lecture 1 - overview Flashcards
What is a tumour?
an abnormal mass that arises when cells grow more than they should &/or do not die when they should
What is the difference between benign and malignant tumours?
Benign (non-malignant) tumours do not spread to distant sites (metastasize)
Cancers are malignant tumours that spread (metastasize) to other sites through blood & lymph systems.
How do cancers develop?
Multistep process reflecting stochastic genetic or epigenetic changes in key genes
Normal cells undergo progressive stepwise transformation into cancer cells
Typically requires 4-7 rate-limiting events
Early & intermediate stages may be benign e.g. polyp
Accumulation of changes in key genes can take decades - age is the principle risk factor
Cancers arise through multisteps
Changes the occur in expression or sequence of genes randomly – confer selective advantage which is selected upon to create clonal variant
Evolution from healthy normal cell to malignant cancer cell
These steps can take years to occur
Cancer is primarily disease of the elderly
Describe how Cancers Develop Through Genetic & Epigenetic Changes
Cancer development involves loss of function of tumour suppressors e.g. APC, p53
Can occur through gene deletion, epigenetic silencing, or mutation of coding region or regulatory elements
e.g. most colon cancers have deletion or silencing of APC gene & point mutns of p53 gene
Cancer development also involves activation of oncogenes that promote cancer e.g. Ras
Can occur through mutn of coding region or regulatory elements, gene amplification or epigenetic actn
e.g. colon cancers generally have activating point mutns in K-ras gene
Acquisition of oncogenic activity – genes that promote cancer activity are oncogenes. Can vary from one cancer to another
Overexpression/amplification/changes in the regulatory elements of a gene can increase activity of oncogene
Loss of activity of tumour suppressor genes
What is Ras?
First oncogene to be characterised
K-ras involved in colon cancer
Growth factors/mitogens bind to cell surface receptors
Some cancers have much higher incidence of ras mutation eg colorectal cancer
Ras family genes (e.g. K-ras) encode small GTPases that transmit signals in response to growth factors
When activated by growth factors, cell surface receptors cause Ras to release GDP & bind GTP
GTP-bound Ras activates signaling pathways that promote cell growth, prolifn & survival, e.g. MAP kinase & PI3 kinase pathways
Ras hydrolyses GTP & returns to inactive state
Most colorectal cancers (and ~25% of all cancers) have point mutns in Ras that lock it in GTP-bound active form, resulting in constitutive signals that promote cancer development
Describe the MAPK and PI3K pathways
Ras is activated by various cell surface receptors, many of which are hyperactive in cancers due to gene amplification or mutation e.g. EGF & VEGF receptors
Ras activates a MAPK pathway, causing phosphorylation & actn of Erk kinase, that enters nucleus & activates txn factors that promote cell growth & prolifn
Ras also activates signaling through PI3 kinase, leading to suppression of cell death & activation of mTOR to increase protein synthesis
In cancers where Ras is wild-type, upstream or downstream mutns often activate MAP &/or PI3K pathways
Raf, PI3K & Akt kinases are all commonly mutated & activated in cancers
What is APC?
Adenomatous Polyposis Coli (APC)
APC is a tumour suppressor that binds GSK3 kinase & b-catenin in cytoplasm
GSK3 phosphorylates b-catenin, targeting it for ubiquitination & proteasomal degrdn
Signalling through the Wnt pathway blocks phosphn by GSK3 & releases b-catenin to enter nucleus & induce txn of target genes e.g. cyclin D1 & MYC
Wnt signalling is rqrd to maintain intestinal epithelium
APC is mutated & inactivated in most colorectal cancers, releasing b-catenin to allow deregulated (Wnt-independent) txn of target genes
Rare cases have APC intact but activating mutns in b-catenin
Initiating event is mutation of tumour suppressor APC
Binds to transcription coactivator b catenin
B catenin levels kept low
Mechanism responds to wnt pathway
Cofactor rather than DNA-binding factor, binds to other txn factors and promotes transcription of their target genes
Loss of APC leads to deregulation of B catenin
What is familial adenomatous polyposis?
