Cancer 2: Hallmarks of Cancer Flashcards
what is cancer ?
tumours may be malignant or benign
“cancer” implies malignancy
what are the features of malignancy?
tumours may be malignant or benign
“cancer” implies malignancy
what are the hallmarks of cancer ?
autonomy from growth signals evasion of growth inhibitory signals evasion of apoptosis unlimited replicative potential angiogenesis invasion and metastasis
which mutations are inherited?
those in germ cells not somatic cells.
what is the evidence for cancer being a genetic disease?
age incidence
carcinogens are mutagens
DNA of tumours contains many and varied aberrations
mutations in specific genes generate cells bearing hallmarks of cancer
give examples of infection and their cancers
HTLV-1 - adult T cell lymphoma
EBV - Burkitt’s lymphoma
Hepatitis B & C - hepatocellular carcinoma
HPV 16 & 18 - cervical carcinoma
how do carcinogens cause cancer ?
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
how do mutations cause cancer ?
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
how might mutations arise from oncogenes ?
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
how do oncogenes cause cancer?
increase activity of pro-malignant pathways:
cell growth, replication, angiogenesis
invasion, metastasis
inhibit activity of anti-malignant pathways:
apoptosis, cell cycle regulation, growth inhibition
how does EGFR act as an oncogene?
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
how does ras act as an oncogene
loss of GTP-ase activity of RAS protein
RAS remains bound to GTP and is constitutively activated
waht are tumour suppressor genes responsible for?
normal cells are equipped with pathways that suppress pro-malignant processes
these include apoptosis, cell cycle checkpoints, growth inhibition, DNA repair
give an example of a tumour suppressor gene
p53
what is Li-Fraumeni syndrome ?
grossly elevated cancer risk
sarcoma, breast cancer, leukaemia, brain tumours at an early age
more commonly, p53 mutation spontaneous
what is FAP?
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
Describe the mutations seen in multistep carcinogenesis
1) APC
2) K-ras/DCC
3) p53
4) aneuploidy
describe the process of autonomy from growth signals
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
describe the process of evasion of inhibitory growth signals
in cancer cells, pro-growth signals overcome growth inhibitory signals
describe the process of apoptosis
“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.
how is apoptosis triggered ?
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
compare apoptosis vs necrosis
look at chevassut’s slide
how does evasion of apoptosis occur?
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)
how does unlimited replicative potential cause cancer ?
telomerase inactive in most normal tissues
telomerase upregulated in most tumour cells
proteins that activate telomerase contribute to malignant transformation
how does angiogenesis cause cancer?
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
what is the process of angiogenesis
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
how does invasion and metastasis occur?
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
