Cancer (I & II) Flashcards
What are the hallmarks of cancer?
1) Promote cell division
2) Inhibit apoptosis
3) Promote immortality
4) Promote angiogenesis
5) Promote metastasis
What does immortality mean on a molecular level?
Telomeres of chromosomes are no longer shortened due to expression of telomerase activity
The cancer cells will divide infinitely
What is angiogenesis?
Blood vessel growth into tumors
What cell transition is associated with metastasis?
Epithelial to mesenchyme transition (EMT)
What are the two major pathways that can lead to cell death?
1) Death receptor pathway (extrinsic)
2) Mitochondrial signal transduction pathway (intrinsic)
What signal leads to activation of the death receptor pathway?
Fas-Ligand binds to Ras receptor on cell surfaces
What is the name of the protein complex associated with the death receptor pathway?
DISC (Death inducing signaling complex)
Describe the major steps in the death receptor pathway.
Fas ligand binds to Fas death receptor and stimulates activation of caspase 8 through cytoplasmic adaptor proteins (FADD),
Caspase 8 triggers the caspase cascade leading to apoptosis
What signal leads to the activation of the mitochondrial signal transduction pathway?
Activation of pro-apoptotic BH proteins (Bak, Bax) on the surface of the outer mitochondrial membrane
What is the name of the protein complex associated with the mitochondrial signal transduction pathway?
The apoptosome
Describe the major steps in the mitochondrial signal transduction pathway
Bad/Bax on outer membrane create pores that allow cytochrome c to exit into the cytoplasm
Cytochrome c complexes with Apaf1 and caspase 9 to form the apoptosome
The apoptosome triggers the caspase cascade leading to apoptosis
What is the major regulatory protein of the intrinsic apoptosis (mitochondrial pathway)?
Bcl-2 regulates the intrinsic apoptosis pathway by sequestering Bak/Bax to control the release of cytochrome c
Are BH proteins pro or anti-apoptotic?
They can be either. Bcl-2 and Bcl-Xl are anti-apoptotic, but Bad, Bax, Bak and Bid are pro-apoptotic
How do Bid and Bad affect the release of cytochrome c?
They compete with Bak and Bax for binding to Bcl-2/Bcl-XL, leading to release of Bak and Bax
Therfore, Bid and Bad increase the release of cytochrome c
What does the XIAP protein do?
IAP = inhibitor of apoptosis
XIAP inhibits protease activity in order to keep the caspases inactive
XIAP is inactivated by Smac/DIABLO to promote apoptosis
What determines the sensitivity to apoptotic stimuli?
The relative balance between pro-apoptotic and apoptotic proteins active on the cell
Describe the pathway of apoptosis that is independent from cytochrome c release
Endo G and AIF cause apoptosis by degrading nuclear DNA into polynucleosomes
True or false: Ras activates numerous parallel kinase pathways leading to changes in gene transcription
True. Although we focused on the Ras-Raf-Mek-Erk pathway, several other parallel pathways exist
True or false: Ras activation leads to cell death
False
Ras activation can lead to cell death or survival. The survival signals usually win out, but in some cases cell death is promoted by increased Ras activity
Describe the effect of activation of Jnk by Ras
Apoptosis via 2 pathways:
1) Jnk phosphorylates p53, making it more difficult to degrade via Mdm2 and thus increases active p53 (Promotes apoptosis)
2) Jnk phosphorylates Bcl-2, which promotes loss of the anti-apoptotic Bcl-2 from the mitochondrial membrane, thus promoting apoptosis
What effect does activation of MAPKKK (Raf) have on Bad proteins on the mitochondrial membrane?
MAPKKK phosphorylates Bad, thus promoting removal from the pro-apoptotic protein.
Promotes cell survival
What is ARF?
A tumor suppressor protein that promotes the degradation of Mdm2, which results in the stabilization of active p53
ARF is stimulated by Myc and E2F
Describe the differences between benign and malignant tumors
Benign tumors are pre-cancerous non-invasive cells that are hyperproliferative
Malignant tumors are invasive. They are capable of degrading the basement membrane basal lamina leading to metastasis
When does a mesenchymal to epithelial state transition occur?
When metastatic cells reach their target organ, they polymerize and return to epithelial state
Describe the process of metastasis
Benign tumor cells grow in the epithelium. Cells break through the basal lamina and invade capillaries to travel elsewhere. Cancer cells can adhere to blood vessel walls at target organs and exit the bloodstream to form secondary tumors.
Describe the process of cancer cells breaking through the basal lamina
- Laminin receptors on the cancer cell surface bind to laminins found on the basal lamina.
