Angiogenesis Flashcards
Which of the following receptors is preferentially expressed on lymphatic endothelial cells and is responsible for lymphangiogenesis?
a. VEGFR-1/FLT-1
b. VEGFR-3/FLT-4
c. TIE1
d. NOTCH
e. TRKA
Answer: b
Lymphangiogenesis is largely governed by the interaction of VEGF-C and VEGF-D with VEGFR-3/FLT-4. This receptor is preferentially expressed on LECs (and ECs in certain tumors). Other receptors involved in lymphangiogenesis (to a lesser degree) include TIE2 and EPHB4.
Which of the following factors are elevated in the preangiogenic phase of tumor growth?
i. VEGF
ii. PEDF
iii. TSP-1
iv. IL-6
v. ANG1
a. i, iv, v
b. iii, v
c. i, ii, iv
d. ii, iii
e. iii, iv, v
Answer: d
During the preangiogenic phase, angiogenesis inhibitors predominate. High levels of PEX, TSP-1, PEDF (amongst others) override the effects of angiogenic stimulators (VEGF, IL-6, ANG1). During the angiogenic switch, the tables turn and the stimulators > inhibitors.
What form of angiogenesis is most commonly associated with expansion of cancer-related microvasculature?
a. Intussusception
b. Vascular splitting
c. Endothelial dilatation
d. Sprouting
e. Coalescence
Answer: d
Answers a, b and d are all forms of angiogenesis; the other two are made-up. Sprouting is initiated by the angiogenic switch. Blood vessels undergo a series of changes (dissociation of pericytes, dissolution of the basement membrane, recruitment of tip cells). Exposure of endothelial phalanx cells to extravascular angiogenic gradients results in formation, movement and extension of angiogenic sprouts (filopodia containing high concentrations of VEGF receptors). Tip cells drive blood vessel formation and are followed by stalk cells. Neighboring sprouts with anastomose to form a channel. Then, vascular maturation takes place.
What is the maximum distance a mammalian cell can be located from a functional capillary to remain viable?
a. 50 μm b. 180 μm c. 250 μm d. 370 μm e. 1250 μm
Answer: B
A compound is being tested in canine mammary carcinoma for patients with severe increases in microvascular density. The goal is to block this nonproductive angiogenesis. What protein would the compound need to mimic to achieve this goal?
a. COX1 b. COX2 c. HIF-α d. NOTCH e. Jagged 1
Answer: E
Explanation: Increased microvascular density can be associated with an increase in DLL4/NOTCH pathway. When the DLL4/NOTCH interaction is inhibited, multiple tip cells and sprouts emerge, leading to a hyperdense, nonperfused and dysfunction capillary networks. The vascular branching through formation of new sprouts may be fine-tuned with the contribultion of another NOTCH ligand, Jagged 1. Jagged 1 blocks the effects of DLL4 on stalk cells leading to a controlled stimulation of processes leading to formation of additional tip cells and sprouts.
Which of the following are considered inhibitors of angiogenesis?
i. p53 ii. Ras iii. Myc iv. PTEN v. VHL
a. I, iii, iv, v
b. ii, iii, iv, v
c. I, iii, iv
d. ii, iv, v
e. I, iv, v
Answer: E
Identify the true statement about tumor angiogenesis and hypoxia.
a. Hypoxia leads to upregulation of angiogenesis inhibitors, most specifically IL-8
b. Hypoxia is defined as tissue oxygen level of approximately 18-20 mmHg
c. Hypoxia acts as the primary physiological trigger of blood vessel formation
d. Hypoxic regions and areas of necrosis are relatively uncommon in solid tumors and usually associated with a good prognosis
Answer: c
a. hypoxia leads to downregulation of angiogenesis inhibitors, notably thrombospondin 1 (TSP1)
b. hypoxia is defined as tissue oxygen level below 10-15 mmHg
d. hypoxic regions and areas of necrosis are relatively common in solid tumors and usually associated with a poor prognosis
From the list below, identify the most correct statements about the structural, functional, and molecular characteristics of tumor (abnormal) microcirculation.
i. Discontinuous endothelium
ii. Proper tissue oxygenation and viability
iii. Low VEGF/VEGFR pathway activity
iv. High ANG2/TIE2 pathway activity
v. Loose and incomplete pericyte coverage
vi. Leaky and hemorrhagic capillaries
a. i, ii, iii
b. ii, iii
c. ii, iii, iv, vi
d. i, iv, v, vi
Answer: d
Identify the correct answer in regards to the blood vessel targeting agent and what it targets.
a. Sunitinib and VEGFR1-3, PDGFRα/β, KIT, FLT3, RET, CSF1R
b. Cyclophosphamide and HIF1-α, Tubulin
c. Imatinib and HER-2, MET, RET, KIT, FLT3
d. Vinblastine and COX-2, Tublin assembly, EGFR
Answer: a
Which of the following are pan-endothelial markers?
i. CD31/PECAM
ii. Alpha-smooth muscle actin
iii. TIE2/CD202b
iv. CD11b
v. Von Willebrand factor
a. ii, iv
b. iii, iv, v
c. i, ii
d. i, iii, v
Answer: d
Explanation: alpha-SMA is a marker for mural cells, and CD11b is found on tumor-associated M2 macrophages
Identify the correct pairing of ligand, receptor, and downstream effect:
a. VEGF-A : HSPG : lymphangiogenesis
b. ANG2 : TIE2 : vessel maturation
c. DLL4 : FLT4 : angiogenesis
d. PIGF: NOTCH : arterial-venous identity
Answer: b.
Which of the following most strongly governs the direction of endothelial sprouts growth?
a. Contact inhibition prevents angiogenesis toward areas that are already well-vascularized.
b. Movement of tip cells along VEGF gradients guides cohorts of stalk cells.
c. Angiogenesis only occurs towards areas of high nutrient concentration.
d. Growth occurs in areas where EPHRINB2 binding to EPHB4 activates MMPs to degrade the extracellular matrix.
Answer: b.
EPHRINB2/EPHB4 is involved in arterial-venous identity, not MMP activation.
When targeting angiogenesis, inhibition of PDGFRβ would target which cell type primarily?
a. Pericytes
b. Endothelial tip cells
c. Endothelial progenitor cells
d. Tumor associated macrophages (M2-type)
Answer: a
Mural cells (PCs and SMCs) express PDGFRβ. Tip cells will produce large amounts of PDGFBB during angiogenesis to recruit mural cells to endothelial tube. T&H pg. 249.
Which of the following members of the vascular endothelial growth factor family receptor is primarily responsible for binding VEGFA during angiogenesis?
a. VEGFR1
b. VEGFR2
c. VEGFR3
d. VEGFR4
Answer: b.
Although VEGFR1 binds VEGFA with higher affinity the phosphorylation of this receptor in ECs is weak (deletion of VEGFR1 is relatively inconsequential for vascular development). VEGFA signaling is mainly mediated by VEGFR2. T&H pg. 252.
Which of the following most accurately defines angiogenesis?
a. Process of non-epithelial cells adopting endothelial-like phenotype and line vascular channels.
b. The process of cancer cells growing around and enveloping pre-existing vessels.
c. De novo formation of new blood vessels whereby angioblasts differential into endothelial cells.
d. Process of new vascular structures emerging from ones that have already been established.
Answer: d.
a – vascular mimicry, b – vascular cooptation
