14 - Molecular basis of Cancer Flashcards
How is a tumour formed
By the clonal expansion of a single precursor cell that has incurred genetic damage
4 classes of genes that are the main ‘targets’ for ongogenic mutations
- Proto-oncogenes
- Tumour suppressor genes
- Apoptosis regulating genes
- DNA repair genes
Proto-oncogenes
normal cellular genes whose products promote cell proliferation (growth factors, signal transducers, transcription factors)
Tumour supressor genes
mutations are usually “loss of function”, so both copies need to be affected
DNA repair genes
- Impair the ability of the cell to repair DNA damage
- Thus more mutations are acquired: “mutator phenotype”
Driver mutations
Mutations that contribute to the development of the malignant phenotype
What does cancer formation result from
The accumulation of mutations in a stepwise fashion over time
Passenger mutations
Mutations that may have no phenotypic consequence (loss of function mutations are common early step)
How do tumours evolve
- Under Darwinian selection
- Emergence of subclones within the tumour
- Leads to therapy resistance
Epigenetic modifications
Inheritable modifications of DNA which is not related to a coding change (e.g. DNA methylation, histone modification)
Oncogenes
mutated or over-expressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth promoting signals
Oncoprotein
a protein encoded by an oncogene that drives increased cell proliferation through several mechanisms
Mechanisms of Oncoproteins
- Constitutive expression of growth factors and their
receptors, setting up an autocrine cell signalling loop - Activation of signal transduction molecules
- Activation of transcription factors
- Increase the activity of CDK4)
ERBB1
- Encodes the epidermal growth factor receptor (EGFR)
- Point mutations result in constitutive activation of the tyrosine kinase
ERBB2
- Encodes receptor tyrosine kinase HER2
- Amplified in some breast cancers, leading to overexpression of the HER2 receptor
ALK
- Receptor tyrosine kinase on chromosome 5
- In some lung cancers a fusion of EML4-ALK results in a chimeric EML4-ALK protein with constitutive kinase activity
effects of a mutated MYC gene
- Activates the expression of genes involved in cell growth
- Upregulates telomerase expression
- Reprograms somatic cells into a stem cell-like phenotype
Tumour suppressor genes
- Act as a ‘brake’
- Abnormalities of these genes lead to failure of growth inhibition
- Form a network of checkpoints which prevent
uncontrolled growth
How do tumour suppressor genes prevent uncontrolled growth
- Shut down proliferation
- Initiate apoptosis
- Promote differentiation
Retinoblastoma (RB) Gene
- Directly or indirectly inactivated in most human cancers
- A key negative regulator of the G1/S cell cycle transition
Hypophosphorylated RB gene
- RB exerts antiproliferative effects by binding and inhibiting E2F transcription factors
- Growth factor signalling leads to RB hyperphosphorylation and activation
In cancer, how can RB function be compromised
- Loss of function mutations in RB
- Loss of function of CDK inhibitors
- Gain of function of CDK4 and cyclin D
- Viral oncoproteins that bind and inhibit RB
Retinoblastoma tumour
- An intraocular malignancy of children
- Can be familial (autosomal dominant, bilateral) or sporadic (unilateral)
TP53
- Tumour suppressor gene
- Mutations are acquired in both alleles in somatic cells
- Inheritance leads to a predisposition of “Li-Fraumeni syndrome”
p53 in non stressed cells
p53 is degraded via an
association with MDM2
p53 in stressed cells
p53 is released from this
inhibition and accumulates
CDKN2A
Loss of function impacts both RB and p53 tumour suppressing pathways
p16/INK4a
Blocks CDK4/cyclin D mediated phosphorylation of RB, reinforcing the RB checkpoint
p14/ARF
Activates p53 by inhibiting
MDM2 and stabilising p53
Apoptosis
- Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells activate caspases that degrade the DNA and proteins
- Protective response to
conditions which may result in cancer
Are mutations in DNA repair genes oncogenic
No, but enhance the occurrence of other mutations which might be
DNA mismatch repair
- Correct single base errors (GT pairing rather than AT)
- Inheritance of one mutant copy results in Familial carcinomas of the colon
- These tumours are characterised by microsatellite instability
Microsatellites
- Tandem repeats of 1-6 nucleotides found throughout the genome
- Length remains constant
- With loss of mismatch repair these satellites increase or decrease
in length (unstable)
Nucleotide Excision Repair
- UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA replication (pyrimidine dimers)
- Repaired by NER
- Inherited loss of one of the genes involved in this system leads to increased risk of developing skin cancers
Homologous recombination
- Defects in the homologous recombination cause group of disorders characterised by hypersensitivity to DNA damaging agents
- Mutations in BRCA1 or 2 account for 25% of familial breast cancer
- Cells with these mutations develop chromosomal breaks and abnormal numbers of chromosome
Hereditary Leiomyomatosis and Renal Cell Cancer
- develop multiple smooth muscle tumours (leiomyomas) in the skin and uterus, as well as aggressive renal cell carcinomas
- Caused by mutation in Fumarate hydratase
Fumarate hydratase
- Enzyme acting
within the Krebs cycle - catalyses the hydration of fumarate to malate
- Mutations in Krebs cycle components lead to a decrease in oxidative phosphorylation
Warburg effect
- Cancer cells tend to ferment glucose into lactate even in the presence of sufficient oxygen
- “aerobic glycolysis”
Possible explanations for the Warburg effect
- ATP is only an issue when resources are scarce
- Proliferating cells have other metabolic needs besides ATP (Carbon atoms, Acetyl-CoA, NADPH)
Angiogenesis
- Even if a tumour has all of the genetic mutations required for limitless growth, it cannot enlarge to more than 1 or 2mm due to a lack of blood supply
- Promoting the growth of new blood vessels is critical to the survival of neoplasms
Two phases of invasion and metastasis
- Invasion of the extracellular matrix
- Vascular dissemination
Can circulating tumour cells can be identified in patients without clinically overt metastatic disease?
Yes
Immune response to tumour cells
- Tumour antigens are presented on the cell surface
by MHC class I molecules and are recognised by cytotoxic T-lymphocytes. - Immunosuppressed patients have an increased risk for development of cancer, particularly types caused by oncogenic DNA viruses.
Mechanisms of evasion of immune defences
- Selective outgrowth of antigen-negative variants
- Loss or reduced expression of histocompatibility antigens
- Expression of certain inhibitory factors by the tumour cells, which act to dampen the immune response