APC was discovered as the tumour suppressor inactivated in familial adenomatous polyposis, a rare hereditary cancer predisposition syndrome
Sufferers inherit one mutant APC allele
Colon is riddled with polyps, benign outgrowths of epithelial cells in which second APC allele has been inactivated
93% cancer risk by age of 50
Cancers develop when additional mutns arise in polyps, e.g. in Ras & p53 genes
What is p53?
P53 is a transcription factor that binds & regulates specific target genes
P53 gene is deleted or mutated in >50% of human cancers – highest frequency of any known gene
Most p53 mutns arise somatically, but germ-line mutns occur in some cancer-prone families - Li-Fraumeni syndrome
Probably evolved as a coordinator of stress responses - activated by many types of stress
Activates or represses specific sets of genes to protect cell under stress conditions
Gene targets of p53 depend on nature of stress
Inherited mutation in p53 does not dispose for colon cancer but somatic mutation does – this is not well understood
Describe the function of p53
DNA damage triggers actn of p53
Activated p53 induces genes that cause apoptosis or cell cycle arrest & DNA repair
Cell cycle arrest prevents replication of DNA until it has been repaired
a sun-exposed skin cell can sustain ~100,000 UV-induced DNA mutns per hr
safest option may be to kill cells with severely damaged DNA, instead of allowing increased cancer risk if they replicate & pass on mutations – sun-burnt skin is shed
Protection is removed if p53 function is lost – mutations then accumulate more rapidly
Describe how Loss of DNA Repair Machinery Can Accelerate Carcinogenesis
Mutations in DNA repair machinery accelerate accumulation of genomic damage
For example, BRCA1 & BRCA2 are involved in repair of DNA double-strand breaks
Inherited mutations in BRCA1 or BRCA2 genes predispose to breast & ovarian cancers
colon cancers often lose expression of genes responsible for mismatch repair (MMR) of errors that arise during DNA replication
MMR genes are frequently silenced by promoter methylation – example of cancer promotion by epigenetic rather than genetic change
Describe genetic and epigenetic abnormalities in cancer cells
thousands of random mutations & epigenetic changes accumulate within cells over time, but most are inconsequential – “passengers”
Formation of most adult cancers is believed to reflect a succession of clonal expansions, each triggered by chance occurrence of a “driver” mutation or epigenetic change
Driver events confer selective advantage & are retained in progeny cells
Changes to APC, Ras, p53 & MMR are common drivers in colon cancer – others are much less frequent
Can be difficult to distinguish drivers from passengers
Changes in >300 genes have been implicated as driving particular cancer types – some are common (e.g. p53 mutn in many types), but most are context-specific
Most common targets of driver mutns are genes encoding kinases (esp. Tyr kinases) or transcription factors
What are the hallmarks of cancer?
Hanahan & Weinberg (2000) postulated that cancers all share six essential capabilities that contribute to their phenotype – “hallmarks”
Can result from alternative driver events, even within the same cancer type
more than one hallmark can be acquired from a single driver event
acquisition of each capability reflects successful breaching of an anticancer defense mechanism
Sustaining Proliferative Signalling Evading Growth Suppressors Replicative Immortality Resisting Cell Death Angiogenesis Invasion and Metastasis
Explain how cancer cells sustain proliferative signalling
Healthy cells require proliferative signals (mitogens) to grow & divide
Cancer cells are self-sufficient of mitogens
E.g. APC loss in colon allows constitutive actn of Wnt pathway independently of Wnt - - deregulated b-catenin induces txn of MYC gene
E.g. Ras mutn in colon allows constitutive actn of MAP kinase pathway, leading to phosphorylation & stabilization of MYC protein
MYC is a potent driver of cell growth & proliferation
Explain how cancer cells evade growth suppressors
inappropriate growth & proliferation are suppressed in normal tissue
E.g. in absence of mitogens, cell cycle progression from G1 into S phase is blocked by tumour suppressor RB - “Gatekeeper of the cell cycle”
As long as RB is unphosphorylated, cells stay in G1 or leave cell cycle to become quiescent (G0) or senescent
Mitogens induce cyclin D, which activates cyclin-dependent kinase 4 (cdk4) to phosphorylate RB, allowing passage into S phase
APC loss in colon cancer allows induction of cyclin D gene by deregulated b-catenin
