of the ECM In the (Invasion of Extracellular matrix (ECM))
Give me one example of proteolytic enzymes:
Matrix Metalloproteinases or MMPs
What is the Locomotion?
Movement and migration of the cells
Once invasion happens, the cell have to enter through the circulation; which is called………….
intravasation
After local invasion, in order for tumor cells to reach distant sites, several steps are required:
5 th steps :
1 • Intravasation into blood and lymph vessels
2 • Transit through the circulation
3 • Extravasation from vessels.
4 • Formation of micrometastasis
5 • Growth into macroscopic tumors.
there are certain sites where tumors commonly metastasize give me some examples:
-Lung
- Liver
- Brain
- Bone
sites where tumors metastasize very rarely (such as……..&…………).
1-skeletal muscle
2-spleen
The site at which metastasis appears in a given tumor depends on two factors:
- The anatomic location and vascular drainage of the primary tumor
2.The tropism of particular tumors to specific tissues
If breast cancer in the outer quadrant of the breast metastasize to… …………
axillary lymph nodes
Prostatic carcinoma preferentially involves the …………while lung cancer tends to spread to………
(tropism)
bone
brain
Cancer cells in metabolism utilize primarily “………………..”
Aerobic Glycolysis
utilization of glucose and its conversion to lactose( Glycolysis) even in the presence of ample oxygen (Aerobic).
“Warburg Effect”.
Or
“Aerobic Glycolysis”
For what ?PET scan (Positron Emission Tomography).
This effect (the glucose-hunger of cancer cells) has been used to detect tumors by imaging using a radioactive form of Glucose (FDG or F-fluorodeoxyglucose).
Why cancer cells utilize Aerobic Glycolysis?
The reason is that glycolysis provides the cells with (metabolic intermediates ) that are needed for the synthesis of cellular components required for cell division, while oxidative phosphorylation does not.
MDM2 is inhibitor of
P53
RB is directly or indirectly active/ inactivate in most human cancers.
inactivate
RB is named because of its relation with…………
(Retinoblastoma) which is a rare childhood tumor of the eye.
As RB is a tumor suppressor gene, one/two hits are required to produce retinoblastoma.
Two
Retinoblastoma is mostly [unilateral/bilateral] in sporadic cases and [unilateral/ bilateral] in inherited (familial) cases
1- unilateral
2- bilateral
What cause hyperphosphorylation in RB1?
The main cause of hyperphosphorylation of RB is the cyclin/cyclin-dependent kinase (CDK) complex.
Active/inactive RB protein Hypophosphorylated ( few phosphate)
Active
Active/inactive RB protein Hypophosphorylated ( few phosphate)
Active
Active RB protein
- Hypophosphorylated/ Hyperphosphorylated
- Binds to transcription factor called ………
- Prevent/ Releases this E2F
1-Hypophosphorylated
2-E2F
3- prevent
Inactive RB protein :
- Hypophosphorylated/ Hyperphosphorylated
- Prevent/ Releases this E2F
1- Hyperphosphorylated
2-Releases
What is the function of E2F?
Allow the transcription of genes to start the S phase which is responsible for DNA replication such as genes like DNA polymerase
What is the function of E2F?
Allow the transcription of genes to start the S phase which is responsible for DNA replication such as genes like DNA polymerase
If E2F released➡️ allow…………. of these genes ➡️ the cell pass to……… phase
1-transcription
2- S phase
quiescence is activation of temporary/permanent cell cell cycle arrest
temporary
senescence is Induction of temporary/permanent cell cycle arrest .
permanent
p53 functions are :
(3 main mechanisms)
1-quiescence
2-senescence
3- apoptosis
p53 accumulates & Causes Cell Cycle………
p53 Activates DNA repair Mechanisms if the DNA repair is successful p53 is……… & cell cycle……..
If the DNA repair fails p53 Activates…………
1-Arrest
2- Degraded 
3- Resumes
4-Apoptosis
p53 functions through activation of transcription of numerous genes that……….. neoplastic transformation
suppress
Hereditary TP53 mutation
Li-Fraumeni Syndrome
Hereditary TP53 mutation
Li-Fraumeni Syndrome
…………………….is a very rare autosomal dominant cancer syndrome where the patient inherits one mutant p53 allele. It predisposes to the development of numerous types of cancers (such as sarcomas, breast cancer, leukemia, etc).
Li-Fraumeni Syndrome
What is the underlying cause of Li-Fraumeni Syndrome (LFS) ?
Inheritance of a mutation in one copy ( alleles) of the TP53 .
Intrinsic Pathway of Apoptosis is triggered by release of molecules
inside the………… into the……….. (such as……….).
1-mitochondria
2-cytoplasm
3-cytochrome c
the release of cytochrome c triggers ………….
apoptosis
If BCL2 is over-expressed in the cell what will happen ?
it will not allow BAX and BAK to initiate apoptosis.
Senescence occurs because of…………………. with each cell division.
progressive shortening of telomeres
What is the function of Telomer(ase) ?
Telomerase prevents shortening of telomeres with successive cell divisions.
Telomerase is ✨normally✨ expressed in [germ cells/somatic cells] and in stem cells, but is absent in [germ cells/somatic cells] cells
1-germ cells
2- somatic cells
- In cancer cells, telomerase can be seen in any type of cell, even the somatic cells
How do cancer cells avoid senescence & acquire limitless replicative capacity?
By which enzyme ?
By activation of an enzyme known as Telomerase.
