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ANGIOGEN.PPT

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Understanding Cancer and Related Topics Understanding Angiogenesis Developed by: Lewis J. Kleinsmith, Ph. D. Understanding Cancer and Related Topics Understanding Angiogenesis Developed by: Lewis J. Kleinsmith, Ph. D. Donna Kerrigan, M. S. Jeanne Kelly Brian Hollen An illustrated description of angiogenesis and its importance in cancer research. These Power. Point slides are not locked files. You can mix and match slides from different tutorials as you prepare your own lectures. In the Notes section, you will find explanations of the graphics. The art in this tutorial is copyrighted and may not be reused for commercial gain. Please do not remove the NCI logo or the copyright mark from any slide. These tutorials may be copied only if they are distributed free of charge for educational purposes.

What Is Metastasis? Blood vessel 1. Cancer cells invade surrounding tissues and vessels 2. What Is Metastasis? Blood vessel 1. Cancer cells invade surrounding tissues and vessels 2. Cancer cells are transported by the circulatory system to distant sites 3. Cancer cells reinvade and grow at new location

Metastasis Requires Angiogenesis Metastasis Requires Angiogenesis

What Is Tumor Angiogenesis? Small localized tumor Tumor that can grow and spread Angiogenesis What Is Tumor Angiogenesis? Small localized tumor Tumor that can grow and spread Angiogenesis Blood vessel Signaling molecule

Normal Angiogenesis in Children Normal Angiogenesis in Children

Normal Angiogenesis in Adults Angiogenesis in uterine lining Angiogenesis in tissue during wound healing Normal Angiogenesis in Adults Angiogenesis in uterine lining Angiogenesis in tissue during wound healing

Angiogenesis and Vascular Endothelial Cells Blood vessel Vascular endothelial cells Angiogenesis and Vascular Endothelial Cells Blood vessel Vascular endothelial cells

Angiogenesis and Regulatory Proteins Concentration of Angiogenesis Inhibitors high Inhibitors low Activators high Blood Angiogenesis and Regulatory Proteins Concentration of Angiogenesis Inhibitors high Inhibitors low Activators high Blood vessel Rare cell division Frequent cell division

Angiogenesis and Cancer Old Theory New Theory Vessel dilation Angiogenesis Angiogenesis and Cancer Old Theory New Theory Vessel dilation Angiogenesis

Without Angiogenesis, Tumor Growth Stops Infuse nutrient solution Isolated organ (e. g. , thyroid Without Angiogenesis, Tumor Growth Stops Infuse nutrient solution Isolated organ (e. g. , thyroid gland) Injected cancer cells stop growing as mass reaches 1– 2 mm in diameter

With Angiogenesis, Tumor Growth Proceeds Tumor suspended in anterior chamber Cornea Tumor size Tumor With Angiogenesis, Tumor Growth Proceeds Tumor suspended in anterior chamber Cornea Tumor size Tumor growing on the iris Tumor suspended in anterior chamber Iris Lens 2 4 6 8 Days 10

What Prompts Angiogenesis? Chamber Cancer cell Signaling molecule Place chamber beneath an animal's skin What Prompts Angiogenesis? Chamber Cancer cell Signaling molecule Place chamber beneath an animal's skin Angiogenesis

Activators of Angiogenesis Activators of Angiogenesis

The Angiogenesis Signaling Cascade Cancer cell VEGF (or b. FGF) Receptor protein Relay proteins The Angiogenesis Signaling Cascade Cancer cell VEGF (or b. FGF) Receptor protein Relay proteins Endothelial cell surface Genes are activated in cell nucleus Proteins stimulate new endothelial cell growth

Endothelial Cell Activation Secretes MMPs that digest surrounding matrix Activated endothelial cell Matrix Cell Endothelial Cell Activation Secretes MMPs that digest surrounding matrix Activated endothelial cell Matrix Cell migrates and divides

Inhibitors of Angiogenesis Inhibitors of Angiogenesis

Angiogenesis Inhibitors and Primary Tumors Tumor size in mice 0 40 Start 80 Start Angiogenesis Inhibitors and Primary Tumors Tumor size in mice 0 40 Start 80 Start Stop Endostatin Treatment 120 Days 160 200 240

Angiogenesis Inhibitors and Metastasis Inject cancer cells Let initial tumor grow for several weeks Angiogenesis Inhibitors and Metastasis Inject cancer cells Let initial tumor grow for several weeks Remove initial tumor Allow time for metastases to appear Angiostatin injections Few metastases No treatment Many metastases

Angiogenesis and Tumor Dormancy Angiostatin inhibits Large primary tumor Tiny dormant tumor masses Angiogenesis and Tumor Dormancy Angiostatin inhibits Large primary tumor Tiny dormant tumor masses

Cancer in Angiogenesis-Deficient Mice Normal mouse Angiogenesis-deficient mutant mouse Inject breast cancer cells Cancer Cancer in Angiogenesis-Deficient Mice Normal mouse Angiogenesis-deficient mutant mouse Inject breast cancer cells Cancer No cancer

Angiogenesis Inhibitors in the Treatment of Human Cancer cell VEGF (or b. FGF) Receptor Angiogenesis Inhibitors in the Treatment of Human Cancer cell VEGF (or b. FGF) Receptor protein Endothelial cell MMPs Matrix Angiogenesis Inhibitors

Drugs That Inhibit Angiogenesis Directly Cancer cell VEGF (or b. FGF) Receptor protein Endothelial Drugs That Inhibit Angiogenesis Directly Cancer cell VEGF (or b. FGF) Receptor protein Endothelial cell MMPs Integrin Endostatin EMD 121974 TNP-470 Squalamine Apoptosis Combretastatin A 4 Matrix Drug molecule Integrin interacts with drugs to destroy proliferating endothelial cells

Old Drug With a New Use Cancer cell VEGF (or b. FGF) Receptor protein Old Drug With a New Use Cancer cell VEGF (or b. FGF) Receptor protein Endothelial cell MMPs Matrix Thalidomide

Drugs That Block the Angiogenesis Signaling Cascade Cancer cell Receptor protein Endothelial cell MMPs Drugs That Block the Angiogenesis Signaling Cascade Cancer cell Receptor protein Endothelial cell MMPs Matrix Interferon-alpha VEGF (or b. FGF) Anti-VEGF antibody SU 5416 SU 6668 PTK 787/ZK 22584 No endothelial cell growth

Drugs That Block Extracellular Matrix Breakdown Cancer cell VEGF (or b. FGF) Receptor protein Drugs That Block Extracellular Matrix Breakdown Cancer cell VEGF (or b. FGF) Receptor protein Endothelial cell MMPs Matrix Marimistat AG 3340 COL-3 Neovastat BMS-275291 No endothelial cell migration

Drugs With Other Mechanisms of Action Drugs With Other Mechanisms of Action

On to Clinical Trials On to Clinical Trials

We would like to hear from you. . . If you have questions about We would like to hear from you. . . If you have questions about this tutorial’s content, suggestions for new topics, or other feedback on the Web site, please send an e-mail to kerrigad@mail. nih. gov. If you have questions about this tutorial’s artwork or want permission to use it, please send an e-mail to beankelly@verizon. net.