Block 3 Lecture 8 -- Metastasis and Angiogenesis Flashcards
MoA of bevacizumab:
VEGF-inhibitor
MoA of sunitinib:
VEGF-receptor (Src) inhibitor
MoA of sorafenib:
VEGF-receptor (Src) inhibitor
MoA of endostatin:
limit vessel production
MoA of thalidomide
limit vessel production
What are the classes of anti-angiogenic drug therapies?
(all stop growth but do not eradicate vasculature) 1) VEGF-inhibitor, 2) VEGF-receptor Src inhibitors, 3) anti-angiogenics
What are the 6 steps in metastasis?
1) migration 2) intravasation 3) transport 4) extravasation 5) Colonization 6) Angiogenesis
What is the fundamental difference between benign and malignant tumor growth?
metastasis
What is metastasis?
the process by which tumor cells from a primary site invade and migrate to other parts of the body
Function of cadherins:
connect cell-cell (anchoring, signaling, homo/hetero-typic identification)
Function of catenins:
connect cadherins to nucleus to relay messages
function of integrin receptors:
relay information from bound ECM
What substances induce the epithelial-to-mesenchymal transition?
TGF-beta, HGF
Describe the Seed and Soil theory.
distant organ provides a match between migrating cell and a suitable environment
Describe the Pre-metastatic Niche Concept.
factors released by primary tumor provide a good soil at a distant site
What are the 2 metastatic colonization theories?
1) seed and soil, 2) pre-metastatic niche
Why is metastasis often lethal?
1) generally more drug resistant than primary tumor, 2) can end up anywhere. Impossible to id and remove all; 3) angiogenesis destroys colonized tissue
What are ADRs of anti-angiogenic therapies?
reproductive, renal, teratogenic
Define angiogenesis:
forming new blood vessels from existing ones by growth and migration of endothelial cells
Why is metastasis a highly selective process?
tumors are highly heterogenous
What processes are necessary for the EMT?
1) downregulate anchoring cadherins (E-cad), 2) upregulate MMPs
What is the function of MMPs?
1) mature TGF-beta, 2) dissolve basement membrane
What are the 2 characteristics of mesenchymal-like tumor cells?
1) no connections to neighbors, 2) want to find a comfy environment
What proteins/enzymes are involved in VEGF production regulated by O2?
1) prolyl 4-hydroxylase, 2) HIF-a, 3) VHL, 4) uniquitin
What are activators of the angiogenic switch?
VEGF, HER, growth factors
What are inhibitors of the angiogenic switch?
p53, angiostatin, PRL
What are the pathways of VEGF that stimulate angiogenesis?
1) AKT-P activates eNOS (NO, vascular permeability), 2) RAS/MAPK (gene expression)
