Epithelial Carcogenesis Flashcards
What are the 5 characteristics of cancer cells?
- Provides their own growth signals
- Unsustained proliferation
- Sustained angiogenesis
- Avoid growth inhibition / differentiation
- Invade and metastasise
Describe oncogenes.
Proto-oncogenes perform homeostatic functions.
They become mutated and overactive - uncontrolled cell growth and invasion.
Activating mutations, AUTOSOMAL DOMINANT
No oncogenic mutations in the germline.
EX - Ras, B-catenin
Describe tumour suppressors.
RECESSIVE gene effect, leads to a loss of expression.
Promotes tumour growth
Usually, one heterozygous germline mutation and one somatically acquired mutation - Leads to LOH (2HIT HYP)
EX - APC (inherited), SMAD-2 (somatic)
Describe TS stability genes.
Guardians of the genome stability - DNA sequence, chromosome instability and number.
Inactivation = higher mutation rates elsewhere
HNPCC (msh1, mlh1) - mismatch repair genes
BRCA1&2 - DNA ds break repair genes
Function and structure of E-cadherin.
Binds two epithelial cells together at adherens junctions.
Extracellular domain creates the adhesion zipper.
The 72 AA CYTOPLASMIC domain binds to CATENIN proteins.
Loss of e-cadherin = migratory and invasive through the basement membrane.
Coded by CDH1 = tumour suppressor gene
Three ways E-cadherin can be reduced/non-functional in epithelial cancers.
Truncation, frameshift or exon skipping mutations in CDH1.
Gene promoter methylation
Phosphorylation inactivating it, by SRC kinase or HER2
What are the two forms of SRC kinase, the differences and how one becomes unregulated.
C-SRC (proto-oncogene, 540AA), V-SRC (oncogene, 526AA)
C-SRC can be phosphorylated at Tyr527, switching it off.
V-SRC has loss of regulatory domain, including Tyr site, so cannot be regulated - oncogenic
V-SRC localised to plasma membrane by lipid anchor, where it acts on E-cadherin to phosphorylate/inactivate, cells become migratory.
How was B-catenin shown to be important in mammalian development?
Gastrulation = ectodermal invasion during mammalian development, epithelial cells become migratory and invade.
B-catenin knockout mice showed no gastrulation.
How are B-catenin levels regulated in the cell?
How is it mutated in colon cancer?
DESTRUCTION COMPLEX
GSK-3B phosphorylated B-catenin at N-term, targeting it for degradation.
Destruction complex = APC, Axin, GSK3B, CK1a
Leads to ubiquitinated degradation.
Loss of N-terminal phosphorylation site, loss of binding to GSK3B-CK1a, destruction complex cannot be formed.
How is the anaphase promoting complex involved in cancer?
APC binds microtubules by EB1.
Attaches MTs to the kinetochore of metaphase chromosomes.
Loss of chromosomal attachment to mitotic spindle = aberrant segregation and aneuploidy.
What is B-catenin’s role as a transcription factor coactivator?
B-catenin enters the nucleus at high concentrations, binds TCF (T-cell factors) and co-activates transcription of Wnt target genes.
Causes DNA bending so TCF can access transcription sites.
WNT PATHWAY
DIAGRAM
What are the Wnt target genes and their functions?
Wnt target genes are needed for cell motility in wound healing, development and cell division.
Cyclin D1, c-Myc, MMP7, Fibronectin
What occurs when B-catenin is phosorylated on Tyr142?
Loss of a-catenin binding and cell adhesion.
Promoted binding to BCL9-2 - a nuclear cofactor and port-oncogene.
Induces malignant cell transformation, enhances transcription of Wnt target genes by localising B-catenin to the nucleus.
4 modulators of TCF/B-catenin signalling
- NSAIDS - Aspirin inhibits Wnt target COX2, Celecoxib promotes TCF degradation
- Vitamin A + D - Compete for TCF binding site with B-catenin, so B-catenin can relocate to the membrane can help cell adhesion and reduce Wnt signalling.
- Monoclonal Anti-Wnt1/2 - reduce/eliminate Wnt
- Small Mw inhibitors - Suppress B-cat/TCF interactions.
