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FMS part 2 > Angiogenesis and Metastasis > Flashcards

Angiogenesis and Metastasis Flashcards

1
Q

Continuous capillary

A
  • Have tight occluding junctions that seal the spaces between endothelial cells
  • All transport must take place across membranes
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2
Q

Fenestered capillary

A
  • Have perforations (fenestrations) through endothelial cells that allow exchange of small molecules with blood
  • Example; endocrine organs, intestinal wall
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3
Q

sinusoid capillary

A
  • Have wide spaces between endothelial cells, large fenestrations, and a discontinuous basement membrane that allow for exchange of macromolecules and cells with tissues and blood
  • Example; bone marrow, liver, spleen
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4
Q

Tumors require access to circulation in order to grow and survive

A

• Cancer cells grow preferentially around blood vessels
o Tumor cells more than 0.2 mm away are non growing
o Further than that they die
• 0.2 mm is the distance oxygen can effectively diffuse
• Need oxygen and to shed waste and CO2

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5
Q

Conditions as cells move further from vessels

A
  • Higher lactate
  • Lower pH
  • Lower glucose
  • Lower ATP
  • Lower oxygen
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6
Q

Angiogenesis is important in

A
  • Embryonic development
  • Implantation of the placenta
  • Wound healing
  • Many disease processeses
  • Tumorigenesis
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7
Q

Excessive angiogenesis

A 
o	Blindness 
o	Rheumatoid arthritis
o	Cancer
o	AIDS complications
o	Psoriasis
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8
Q

Insufficient angiogenesis

A 
o	Stroke
o	Infertility
o	Heart disease
o	Ulcers
o	scleroderma
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9
Q

VEGF and bFGF

A
  • Receptors for these on the surfaces of endothelial cells
  • Stimulate endothelial cell proliferation
  • Tyrosine kinase receptors
  • Transphosphorylation activates
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10
Q

VEGF production in low oxygen

A

o HIF-1alpha is dephosphorylated

o Enters nucleus and along with HIF-1beta induces transcription of VEGF gene

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11
Q

VEGF in normal oxygen

A

o HIF-1alpha is hydroxylated by proline hydroxylase
o Bound by pVHL and other proteins
o Tagged by ubiquitin and degraded by proteasome

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12
Q

As tumor grows, capillaries increase

A

• Circulating endothelial cells from bone marrow are recruited to settle in the tumor stroma and differentiate
• Capillaries are also being assembled from endothelial cells present within the tumor stroma
• Other key players
o TGF-beta, EL-8, angiopoietin, angiogenin (1&2)

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13
Q

angiogenesis in tumors

A

• Cell of vasculature
o Endothelial cells
o Pericytes
o Smooth muscle cells

• Nonvascular cells
o Neoplastic cells
o Supporting cells of the stroma

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14
Q

Step 1 in angio

A

Stimulation of endothelial cells by angiogenic growth factors

• Basic fibroblast growth factor
o bFGF
• Vascular endothelial Growth factor
o VEGF

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15
Q

Step 2 in angio

A

Degradation of the parental vessel basal lamina by activated endothelial cells to facilitate the formation of capillary sprout

• Secreted proteases
o Matrix metalloproteinases (MMPs)
o Plasminogen activator urokinase (uPA)
• MMPs are secreted to allow cells to migrate through the ECM

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16
Q

step 3 in angio

A

endothelial cell migration and proliferation

• Regulation of cell migration
o Integrins
o Extracellular proteinases

17
Q

step 4 in angio

A

maturation of endothelial cells involving the formation of capillary tubes, reformation of the basal lamina and recruitment of pericytes

  • Angiopoietin 1 (Ang 1)
  • Platelet Derived Growth Factor (PDGF)
18
Q

angiogenic activators

A 
o	VEGF-A
o	VEGF-B, C
o	FGF1 (aFGF)
o	FGF2 (bFGF)
o	Other FGFs
19
Q

angiogenic inhibitors

A 
o	Thrombospondin-1, 2
o	Interferon alpha/beta
o	Angiostatin
o	Endostatin
o	Collagen IV fragments
20
Q

purpose of angiogenic switch

A

Tripping the angiogenic switch is essential for tumor expansion because many tumor cells populations initially lack the ability to attract blood vessels

