Understanding Angiogenesis
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Understanding Angiogenesis

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Understanding Angiogenesis Understanding Angiogenesis Presentation Transcript

  • 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 PowerPoint slides are not locked files. You can mix and match slides from different tutorials asyou 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? 1. Cancer cellsBlood invade surroundingvessel 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 Angiogenesis
  • What Is Tumor Angiogenesis? Small localized tumor Tumor that can grow and spread AngiogenesisBlood vessel Signaling molecule
  • Normal Angiogenesis in Children
  • Normal Angiogenesis in Adults Angiogenesis in uterine lining Angiogenesis in tissue during wound healing
  • Angiogenesis andVascular Endothelial CellsBlood vessel Vascular endothelial cells
  • Angiogenesis and Regulatory Proteins Concentration of Angiogenesis Inhibitors Inhibitors high Inhibitors low Activators low Activators high Blood vessel Rare cell division Frequent cell division
  • Angiogenesis and Cancer Old Theory New TheoryVessel dilation Angiogenesis
  • Without Angiogenesis, Tumor Growth StopsInfuse 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 Tumor growing on the iris TumorCornea growing Tumor size on the iris Tumor suspended in anterior Iris chamber Lens 2 4 6 8 10 Days
  • What Prompts Angiogenesis? Chamber Cancer cell Signaling molecule Place chamber beneath an animals skin Angiogenesis
  • Activators of Angiogenesis
  • The Angiogenesis Signaling Cascade Cancer cell VEGF (or bFGF) Receptor protein Endothelial Relay cell surface proteins Genes are activated in cell nucleus Proteins stimulate new endothelial cell growth
  • Endothelial Cell Activation Secretes MMPs that Activated digest endothelial surrounding cell matrix Matrix Cell migrates and divides
  • Inhibitors of Angiogenesis
  • Angiogenesis Inhibitors and Primary TumorsTumor size in mice 0 40 80 120 160 200 240 Days Start Start Stop Stop Endostatin Treatment
  • Angiogenesis Inhibitors and Metastasis Inject cancer cells Let initial tumor grow for several weeks Remove initial tumor Allow time for metastases to appear Angiostatin No injections treatment Few metastases Many metastases
  • 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 No cancer
  • Angiogenesis Inhibitors in the Treatment of Human Cancer Cancer cell VEGF (or bFGF) Receptor protein Endothelial Angiogenesis cell Inhibitors MMPs Matrix
  • Drugs That Inhibit Angiogenesis Directly Cancer cell Endostatin VEGF EMD121974 (or bFGF) TNP-470 Squalamine Receptor protein Apoptosis Endothelial cell Combretastatin A4 MMPs Matrix Integrin Drug molecule Integrin interacts with drugs to destroy proliferating endothelial cells
  • Old Drug With a New Use Cancer cell VEGF (or bFGF) Receptor protein Endothelial cell Thalidomide MMPs Matrix
  • Drugs That Block theAngiogenesis Signaling Cascade Cancer cell Interferon-alpha VEGF (or bFGF) Receptor protein Anti-VEGF antibody SU5416 SU6668 Endothelial PTK787/ZK 22584 cell MMPs No endothelial cell growth Matrix
  • Drugs That BlockExtracellular Matrix Breakdown Cancer cell VEGF (or bFGF) Receptor protein Marimistat AG3340 COL-3 Neovastat Endothelial BMS-275291 cell No MMPs endothelial cell migration Matrix
  • Drugs With Other Mechanisms of Action
  • On to Clinical Trials
  • We would like to hear from you . . .If you have questions about this tutorial’s content, suggestions for new topics, orother 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.