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Cancer > Angiogenesis & Metastasis > Flashcards

Angiogenesis & Metastasis Flashcards

1
Q

Define Angiogenesis

A

<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.

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2
Q

Erythropoietin (Epo)

A

NAME?

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3
Q

Hypoxia Inducible Factor (HIF)

A
  • 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
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4
Q

Von Hippel-Lindau Syndrome

A

NAME?

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5
Q

VHL Structure

A

<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

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6
Q

Hypoxia and HIF Fate

A

NAME?

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7
Q

Oxygen Sensing

A
  • 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>
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8
Q

HIF Targets

A
  1. Glycolytic isozymes<br></br>2. Erythropoietin<br></br>2. Vascular endothelial growth factor
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9
Q

HIF & Glycolytic Isozymes

A
  • 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
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10
Q

HIF & Vascular Endothelial Growth Factor

A
  • 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
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11
Q

VEGF Receptor

A
  • 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>
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12
Q

VEGFR Family

A
  1. VEGFR-1: vascular permeability<br></br>2. VEGFR-2: vascularization<br></br>3. VEGFR-3: lymphangiogenesis
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13
Q

Overview of Angiogenesis

A

NAME?

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14
Q

Avastin

A
  • 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
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15
Q

Sorafenib/Sunitinib

A
  • 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
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16
Q

Angiogenesis Paradox

A

NAME?

17
Q

Describe the process of metastasis

A

<img></img>

18
Q

Issues facing tumor cell metastases

A

NAME?

19
Q

Adhesions and Interactions in cells

A

NAME?

20
Q

Integrins & cell cycle

A

NAME?

21
Q

Integrin Signalling

A
  • 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>
22
Q

Integrins & Cancer

A
  1. 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
23
Q

Integrin Targeting in Cancer

A
  • 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.
24
Q

Cadherins

A
  • 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
25
Q

Cadherin signalling

A
  • Downstream signalling via p120, a, & B catenin that connect cadherin to actin filaments<br></br>- Help cytoskeletal organisation to prevent motility if neighbours are present
26
Q

B-catenin

A

NAME?

27
Q

APC

A
  • APC mutations cause polyp growth/colon cancer / Familial Adenomatous Polyposis<br></br>- 300kDa protein<br></br>- Specific binding sites for GSK3 and B-catenin<br></br>- Most tumor-associated mutations occur in the first 1500 codons disrupting B-catenin binding
28
Q

Cytoplasmic B-catenin

A

NAME?

29
Q

Cadherin-p120 Function

A

NAME?

30
Q

Epithelial-Mesenchymal Transition

A
  • Important in development to allow organ development/reorganisation but also in tumor metastasis<br></br>- Epithelial cells are rigid and mesenchymal cells are motile<br></br>- This process involves cadherin off/on that then regulates cell motility<br></br><br></br><img></img>
31
Q

Matrix Metalloproteases

A
  • Around 30 MMPs<br></br>- Mainly secretory proteins and act extracellularly to cleave ECM components<br></br>- Useful in promoting metastasis/upregulated in tumors<br></br>- Cleave hydrophobic amino acids/collagen/gelatin/ECM components with low selectivity<br></br>- ECM cl
32
Q

Matrix Metalloprotease Control

A
  • Zn in active site capped by Cys in pro-domain holding the inactive conformation<br></br>- Pro-domain cleavage allows active site to be accessible<img></img><br></br><br></br>
33
Q

Seed and Soil Hypothesis

A

Primary tumor cells of certain types flourish in certain environments specifically<br></br>Eg. Melanoma perferentially survives in lungs rather than kidneys<br></br>Potentiall involves expression profiles/stromal interactions/secreted factors/etc.

34
Q

Expression Profiles in Metastasis

A

NAME?

35
Q

Stromal Interactions

A

NAME?

36
Q

Exosomes

A
  • Vesicles released from cells transporting lipids, proteins, nucleic acids<br></br>- Carry potent payloads targeting many locations<br></br>- Can help prepare locations for tumor formation (pre-metastatic niche formation)<br></br>- Recruitment of vasculogenic/hem
37
Q

Metastatic Attrition

A
  • Cumulative attrition of tumor cells is huge<br></br>- 99.98% cumulative attrition<br></br>- Very low efficieny due to many requirements needing to be fulfilled

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