Molecular Basis of Cancer Flashcards
List the 7 major classes of genes involved in carcinogenesis
- growth promoting proto-oncogenes
- growth inhibiting tumor suppressor genes
- genes that regulate DNA repair
- genes that regulate apoptosis
- genes that regulate telomere function
- genes that regulate angiogenesis
- genes that promote invasion and metastasis
caretaker genes vs. gatekeeper genes
both are genes susceptible to mutation:
Caretaker genes = genes that regulate DNA repair; a mutation makes them unable to fix problems
Gatekeeper genes = suppress tumor formation by regulating cell growth
What happens if mutations activate telomerase?
Telomerase allows cells to replicate indefinitely
List 5 major targets for genetic alterations in cancer
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Chromosomes
- abberant copy number, translocations, deletion, telomere extension, Loss of heterozygosity
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DNA
- point mutations, micosatellite alterations, promoter hypermethylation, viral sequences
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RNA
- over/underexpression, point mutations, miRNAs
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Protein
- structural alterations/modifications, changes in enzymatic activity, mislocalization, altered expression
-
Mitochondria
- DNA mutations
What are the 6 major skills a cancer cell needs to survive?
- self sufficiency in growth signals (control of accelerator)
- insensitive to anti-growth signals (brakes)
- able to evade apoptosis (preventing car from driving off cliff)
- limitless proliferative potential (continue forever)
- sustained angiogenesis (enough fuel supply)
- tissue invasion and metastasis
What do normal cells need in order to move from quiescence to an active proliferating state?
Mitogens! (growth signals)
What are the four classes of proto-oncogenes? (activating growth)
- growth factors
- growth factor/intracellular receptors
- intracellular transducers
- transcription factors
How do growth factors work in normal cells? Provide 3 examples of GFs
Most soluble mitogenic growth factors are made by one cell in order to stimulate proliferation of another cell
examples: PDGF, EGF, TFG-a
* Platelet makes PDGF, binds receptor on fibroblast, stimulates cell to undergo round of replication, produces 2 daughter cells *
(note: GF = growth factor….)
Autocrine stimulation
Process where cancer cells in tumors are able to synthezie growth factors that stimulate THEMSELVES–> signal continues to drive itself and you get unregulated cell divisions
Explain how growth factor receptors work as a class of proto-oncogenes
list two examples of them
Mutation in receptors generates proliferative signal to a cell all by itself without the binding of an extracellular signal.
Overexpression of receptors –> hyperresponsive cancer cells
examples: EGFR/erbB, HER2/neu
integrins - growth factor/intracellular receptors
Integrin is an example of how cancer cells can switch the TYPES of receptors they express, favoring ones that transmit PRO-GROWTH signals
integrins loosen binding (decrease affinity) to ECM, allow cells to move, proliferate, and metastasize
ex. mutation in H-ras leads to decreases in integrin affinity for the ECM
How to intracellular transudcers act as a proto-oncogene, and provide an important example
altered form of signaling pathway protein allows them to release mitogenic signals with no stimulation by their upstream regulators
ras mutations (SOS-Ras-Raf-MAPK cascade)
What is the signaling action of ras, and what part of the cycle is blocked in a mutant ras? What is a mutation of ras an example of?
growth factor binds GF receptor –> inactive RAS is activated by converting GDP to GTP –> activation of MAP-kinase pathway –> transcription –> cell cycle progression
active RAS gets inactivated by hydrolysis of GTP (lose a phosphate). this part is blocked in a mutant ras.
example of intracellular transudcers, a class of proto-oncogenes
How do transcription factors act as a proto-oncogene? Give 3 examples
a mutation in TF results in inapprorpriate transcription that can UP REGULATE growth promoting genes, or, DOWN REGULATE growth inhibitory genes
(encourage the ones helping them out, block the ones slowing them down)
Examples: c-jun, c-fos, c-myc
Myc-Max-Mad relationship: what is this an example of
example of transcription factors as class of proto-oncogenes:
- mad-max = growth inhibitory complex, promots differentiation = good guy
- myc-max = strong growth signal = cancer
- competition of these exist in equilibrium normally, but overexpression of c-myc can shift the balance, promoting growth and impairing differentiation
Strongest anti-growth signal
RB1 pathway: regulates the transit of cells through the G1/S transition, can shut down process even if there’s a strong growth signal
“I **R **Blocking u!!”
