Lecture 5: The Five Horsemen Flashcards
In order to get cancer, you need what five types of mutations?
1) Evading apoptosis.
2) Limitless replicative potential.
3) Self-sufficiency in growth signals.
4) Insensitivity to anti-growth signals.
5) Tissue invasion and metastasis.
Who theorized that tumors grow outward searching for a blood supply and that one could kill a tumor by starving it of its blood supply? Was he right?
Judah Folkman; no.
What protein and protein receptor did Folkman discover that allowed tumors to make blood vessels?
VEGF; VEGFR
Why have anti-angiogenic therapies not been effective in treating cancer by starving the cancer of nutrients?
1) These therapies only affect the primary tumor and the primary tumor is not the reason patients die; it is metastasis that kills.
2) Tumor cells use vascular mimicry to get nutrients.
What is the process by which tumors create their own tumor-lined channels for fluid transport independent of typical modes of angiogenesis?
Vascular mimicry
What four types of mutations (emerging hallmarks) do no make tumor cells but make a tumor cell a better tumor cell?
1) Genomic instability and mutation
2) Tumor-promoting inflammation
3) Avoiding immune destruction
4) Deregulating cellular energetics
Which type of emerging hallmark affects the cell’s ability to repair DNA?
Genomic instability and mutation
Which type of emerging hallmark changes the way a cell produces ATP?
Deregulating cell energetics
What is the most important of the 5 horsemen? How do we know?
Immortality; because of all the trouble the cell goes to to defend against it.
Irreversible growth arrest; cells cannot reenter the cell cycle, and the function of the cell remains despite loss of replicative potential.
Replicative senescence
What two proteins trigger replicative senescence in mouse cells?
ARF and p53
The repetitive nucleotide sequence on the ends of chromosomes that protects the ends of chromosomes from deterioration or fusion with neighboring chromosomes.
telomeres
Why does senescence occur over time to almost all cells?
Because during each cell division, a bit is lost from the telomeres on the ends of the chromosomes
An enzyme that can prevent the loss of telomeres from the ends of chromosomes, but is mostly switched off in normally dividing adult cells.
telomerase
True or false: Telomerase is an oncogene.
True
What are the two components of telomerase?
1) TERT (enzyme)
2. TERC (RNA template)
Why is telomere shortening good? Why is it also bad?
It limits the lifespan of cells, keeping them from becoming immortal (good); it also exposes DNA to damage, leading to genomic instability (bad).
What did Todoro name his immortal mouse cells?
NIH3T3
What triggers senescence in mouse cells?
p53 and ARF
What causes immortality in mouse cells?
Either inactivation of p53 or ARF (only takes one hit)
Why are experiments using Todoro’s immortal mouse cells often not repeatable?
Because some of the NIH3T3 cells have ARF mutations and some have p53 mutations
True or false: In mouse cells only one genetic hit is needed to become immortal.
True
Weinberg’s experiment: WT mouse fibroblasts + ras = ?
senescence (because of ARF and p53)
Weinberg’s experiment: Todoro’s cells (NIH3T3) + RAS = ?
tumors (because ARF and p53 are inactivated)
What did Weinberg call Ras?
A “transforming oncogene”
What molecule did Weinberg call an immortalizing oncogene?
Myc; because it deactivates p53 and ARF
Weinberg’s experiment: WT mouse fibroblasts + Myc (oncogene) + Ras = ?
tumors (because Myc deactivates p53 and ARF)
How many hits are needed for a mouse cell to become immortal?
1
How many genetic hits are needed for a mouse cell to become cancer?
2; an immortalizing oncogene and a transforming oncogene
Weinberg study: ARF inactivated (deleted in both alleles) + Ras = ?
tumors
Weinberg study: P53 inactivated + Ras = ?
tumors
When the Todaro experiment was done using human cells, what does M1 represent?
senescence (caused by shortening telomeres)
When the Todaro experiment was done using human cells, what does the flattening out of the graph represent?
inactivation of both Rb and p53 (so senescence stopped)
When the Todaro experiment was done using human cells, what does M2 represent?
crisis (severe telomere loss)
When the Todaro experiment was done using human cells, what does the sharp upward trajectory indicate?
Immortality (activation of telomerase)
How many hits does it take to get immortality in humans?
3 (Rb, p53, and telomerase)
What 5 hits did Weinberg use to cause cancer in human cells?
1) Rb
2) p53
3) telomerase
4) Ras
5) Small T
Conceptualizes the mass of tumor is just packed tumor cells.
Reductionist (old) view
Conceptualizes tumor as made of many different kinds of cells (some tumor cells, some normal)
Heterotypic view
What treatment option does the heterotypic view of cancer open up?
We can treat the microenvironment of a local tumor, we can keep it from spreading; this would make cancer a chronic disease.
