Angiogenesis and Metastasis

Question 1

Types of capillaries

Answer 1

Continuous

Fenestrated

Sinusoid

Question 2

Continuous capillaries

Answer 2

Tight occluding junctions that seal the space between endothelial cells. All transport must take place across membranes.

Question 3

Answer 3

Continuous capillary

Question 4

Answer 4

Fenestrated Capillary

Question 5

Fenestrated capillary

Answer 5

Have perforations (fenestrations) through the endothelial cells that allow exchange of small molecules with blood (eg endocrine orgnas, intestinal wall)

Question 6

Answer 6

Sinusoid capillaries

Question 7

Sinusoid capillaries

Answer 7

Have wide spaces between the endothelial cells, large fenestrations, and a discontinuous basement membrane that allow for exchange of macromolecules and cells with tissues and blood (eg bone marrow, liver, and spleen.

Question 8

Answer 8

Picture of a vessel. Pericytes stabilize vessel.

Question 9

How far can oxygen effectively diffuse through living tissue

Answer 9

0.2mm

Question 10

Proximity to vasculature is important to…

Answer 10

give O2. But also to shed waste products and carbon dioxide.

Question 11

Answer 11

Know that between two vessels you may have an are of hypoxia. In an area of hypoxia you will have a lower ph and a higher lac- (lactic acid is being made by anaerobic glycolysis).

You also have lowe glucose, ATP, and oxygen.

Question 12

Answer 12

Note that here you have a vessel in the middle and then tumor surrounding the vessel. However, you can see there is not angiogenesis and there is an area of dropoff because cells are not viable in the hypoxic environment.

Question 13

The process of angiogenesis is essential for tissue survival and is seen in

Answer 13

Embryonic development

Implantation of the placenta

Wound healting

Many diease processes

Tumorigenesis

Question 14

Answer 14

Tyrosine Kinase dimerizes to become functional in signaling cascade. You can have VEGF and bFGF turn it on

Question 15

Production of VEGF is goverened by

Answer 15

the availability of oxygen

Question 16

Answer 16

In normoxic enviroment, HIF-1a gets a hydroxyl group added by proline hydroxylase and ultimately gets degraded by proteosome

In hypoxic condition, HIF-1a goes to the transcription of the VEGF gene

Question 17

Answer 17

View of a vessel with endothelial cells and pericyte

Question 18

As tumor growth continues, capillaries are increasing

Answer 18

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 tumor stroma

Question 19

Answer 19

Normal vs tumor vasculature.

Normal is more organized

tumor is more permeable

Question 20

Steps in the formation of new capillaries

Answer 20

1) stimulation of endothelial cells by angiogenic growth factors
2) Degradation of the parental vessel basal lamina by activated endothelial cells to facilitate the formation of a capillary sprout
3) Endothelial cell migration and proliferation
4) Maturation of endothelial cells involving the formation of capillary tubes, reformation of the basal lamina and recruitment of pericytes

Question 21

Angiogenesis in tumors

Cells of the vasculature vs nonvascular cells

Answer 21

Cells of the vasculature: Endothelial cells, pericytes, and smooth muscle cells

Nonvascular cells: neoplastic cells, supporting cells of the stroma

Question 22

Step 1: Stimulation of Endothelial cells by angiogenix growth factors

GROWTH FACTORS INVOLVED

Answer 22

Basic fibroblast growth factor (bFGF)

Vascular endothelial growth factor (VEGF)

Question 23

Step 2: degradation of the capillary basal lamina by activated endothelial cells

SECRETED PROTEASES

Answer 23

matrix metalloproteinases (MMPs)

Plasminogen Activator Urokinase (uPA)

Question 24

Step 3: Capillary sprout formaiton and migration of endothelial cells

Answer 24

Regulation of cell migration

Integrins

Extracellular proteinases

Question 25

Step 4: New vessel maturation THINGS INVOLVED

Answer 25

pericyte comes and wraps newly formed vessel Angiopoetin 1( Ang1) (tells it to stop growing) Platelet derived growth factor (PDGF)

Question 26

Activators of angiogenesis

Answer 26

VEGF-A VEGF-B VEGF-C aFGF bFGF other FGFs

Question 27

Inhibitors of angiogenesis

Answer 27

thrombospondin 1 and 2 interfereon alpha/beta angiostatin endostatin collagen IV fragments

Question 28

Tripping of ____ is essential for tumor expansion

Answer 28

"Angiogenic switch" Many tumor cell populaitons lack the ability to attract blood vessels

Question 29

Answer 29

You see recruiting signals signal bone marrow. Mast cells and macrophages come to the party. MPP9 helps inactive sequestered VEGF in the ECM to be release and become soluable active VEGF

Question 30

The angiogenic switch

Answer 30

the induction of angiogenesis is a component of the tumor phenotype that is activated during early pre-neoplastic stages in the development of the tumor Most tumors arise without angiogenic activity exest in the "dormant" stage (carcinoma in situ, CIS) without vascularization for long periods of time, and become vascularized when a subset of cells within the tumor "stitches" to the angiogenic phenotype In dormant microscopic lesion, proliferation=angiogenesis Angiogenic inducers low, angiogenic inhibitors high In metastatic lesion proliferation\>\>apoptosis angiognetic inducers high angiogenic inhibitors low

Question 31

The vascular stage

Answer 31

Characterization by tumors which have enetered a phase of rapid growth, intensified invastion, and increased matastatic potential Bi-directional 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 gorwth Associated with increased appearance of sx. Bleeding, local edema, inappropriate hormonal activited, hypercoagulation states and chacexias

Question 32

Heterogeneity of angiogenic activity in tumors

Answer 32

Neovascularization of tumor usually originates is a subset of cells due to the presence of mixture of angiogenic and nonangiogenic cells

Question 33

Metastases derived from angiogenic portion of the tumor..

Answer 33

are already angiogenic and therefore have an increased chance of becoming a detachable metastasis

Question 34

Antiangiogenic therapy: a novel approach to cancer tx possible advantages

Answer 34

Specificity may mena fewer undesirable effects Angiogenesis in adults is limited to reproductive tissue and wound healing Acquired drug resistance reduced bc endothelilal cells usually genetically stable and dont mutate easily Structure of tumor vascularute represents barrier to traditional drug delivery to tumor cells (shape)

Question 35

Metastasis is angiogenesis....

Answer 35

dependent

Question 36

Sequence of events in tumor cell metastatis

Answer 36

initial transforming of cell proliferation of transformed cells conpromised 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 parencymal cells leading to migration of tumor cells away from the primary tumor mass Penetration of cancer cells through 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 (metastasis)

Question 37

Tumor cells can secrete enzymes that degreade

Answer 37

adhesion proteins between cells of the vasculature

Question 38

Epithelial mesenchymal transitions in cancer

Answer 38

epithelial cells turn into mesenchymal cells so that they can move around. Allows it to invade. cytoskeletal reorganization membrane reorganization increased growth increased motility

Question 39

Carcinoma in situ vs invasive

Answer 39

In situ has spacific phenotype. In EMT these phenotypically change and are able to invade. in situ has E cadherein that connects it to other

Question 40

Seed and soil model

Answer 40

preferential sites for metastasis micrometastases often seed organs. most fail to grow into clinically observed tumors organs provide hospitable environment (soil) for the metastisized tumors to grow

Question 41

Factors that affect the location and efficiency of metastasis

Answer 41

chemokines in the specific tissue that attract the tumor cells to the site the differentiation, developmental, and growth conditions of the tissue (mitogens and GFs) The nature of the trafficking circulation (blood and lymphatic) systems in the specific organ