21
Q

angiogenic switch

A
  • angiogenesis is a component of the tumor phenotype that is activated during early pre-neoplastic stages
  • Most tumors arise without angiogenic activity, exist in ‘dormant’ stage (carcinoma in situ) without vascularization
  • become vascularized when subset of cells switches to angiogenic phenotype
22
Q

dormant lesion characteristics

A

o Proliferation rate is equal to apoptosis
o Angiogenic inducers are low
o Angiogenic inhibitor are high

23
Q

metastatic lesion characteristics

A

o Proliferation rate is greater than apoptosis rate
o Angiogenic inducers are high
o Angiogenic inhibitors are low

24
Q

Prevascular phase

A
  • Angiogenic activity is absent or low
  • Tumors remain small with volumes in a few cubic millimeters (prolif=apop)
  • Tumors are generally thin or flat, stable, asymptomatic and rarely metastatic
  • Micrometastases may have similar pre-vascular phase
25
Q

Vascular phase

A
  • Characterized by tumors which have entered a phase of rapid growth, intensified invasion, increased metastatic potential
  • A bidirectional paracrine relationship between the tumor cells and endothelial cells is established. Endothelial- derived growth factors stimulate the growth of the tumor cells
  • Hypoxic areas of the tumor stimulate VEGF production and subsequent endothelial cell growth
  • Associated with increased appearance of symptoms. Bleeding, local edema, inappropriate hormonal activities, hypercoagulation states and cachexia
26
Q

Heterogeneity of angiogenic activity in tumors

A
  • Neovascularization of a tumor usually originates is a subset of cells due to the presence of a mixture of angiogenic and non-angiogenic cells
  • Metastases derived from the angiogenic portion of the tumor are already angiogenic upon arrival at the target organ and therefore have an increased chance of becoming a detectable metastasis
27
Q

Possible advantage of using anti-angiogenic therapy

A
  • Specificity may result in few side effects
  • Angiogenesis in adults is limited to reproductive tissues and wound healing
  • Structure of tumor vasculature is a barrier for traditional drug delivery (irregularly shaped, dilated, tortuous, dead ends)
  • Anti-angiogenesis therapies target accessible vessel endothelial cells
  • Drug resistance is reduced because endothelial cells are stable and have low mutation rates
  • In theory, should be applicable to all solid tumors regardless of origin since endothelial cells do not vary from one type to another
28
Q

Sequence of events in tumor metastasis

A
  • Initial transformation event
  • Proliferation of transformed cells
  • Compromised nutritional supply to the tumor mass requiring the release of tumor angiogenesis factors
  • Endothelial cell expansion and reorganization
  • Local invasion and destruction of extracellular matrix components and parenchymal cells leading to migration of tumor cell aways from the primary tumor mas
  • Penetration of cancer cells through the blood vessel wall (intravasation)
  • Arrest of cancer cells in the lumen of small blood vessels or lymphatics
  • Reverse penetration of blood vessels
  • Organ colonization resulting in the formation of secondary tumor (metastases)
29
Q

Epithelial- mesenchymal transitions in cancer

A
  • Cytoskeletal reorganization
  • Membrane reorganization
  • Increased growth
  • Increased motility
  • Take on more connective tissue properties and elements
  • Repress epithelial markers like: e-cadherin, u-cadherin, y-cadherin
  • Induce mesenchymal markers like: vimentin, fibronectin, n-cadherin
30
Q

Seed and soil model for preferred sites of metastasis

A
  • Colonization of metastasized tumor cells is inefficient
  • Micrometastases often “seed” organs but most fail to grow into clinically observed tumors
  • Organs must provide a hospital environment (soil) for metastasized tumors to grow
31
Q

Factors that affect the location and efficiency of metastasis

A
  • Chemokines in the specific tissue that attract the tumor cells to the site
  • The differentiation, development and growth conditions of the tissue (mitogens and growth factors)
  • The nature of the trafficking circulation (blood and lymphatic) systems in the specific organ

FMS part 2 (7 decks)

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