Neoplasia 2 8-10-15

Question 1

What are the fundamental principles of cancer?

Answer 1

1. cancer is a genetic disorder caused by DNA mutations
2. most mutations are spontaneous or induced by environmental insults
3. Some mutations are inherited in the germ line
4. cancer arises from clonal expansion of a single progenitor cell that has incurred damage (monoclonal)

Question 2

What are the 4 target regulatory genes?

Answer 2

1. growth promoting
2. growth inhibiting tumor suppressor gene
3. genes that regulate apoptosis
4. genes involved in DNA repair

Question 3

What are proto-oncogenes?

Answer 3

normal cellular genes whose products promote cell proliferation

Question 4

oncogenes

Answer 4

mutant or over-expressed versions of normal proto-oncogenes

• function autonomously
• encode transcription factors, growth regulatory proteins and cell survival proteins
• lost dependence on normal growth promoting signals
• potent carcinogenic factors
• dominant-mutation of a single allele can lead to cellular transformation

Question 5

RAS the most commonly mutated proto-oncogene is a member of what family? What does it do?

Answer 5

-G protein that binds GTP(active) and GDP(inactive)

• active RAS stimulates downstream regulators of proliferation
• cell forced into continuously proliferating state

Question 6

What are tumor suppressor genes?

Answer 6

normally prevent uncontrolled growth

• mutation leads to transformed cell
• usually both normal alleles must be damaged

Question 7

What does RB do?

Answer 7

blocks G1—>S phase of the cell cycle

Question 8

WHat are the associated tumor with mutation of RB?

Answer 8

-retinoblastoma, osteosarcoma

Question 9

RB is the basis for the Knudson’s two hit hypothesis, what is Knudson’s two hit hypothesis?

Answer 9

cancer is the result of accumulated mutations to a cell’s DNA

Question 10

What is a retinoblastoma?

Answer 10

intra-ocular neoplasm of children

• median age at presentation 2 years
• poor vision, strabismus, white-ish hue to pupil
• neuronal origin

Question 11

What do you see in a higher-power view of retinoblastoma?

Answer 11

-Flexner Winterstein rosettes and numerous mitotic figures

Question 12

How does RB affect E2F?

Answer 12

Hyperphosphorylated doesn’t bind to E2F
–>transcriptional activation

Hypophosphorylated binds E2F
—>transcriptional block

Question 13

Whats the difference between the sporadic form of retinoblastoma and the familial form?

Answer 13

• sporadic-2 hits-older

- familial-1 hit- younger

Question 14

What does P53, the most commonly mutated gene in cancer do? What are the associated tumors?

Answer 14

blocks G1–> S phase in cell cycle

• most human cancers
• Li Fraumeni Syndrome

Question 15

What 3 things does the p53 do in face of stress?

Answer 15

1. activates temporary cell cycle arrest(quiescence)
2. induces permanent cell cycle arrest (senescence)
3. triggers programmed cell death (apoptosis)

Question 16

What is Li-Fraumeni syndrome?

Answer 16

• patient inherit one defective copy of p53 in the germ line
• one additional hit
• 25X greater risk of developing cancer by age 5-sarcomas, breast cancer, leukemia, brain tumors, adrenal cortex carcinomas, multiple primary tumors

Question 17

What two proteins are anti-apoptotic?

Answer 17

BCL-2 and BCL-XL

Question 18

What two proteins are pro-apoptotic, intrinsic pathway? How do they work?

Answer 18

Bax and Bak
-poke holes in mito membrane 
-cyto c leaks out
-activates caspases
-nucleus starts fragmenting 
-cells starts pinching portions off
-phagocytes come
Apoptosis

Question 19

What is the extrinsic death receptor pathway?

Answer 19

fas-death receptor

• caspases 8-9 initiators
• other caspase executioners

-responsible for elimination of self reactive lymphocytes

Question 20

What happens if BLC-2 is activated by translocation?

Answer 20

perpetuation of anti-apoptosis
-follicular b-cell lymphoma
t(14;18)

Question 21

What things lead need to happen for cancer to occur?

Answer 21

1. loss of growth restraints
2. limitless replicative potential
   - activation of telomerase
3. sustained angiogenesis
4. malignant neoplasms develop the ability to evade and metastasize

Question 22

What do new endothelial cells secrete?

Answer 22

PDGF

insulin-like growth factor

Question 23

What is an inducer and inhibitor of angiogenesis?

Answer 23

Inducer: VEGF

• Hypoxia inducible factor (HIF-1alpah) transcription factor
• von hippel lindau (VHL) suppressor

Inhibitor: Thrombospondin 1 (TSP-1)

Question 24

Is there a homing mechanism that causes certain cancers to spread to certain places?

Answer 24

yes

Question 25

What is the sequence of events in the invasion of the epithelial basement membranes by tumor cells?

Answer 25

1. E-cadherins mediate adhesion of epithelial cells-function lost in some cancers–>facilitates detachment from primary tumor
2. degradation of basement membrane and interstitial connective tissue
3. attachment of cells to ECM proteins
4. migration of tumor cells through degraded basement membrane and zones of matrix proteolysis

Question 26

Tumors start out as monoclonal but as new subclones arise what happens?

Answer 26

mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive