Cancer 2: Hallmarks of Cancer

Question 1

what is cancer ?

Answer 1

tumours may be malignant or benign

“cancer” implies malignancy

Question 2

what are the features of malignancy?

Answer 2

tumours may be malignant or benign

“cancer” implies malignancy

Question 3

what are the hallmarks of cancer ?

Answer 3

autonomy from growth signals
evasion of growth inhibitory signals
evasion of apoptosis
unlimited replicative potential
angiogenesis
invasion and metastasis

Question 4

which mutations are inherited?

Answer 4

those in germ cells not somatic cells.

Question 5

what is the evidence for cancer being a genetic disease?

Answer 5

age incidence
carcinogens are mutagens
DNA of tumours contains many and varied aberrations
mutations in specific genes generate cells bearing hallmarks of cancer

Question 6

give examples of infection and their cancers

Answer 6

HTLV-1 - adult T cell lymphoma
EBV - Burkitt’s lymphoma
Hepatitis B & C - hepatocellular carcinoma

HPV 16 & 18 - cervical carcinoma

Question 7

how do carcinogens cause cancer ?

Answer 7

interact with components of DNA to cause damage
damage may be to bases or sugar-phosphate backbone
damage may be repaired, misrepaired or unrepaired
unrepaired or misrepaired damage that does not trigger cell death will be passed on to daughter cells

Question 8

how do mutations cause cancer ?

Answer 8

oncogenes = mutations must affect expression of protein products of genes involved in pathways associated with the cancer phenotype
usually growth, differentiation and cell death
mutated genes and their products may become overactive

tumour suppresor genes = other carcinogenic mutations lead to a loss of function of the gene

Question 9

how might mutations arise from oncogenes ?

Answer 9

increase level of expression of the gene
de-regulate expression of the gene
alter the protein product so it is more active
alter the protein product so it is not degraded

Question 10

how do oncogenes cause cancer?

Answer 10

increase activity of pro-malignant pathways:
cell growth, replication, angiogenesis
invasion, metastasis
inhibit activity of anti-malignant pathways:
apoptosis, cell cycle regulation, growth inhibition

Question 11

how does EGFR act as an oncogene?

Answer 11

e.g. erbB1 encodes the EGFR receptor
oncogenic mutations generate EGFR that is activated even in the absence of EGF
amplification of erbB increases membrane expression of EGFR
end result is over-activity of RAS - MAPK pathway and over-expression of growth promoting genes

Question 12

how does ras act as an oncogene

Answer 12

loss of GTP-ase activity of RAS protein

RAS remains bound to GTP and is constitutively activated

Question 13

waht are tumour suppressor genes responsible for?

Answer 13

normal cells are equipped with pathways that suppress pro-malignant processes
these include apoptosis, cell cycle checkpoints, growth inhibition, DNA repair

Question 14

give an example of a tumour suppressor gene

Answer 14

p53

Question 15

what is Li-Fraumeni syndrome ?

Answer 15

grossly elevated cancer risk
sarcoma, breast cancer, leukaemia, brain tumours at an early age
more commonly, p53 mutation spontaneous

Question 16

what is FAP?

Answer 16

inherited mutations in the APC gene responsible for familial adenomatous polyposis coli (FAP)
one mutant allele inherited, spontaneous mutations in other allele in colonic epithelial cells
develop multiple colonic polyps in early adulthood
polyps predispose to cancer
patients have very high risk of colon cancer

Question 17

Describe the mutations seen in multistep carcinogenesis

Answer 17

1) APC
2) K-ras/DCC
3) p53
4) aneuploidy

Question 18

describe the process of autonomy from growth signals

Answer 18

normal cells grow in response to extracellular growth factors
growth factors bind to membrane-bound growth factor receptors
this stimulates intracellular signalling pathways…
which activate nuclear transcription factors, switching on expression of genes responsible for cell growth

Question 19

describe the process of evasion of inhibitory growth signals

Answer 19

in cancer cells, pro-growth signals overcome growth inhibitory signals

Question 20

describe the process of apoptosis

Answer 20

“programmed cell death”
“efficient cell death”
cell death that benefits tissue/organism
1) cytoplasmic shrinkage 
2) nuclear breakdown 
3) cleavage of structural disease 
4) membrane blebbing and apoptotic bodies.

Question 21

how is apoptosis triggered ?

Answer 21

executed by pathways involving degradation of chromatin and proteolysis by caspases
apoptosis activated extrinsically (eg. response to TNF)
or intrinsically, in response to oxidative stress or DNA damage

Question 22

compare apoptosis vs necrosis

Answer 22

look at chevassut’s slide

Question 23

how does evasion of apoptosis occur?

Answer 23

families of proteins are pro-apoptotic and anti-apoptotic
cells deficient in pro-apoptotic signals at risk of carcinogenesis
upregulation of anti-apoptotic proteins also increases risk
Bcl-2 anti-apoptotic (more later)
Bax pro-apoptotic
p53 pro-apoptotic (much more later)

Question 24

how does unlimited replicative potential cause cancer ?

Answer 24

telomerase inactive in most normal tissues
telomerase upregulated in most tumour cells
proteins that activate telomerase contribute to malignant transformation

Question 25

how does angiogenesis cause cancer?

Answer 25

cell growth dependent on proximity to blood vessels
unrestricted growth of tumours increases distance from cells to vessels
distant cells become hypoxic and either senescent or necrotic
growing tumours require proliferation of new vessels - angiogenesis

Question 26

what is the process of angiogenesis

Answer 26

angiogenesis stimulated by hypoxia in normal tissues and tumours
Vascular Endothelial Growth Factor (VEGF) major stimulant
VEGF upregulated in many tumours
inhibitors of angiogenesis downregulated

Question 27

how does invasion and metastasis occur?

Answer 27

tumour cells can break free from inter- and extra-cellular connections via abnormal expression of integrins
invasive capacity mediated by matrix metalloproteases (MMPs) and inhibited by TIMPs - abnormal balance in tumour cells
entry into and exit from blood vessels achieved by similar mechanisms