question

Angiogenesis is the ________________. This process involves the ______________ of endothelial cells, which line the inside wall of blood vessels.

answer

formation of new blood vessels migration, growth, and differentiation

question

Angiogenesis involves ___ and ____ to make new blood vessels.

answer

Sprouting via a pseudopodial process and hollowing of a tube, and branching

question

Vasculogenesis

answer

Formation of new blood vessels from angioblasts or progenitor stem cells (i.e. de novo vessel synthesis)

question

The term angiogenesis denotes the formation of ___________ , whereas vasculogenesis is the term used for the formation of _________________.

answer

new blood vessels from pre-existing ones new blood vessels when there are no pre-existing ones

question

Excessive Angiogenesis occurs in what disease conditions?

answer

Occurs in cancer, Diabetic retinopathy, macular degeneration, Rheumatoid arthritis, psoriasis, ...

question

Excessive angiogenesis occurs when cells produce __________________, overwheming the effects of _______________. It feeds ______ tissues, destroys ______ tissues, and allows _________.

answer

abnormal amounts of angiogenic GFs natural angiogenesis inhibitors disease tissues normal tissues metastasis

question

Insufficient Angiogenesis occurs in what illness conditions?

answer

Occurs in coronary artery disease, stroke, and delayed wound healing

question

Insufficient angiogenesis occurs when the tissue cannot ________________. It leads to________ and tissue death.

answer

produce adequate amounts of angiogenic GFs improper circulation

question

Tumor Angiogenesis: Angiogenesis is a fundamental step in the ____________________. Angiogenesis necessary for tumor growth beyond __________.

answer

transition of tumors from a dormant state to a malignant state a few millimeters in size

question

_______ "feed" the cancer cells with _________ and _____, allowing these cells to grow, _____ nearby tissue, spread to other parts of the body, and form _________ (metastasis).

answer

New blood vessels oxygen and nutrients invade new colonies of cancer cells

question

It was found that the same starting injection of cancer cells grew to _____ in diameter and then stopped in the region without nearby blood vessels. But, they grew well beyond ____ when placed in the area where angiogenesis was possible. With angiogenesis, tumor growth ____.

answer

1-2mm; 2 mm; continued

question

Growth of a small group of subcutaneously implanted human colorectal adenocarcinoma cells over a 20 days. Within days, ________ of capillaries and larger vessels are seen to emerge from preexisting capillary beds and to converge on the implanted tumor chunks.

answer

dense networks

question

what is tumor angiogenesis?

answer

a gradual process of recruitment of capillaries by an implanted tumor

question

How do tumor vessels differ from normal vessels? (6)

answer

Tumor vessels have 1. Increased vessel number 2. Chaotic architecture and blood flow 3. Decreased endothelial cell-cell adhesion 4. Leaky vessels; Endothelial Cells (Ecs) overlap and show gaps 5. Decreased vessel stability: decreased association of smooth muscle cells with ECs 6. Loss of close association of basement membrane with ECs

question

Tumor angiogenesis is circumscribed as long as ___________. Once they become invasive, the intensity of angiogenesis _______, leading to a higher density of _____(brown) threading their way through tumors.

answer

human carcinomas remain benign. increases capillaries

question

Angiogenesis Imaging Methods include (4)

answer

Computed Tomography (CT Scan) Ultrasound MRI PET

question

How does Computed Tomography (CT Scan) work with angiogenesis?

answer

Performed with contrast agents to define the intravascular compartment, including blood flow, blood volume, transit time, and capillary permeability.

question

How does Ultrasound work with angiogenesis?

answer

Can identify vascular features at resolution of 50-200 um vessels Contrast-enhancement using an intravascular agent can generate an index of blood flow, blood volume, or vascularity within tumor Targeted imaging using ultrasound destruction of microbubbles may provide even further resolution of the tumor vascular tree.

question

How does MRI work with angiogenesis?

answer

Can define blood volume and permeability using dynamic enhancement of blood pool contrast agents. Gadolinium-DTPA can distinguish between normal versus malignant leaky tissues Contrast uptake also correlates with microvessel density in experimental tumors.

question

How does PET work with angiogenesis?

answer

Evaluates tumor metabolism, as well as blood flow and volume. H2015, 11CO, and 18FDG, characterizes neoplastic tissue Antiangiogenic agents should diminish blood flow and decrease tumor metabolism

question

MR images of breasts showing color-encoded pharmacokinetic maps of a tumor and corresponding time-signal intensity curves. Before treatment, the tumor has an active rim of angiogenesis (white). The time signal curve shows ________ over a 10-min period. After treatment, the lesion is _____ and its vascular signature is ______, indicating a less vascular phenotype. The time-signal curve shows a much ________ within the tumor and _____ washout over a 10-min period.

