Cancer Flashcards
Metaplasia
Transformation from one differentiated cell type to another
Hyperplasia
Increased proliferation of cells
Dysplasia
Abnormal development of cells within tissues
Neoplasia
Uncontrolled abnormal growth of cells
Malignant tumour of mesenchyme
- Sarcoma
Malignant tumour of epithelium
- Carcinoma
Benign tumour
tissue name - Oma
Liquid/solid lymph related tumours
Leukaeima = liquid neoplasms Lymphoma = solid lymphatic neoplasms
Tumour suppressors in the cell cycle
Rb
p21, p16aka
Oncogene in cell cycle
CyclinD1
CDK4
p53 mutations
Tumour suppressor but binds as a tetramer so lots affected even by one alley loss
Stress signalling hub
Activates BAX to inactivate anti-apoptotic BCl2
Acts as a promoter for p21 to arrest cell cycle
Sequence level instability
For failure at DNA repair: MLH1 (mismatch repair) e.g Lynch syndrome
For replication: polymerase epsilon mutation
Chromosome level instability
For failure at DNA repair: BRCA1/2 mutations for homologous repair in breast cnacer
For replicatioN: lagging chromosomes
Familial adenomatous polyposis
Inherit mutation in APC (controls cell cycle)
Rapidly get lots of polyps
Eventually one will lose the other gene and become malignant
Retinoblastomas
Inherit mutation in Rb gene that normally inhibits the cell cycle
Is genetic instability needed to kill
No!
BRCA2 double mutant tumour treated with cis-platen to select for frameshift to recover ability to make BRCA2 and do HR
BUT: tumour still kills even if no longer malignant
RTK signalling pathway
Growth factor binds to RTK
- Activates RAS via adaptor -> RAF -> MAPK
- Activates P13Ka -> PIP3 -> AKT
Second pathway has PTEN as a tumour suppressor that reverses this
Wnt signalling pathway
Wnt binds to Wnt receptor
This inhibits APC complex which usually inhibits beta-catenin
Beta-catenin now free to cause proliferation
TGFbeta signalling pathway
TGFbeta binds to receptors which activates Smads
These inhibit proliferation
Chronic myeloid leukaemia
Myeloid precursor cell mutates so can do unlimited proliferation
Still differentiates so blood fills with PMNs, monocytes, , RBC, megakaryocytes
Acute myeloid leukaemia
Myeloid progenitor cell mutates for unlimited proliferation but there is differentiation block on progenitor so blood fills with precursor stem cells
Chronic lymphocytic leukaemia
Mutation in lymphocyte precursor means unlimited differentiation, blood fills with mature B and T cells
Acute lymphocytic leukaemia
Mutation in lymphocyte precursor means unlimited differentiation but differentiation block means circulation fills with precursors
Hayflick’s limit
Limit on the humber of times a cell can replicate (50-70)
Telomerase activity due to mutation in promoter or swap with another promoter means this can be bypassed
Senscense signalling
Telomeres get short, signal via p53 to arrest the cell cycle by acting as a TF for p21
Li Fraumeni syndrome
Mutation in p53
Critical step in metastasis
Ability to survive in foreign tissue after extravascularisation
Are cells in primary tumour able to metastases
YES!
So metastasis may just be leakage from the primary tumour
Single base pair changes
Ras, p53, Raf (B-RAF has mutation from valine-glutamic acid which is positive so acts as if it is always phosphorylated)
Indels
APC (frameshift causing premature truncation)
PTEN deletion
Chromosome rearrangement example
Rb
Amplification mutations
EGFR, HER2
Philadelphia chromosome
Chromosome translocation between Chr9 and Chr22
Fusion of Bcr gene with Abl (kinase) gene
Means inhibitory terminus of Abl is lost
Tyrosine kinase gets activated by dimerisation of the Bcr
Bcr promoter controls both and is more active
TMPRSS2-EGR fusion gene
Prostate cancer
EGR gene is linked to the other promoter so expressed at higher levels
- This is involved in cell differentiation
Genes silenced by DNA methylation
MLH1 in colorectal cancer
CadherinE in lobular breast cancer; involved in cell to cell adherence
Driver mutations
Give cell a selective advatnage
Adults cancers likely to have 10-20 of these
Colon cancer has 7
UV light
Causes adjacent thymidine to dimerise
Can cause C to T changes
Beta-napthylamine
Bladder carcinogen
In bladder, an enzyme removes the glycosyl group to reactivate it
Aflatoxin
Most potent carcinogen
Causes liver cancer
Activated to reactive epoxide that reacts with DNA via xenobiotic metabolism
Aristolochic acid
causes kidney and upper urinary tract cancer
Change from A to T in ACTAGG
Chemical promoter
Enhances the emerge of mutant cells as tumours
Doesn’t directly cause mutations
May cause inflammation, increased cell turnover, increased division
TPA = most powerful promoter (mimics DAG which is a PKC agonist
Asbestos
Promoter without being mutagenic
Acceleartes mesotheliomas in mesothelial cells lining space via causing chronic wounding and scar tissue
Ames test
Used on mutant bacteria which can’t synthesis histidine
Rat liver extract is included incase the chemicals need xenobiotic metabolism
Look for colony growth
Alpha particles (high LET) compared to X rays (low LET)
Alpha is more ionising
Bacteria that cause cancer
Helicobacter pylori causes stomach cancer
Schistosomiasis causes bladder cancer
HPV
Cervical cancer
EBV
Nasopharyngeal cancer and Burkitt’s lymphoma
HBV
Hepatocellular carcinoma
HTLV1
T cell leukaemia and lymphoma
HHV8
Kaposi’s sarcoma
Vinca alkaloids
Binds dimers of tubulin to cause dissociation and prevent polymerisation
Taxols
Binds tubular microtubules to stabilise
DNA damaging drugs
Antimetabolites to inhibit DNA synthesis
Topoisomerase inhibitors
Bind covalently via alkylating/cross linking or non-covalently via intercalation
Cis-platin
alkylating/cross linking
PARP inhibitors
PARP is part of single strand repair
So PARP inhibitors cause single strand breaks to be converted to double strand breaks SO if cell lacks BRCA2 then will have to apoptosis
Gleevec
Used to block ABL kinase
Vemurafenib
Targets B-RAF kinase
Using viruses to treat cancer
oncolytic adenoviruses
E1A to inhibit Rb1
E1B55k to inhibits p53
Ipilimumab
Anti CTLA-4
