Angiogenesis & Metastasis Flashcards
(37 cards)
Define Angiogenesis
<b>The formation of new blood vessels</b><span>. This process involves the migration, growth, and differentiation of endothelial cells, which line the inside wall of blood vessels.<br></br>This is a common process in solid tumors in order to allow expansion and nutrient availability.<br></br></span>Restriction of this vasculature causes tumor regression.<br></br>Angiogenesis also provides avenues for metastasis, which is dependent on tumor cell travelling via vasculature.
Erythropoietin (Epo)
NAME?
Hypoxia Inducible Factor (HIF)
- TFs (helix-loop-helix structure) that binds to the Epo promoter for expression<br></br>- Heterodimers with an alpha + beta subunit<br></br>- Binds to the HRE (hypoxia response element) with the CGTG core sequence<br></br>- In normoxic conditions, HIF is rapidly degrad
Von Hippel-Lindau Syndrome
NAME?
VHL Structure
<br></br><img></img><br></br>- 29kDa<br></br>- B domain binds directly to HIF<br></br>- Cancer associated mutations occur in B domain<br></br>- a domain has a region of homology to Skp2<br></br>- Enables VHL to contact ubiquitin ligase machinery (Elo B/C and Cullin 2)<br></br>- This complex acts as a ubiquitin ligase with VHL acting as the adaptor subunit connect HIF to ligase
Hypoxia and HIF Fate
NAME?
Oxygen Sensing
- Prolyl 4-hydroxylase enzyme hydroxylates prolines using a-ketoglutarate (abundant in oxygen based metabolism) and molecular oxygen<br></br>- Direct sensing of oxygen levels by this enzyme<br></br>- HIF is a substrate for prolyl 4-hydroxylase (proline 402/564)<br></br>
HIF Targets
- Glycolytic isozymes<br></br>2. Erythropoietin<br></br>2. Vascular endothelial growth factor
HIF & Glycolytic Isozymes
- Tumors usually preferentially use glycolysis for ATP generation due to their hypoxic conditions<br></br>- HIF upregulates hexokinase, phosphofructokinase, & pyruvate kinase, which are the three rate limiting enzymes of glycolysis
HIF & Vascular Endothelial Growth Factor
- Secreted into the environment acting on surrounding cells<br></br>- Homodimeric secreted hormone<br></br>- Causes increased vascularization and increased vascular permeability<br></br>- Endothelial cells have VEGF receptors on cell surface
VEGF Receptor
- Receptor tyrosine kinase<br></br>- Ligand binding leads to dimerization and trans-auto phosphorylation<br></br>- Downstream signalling targets include, Ras/MAPK/PI3K<br></br><br></br><img></img>
VEGFR Family
- VEGFR-1: vascular permeability<br></br>2. VEGFR-2: vascularization<br></br>3. VEGFR-3: lymphangiogenesis
Overview of Angiogenesis
NAME?
Avastin
- Anti-VEGF antibody<br></br>- Prevent extracellular ligand binding and therefore intracellular effects<br></br>- However, there is only ~5 months of increased survival which is not very effective
Sorafenib/Sunitinib
- Tyrosine kinase inhibitors towards VEGFR<br></br>- However, we have 514 protein kinases with conserved fold and ATP binding site<br></br>- Difficult to make VEGFR inhibitors that are not pan-reactive with off-target effects
Angiogenesis Paradox
NAME?
Describe the process of metastasis
<img></img>
Issues facing tumor cell metastases
NAME?
Adhesions and Interactions in cells
NAME?
Integrins & cell cycle
NAME?
Integrin Signalling
- Heterodimer transmembrane proteins<br></br>- Cytoplasmic tail and extracellular regions<br></br>- Can participate in inside-out/outside-in signal transduction<br></br><br></br><img></img>
Integrins & Cancer
- Migration and invasion: aid motility for metastasis<br></br>2. Metastasis and anchorage independent survival<br></br>3. Formation of metastatic niche/colonization<br></br>4. Resistance to drugs/radiation
Integrin Targeting in Cancer
- Integrins bind to peptide motif R-G-D<br></br>- This is used as a targeting motif to target therapeutics to cells with altered integrin signalling<br></br>- By using peptides recognising cancer associated integrin combinations, you attach a cytotoxic payload (eg.
Cadherins
- Calcium dependent homotypic interactions in solid tissues important in formation of adherens junctions between cells<br></br>- Large family of cadherin molecules<br></br>- Calcium ion binding interdigitates between repeats and allows rigidification<br></br>- For
- Help cytoskeletal organisation to prevent motility if neighbours are present
- 300kDa protein
- Specific binding sites for GSK3 and B-catenin
- Most tumor-associated mutations occur in the first 1500 codons disrupting B-catenin binding
- Epithelial cells are rigid and mesenchymal cells are motile
- This process involves cadherin off/on that then regulates cell motility
- Mainly secretory proteins and act extracellularly to cleave ECM components
- Useful in promoting metastasis/upregulated in tumors
- Cleave hydrophobic amino acids/collagen/gelatin/ECM components with low selectivity
- ECM cl
- Pro-domain cleavage allows active site to be accessible
Eg. Melanoma perferentially survives in lungs rather than kidneys
Potentiall involves expression profiles/stromal interactions/secreted factors/etc.
- Carry potent payloads targeting many locations
- Can help prepare locations for tumor formation (pre-metastatic niche formation)
- Recruitment of vasculogenic/hem
- 99.98% cumulative attrition
- Very low efficieny due to many requirements needing to be fulfilled
