Carcinogenesis Flashcards
Hyperplasia? Metaplasia? Dysplasia?
H: increase # of normal cells
M: replacement of 1 differentiated somatic cell with another
D: presence of abnormal cells
Why does metaplasia occur?
Response to chronic irritation
reprogramming of stem cells or undifferentiated mesenchymal cells found in connective tissues
ex. The ciliated columnar epithelium converted to squamous epithelium in the trachea so that the trachea can better withstand the stress of smoking, however it is no longer as functional, and can lead to tracheal cancer.
Types of mutations
1.) initiating mutation: begins process toward malignant transformation (FIRST DRIVER) often includes loss-of-function mutations leading to instability
2.) driver mutation: INCREASE malignant potential
3.) passenger mutation: LOW malignant effect
Classes of commonly mutated genes (driver mutations):
1.) Proto-oncogenes
GOF mutations => oncogenes
2.) Tumour suppressor genes
LOF
3.) Genes regulating apoptosis
GOF or LOF
4.) Genes responsible for DNA repair = LOF
Affected cells acquire mutations at an accelerated rate (aka genomic instability)
Growth factors or their receptors, signal transducers, transcription factors, or cell cycle components are all what type of mutation class?
Oncogenes
Ras, PI3 K, Myc, and cyclics/cdks are all types of what?
Oncogenes
Mode of activation of tumor:
1.) RAS signal transduction (BRAF)
2.) Transcriptional activators MYC
3.) Cyclins CCND1 (cyclin D1)
4.) Cyclin-dependent kinase (CDK4
1.) Point mutation, translocation (melanomas, leukemia, colon carcinoma)
2.) Translocation (Burkitt lymphoma)
3.) Translocation (mantle cell lymphoma, multiple myeloma)
4.) AMPLIFICATION or point mutation (melanoma, glioblastoma, sarcoma)
How are growth factors involved in the cell cycle?
They bind to tyrosine kinase –> activates RAS. RAS –> activation of MAP-kinase –> activation of growth factors of transcription factors (MYC) –> increase production of CDKs
Which is the most common abnormality of proto-oncogenes in human tumors?
Point mutation of RAS family genes
What is the downstream signaler for EGF, PDGF, and CSF-1?
RAS
Summary of P13K pathway.
Receptor Activation:
Ligands activate cell surface receptors.
PI3K Activation:
Activated receptors activate PI3K.
Akt Activation:
PI3K generates PIP3, recruiting and activating Akt.
mTORC1 Activation:
Akt activates mTORC1, regulating cell growth.
Downstream Effects:
Akt regulates apoptosis, glucose metabolism, and cell proliferation.
Dysregulation in Diseases:
Dysregulation of the PI3K pathway is associated with cancer and other diseases.
Ras Pathway
Receptor Activation:
Ligands activate cell surface receptors.
Ras Activation:
Activated receptors recruit and activate Ras.
Raf-MEK-ERK Cascade:
Ras activates Raf, initiating a phosphorylation cascade involving MEK and ERK.
Nuclear Translocation:
Activated ERK translocates to the nucleus.
Gene Expression:
ERK activates transcription factors, influencing gene expression.
Cellular Responses:
The pathway regulates cell proliferation, differentiation, and survival.
Dysregulation in Diseases:
Dysregulation of the Ras pathway is associated with cancer.
In a healthy cell, PI3K, is dependent on ___________, but can work independently when mutated.
tyrosine kinase
Both P21 and P27 are involved in regulation of the cell cycle, they act as inhibitors of what?
cyclin-CDK complexes
Active Akt inhibits _________________ by inactived ______ and ________.
apoptosis, p 21 and p 27
What is Myc induced by?
Ras/MAPK
When activated what does Myc do?
increases cell proliferation and growth
Myc stimulates transcription of _______?
cdk’s
Which transcription factor contributes to warburg effect, increased telomerase activity, and allow more terminally differentiated cells to gain characteristics of stem cells.
Myc
Important cell cycle checkpoint regulated by cdk-cyclin is important in cancer?
G1/S
If there is a GOF in cyclin D and CDK4, how does this affect the cell cycle?
Rapid progression
_____ ______ genes apply brakes to cell proliferation.
tumor suppressor genes.
What are 2 tumour suppressor genes that recognize genotoxic stress?
RB and P53
Is activation of oncogenes enough for cancer induction? What else does it require?
no, requires loss of tumour suppressor genes as well
Inhibitors of cell cycle progression (x2)? What is the protein? Where in the cell cycle?
1.) RB: retinoblastoma protein: inhibitor of G1/S transition during cell cycle progression (negative regulator)
2.) CDKN2A: P16 and p14: P16=negative regulator of cyclin-dependent kinases p14=indirect activator of p53
T or F: P16 mutation would be very detrimental.
True
Enabler of genomic stability (1). Protein? Function?
TP53/p53 protein/ cell cycle arrest and apoptosis in response to DNA damage
RB is a negative regulator of which checkpoint?
G1/S
What form do we normally find RB?
hypophosphorylated
What form is RB in to facilitate passing through the G1/S checkpoint?
hyperphosphorylated
Is RB involved in both the directly and indirectly inactivated in most human cancers?