answer

rapid enhancement and gradual washout smaller, less bright slower accumulation of contrast agent minimal

question

Key Steps in Tumor Angiogenesis

answer

1. Induction: Vascular Basement Membrane degrades via MMPs (Matrix metalloproteinases). 2. Fibroblasts, Immune cells (macrophage 2), tumour cells, and nearby endothelial cells release VEGF (vasc. endothelial growth factor), bFGF (basic fibroblast growth factor), and PDGF (platelet-derived growth factor). 3. Proliferation of ECs. 4. Migration of ECs. 5. Resolution: Downregulation of proliferation and migration/ VBM assembly (closer to cancer cell).

question

Key cell types in angiogenesis

answer

1.) Endothelial cells 2) Pericytes 3) Circulating progenitor cells 4) Macrophages 5) Myofibroblasts 6) Inflammatory cells

question

Role of key cell types in angiogenesis

answer

1.) Endothelial cells - makes up vasculature 2) Pericytes- contractile cells that wrap around the endothelial cells of capillaries and venules throughout the body 3) Circulating progenitor cells - release fibroblast growth factors 4) Macrophages - release fibroblast growth factors 5) Myofibroblasts - release fibroblast growth factors 6) Inflammatory cells - release fibroblast growth factors

question

Myofibroblasts (SMA/vimentin positive) _____ angiogenesis by releasing ____, that recruits EPCs and _____ cells into the tumor stroma.

answer

expedite SDF1 myeloid

question

When a tumor cell is beyond 100 mm from a capillary, it ________.

answer

does not have oxygen

question

When a tumor cell is too far from a capillary, it becomes hypoxic. Angiogenesis supports the ______ by providing ____ and _____. Hypoxia causes ___ to transcribe _____, which causes the production of more _____ or ____. Every cell must be within ______ of a capillary

answer

growth of a tumor nutrients and gas exchange HIF HRE VEGF or PDGF-B 50 to 100 mm

question

Which of the following substances contributes most to blood vessel development in a tumor? Her-2 VE-cadherin IFN-gamma Basic fibroblast growth factor

answer

Basic fibroblast growth factor

question

A tumor cell (less than 2 mm large) will be ______ until ______ occurs.

answer

dormant angiogenesis

question

Angiogenic Switch: Name all the 5 steps of switching to from none to tumor vasculature.

answer

1. Dormant 2. Perivascular detachment and vessel dilation 3. Onset of angiogenic sprouting 4. Continuous sprouting: new vessel formation and maturation; recruitment of perivascular cells 5. Tumor vasculature

question

Angiogenesis is tightly controlled by the balance of two sets of ___________.

answer

counteracting factors - angiogenic activators and inhibitors.

question

VEGF is the _______ of angiogenesis. It is unique among angiogenic growth factors. It is also known as ______. It is selective for _________ and is required for their development. It is also produced in response to _______>

answer

the predominant mediator VPF: "Vascular Permeability Factor" endothelial cells hypoxia

question

Activators of angiogenesis

answer

VEGF (-A, -B, -C), FGF (aFGF, bFGF)

question

Inhibitors of angiogenesis

answer

Thrombospondin-1,-2 Interferon alpha/beta Angiostatin Endostatin Collagen IV fragments

question

VEGF-A can bind to the receptors, _____. It functions in _____ and ____.

answer

VEGFR-1, VEGFR-2, neuropilin-1 Angiogenesis, vascular maintenance

question

VEGF-B binds to the receptor ____.

answer

VEGFR-1

question

VEGF-E binds to the receptor ____ for ____.

answer

VEGFR-2; angiogenesis

question

What are the steps for VEGF receptor binding and signaling?

answer

1. VEGF binds to VEGFR. 2. VEGFR autophosphorylates and activates PI3K, RAF, and p38MAPK 3a. Raf leads to Endothelial Cell proliferation via MEK/Erk 3b. p38MAPK leads to Endothelial Cell migration 3c. PI3k leads to Akt/PKB which leads to endothelial cell survival and vascular permeability.

question

Thrombospondin blocks _____ for only ______ endothelial cells by binding to _______, leading to _____.

answer

angiogenesis Recently formed FasL Apoptosis

question

Potential benefits of attacking the tumor blood supply

answer

1. All tumors require a blood supply 2. Blood vessels are comprised of normal, genetically stable ECs and do not develop resistance 3. ECs are most accessible to drugs in the blood stream 4. ECs in tumors have distinct molecular targets

question

The first antiangiogenic drug to be approved by the FDA was _____ to treat ____.

answer

Avastin Colorectal cancer

question

Antiangiogenic targets what 2 types of vasculature?

