Lect 21 - Carcinogenesis: Molecular Hallmarks of Cancer Cells

Question 1

how can carcinogenesis be modelled using a Darwinian process of natural selection

Answer 1

spontaneous replication errors in a cell population can give a selective growth advantage

Question 2

what are caretaker genes?

Answer 2

Caretaker genes - maintain genetic stability by repairing damaged DNA and replication errors

Mutant forms of these genes cause genomic instability

Question 3

what are the types of Tumour suppressor genes (TSGs)

Answer 3

GATEKEEPERS

CARETAKERS

Question 4

what are GATEKEEPERS

Answer 4

Negative regulators of the cell cycle and proliferation
Positive regulators of apoptosis
Positive regulators of cell differentiation

Question 5

what is the idea of a second hit?

Answer 5

as two copies of genes, two mutations are required to completely take out a TSG.

Question 6

in terms of caner “hits” what is significant about familial cancer syndromes?

Answer 6

In the case of a familial cancer syndrome every cell in the individuals body will carry the first hit, meaning only one is required to inactivate a TSG.

Question 7

what gene is affected in Familial breast cancer

Answer 7

BRCA1, BRCA2 (both care

Question 8

what gene is affected in Hereditary non-polyposis colorectal cancer?

Answer 8

hMLH1, hMSH2 (both care)

Question 9

what gene is affected in Familial adenomatous polyposis?

Answer 9

APC (gate)

Question 10

what gene is affected in Li-Fraumeni?

Answer 10

p53 (gate AND care)

Question 11

what gene is affected in Retinoblastoma

Answer 11

RB1 (gate)

Question 12

what is the lifetime risk of a carrier of a familial cancer syndrome developing cancer?

Answer 12

70-90%

Question 13

what are proto-oncogenes?

Answer 13

promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis

Question 14

what casues proto-oncogenes to become Oncogenes

Answer 14

mutations leading to activated versions or increased expression of proto-oncogenes

Question 15

how can translocation activate an oncogene?

Answer 15

Translocation of a proto-oncogene from a low transcriptionally active site to an active site - aberrant expression of the oncogene

Question 16

how can a point mutation activate an oncogene?

Answer 16

substitution of a single base pair can alter an amino acid in the protein causing it to become hyperactive

Question 17

how can amplification cause activation of an oncogene?

Answer 17

by insertion of multiple copies of an oncogene – increased expression

Question 18

how many genetic alterations are required to transform a normal cell into a neoplastic cell?

Answer 18

Minimum of 3. there will be loads before there are 3 important enough to cause neoplasm.

tumorigenesis has many many steps.

Question 19

what are the hallmarks of cancer cells?

Answer 19

self sufficient for growth signals
insensitive to antigrowth signals
tissue invasion and metastasis
limitless potential for replication
sustained angiogenesis
evasion of apoptosis.

Question 20

give an example by which cancer cells become self sufficient for growth signals

Answer 20

mutated RAS which is always active as it is unable to cleave phosphate from GTP to become inactive.

makes cell think there is GF around.

Question 21

how do cancer cells become resistant to negative growth factors

Answer 21

Inactivation of the RB gene

Question 22

what is the RB gene?

Answer 22

a key regulator of cell cycle by preventing progression from G1 to S phase.

Question 23

why are cancer cells immortal?

Answer 23

Tumour cells express telomerase that replaces the lost material and cells become immortal.

Question 24

why do normal cells have a limited lifespan?

Answer 24

After a number of cell divisions they die due to loss of DNA from the telomeres.

Question 25

which two genes are important in cancer cells avoiding apoptosis?

Answer 25

TP53 and P53.

Question 26

what does P53 do?

Answer 26

induces cell cycle arrest to allow repair of DNA damage, and causes apoptosis if damage is too great

Question 27

what does TP53 do?

Answer 27

codes for transcription factor that induces transcription of >100 genes.

TP53 inactivation leading to loss of apoptotic response is the most common genetic abnormality in human tumours

Question 28

what is angiogenesis

Answer 28

new blood vessels

Question 29

at what size do tumours need angiogenesis to get any bigger

Answer 29

2mm

Question 30

what growth factors are released by tumour cells to cause angiogenesis?

Answer 30

vascular endothelial growth factor

Question 31

what molecule that holds Epithelial cells together is lost in cancerous cells?

Answer 31

E-cadherin

Question 32

what does loss of E-cadherin cause?

Answer 32

epithelial-mesenchymal transition (EMT)

allows cells to break through basement membrane and invade the underlying stroma

Question 33

what genetic testing can be used to estimate prognosis of cancers?

Answer 33

Gene expression profiling - for example subtypes with different translocations can be better or worse for outcome.

Question 34

give an example of a drug that can only be used in cancers expressing certain types of mutated receptors.

Answer 34

Herceptin is an antibody drug targeted to HER2 and dampens the effects of an overactive HER2 receptor

(HER2 (erbB2/neu) codes for a +ve growth factor receptor)