Bio316

What are MMPs and why are they important in angiogenesis?

Matrix metalloproteinases (MMPs) family zinc-dependent proteases degrade ECM

3. List/describe the steps of the angiogenic cascade

1. Oncogenic mutations (RAS) and tumor suppressor mutations (p53) lead to an increase in angiogenic factors and a decrease in antiangiogenic factors. 2. One major result is that cancer cells start producing a potent growth factor: vascular endothelial growth factor (VEGF). 3. Cancer cells also recruit other cells (fibroblasts, immune cells) to secrete VEGF and proteases to dissolve the matrix 4. VEGF binds to VEGF receptors on endothelial cells 5. This causes the endothelial cells to: Proliferate Degrade the surrounding matrix And migrate toward the cancer cells 6. The endothelial cells fuse to form the angiogenic

9. Describe the steps that lead to angiogenic switch and new vessel growth.

1. Oncogenic mutations (RAS) and tumor suppressor mutations (p53) lead to an increase in angiogenic factors and a decrease in antiangiogenic factors. 2. One major result is that cancer cells start producing a potent growth factor: vascular endothelial growth factor (VEGF). 3. Cancer cells also recruit other cells (fibroblasts, immune cells) to secrete VEGF and proteases to dissolve the matrix 4. VEGF binds to VEGF receptors on endothelial cells 5. This causes the endothelial cells to: ▪ Proliferate ▪ Degrade the surrounding matrix ▪ And migrate toward the cancer cells 6. The endothelial cells fuse to form the angiogenic vessesl

6. What are the three basic "triggers" that lead to the angiogenic switch?

1Oncogene Activation RAS VEGF 2Tumor Suppressor Gene Inactivation P53 VEGF 3 Environmental cues: Hypoxia: lack of O2

5. How does angiogenic vasculature differ from normal vasculature? Why is this important for developing antiangiogenic therapies?

Angiogenic vasculature differs from normal vasculature... Tumor vessels tortuous,disorganized Diameters irregular; thin walls "leaky"; improper cell junctions; abnormal cellular processes Improper basement membrane structure Poorly-associated support cell (pericyte) structure/function This is in contrast to normal vasculature that has a very organized tissue structure composed of a layer of endothelial cells surrounded by a discrete basement membrane and a layer of supporting cells, pericytes.

6. List two advantages of anti-angiogenic therapy for cancer treatment

Antiangiogenic therapy Endothelial cells represent a genetically stable target Killing a EC cell can result in killing 100s of cancer cells supported by it Antiangiogenic drugs can be combined with anti-cancer drugs One type of anti-angiogenic therapy looks for ways to inhibit VEGF action. Include soluble VEGF receptors to "trap" the VEGF Antibodies against VEGF and VEGF receptors. Intracellular inhibitors to VEGF pathway

In the article "Emissaries",which cells do cancer cells cause go to the metastatic site

Bone Marrow cells

Type 1 cancer metastases will grow well in:

Bone only type 1 bFGF

7. Name a major activator of angiogenesis

Cell Proliferation ◆ Matrix degradation ◆ Cell Migration ◆ Reestablishment of structure - Angiogenic vessel or metastatic growth

3. List the steps of the metastatic cascade, including naming important molecules associated with progression.(15 pts)

Cell detachment/invasion 1.Decrease in cell-cell interactions Loss of E-cadherin 2.Decrease in normal cell-basement membrane interactions 3. Migration of cells along ECM 4.Intravasation into the circulatory system 5. Survival in circulation 6. Arrest in capillary bed 8. Secondary growth(of metastasis)

5. Describe and give support for the mechanistic and seed and soil hypotheses by which cancer cells seem to form metastases at specific sites.

Certain cancers metastasize to specific organs ◆ Stephen Paget (1889) proposed cancer cells (seeds) targeted and grew in specific microenvironments (soil) ◆ James Ewing (1929) suggested metastasis purely mechanical...cancer cells arrested in 1st or largest capillary bed they encountered. ◆ Answer appears to be: Both theories are correct ◆ Most cancer cells appear to arrest in 1st capillary bed due to size restrictions ◆ However, subsequent survival and growth of cells is largely dependent upon the tissue microenvironment (i.e. the soil)

Explain the "seed and soil" hypotheses concerning why certain cancers metastasize to specific organs

Certain cancers metastasize to specific organs ◆ Stephen Paget (1889) proposed cancer cells (seeds) targeted and grew in specific microenvironments (soil) ◆ James Ewing (1929) suggested metastasis purely mechanical...cancer cells arrested in 1st or largest capillary bed they encountered. ◆ Answer appears to be: Both theories are correct ◆ Most cancer cells appear to arrest in 1st capillary bed due to size restrictions ◆ However, subsequent survival and growth of cells is largely dependent upon the tissue microenvironment (i.e. the soil)

. Why is anti-angiogenic therapy an attractive attack method against cancer

Endothelial cells are relatively stable cells Killing one endothelial cell effectively kills hundreds of cancer cells Antiangiogenic therapy can be combined with existing cancer therapies

What is extravasation?

