Neoplasia VI: Angiogenesis and Metastasis

Question 1

Continuous capillaries

Answer 1

Have tight occluding junctions that seal the spaces between endothelial cells. Transport must take place across membranes.

Question 2

Fenestrated Capillaries

Answer 2

Have perforations (fenestrations) through endothelial cells that allow for exchange of small molecules with blood

Question 3

Sinusoid Capillaries

Answer 3

Wide gap between endothelial cells, fenestrations, and a discontinuous basement membrane that allows for exchange of macromolecules and cells with tissue and blood

Question 4

VEGF AND bFGF

Answer 4

• Receptors display on surface of endothelial cells
• Stimulate endothelial cell proliferation

Question 5

Production of VEGF

Answer 5

• Governed by availability of oxygen
• Activation:HIF-1a senses hypoxia–>HIF-1b binds to HIF-1a, activates VEGF and transcription can go
• Deactivation: Proline hydroxylase hydroxylzes HIF-1a–>pHVL and two other proteins recognize and bind, polyubiquitylation, and degradation

Question 6

Steps in formation of new capillaries

Answer 6

1. Stimulation of endothelial cells by angiogenic GF’s
2. Degradation of parental basal lamina by activated endothelial cells to facilitate formation of capillary spout
3. Endothelial cell migration and proliferation
4. Maturation of endothelial cells involving the formation of capillary tubes, reformation of basal lamina and recruitment of pericytes

Question 7

Cells of the vasculature

Answer 7

endothelial, perictyes, smooth muscle

Question 8

Nonvascular cells

Answer 8

neoplastic cells, supporting cells of the stroma

Question 9

Step 1 in angiogenesis

Answer 9

stimulation of endothelial cells by GF’s

• VEGF and bFGF

Question 10

Step 2 in Angiogenesis

Answer 10

Degredation of capillary basal lamina by activated endothelial cells

• Secreted Proteases:
  
  • Matrix metalloproteases (MMP’s)
  • Plasminogen activator urokinase (uPA)

Question 11

Step 3 in Angiogenesis

Answer 11

Capillary sprout formation and migration of endothelial cells

• Regulation of cell migration
  
  • Integrins
  • extracellular proteases

Question 12

Step 4 of Angiogenesis

Answer 12

New Vessel Maturation

• Angiopoeitin 1 (ANG-1)
• Platelet derived growth factor (PDGF)

Question 13

Activators of Angiogenesis

Answer 13

• VEGF-A,B,C
• FGF1(aFGF)
• FGF2(bFGF)
• other FGF’s

Question 14

Inhibitors of Angiogenesis

Answer 14

• Thrombospondin 1,2
• Interferon a,b
• angiostatin
• endostatin
• collagen IV fragments

Question 15

MMP9

Answer 15

From mast cells and macrophages in bone marrow

• release VEGF that is sequestered in extracellular matrix

Question 16

The angiogenic switch

Answer 16

• proliferation>>apoptosis
• angiogenic inducers high
• angiogenic inhibitors low

Question 17

in situ

Answer 17

• local tumor that hasnt breached basement membrane
• proliferation = apoptosis
• angiogenic inducers low
• angiogenic inhibitors high

Question 18

Prevascular phase

Answer 18

• angiogenic activity is absent or low
• tumors are small, thin, flat, stable, asympomatic
• micrometasteses have similar pre-vascular phase

Question 19

vascular phase

Answer 19

• rapid growth, intensified invasion, increased metastatic potential
• bidirectional paracrine relationship between tumor cells and endothelial cells established.
• endothelial derived GF’s stimulate growth of tumor cells
• Hypocis areas stimulate VEGF production and subsequent cell growth
• this is when you get the increased appearance of symptoms

Question 20

Heterogeinity in tumors

Answer 20

• tumors can be mixed with cells that have angiogenic capabilities and some that dont
• can have a dormant micrometastisis (undetectable)

Question 21

Anti-angiogenic therapies

Answer 21

• fewer side effects
• target vessels
• drug resistance is reduced because endothelial cells are geneticall stable
• applicable to all solid tumors in theory since all endothelial cells are the same in tumors

Question 22

metastisis is _______ dependent

Answer 22

Angiogenesis

Question 23

sequence of events in tumor cell metastisis

Answer 23

• initial transforming event
• proliferation of transformed cells
• compromised nutritional supply–>release of angiogenesis GF’s
• endothelial cell expansion/reorganization
• local invasion and destruction of extracellular matrix and parenchymal cells leading to migration of tumor cells
• penetration through blood vessel wall
• arrest of cancer cells in lumen of small blood vessels or lymphatics
• reverse penetration of blood vessels
• organ colonization resulting in formation of secondary tumor (aka metastisis)

Question 24

Tumor cells can secrete enzymes that

Answer 24

degrade adhesion proteins between cells of vasculature

i.e: mutation or decreased expression in cadherins

Question 25

Epithelial mesenchymal transition

Answer 25

* Epithelial cannot migrate, so cell suppresses expression of epithelium (with e cadherin etc.) and express features of mesenchymal cell so they can penetrate blood vessel * must acquire mesenchymal phenotype to invade

Question 26

Seed and Soil

Answer 26

* Colonization is no efficient-tumor must have good environment to grow * some can go somewhere where it wont survive * Some tumors have a preference for where they like to metastasize * chemokines can attract tumors * favorable circulation systems * mitogens and GF's *