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Week 7 Pathology > Angiogenesis and Metastasis > Flashcards

Angiogenesis and Metastasis Flashcards

1
Q

Types of capillaries

A

Continuous

Fenestrated

Sinusoid

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2
Q

Continuous capillaries

A

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

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3
Q
A

Continuous capillary

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4
Q
A

Fenestrated Capillary

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5
Q

Fenestrated capillary

A

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

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6
Q
A

Sinusoid capillaries

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7
Q

Sinusoid capillaries

A

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.

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8
Q
A

Picture of a vessel. Pericytes stabilize vessel.

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9
Q

How far can oxygen effectively diffuse through living tissue

A

0.2mm

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10
Q

Proximity to vasculature is important to…

A

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

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11
Q
A

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.

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12
Q
A

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.

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13
Q

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

A

Embryonic development

Implantation of the placenta

Wound healting

Many diease processes

Tumorigenesis

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14
Q
A

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

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15
Q

Production of VEGF is goverened by

A

the availability of oxygen

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16
Q
A

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

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17
Q
A

View of a vessel with endothelial cells and pericyte

18
Q

As tumor growth continues, capillaries are increasing

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 tumor stroma

19
Q
A

Normal vs tumor vasculature.

Normal is more organized

tumor is more permeable

20
Q

Steps in the formation of new capillaries

A

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

21
Q

Angiogenesis in tumors

Cells of the vasculature vs nonvascular cells

A

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

Nonvascular cells: neoplastic cells, supporting cells of the stroma

22
Q

Step 1: Stimulation of Endothelial cells by angiogenix growth factors

GROWTH FACTORS INVOLVED

A

Basic fibroblast growth factor (bFGF)

Vascular endothelial growth factor (VEGF)

23
Q

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

SECRETED PROTEASES

A

matrix metalloproteinases (MMPs)

Plasminogen Activator Urokinase (uPA)

24
Q

Step 3: Capillary sprout formaiton and migration of endothelial cells

A

Regulation of cell migration

Integrins

Extracellular proteinases

25
Q

Step 4: New vessel maturation

THINGS INVOLVED

A

pericyte comes and wraps newly formed vessel

Angiopoetin 1( Ang1) (tells it to stop growing)

Platelet derived growth factor (PDGF)

26
Q

Activators of angiogenesis

A

VEGF-A

VEGF-B

VEGF-C

aFGF

bFGF

other FGFs

27
Q

Inhibitors of angiogenesis

A

thrombospondin 1 and 2

interfereon alpha/beta

angiostatin

endostatin

collagen IV fragments

28
Q

Tripping of ____ is essential for tumor expansion

A

“Angiogenic switch”

Many tumor cell populaitons lack the ability to attract blood vessels

29
Q
A

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

30
Q

The angiogenic switch

A

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

31
Q

The vascular stage

A

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

32
Q

Heterogeneity of angiogenic activity in tumors

A

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

33
Q

Metastases derived from angiogenic portion of the tumor..

A

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

34
Q

Antiangiogenic therapy: a novel approach to cancer tx

possible advantages

A

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)

35
Q

Metastasis is angiogenesis….

A

dependent

36
Q

Sequence of events in tumor cell metastatis

A

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)

37
Q

Tumor cells can secrete enzymes that degreade

A

adhesion proteins between cells of the vasculature

38
Q

Epithelial mesenchymal transitions in cancer

A

epithelial cells turn into mesenchymal cells so that they can move around. Allows it to invade.

cytoskeletal reorganization

membrane reorganization

increased growth

increased motility

39
Q

Carcinoma in situ vs invasive

A

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

40
Q

Seed and soil model

A

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

41
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, developmental, and growth conditions of the tissue (mitogens and GFs)

The nature of the trafficking circulation (blood and lymphatic) systems in the specific organ

Week 7 Pathology (2 decks)

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