Extravasation Once attached cells must transmigrate through capillaries (endothelial cells, basement membranes,pericytes) into underlying tissue .

1. List three examples associated with normal angiogenesis

Female reproductive cycle Wound healing Growth Tightly regulated spatio-temporal control of proangiogenic and antiantiogenic factors

2. Describe some examples of normal angiogenic processes that occur within our body

Female reproductive cycle Wound healing Growth Tightly regulated spatio-temporal control of proangiogenic and antiantiogenic factors

1. Define angiogenesis.

Formation of new capillaries from pre-existing vasculature. Angiogenesis is a normal process during development. In the adult there are also several physiological processes that rely on angiogenesis

What is hypoxia and why is it important for tumor angiogenic growth?

HIFa is not hydroxylated,ubiquinated or degraded and therefore can transcribe pro-angiogenic proteins such as VEGF Hypoxia induces hypoxia inducible factor 1alpha(HIF) resulting in increase VEGF production

The term describes the lack of adequate oxygen is:

Hypoxia

All of the following are functions of VEGF except:

Increase the production of thrombospondin

2. list/Describe two differences between normal and angiogenic vessels

NormalSmooth luminal surface Tight endothelial junctions.Smooth luminal surface Tight endothelial junctions Angiogenic Disorganized network No clear distinctions."Hole" revealing underlying basement membrane

Which of the following is a major trigger for the "angiogenic switch"

Overproduction of Ras protein

4. List at least one pro-angiogenic and two anti-angiogenic factors

Pro:EGF, FGF, PDGF, anti angiostatin; endostatin

All of the following represent normal angiogenic events except:

Psoriasis

All of following represent anti-angiogenic therapies except:

Soluble VEGF.

The "seed and soil" hypothesis states

The seed is the cancer cell; the soil is the growth factors

What is therapeutic angiogenesis? Give an example.

Therapeutic angiogenesis is a method used to increase the formation of new blood vessels in order to increase blood flow. It is being developed to : Repair/diminish damage from heart attack Minimize neural damage after injury or stroke Improve bone healing Improve circulation

How are the processes of angiogenesis and metastasis similar

They both rely heavily on cell migration They both rely heavily on matrix degradation They both rely heavily on cellular proliferation

4. Cancer cell growth in a metastatic site depends upon the microenvironment of the metastatic site. We saw that sometimes this is already optimal for tumor growth. BRIEFLY DESCRIBE 3 other basic ways (discussed in class and articles) that can change a poor metastatic site into one that is optimal for metastasis.

Tumor cells may "create" proper micro environment either before or after arrival

Explain why tumors need new blood vessels to grow beyond around 1-2mm.

Tumors require adequate supply of oxygen and nutrients Rate-limiting step in tumor growth and progression Generally, limits growth to 1-2mm.

Which cancer metastases will grow well in the liver

Type 2 HGF receptor

8. Name a major inhibitor of angiogenesis.

VEGF inhibitors Include soluble VEGF receptors to "trap" the VEGF Antibodies against VEGF and VEGF receptors.

Briefly describe what VEGF is and how it promotes angiogenesis

binds to VEGF receptors on endothelial cells 5. This causes the endothelial cells to: Proliferate Degrade the surrounding matrix And migrate toward the cancer cells

Explain how cancer cells themselves may be able to change the metastatic microenvironment to be better suited for tumor growth.

involve cellular proliferation, migration, and tissue remodeling

What is Intravasation?

malignant cells encounter capillaries and penetrate the blood vessels to enter microcirculation

7. What is Avastin, how does it work, what are some of its side-effects, and how might Avastin therapy make things worse

to treat people with metastatic HER2-negative breast cancer who haven't yet received chemotherapy for metastatic breast cancer. vastin blocks VEGF. By blocking VEGF, Avastin can interfere with the growth of new blood vessels into breast cancer tissue and starve the cancer. Doctors use the term anti-angiogenic to describe Avastin, because it works against the formation of blood vessels. Avastin can also change blood vessels already feeding the cancer in ways that make it harder for the cancer to survive and more vulnerable to chemotherapy. Avastin is an immune targeted therapy. Side Effect: nosebleeds high blood pressure extra protein in the urine pain diarrhea Worser by:More serious side effects have been experienced in a small percentage of people taking Avastin, including blood clots in a vein, slow wound healing, perforation of the intestines, higher risk of stroke or heart problems, kidney malfunction, and reduced white blood cell count. If you experience any of these serious side effects, your doctor will stop treatment with Avastin.