answer

Neovasculature, Preexisting Vasculature

question

Neovasculature can be targeted specifically to: (4 things)

answer

1. Growth factors that stimulate endothelial cell proliferation 2. Proteases that breakdown the ECM 3. Integrins that allow adhesion of endothelial cells 4. Endothelial cell apoptosis

question

Types of Angiogenesis Inhibitors: Type I and function

answer

Avastin - antibody that binds to and blocks VEGF VEGF Trap- blocks VEGF (protein binds to it)

question

Types of Angiogenesis Inhibitors: Type II

answer

Blocks 2-3 angiogenic proteins Sutent: downregulates VEGF receptor 2, PDGF receptor, cKIT receptor Tarceva: Downregulates VEGF production, bFGF production, TFG-alpha by tumor cell

question

Types of Angiogenesis Inhibitors: Type III

answer

Blocks a broad range of angiogenic regulators Endostatin: Downregulates VEGF, bFGF, bFGF receptor, HIF1-alpha, EGF receptor, ID1, neuropilin, upregulates thrombospondin1, maspin, HIF1alpha, TIMP2 Caplostatin: Broad anti-angiogenic and anticancer spectrum

question

Three general mechanisms of angiogenesis inhibitors currently approved by the FDA

answer

1. Iressa: blocks production of VEGF and other angiogenic stimulators (from tumor) 2. Avastin: Neutralizes VEGF by binding to it 3. Sutent: Blocks receptor for VEGF and other angiogenic stimulators at the Endothelial cell

question

Mechanism of activity of VEGF - directed agents: Various agents can target different effector proteins, such as ____, ____, and ____. Agents can also directly inhibit __________. Also Thalidomide can affect ____.

answer

Raf, p38MAPK, and PI3K. VEGF binding to its receptor production of VEGF

question

Small molecules can increase endogenous angiogenesis inhibitors. For example, for ____, tamoxifen, celecoxib and prednisolone + salazosulphapyridine can be used. For ________, cyclophosphamide, doxycycline, and rosiglitazone can be used to increase the inhibitors.

answer

Endostatin, thrombospondin 1

question

Sample drugs that prevent cell proliferation

answer

Suramin-- Avastin (Bevacizumab)-- Angiostatin--

question

Function of Suramin

answer

prevents bFGF and VEGF from binding to the active site of their receptors through competitive inhibition

question

Function of Avastin (Bevacizumab)

answer

antibody that targets VEGF (binds to VEGFa to inhibit VEGFR1 and VEGFR2) Enables normalization: reduced blood vessel permeability and interstitial pressure

question

Function of Angiostatin

answer

binds to HGF (hepatocyte growth factor); blocks endothelial cell surface ATP-synthase

question

For Inducing apoptosis: Target ____ and _____.

answer

Tumor Necrosis Factor Down-regulating/blocking Bcl-2 interactions with pro-apoptotic proteins

question

Tumor Necrosis Factor causes?

answer

causes endothelial cell apoptosis in tumor cells (induces inflammation and endothelial cell growth in normal cells)

question

For Down-regulating/blocking Bcl-2 interactions with pro-apoptotic proteins, we target ___ and___.

answer

Endostatin Angiostatin

question

What does Bcl-2 do?

answer

It blocks apoptosis

question

Avastin was used to treat ____ and was declared damaging. It lost its approval from FDA to treat this condition.

answer

Breast Cancer

question

Therapeutic targeting of the tumor microenvironment: We must keep in mind that in a mature tumor, there are many ______ interactions. So we have to use many targets for therapeutic intervention.

answer

Heterotypic

question

Examples of COMBINATION THERAPY

answer

1. Antiangiogenic + chemotherapeutic drug: Inhibit vascularization + cytotoxic agent 2. Avastin + PDGFR inhibitor: Avastin clinical dose = 5-10mg/kg -Dose limiting toxicity = 20mg/kg Selection against Avastin 3. Thalidomide combinational therapy

question

Angiogenesis is critical for the growth of tumors beyond _____ .

answer

2 mm

question

_________ cells and recruited ____ cells participate in the construction of tumor-associated vasculature.

answer

Neoplastic epithelial; stromal

question

Tumors induce angiogenesis via _____.

answer

VEGF and other angiogenic factors

question

________ represents an attractive target for the development of anti-cancer agents.

answer

Neoangiogenesis

question

Anti-VEGF/R may ____ growth of primary tumors.

answer

delay

question

A 54-year-old woman was diagnosed with breast cancer. Histology shows that mass contains a large number of blood vessels. Patient underwent surgery and several metastases were found 2 months after surgery. A decrease in which of the following is the most likely cause for the development of metastases after surgery? Basic fibroblast growth factor Thrombospondin 1 Platelet derived growth factor Epidermal growth factor

answer

Thrombospondin 1

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