Robbins Neoplasia pg 45-

Question 1

How does an APC mutation affect the WNT pathway?

Answer 1

When APC is mutated/absent, beta-catenin is not degraded

Therefore, beta-Catenin can translocate into the nucleus and bind TCF

TCF can coactivate genes and drive cell proliferation (as if they were being signaled to prolif by WNT)

Question 2

Intrinsic or extrinsic apoptosis pathway:

Intracellular adapter protein recruits procaspase-8, ultimately generating caspase-8

Answer 2

Extrinsic

Question 3

Intrinsic or extrinsic apoptosis pathway:

mitochondrial permeabilization

Answer 3

intrinsic

Question 4

Intrinsic or extrinsic apoptosis pathway:

“death receptor” pathway, which cleaves DNA

Answer 4

extrinsic

Question 5

Intrinsic or extrinsic apoptosis pathway:

regulated by the balance of BAX/BAK (pro-apop) and BCL (anti-apop) molecules

Answer 5

intrinsic

Question 6

How is the survival of lymphomas affected by overexpression of BCL2?

Answer 6

Reduced apoptosis (longer survival time)

*BCL2 is anti-apoptotic

Question 7

2 mechanisms by which cells prevent tumor growth (in a big way)

Answer 7

1. apoptosis

2. Beclin-1 induced autophagy

Question 8

Tumors block autophagy by:

Answer 8

accumulate mutations to inhibit it

Question 9

Tumors corrupt autophagy in order to:

Answer 9

generate parts so it can continue to grow

Question 10

How does DNA repair machinery interpret shortened telomerase?

Answer 10

as dsDNA breaks (which result in p53/RB arresting the cell cycle)

Question 11

In the absence of the appropriate DNA repair mechanisms, what is generated from shortened telomeres?

Answer 11

dicentric chromosomes (they are stuck together), which ultimately generates mitotic catastrophe

*once the cell eneters anaphase, the dicentric chromosome is ripped apart–generating brand new dsDNA breaks

Question 12

What three things must tumors do in order to continue to grow indefinitely?

Answer 12

1. loss of growth restraints
2. avoidance of cellular senescence
3. avoidance of mitotic catastrophe

Question 13

How can a cell prevent the bridge-fusion-breakage cycles that occur when cells get old?

Answer 13

reactivate telomerase
(by the time it does this, a bunch of mutations probably accumulated)

Question 14

T/F: Telomerase is active in all somatic cells in the body, but is more efficient in tumors.

Answer 14

F: active in germ cells and (virtually) all tumor cells, but not very active or absent somatic cells

Question 15

According to this lovely picture in the text, what precedes the bridge-fusion-breakage cycle?

Answer 15

loss of p53

Question 16

If telomerase is highly active in a tumor, what would you expect the cell’s karyotype to look like?

Answer 16

“complex”
genomic instability –> mutations
(until the telomerase can be expressed in the cell)

Question 17

What is necessary for a tumor to extend beyond 1-2mm?

Answer 17

vascularization

Question 18

What makes tumor vascularization abnormal?

Answer 18

leaky

odd connection patterns

Question 19

Why do tumors require angiogenesis?

Answer 19

eliminate waste
nutrients/oxygen
access to vasculature for metastasis

Question 20

How does p53 prevent tumor angiogenesis?

Answer 20

induces TSP-1 synthesis

angiogenesis inhibitor

Question 21

What protein binds to HIF-1alpha (hypoxia inducible factor), resulting in its degradation?

Answer 21

von Hippel-Lindau protein

this occurs in “normocix settings”

Question 22

How is HIF-1alpha affected by hypoxia?

Answer 22

it cannot be recognized by VHL protein, thus it can enter the nucleus and drive VEGF transcription

Question 23

Pathway which regulates the branching and signaling of new vessels:

Answer 23

NOTCH

activation of pathway is VEGF driven

Question 24

Four steps involved in invasion of ECM:

Answer 24

1. Loosening of tumor cells (via loss of e-cadherins)
2. Degradation of basement membrane and interstitial CT
   (proteolytic enzymes tumor or stromal cells)
3. Changes in attachment of tumor cells to ECM proteins
   (partially due to MMP cleavage of basement membrane, which generates novel attachment sites)
4. Locomotion
   (through degraded basement membrane and zones of matrix proteolysis; regulated by growth factors and matrix products)