Lecture 9: Tumor Angiogenesis

Question 1

Tumor growth beyond _____________ in diameter requires induction and maintenance of a new blood supply (Angiogenesis)

Answer 1

1-2 millimeters

Question 2

In the absence of vascular support, tumors may become __________________. Therefore, angiogenesis is an important factor in cancer progression

Answer 2

Necrotic or apoptotic

Question 3

Thrombosis

Answer 3

Formation of a thrombus (Blood clot) inside a blood vessel.

Question 4

Angiogenic growth factors (Proangiogenic)

Answer 4

Class of molecules that stimulate the process of blood vessel formation
-Vascular endothelial growth factor
-Fibroblast growth factor-2
-Platelet derived growth factor
-Angiopoietins

Question 5

Anti-angiogenic factors

Answer 5

Inhibitors of angiogenesis
-Thrombospondins
-Endostatin is a 20 kD C-term fragment of Collagen XVIII
-Angiostatin, fragment of plasminogen

Question 6

Blood vessels are located around the ________ of cancer epithelial cells in the ________________

Answer 6

1. Island
2. Tumor Stroma

Question 7

When injected into ______________ dyes leak out of the capillaries and diffuses into nearby parenchyma yielding diffusely staining of the blood vessels

Answer 7

Tumor vasculature

Question 8

Consequence of the leakiness of tumor-associated vasculature

Answer 8

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.

Question 9

Cancer-associated thrombosis is __________ times more fatal for cancer patients compared to people without cancer

Answer 9

Three

Question 10

If cancer-associated thrombosis is not treated it can break off and travel to lungs causing_______

Answer 10

-Deep vein thrombosis
-Pulmonary embolism
-Heart –> Heart attack
-Brain –> Stroke

Question 11

2 sources of proliferation of vascular endothelial cells

Answer 11

1. Existing vascular endothelial cells, including adjacent normal tissue
2. Distant sites: VEGF secreted by tumor cells, fibroblasts, immune cells, and local vascular endothelial cells recruit circulating endothelial progenitor cells (EPCs) from bone marrow.

Question 12

Alternative source for tumor vascularization

Answer 12

Transdifferentiating: Endothelial differentiation of glioblastoma stem-like cells. Glioblastoma stem-like cells become endothelial cells

Question 13

Role of tumor-associated fibroblasts in tumor angiogenesis

Answer 13

TAFs recruit vascular endothelial precursor cells and stimulate their differentiation to increase tumor angiogenesis

Question 14

Myofibroblasts of tumor-associated stroma express _________

Answer 14

High levels of VEGF-A, which recruits circulating EC and stimulates EC proliferation at tumor site, in the TME

Question 15

Vascular endothelial growth factor-A

Answer 15

Growth factor expressed both on lymphoma cells and endothelial cells in angioimmunoblastic T-cell lymphoma and related to lymphoma progression

Question 16

Conclusion of glioblastoma experiment where mice were injected with human glioblastoma cells

Answer 16

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

Question 17

Threshold of distance a tumor can be away from blood vessels so that oxygen can effectively diffuse in order for tumor growth to occur

Answer 17

0.2 mm

Question 18

Cells situated more than 0.2 mm away from blood vessels

Answer 18

Non-growing, white, hypozemic, low-pH, and necrotic.

Question 19

ZD6474

Answer 19

Inhibitor of VEGF-R2 in mice bearing human adenocarcionma xenographs.

Question 19

The necrotic regions

Answer 19

Region as close as 85 micrometers from melanoma capillary

Question 20

Cellular and structural abnormalities of tumor vasculature

Answer 20

-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

Question 21

Effect of vascular density during tumor growth

Answer 21

Vascular tendency decreases leading to zones of ischemia and ultimately necrosis as tumors outgrow their blood supply

Question 22

Consequences of VEGF administration

Answer 22

Tumor microvessels became increasingly permeable after administration of VEGF

Question 23

Pericytes

Answer 23

Perivascular cells surrounding capillaries that help maintain capillary rigidity and intraluminal blood pressure.

Question 24

Pericytes in tumors

Answer 24

Endothelial cells forming the vessel lumen are only partially overlayed by pericytes and smooth muscle cells.

Question 25

Consequence of leaky blood vessels

Answer 25

Tumor cells can penetrate into circulation and metastasize to other parts of the body

Question 26

Pericytes in normal cells

Answer 26

Pericytes and smooth muscle cells cover completely the endothelial cells in normal vasculature

Question 27

Lymphatic vessel characteristics

Answer 27

Diameter far larger than capillaries. Lymphatic vessels are also not supported by pericytes and smooth muscle tissue

Question 28

2 potential attributions for lack of lymphatic vessels in tumors

Answer 28

1. Lack of formation of these ducts
2. Collapse and degeneration of these ducts because of the high hydrostatic pressure of solid tumors

Question 29

Normal instances of angiogenesis

Answer 29

-Embryonic development
-Wound healing
-Vascularization of endometrium
-Placental growth

Question 30

Most active form of VEGF

Answer 30

VEGF-A165

Question 31

Vascular quiescence

Answer 31

A process in normal tissues maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli

Question 32

Clinical outcomes of angiogenesis

Answer 32

Patients with high microvessel count has a lower probability of disease-free survival in the 20 years following initial diagnosis

Question 33

Angiogenic switch activators

Answer 33

-VEGF-A
-VEGF-B, C
-FGF1
-FGF2

Question 34

Angiogenic switch inhibitors

Answer 34

-Thrombospondin-1.-2
-Interferon a/B
-Angiostatin
-Endostatin
-Collagen IV fragments

Question 35

SU6668

Answer 35

PDGF receptor inhibitor

Question 36

SU5416

Answer 36

VEGF-R inhibitor

Question 37

Avastom/Bevacizumab

Answer 37

Monoclonal antibody of VEGF that would extend life <5 months. Eventually withdrew by FDA.

Question 38

DC101

Answer 38

Monoclonal antibody against VEGF-R2