Lecture 5: The Five Horsemen

Question 1

In order to get cancer, you need what five types of mutations?

Answer 1

1) Evading apoptosis.
2) Limitless replicative potential.
3) Self-sufficiency in growth signals.
4) Insensitivity to anti-growth signals.
5) Tissue invasion and metastasis.

Question 2

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?

Answer 2

Judah Folkman; no.

Question 3

What protein and protein receptor did Folkman discover that allowed tumors to make blood vessels?

Answer 3

VEGF; VEGFR

Question 4

Why have anti-angiogenic therapies not been effective in treating cancer by starving the cancer of nutrients?

Answer 4

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.

Question 5

What is the process by which tumors create their own tumor-lined channels for fluid transport independent of typical modes of angiogenesis?

Answer 5

Vascular mimicry

Question 6

What four types of mutations (emerging hallmarks) do no make tumor cells but make a tumor cell a better tumor cell?

Answer 6

1) Genomic instability and mutation
2) Tumor-promoting inflammation
3) Avoiding immune destruction
4) Deregulating cellular energetics

Question 7

Which type of emerging hallmark affects the cell’s ability to repair DNA?

Answer 7

Genomic instability and mutation

Question 8

Which type of emerging hallmark changes the way a cell produces ATP?

Answer 8

Deregulating cell energetics

Question 9

What is the most important of the 5 horsemen? How do we know?

Answer 9

Immortality; because of all the trouble the cell goes to to defend against it.

Question 10

Irreversible growth arrest; cells cannot reenter the cell cycle, and the function of the cell remains despite loss of replicative potential.

Answer 10

Replicative senescence

Question 11

What two proteins trigger replicative senescence in mouse cells?

Answer 11

ARF and p53

Question 12

The repetitive nucleotide sequence on the ends of chromosomes that protects the ends of chromosomes from deterioration or fusion with neighboring chromosomes.

Answer 12

telomeres

Question 13

Why does senescence occur over time to almost all cells?

Answer 13

Because during each cell division, a bit is lost from the telomeres on the ends of the chromosomes

Question 14

An enzyme that can prevent the loss of telomeres from the ends of chromosomes, but is mostly switched off in normally dividing adult cells.

Answer 14

telomerase

Question 15

True or false: Telomerase is an oncogene.

Answer 15

True

Question 16

What are the two components of telomerase?

Answer 16

1) TERT (enzyme)

2. TERC (RNA template)

Question 17

Why is telomere shortening good? Why is it also bad?

Answer 17

It limits the lifespan of cells, keeping them from becoming immortal (good); it also exposes DNA to damage, leading to genomic instability (bad).

Question 18

What did Todoro name his immortal mouse cells?

Answer 18

NIH3T3

Question 19

What triggers senescence in mouse cells?

Answer 19

p53 and ARF

Question 20

What causes immortality in mouse cells?

Answer 20

Either inactivation of p53 or ARF (only takes one hit)

Question 21

Why are experiments using Todoro’s immortal mouse cells often not repeatable?

Answer 21

Because some of the NIH3T3 cells have ARF mutations and some have p53 mutations

Question 22

True or false: In mouse cells only one genetic hit is needed to become immortal.

Answer 22

True

Question 23

Weinberg’s experiment: WT mouse fibroblasts + ras = ?

Answer 23

senescence (because of ARF and p53)

Question 24

Weinberg’s experiment: Todoro’s cells (NIH3T3) + RAS = ?

Answer 24

tumors (because ARF and p53 are inactivated)

Question 25

What did Weinberg call Ras?

Answer 25

A “transforming oncogene”

Question 26

What molecule did Weinberg call an immortalizing oncogene?

Answer 26

Myc; because it deactivates p53 and ARF

Question 27

Weinberg’s experiment: WT mouse fibroblasts + Myc (oncogene) + Ras = ?

Answer 27

tumors (because Myc deactivates p53 and ARF)

Question 28

How many hits are needed for a mouse cell to become immortal?

Answer 28

1

Question 29

How many genetic hits are needed for a mouse cell to become cancer?

Answer 29

2; an immortalizing oncogene and a transforming oncogene

Question 30

Weinberg study: ARF inactivated (deleted in both alleles) + Ras = ?

Answer 30

tumors

Question 31

Weinberg study: P53 inactivated + Ras = ?

Answer 31

tumors

Question 32

When the Todaro experiment was done using human cells, what does M1 represent?

Answer 32

senescence (caused by shortening telomeres)

Question 33

When the Todaro experiment was done using human cells, what does the flattening out of the graph represent?

Answer 33

inactivation of both Rb and p53 (so senescence stopped)

Question 34

When the Todaro experiment was done using human cells, what does M2 represent?

Answer 34

crisis (severe telomere loss)

Question 35

When the Todaro experiment was done using human cells, what does the sharp upward trajectory indicate?

Answer 35

Immortality (activation of telomerase)

Question 36

How many hits does it take to get immortality in humans?

Answer 36

3 (Rb, p53, and telomerase)

Question 37

What 5 hits did Weinberg use to cause cancer in human cells?

Answer 37

1) Rb
2) p53
3) telomerase
4) Ras
5) Small T

Question 38

Conceptualizes the mass of tumor is just packed tumor cells.

Answer 38

Reductionist (old) view

Question 39

Conceptualizes tumor as made of many different kinds of cells (some tumor cells, some normal)

Answer 39

Heterotypic view

Question 40

What treatment option does the heterotypic view of cancer open up?

Answer 40

We can treat the microenvironment of a local tumor, we can keep it from spreading; this would make cancer a chronic disease.