this is what cancer cells want to eliminate
How do cancer cells acquire insensitivity to anti-growth signals, speciically RB1? Describe a few mechanisms and examples
- inhibition of RB via phosphorylation (TGF-B), protein interaction, mutation
- miRNAs can bind single stranded RNA and suppress it-does the opposite action of what the body wants to regulate oncogenes
- specifically miRNA bind to _complementary sequences _ on target mRNAs –> translational repression, RNA degradation, and gene silencing
- in cancer: up regulates oncogenes (by silencing a suppressor) or down regulates tumor suppressor genes (by silencing the tumor suppressor)
ability of tumor cell to expand is determined by these two factors. Apoptosis is the major source for which factor?
- cell proliferation
- rate of cell attrition (reduction in size) << apoptosis
What is the major mediator of intracellular stress signals?
Bcl2 family
p53- its job and what happens if you lose it
- acts like RB
- also a pro apoptotic regulator
- if you inactivate p53, you can’t regulate apoptosis, and a cell wont commit suicide when its damaged
What are the 2 common methods for evading apoptosis?
- mutation of p53 (proapoptotic regulator)
- deregulation of the PI3 kinase-AKT/PKB pathway
usually from loss of PTEN, negative regulator of AKT
Limitless proliferative potential
- what normal cells have this? what makes them capable?
- how do cancer cells acquire it?
- normally, end of chromosomes (telomeres) cant be duplicated or read by DNA polyermase, resulting in shorter ends with each replication round
- only stem cells have limitless proflieration due to TELOMERASE (adds a whole series of 6 nucleotide repeats to maintain length)
- 90% of cancer cells activate telomerase by upregulating expression of telomerase system
How might cancer stem cell targetd therapies work?
- develop chemotherapies that attack stem cells
- kills those off, remaining differentiated cells will have limited proliferative ability
- tumor loses capacity to generate cancer cell progeny, tumor regresses
conventional therapies kill only the differentiated cancer cells, and the CSCs remain, allowing the tumor to grow
- What is the limit to tumor size without new vasculature
- What are the 4 positive signals for sustained angiogenesis?
- What are 2 important negative signals?
- how do tumors activate angiogenesis?
- 110 um is the limit
- Soluble facctors and their receptors:
- vascular endothelial growth factor (VEGF)
- basic fibroblast growth factor (bFGF)
- acidic fibroblast growth factor
- transforming growth factor alpha
- Negative signals / angiogenesis inhibitors
- thrombospondin 1 (TSP)
- ß- interferon
- tumors change the balance of angiogenic inducers and inhbiiters by altering **gene transcription **
Tissue invasion and metastasis: several classes of genes are needed to tethor the tumor cell to its surroundings. List 7
- cadherins
- NCAM
- MMP (to get out of vessels)
- Met
- HGF
- Semaphorins
- Chemokine receptors
Where do the following usually spread?
- bone cancers
- breast cancers
- lung tumors
- bone cancers –> lung
- breast cancers –> bone
- lung tumors –> liver
Li-Fraumeni syndrome
what are the requirements and implications
what type of inheritance
born with only one functional copy of p53 gene
sarcoma under the age of 40, with two first degree relatives with sarcoma or another cancer before age 40
autosomal dominant
carry increased risk for development of multiple cancers (only need “1 hit” to their normal p53 gene to fully lose the protection it provides)
What are the 3 main actions of the p53 protein
- activates temporary cell cycle arrest (quiescence)
- arrest cell cycle permanently (senescence)
- trigger programmed cell death (apoptosis)
all in response to damaged DNA
HPV oncoprotein E6
binds p53, diables the protein, prevents apoptosis of cervical epithelial cells that have developed DNA damage