Yes.
Directly=LOF
Indirectly=GOF–> upregulating CDK4 / cyclin D & LOF mutation of CKIs (p16)
Which is the “guardian of the genome”?
TP53
What does p 53 do?
regulates cell cycle progression, DNA repair, celluar senescence, and apoptosisf
Which is the most frequently mutated gene in human cancer?
p53
How does p53 function in the presence of DNA damage?
Arrests the cell cycle until DNA can be repaired through p21
Stimulates DNA repair
If DNA repair is successful => cell cycle can resume
If DNA repair fails => p53 will activate pro-apoptotic pathways
p53 mutations are commonly responsible for genomic instability, driving tumour progression
With the loss of ________ DNA damage goes unrepaired & driver mutations accumulate in oncogenes & other cancer genes leading to malignant transformation
p53
CDKIs are frequently mutated or otherwise silenced in many malignancies. _______ is an example of a tumour suppressor gene that is inherited.
p16
What does p16 inhibit?
CDK4-cyclin D complex (G1- cdk complex) which is needed for progression through the cell cycle
All common oncogenes and tumor suppressor genes affect the cell cycle where?
G1 = start transition
At least 1 of which 4 key regulators of cell cycle is dysregulated in the sig. fig majority of all human cancers?
p16, RB, cyclin D, Cdk4
APC and E-cadherin are 2 ______________. APC is part of what pathway? What can LOF of E-cadherin contribute to?
inhibitors, loss of contact-inhibition in tumours and metastasis
Of the 8 fundamental changes in cell physiology of all cancers, what 2 are the focus?
altered cellular metabolism and limitless replicative potential
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Altered cellular metabolism
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasize
- Ability to evade the host immune system
What is it called when cancer cells take up high levels of glucose and demonstrate increased conversion of glucose to lactate?
Why do you suppose a cancer cell is relying on glycolysis alone for ATP production?
warburg effect
Provides rapidly diving tumour cell with metabolic intermediates needed for synthesis of cellular components, mitochondrial oxidative phosphorylation does not!
What is it called when a cell permanently exits the cell cycle & never divides again?
senescent
Cancer cells can evade senescence. How?
Likely due to loss of functions mutations in p53 and p16
Allows cell to pass through G1/S checkpoint
Cancer cells have demonstrated the ability to express telomerase, what does this allow them to do?
continue replicating indefinitely
Have RNA and DNA viruses been proven to be oncogenic?
Yes
RNA Viruses:
Human T-cell Leukemia Virus Type 1 (HTLV-1)
Associated with Leukemia
DNA Viruses
HPV – Human Papillomavirus
EBV – Epstein Barr virus
HBV (& HCV) – Hepatitis B virus
Merkel cell Polyomavirus
HHV8 – Human herpesvirus 8
Name the 4 protooncogenes.
Name the 3 tumour suppressor genes.
PO: MYC, cyclin CBK, PI3K, RAS
RS: RB, p16, p53
Which of the following cyclin-cdk complexes does p16 inhibit?
cyclin D cdk-4
P53 promotes the transcription of which Cdk inihibitor (CKI)
p21 and p27
T or F?
RB is inactivated by phosphorylation by an active Cyclin D-cdk4 (G1 cyclin-cdk) complex, releasing transcription factor, E2F
True
Which of the following is TRUE regarding DNA synthesis (aka DNA replication):
RNA primase is needed to build an RNA primer with a free 3’-OH group for elongation by DNA polymerase.
Which enzyme is involved in reducing supercoiling during DNA replication?
DNA topoisomerase
Which of the following is most correct regarding anaplasia?
Anaplasia may include cellular pleiomorphism and loss of polarity.
A mutation in Myc was identified via genetic testing in your patient with breast cancer. How could a mutation in Myc increase the likelihood of developing cancer?
Myc promoted the transcription of cyclin D.
Which of the following mutations would contribute the most significantly to genomic instability?
p53
True or False, Marfan’s syndrome is inherited in an autosomal dominant pattern.
true
T or F:
1.) A father can pass an X-linked gene to his daughter, but not to his son
2.) A mother can pass an X-linked gene to her son, but not to her daughter
3.) Most X-linked disorders are dominant
4.) Most X-linked disorders are expressed in women, since they have two X-chromosomes
1.) true
2.) false
3.) false
4.) false
What is caused by involuntary muscle contraction of the abdominal wall?
rigidity
-oma denotes what kind of tumour?
benign
Well differentiated vs. poorly differentiated?
well=resemble normal cells
poorly=do not resemble normal cells
Term for when cells vary in size and shape
Pleaomorphism (type of anaplasia)
Anaplasia
poorly differentiated cells
Nuclei with more chromatin will stain lighter or darker than normal?
darker
3 characteristics of anaplasia.
1.) pleomorphism
2.) abnormal nuclear morphology (size, chromatin #, abnormal mitosis)
3.) loss of cell polarity
What is it called when tumour growth exceeds blood supply? Because of lack of blood supply, many cells die.
Ischemic necrosis
