Neoplasia VI: Angiogenesis and Metastasis Flashcards

1
Q

Continuous capillaries

A

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

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2
Q

Fenestrated Capillaries

A

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

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3
Q

Sinusoid Capillaries

A

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

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4
Q

VEGF AND bFGF

A
  • Receptors display on surface of endothelial cells
  • Stimulate endothelial cell proliferation
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5
Q

Production of VEGF

A
  • 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
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6
Q

Steps in formation of new capillaries

A
  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
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7
Q

Cells of the vasculature

A

endothelial, perictyes, smooth muscle

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8
Q

Nonvascular cells

A

neoplastic cells, supporting cells of the stroma

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9
Q

Step 1 in angiogenesis

A

stimulation of endothelial cells by GF’s

  • VEGF and bFGF
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10
Q

Step 2 in Angiogenesis

A

Degredation of capillary basal lamina by activated endothelial cells

  • Secreted Proteases:
    • Matrix metalloproteases (MMP’s)
    • Plasminogen activator urokinase (uPA)
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11
Q

Step 3 in Angiogenesis

A

Capillary sprout formation and migration of endothelial cells

  • Regulation of cell migration
    • Integrins
    • extracellular proteases
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12
Q

Step 4 of Angiogenesis

A

New Vessel Maturation

  • Angiopoeitin 1 (ANG-1)
  • Platelet derived growth factor (PDGF)
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13
Q

Activators of Angiogenesis

A
  • VEGF-A,B,C
  • FGF1(aFGF)
  • FGF2(bFGF)
  • other FGF’s
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14
Q

Inhibitors of Angiogenesis

A
  • Thrombospondin 1,2
  • Interferon a,b
  • angiostatin
  • endostatin
  • collagen IV fragments
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15
Q

MMP9

A

From mast cells and macrophages in bone marrow

  • release VEGF that is sequestered in extracellular matrix
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16
Q

The angiogenic switch

A
  • proliferation>>apoptosis
  • angiogenic inducers high
  • angiogenic inhibitors low
17
Q

in situ

A
  • local tumor that hasnt breached basement membrane
  • proliferation = apoptosis
  • angiogenic inducers low
  • angiogenic inhibitors high
18
Q

Prevascular phase

A
  • angiogenic activity is absent or low
  • tumors are small, thin, flat, stable, asympomatic
  • micrometasteses have similar pre-vascular phase
19
Q

vascular phase

A
  • 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
20
Q

Heterogeinity in tumors

A
  • tumors can be mixed with cells that have angiogenic capabilities and some that dont
  • can have a dormant micrometastisis (undetectable)
21
Q

Anti-angiogenic therapies

A
  • 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
22
Q

metastisis is _______ dependent

A

Angiogenesis

23
Q

sequence of events in tumor cell metastisis

A
  • 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)
24
Q

Tumor cells can secrete enzymes that

A

degrade adhesion proteins between cells of vasculature

i.e: mutation or decreased expression in cadherins

25
Q

Epithelial mesenchymal transition

A
  • 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
26
Q

Seed and Soil

A
  • 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
      *