Neoplasia 5

Question 1

What are the apoptotic pathway genes frequently involved in human cancer?

Answer 1

1. Decreased pro-apoptotic activity:

decrease in Bax (intrinsic), FAS (extrinsic), p53

2. Increased anti-apoptotic activity:
   increase in BCL2
   increase in FLIP, which inhibits caspase 8

Question 2

How and when does p53 affect apoptosis?

Answer 2

If permanent DNA damage, then p53 leads to transcription of pro-apoptotic genes (BAX, PUMA)

Question 3

t(14, 18) is a characteristic translocation from 14 -> 18. What is on 14, what is on 18? What does this indicate? How can you identify?

Answer 3

14 has immunoglobulin heavy chain
18 has BCL2

BCL2 is then overexpressed next to transcriptionally active igH,
inhibiting apoptosis

karyotype, FISH
indicates a malignant neoplasm of mature B-cells, or “follicular lymphoma”

Question 4

What is the most common low-grade non-Hodgkin’s Lymphoma? If it transforms, what is the common mutation?

Answer 4

follicular lymphoma, commonly associated with t(14,18) in 90%

TP53 mutation in up to 80% transformation

Question 5

Cancer cells in stress, nutrient-limited environments, rely on ____ pathway. What does this do?

Answer 5

TOR pathway, allows autophagy so they digest own organelles to produce nutrients

Question 6

Cancer cells evade senescence, which naturally occurs after 60-70 cell divisions due to ___.
They do so by what activity of what enzyme?

Answer 6

Cancer cells evade senescence, which naturally occurs after 60-70 cell divisions due to telomere shortening promoting cell cycle arrest

Telomerase (mostly active in germ and stem and cancer cells) adds those telomeres back on to resist senescence.

Question 7

If p53 is nonfunctional, what happens to chromosomes that have shortened telomeres?

Answer 7

Normally, p53 would detect DNA breaks and undergo apoptosis.

But nonhomologous end-joining pathways happens, DNA breaking and joining and mitotic crisis occurs–cell death

telomerase, if activated after induction of DNA damage, puts cells at high risk for malignant transformation. CANCER

Question 8

How do you treat cancer?

Answer 8

Low doses of telomerase inhibitors with chemotherapy

Question 9

Cancers have cancer stem cells that can self-renew. What are they derived from?

Answer 9

either transformed tissue stem cells (intrinsic)

or differentiated cancer cells that s via mutation reacquire stem cell properties (extrinsic)

Question 10

What is neo-angiogenesis? tumors above what size cannot grow without this?

Answer 10

formation of new vessels (angiogenesis) to supply a neoplasm

1- 2 mm

Question 11

The angiogenic switch involves pro-angiogenic signals going up, including VEGF. Who secretes it, and who expresses its receptor

Answer 11

VEGF: vascular endothelial growth factor
secreted by tumor/stromal cells (macrophages, endothelium, fibroblasts)

receptor is on:

1. endothelium -> angiogenesis
2. regulatory T cells ->inhibit anti-tumor immune response
3. tumor cells: renewal of cancer stem cells

Question 12

Other than VEGF, what is another pro-angiogenic signal? Where is it stored, and how does it exert its effects?

Answer 12

bFGF: basic fibroblast growth factor: normally stored in extracellular matrix, activated by cleavage via proteases.

induces angiogenesis predominantly via effects on local endothelial cells.

Question 13

Three angiogenesis inhibitors include:

Answer 13

1. thrombospondin
2. angiostatin
3. endostatin

Question 14

What does BCL2 do? when is it overexpressed

Answer 14

anti-apoptotic: stabilizes mitochondrial membrane to prevent the release of cytochrome c

follicular lymphoma because of t14:18

Question 15

For invasion of ECM, how does epithelial tumor loosen intercellular junctions?

Answer 15

E-cadherin loss of function (you can use IHC and stain to see loss )

Question 16

For invasion of ECM, how do tumor cells degrade extracellular matrix?

Answer 16

secrete proteolytic enzymes: matrix metalloprotease (MMPs) which remodel insoluble components of basement membrane and stroma, release growth factors in ECM

(you can use IHC and stain to see increased expression)

Question 17

What do MMPs cleave and how does this allow for migration?

Answer 17

They cleave basement membrane proteins collagen IV and laminin. this is what integrins of the cell usually bind to, so loss of adhesion…migration

Question 18

What directs migration and invasion of tumor cells?

Answer 18

chemotaxis towards signasl provided by tumor cell-derived cytokines, cleavage products of matrix components, growth factors,

Question 19

After tumor cells make it to the blood, they risk destruction due to anoikis, attack by immune cells, and mechanical shear stress. What is anoikis?

Answer 19

Apoptosis stimulated by loss of adhesion

Question 20

How do tumor cells enhance survival in blood?

Answer 20

They adhere to eachother (travel in packs), as well as to platelets in circulation. They also stimulate coagulation cascade to form a protective fibrin clot.

Question 21

What two elements are involved in tumor cell binding endothelium at site of vascular exit?

Answer 21

CD44 adhesion molecule on tumor cells

binds to hyaluronate on endothelial cells

Question 22

Prostate carcinomas often metastasize to ____

Lung to _____

Colon to ____

Answer 22

Prostate -> bone
Lung -> adrenal
Colon -> liver