Block 3 Lecture 8 -- Metastasis and Angiogenesis

Question 1

MoA of bevacizumab:

Answer 1

VEGF-inhibitor

Question 2

MoA of sunitinib:

Answer 2

VEGF-receptor (Src) inhibitor

Question 3

MoA of sorafenib:

Answer 3

VEGF-receptor (Src) inhibitor

Question 4

MoA of endostatin:

Answer 4

limit vessel production

Question 5

MoA of thalidomide

Answer 5

limit vessel production

Question 6

What are the classes of anti-angiogenic drug therapies?

Answer 6

(all stop growth but do not eradicate vasculature) 1) VEGF-inhibitor, 2) VEGF-receptor Src inhibitors, 3) anti-angiogenics

Question 7

What are the 6 steps in metastasis?

Answer 7

1) migration 2) intravasation 3) transport 4) extravasation 5) Colonization 6) Angiogenesis

Question 8

What is the fundamental difference between benign and malignant tumor growth?

Answer 8

metastasis

Question 9

What is metastasis?

Answer 9

the process by which tumor cells from a primary site invade and migrate to other parts of the body

Question 10

Function of cadherins:

Answer 10

connect cell-cell (anchoring, signaling, homo/hetero-typic identification)

Question 11

Function of catenins:

Answer 11

connect cadherins to nucleus to relay messages

Question 12

function of integrin receptors:

Answer 12

relay information from bound ECM

Question 13

What substances induce the epithelial-to-mesenchymal transition?

Answer 13

TGF-beta, HGF

Question 14

Describe the Seed and Soil theory.

Answer 14

distant organ provides a match between migrating cell and a suitable environment

Question 15

Describe the Pre-metastatic Niche Concept.

Answer 15

factors released by primary tumor provide a good soil at a distant site

Question 16

What are the 2 metastatic colonization theories?

Answer 16

1) seed and soil, 2) pre-metastatic niche

Question 17

Why is metastasis often lethal?

Answer 17

1) generally more drug resistant than primary tumor, 2) can end up anywhere. Impossible to id and remove all; 3) angiogenesis destroys colonized tissue

Question 18

What are ADRs of anti-angiogenic therapies?

Answer 18

reproductive, renal, teratogenic

Question 19

Define angiogenesis:

Answer 19

forming new blood vessels from existing ones by growth and migration of endothelial cells

Question 20

Why is metastasis a highly selective process?

Answer 20

tumors are highly heterogenous

Question 21

What processes are necessary for the EMT?

Answer 21

1) downregulate anchoring cadherins (E-cad), 2) upregulate MMPs

Question 22

What is the function of MMPs?

Answer 22

1) mature TGF-beta, 2) dissolve basement membrane

Question 23

What are the 2 characteristics of mesenchymal-like tumor cells?

Answer 23

1) no connections to neighbors, 2) want to find a comfy environment

Question 24

What proteins/enzymes are involved in VEGF production regulated by O2?

Answer 24

1) prolyl 4-hydroxylase, 2) HIF-a, 3) VHL, 4) uniquitin

Question 25

What are activators of the angiogenic switch?

Answer 25

VEGF, HER, growth factors

Question 26

What are inhibitors of the angiogenic switch?

Answer 26

p53, angiostatin, PRL

Question 27

What are the pathways of VEGF that stimulate angiogenesis?

Answer 27

1) AKT-P activates eNOS (NO, vascular permeability), 2) RAS/MAPK (gene expression)