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