- The tumor cell (and neighboring cells) produces and secreates proteases that degrade type IV collagen
- The tumor cell can then cross through the degraded basal lamina and travel elsewhere
Describe the molecular pathway leading to breakdown of the basement membrane and extracellular matrix
1) Urokinase Plasminogen activator cleaves plasminogen into plasmin, an active protease
2) Tumor cells produce procollagenases
3) Plasmin can cleave procollagenases into collagenases (MMPs), which can degrade the basement membrane and ECM
Describe the molecular steps involved in angiogenesis
Tumor cells produce growth factors VEGF and FGF
VEGF/FGF promotes the proliferation of endothelial cells
What are the two fragments that plasminogen is cleaved into by uPA?
N-terminal fragment = angiostatin
C-terminal fragment = plasmin
What is the effect of angiostatin?
Angiostatin inhibits angiogenesis, keeping secondary tumors from growing into large tumors.
This activity is not as potent as the pro-angiogenic plasmin signal in primary tumors
What can collagen XVIII be cleaved into by plasmin?
C-terminal fragment = Endostatin, which has the same effect as angiostatin, inhibits angiogenesis
What are cancer stem cells?
The cancer cells that can self-renew to produce additional malignant stem sells
How are cancer stem cells formed?
Either from normal stem cells that sustain mutations making them cancerous, or from more differentiated cells obtaining stem cell properties
What are cancer transit amplifying cells?
Cells in tumors that do not have stem cell markers, but are hyperproliferative
These cells can revert to obtain stem cell properties
What role do ABC transporters play in stem cells?
ABC transporters are highly expressed in cancer cells, which gives them drug resistance
Are proliferation rates low or high in stem cells?
Stem cell proliferation rates are low
- This gives them drug resistance
- *Transit amplifying cells have high proliferation rates
What signaling proteins are required by cancer stem cells?
TGF-B and Wnt, which induce pluripotency giving the cell a stem cell phenotype
What proteins are involved with Wnt activation?
B-catenin, activated Myc, and downregulated E-cadherins
Describe the role that TGF-B plays in normal and cancer cells
In normal cells, TGF-B is a tumor suppressor that inhibits cell proliferation and migration
In cancer cells, a different TGF-B receptor leads to the opposite effect: stimulation of proliferation and migration
Describe the changes made during the epithelial to mesenchyme transition
1) Loss of E-cadherin
2) Loss of ECM contacts, cells take on round shape
3) Survival signals (PI3K/AKT) and Ras/MAPK pathways activated
4) Increased protease secretion and activity
How does expression of telomerase affect chromosomal stability?
Low telomerase: chromosomal instability
High telomerase: Immortality
Describe the expression of telomerase and p53 during the development of cancer
1) Initially, telomerase is not active.
2) If p53 is mutated, the cell will replicate without control
3) With low telomerase and no p53, genomic instability will occur
4) Telomerase reactivation leads to survival of mutant cells, and thus cancer
What is a driver mutation?
Mutations essential to the maintenance of transformed phenotype
There are very few (5-7) per cancer type
What are passenger mutations?
Non-essential mutations that do not affect the cancer phenotype
These occur from genomic instability
If one driver mutation occurs, will the individual develop cancer?
Not necessarily. Multiple driver mutations are required to cause a cancer in human cells.
This is why cancer rates increase with age, because there has been more time for mutations to occur
Are tumor cells derived from many mutated cells, or only one?
Tumors are derived from a single abnormal cell
What experiment demonstrates heterogeneity of cells within a tumor?
If you remove cells from opposite sides of a tumor and test for metastatic potential, one set of cells will have a much greater metastatic potential resulting in a more severe cancer
Is a mutagenic event sufficient to cause cancer?
No. Mutagenic events produce driver mutations, but tumor promoter mutations (often growth factor) mutations are required to initiate carcinogenesis
If an individual moves into a different culture, does their cancer risk change?
Yes. Environmental factors of culture and diet play a huge role in risk for cancer
What percentage of cancer can be prevented by improved diet?
About 35% of cancers could be prevented by changing diets
Describe the mutations that occur during the development of colorectal cancer
1) Apc is lost first leading to the formation polyps, early adenomas
2) K-Ras is activated
3) Smad4 and other TSGs are lost
4) p53 is lost
5) Additional mutations lead to metastasis
How do order and type of mutations affect the cancer type?
Certain cancer types have a characteristic group of mutations that are observed in that type
-The order of mutations matters
What type of analysis for cancer is increasingly used in “personalized medicine”?
Proteomic analyses to characterize the type of cancer and make personalized treatment plans