Neoplasia 3 Lecture

Question 1

Tumor suppressor genes

Answer 1

Inactivation of genes that normally suppress cell proliferation
- loss of function of these genes are key in what initiates carcinogenesis in majority of human cancers

Question 2

Tumor suppressor retinoblastoma gene

Answer 2

Active when dephosphorylated or underphosphorylated and inactivated when hyperphosphorylated (prevents S phase by binding to E2F)
- Growth factors induce phosphorylation and growth inhibitors dephosphorylate

Question 3

Pathogenesis of Retinoblastoma

Answer 3

Sporadic form: both mutations acquired after birth
Familial form: inherited one mutation and the second was acquired after birth
– Has to be homozygous for the gene, one is not enough

Question 4

p53

Answer 4

Guardian of the genome, gate keeper against tumor genesis, mutated in greater than 50% of all cancers
- Homozygous loss, DNA damage goes unrepaired and cells carrying mutant genes continue to divide –> cancer

Question 5

How does p53 prevent neoplastic transformation?

Answer 5

Activation of temporary cell cycle arrest
Induction of DNA repair
Activation of permanent cell cycle arrest (senescence)
Induction of apoptosis

Question 6

What happens if DNA is damage and p53 is activated and binds?

Answer 6

Transcription dependent and independt effects on targets

p21 and GADD45 lead to successful repair (normal cell again) BUT BAX and GADD45 lead to repair failure (apoptosis)

Question 7

What happens if DNA is damage and p53 is not activated?

Answer 7

No cell arrest, no DNA repair –> mutant cells that go through expansion and additional mutations leading to a malignant tumor

Question 8

What happes in DNA is damage and p53 is activated and binds involving microRNA?

Answer 8

mir-34 is transcribed and processed leading to inhibition of translation of growth-promoting genes (senescence) OR inhibits translation of anti-apoptosis genes (apoptosis)

Question 9

Define senscence

Answer 9

Process of deterioration with age

Question 10

Telomerase activity?

Answer 10

Telomers are shortened and the ends will fuses
p53 would recognize this and kill it but if you do not have it this moves on and divides –> possibility of uncontrolled breaks leading to mitotic catastrophe or formation of new doubel stranded breaks + more telomers leading to reexpression and ultimately cancer

Question 11

miRNA possibilities?

Answer 11

Reduce activity: inhibit translation of oncoproteins
Over-activity: inhibit tumor suppressor genes leading to cancer
—-Depends on where the microRNA binds

Question 12

APC

Answer 12

beta-catenin controlled by APC prevent genes stimulate cell division

• Wnt signaling inhibits the destruction of complex and nuclear translocation of beta-catenin
• When APC is mutated or absent, the destruction of beta-catenin cannot occur so it cannot enter the nucleus

Question 13

BRCA-1/2

Answer 13

DNA repair genes

- 80% of breast cancer cases as well as ovarian cancers and if within the germ lines than ovaries and male breast cancer

Question 14

NF-1

Answer 14

Loss impairs the conversion of active GTP bound ras to inactive ras –> continuously stimulated to divide

Question 15

Cell surface receptors (TGF-beta)

Answer 15

Upregulates the growth inhibitory genes

- Cancer: mutated receptors prevent the growth-restraining effects of TGF-beta

Question 16

WT-1

Answer 16

Tumor suppressor gene

– Development of Wilms tumors

Question 17

Genes that regulate apoptosis

Answer 17

BCL-2 prevents programmed cell death
- Over expression leads to extended cell survival —> proliferation
BAX controls by regulating the exit of cytochrome C from the mito, activating caspase 9 (proteolytic enzyme) –> apoptosis

Question 18

Mut-S-Homolog 2 and human Mut-L-Homolog1

Answer 18

Involved in DNA mismatch repair

- Accumulation of mismatch –> cancer

Question 19

Kinetics of tumor cell growth

Answer 19

Doubling time of tumor cells
Growth Fraction
Cell production and loss

Question 20

Doubling time of tumor cells

Answer 20

Cell cycle has the same five phases

Usually equal to or longer than normal cells

Question 21

Growth fraction

Answer 21

Proportion of cells within the tumor population that are in the replicative pool
– Usually about 20%

Question 22

Cell production and loss

Answer 22

Imbalance between cell production and cell loss

• More rapid growth
• Unwanted growth = tumor (but can be benign)

Question 23

Two tumor angiogenic factors are?

Answer 23

Vascular endothelial growth factor
Basic fibroblast growth factor (angistatin, endostatin, vasculostatin)
- Tumor growth is controlled by the balance between angiogenic and antiangiogenic factors

Question 24

Detachment of tumor cells from each other?

Answer 24

Cell remain attached to each other by adhesion molecules (cadherins)
Down regulation of E-cadherins, reducing the adhesiveness of tumor cells

Question 25

Attachment to matrix components?

Answer 25

Tumor cells detach from each other because of reduced adhesiveness and cells then attach to the basement membrane via the laminin and fibronectin cell surface receptors

Question 26

Degradation of extracellular matrix?

Answer 26

Tumor cells secrete proteolytic enzymes that degrade the matrix components and create passageways for migration

Question 27

Migration of tumor cells

Answer 27

Autocrine motility factors and cleavage products

Question 28

How does a cell move through circulation and get to another site?

Answer 28

Detach from each other
Attach to the membrane
Degrade the matrix
Migrate via autocrine motility factors and cleavage products