Angiogenesis and Metastasis Flashcards
Continuous capillary
- Have tight occluding junctions that seal the spaces between endothelial cells
- All transport must take place across membranes
Fenestered capillary
- Have perforations (fenestrations) through endothelial cells that allow exchange of small molecules with blood
- Example; endocrine organs, intestinal wall
sinusoid capillary
- 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
Tumors require access to circulation in order to grow and survive
• 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
Conditions as cells move further from vessels
- Higher lactate
- Lower pH
- Lower glucose
- Lower ATP
- Lower oxygen
Angiogenesis is important in
- Embryonic development
- Implantation of the placenta
- Wound healing
- Many disease processeses
- Tumorigenesis
Excessive angiogenesis
o Blindness o Rheumatoid arthritis o Cancer o AIDS complications o Psoriasis
Insufficient angiogenesis
o Stroke o Infertility o Heart disease o Ulcers o scleroderma
VEGF and bFGF
- Receptors for these on the surfaces of endothelial cells
- Stimulate endothelial cell proliferation
- Tyrosine kinase receptors
- Transphosphorylation activates
VEGF production in low oxygen
o HIF-1alpha is dephosphorylated
o Enters nucleus and along with HIF-1beta induces transcription of VEGF gene
VEGF in normal oxygen
o HIF-1alpha is hydroxylated by proline hydroxylase
o Bound by pVHL and other proteins
o Tagged by ubiquitin and degraded by proteasome
As tumor grows, capillaries increase
• 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)
angiogenesis in tumors
• Cell of vasculature
o Endothelial cells
o Pericytes
o Smooth muscle cells
• Nonvascular cells
o Neoplastic cells
o Supporting cells of the stroma
Step 1 in angio
Stimulation of endothelial cells by angiogenic growth factors
• Basic fibroblast growth factor
o bFGF
• Vascular endothelial Growth factor
o VEGF
Step 2 in angio
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
step 3 in angio
endothelial cell migration and proliferation
• Regulation of cell migration
o Integrins
o Extracellular proteinases
step 4 in angio
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)
angiogenic activators
o VEGF-A o VEGF-B, C o FGF1 (aFGF) o FGF2 (bFGF) o Other FGFs
angiogenic inhibitors
o Thrombospondin-1, 2 o Interferon alpha/beta o Angiostatin o Endostatin o Collagen IV fragments
purpose of angiogenic switch
Tripping the angiogenic switch is essential for tumor expansion because many tumor cells populations initially lack the ability to attract blood vessels
angiogenic switch
- 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
dormant lesion characteristics
o Proliferation rate is equal to apoptosis
o Angiogenic inducers are low
o Angiogenic inhibitor are high
metastatic lesion characteristics
o Proliferation rate is greater than apoptosis rate
o Angiogenic inducers are high
o Angiogenic inhibitors are low
Prevascular phase
- 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
Vascular phase
- 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
Heterogeneity of angiogenic activity in tumors
- 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
Possible advantage of using anti-angiogenic therapy
- 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
Sequence of events in tumor metastasis
- 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)
Epithelial- mesenchymal transitions in cancer
- 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
Seed and soil model for preferred sites of metastasis
- 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
Factors that affect the location and efficiency of metastasis
- 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
