Lecture 9: Tumor Angiogenesis Flashcards
Tumor growth beyond _____________ in diameter requires induction and maintenance of a new blood supply (Angiogenesis)
1-2 millimeters
In the absence of vascular support, tumors may become __________________. Therefore, angiogenesis is an important factor in cancer progression
Necrotic or apoptotic
Thrombosis
Formation of a thrombus (Blood clot) inside a blood vessel.
Angiogenic growth factors (Proangiogenic)
Class of molecules that stimulate the process of blood vessel formation
-Vascular endothelial growth factor
-Fibroblast growth factor-2
-Platelet derived growth factor
-Angiopoietins
Anti-angiogenic factors
Inhibitors of angiogenesis
-Thrombospondins
-Endostatin is a 20 kD C-term fragment of Collagen XVIII
-Angiostatin, fragment of plasminogen
Blood vessels are located around the ________ of cancer epithelial cells in the ________________
- Island
- Tumor Stroma
When injected into ______________ dyes leak out of the capillaries and diffuses into nearby parenchyma yielding diffusely staining of the blood vessels
Tumor vasculature
Consequence of the leakiness of tumor-associated vasculature
Continuous leaking of thrombin and fibrinogen molecules from the plasma into the parenchyma surrounding blood vessels leading to thrombosis. Resulting in extensive network of fibrin bundles at the border between growing cancer and stroma.
Cancer-associated thrombosis is __________ times more fatal for cancer patients compared to people without cancer
Three
If cancer-associated thrombosis is not treated it can break off and travel to lungs causing_______
-Deep vein thrombosis
-Pulmonary embolism
-Heart –> Heart attack
-Brain –> Stroke
2 sources of proliferation of vascular endothelial cells
- Existing vascular endothelial cells, including adjacent normal tissue
- Distant sites: VEGF secreted by tumor cells, fibroblasts, immune cells, and local vascular endothelial cells recruit circulating endothelial progenitor cells (EPCs) from bone marrow.
Alternative source for tumor vascularization
Transdifferentiating: Endothelial differentiation of glioblastoma stem-like cells. Glioblastoma stem-like cells become endothelial cells
Role of tumor-associated fibroblasts in tumor angiogenesis
TAFs recruit vascular endothelial precursor cells and stimulate their differentiation to increase tumor angiogenesis
Myofibroblasts of tumor-associated stroma express _________
High levels of VEGF-A, which recruits circulating EC and stimulates EC proliferation at tumor site, in the TME
Vascular endothelial growth factor-A
Growth factor expressed both on lymphoma cells and endothelial cells in angioimmunoblastic T-cell lymphoma and related to lymphoma progression
Conclusion of glioblastoma experiment where mice were injected with human glioblastoma cells
Human glioblastoma cells have stem-cell plasticity that allows these tumor cells to become endothelial. Tumor vascularization occurred via endothelial differentiation of glioblastoma stem-like cells
Threshold of distance a tumor can be away from blood vessels so that oxygen can effectively diffuse in order for tumor growth to occur
0.2 mm
Cells situated more than 0.2 mm away from blood vessels
Non-growing, white, hypozemic, low-pH, and necrotic.
ZD6474
Inhibitor of VEGF-R2 in mice bearing human adenocarcionma xenographs.
The necrotic regions
Region as close as 85 micrometers from melanoma capillary
Cellular and structural abnormalities of tumor vasculature
-Excessive branching
-Leaky vessels
-Fenestrated appearance
-Loose association between pericytes and EC
-Chaotic organizations & blood flow
-Increased diameter of tumor associated capillaries
-Lack of arteriole-venule-capillary hierarchy
-High vascular density
-Lack lymphatic vasculature
Effect of vascular density during tumor growth
Vascular tendency decreases leading to zones of ischemia and ultimately necrosis as tumors outgrow their blood supply
Consequences of VEGF administration
Tumor microvessels became increasingly permeable after administration of VEGF
Pericytes
Perivascular cells surrounding capillaries that help maintain capillary rigidity and intraluminal blood pressure.
Pericytes in tumors
Endothelial cells forming the vessel lumen are only partially overlayed by pericytes and smooth muscle cells.
Consequence of leaky blood vessels
Tumor cells can penetrate into circulation and metastasize to other parts of the body
Pericytes in normal cells
Pericytes and smooth muscle cells cover completely the endothelial cells in normal vasculature
Lymphatic vessel characteristics
Diameter far larger than capillaries. Lymphatic vessels are also not supported by pericytes and smooth muscle tissue
2 potential attributions for lack of lymphatic vessels in tumors
- Lack of formation of these ducts
- Collapse and degeneration of these ducts because of the high hydrostatic pressure of solid tumors
Normal instances of angiogenesis
-Embryonic development
-Wound healing
-Vascularization of endometrium
-Placental growth
Most active form of VEGF
VEGF-A165
Vascular quiescence
A process in normal tissues maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli
Clinical outcomes of angiogenesis
Patients with high microvessel count has a lower probability of disease-free survival in the 20 years following initial diagnosis
Angiogenic switch activators
-VEGF-A
-VEGF-B, C
-FGF1
-FGF2
Angiogenic switch inhibitors
-Thrombospondin-1.-2
-Interferon a/B
-Angiostatin
-Endostatin
-Collagen IV fragments
SU6668
PDGF receptor inhibitor
SU5416
VEGF-R inhibitor
Avastom/Bevacizumab
Monoclonal antibody of VEGF that would extend life <5 months. Eventually withdrew by FDA.
DC101
Monoclonal antibody against VEGF-R2
