8-Hallmarks - Angiogenesis and Metastasis (PDF)

1 Hallmarks: Angiogenesis and Metastasis CNBY 320 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Learning Objectives...

1 Hallmarks: Angiogenesis and Metastasis CNBY 320 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Learning Objectives 2 Describe how cancer cells recruit blood supply and key proteins involved. Describe the seed and soil hypothesis of metastasis. Describe the metastatic cascade. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Outline Part II 3 I. Hallmarks – Angiogenesis I. Definitions II. Angiogenic Switch III. Angiogenesis and Cancer IV. Other Methods of Angiogenesis II. Hallmarks – Metastasis I. Definitions II. Seed and Soil Hypothesis III. Metastatic Cascade College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Hallmark – Inducing Angiogenesis 4 Angiogenesis – creation of new blood vessels. Cancer cells need oxygen from blood vessels. They recruit and grow their own blood supply. Hanahan and Weinberg 2011 Cell College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Angiogenesis 5 Angiogenesis = the process of forming new blood vessels from pre-existing ones. Greek angeion ="case, capsule, vessel of the body” + “genesis” = creation This Photo by Unknown Author is licensed under CC BY-SA Normally occurs during embryogenesis, wound healing, and uterine female reproductive cycle. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Angiogenesis 6 First described in cancer by Dr. Judah Folkman, 1971. Occurs by the growth and migration of endothelial cells called “sprouting.” Secreted factors entice vessels to grow towards the tumor. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Angiogenic Switch 7 Angiogenesis is a balance of angiogenic inhibitors and activators. Figure to draw Increase in activators promotes the angiogenic switch to “on.” Activator = VEGF Inhibitor = Angiostatin Bergers and Bejamin. 2003. Nature Reviews Cancer College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Angiogenic Inducers 8 VEGF VEGF = Vascular Endothelial Growth Factor Endothelial Cell = Blood Vessel Cell VEGFR VEGF is the star player – main activator. Ligands: VEGF (A-D) Endothelial Receptors: VEGFR (1,2,3) Cell VEGFA and VEGFR2 is main signaling pathway Migration and Proliferation for angiogenesis. VEGFA is secreted by tumor cells! College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Angiogenic Inhibitors 9 Endogenous inhibitors - normally found in the body. N Plasminogen C Plasminogen cleaved to release angiogenic inhibitor Angiostatin. Angiostatin binds to receptors on surface of endothelial cells to prevent Angiostatin angiogenesis. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Angiogenesis in Cancer 10 Cells must be within 100-200 µm of a blood vessel (the diffusion limit of oxygen) in order to receive essential oxygen and nutrients. Cells in a tumor core that do not receive sufficient oxygen and nutrients die by necrosis. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Angiogenic Switch 11 What causes the balance to tip? à Hypoxia As the tumor grows, it creates areas of hypoxia. Hypoxia (low oxygen) activates HIF- 1a accumulation. HIF1a = hypoxia inducible factor HIF1a is a transcription factor = goes into nucleus and turns on VEGF gene! Cancer cells can sense low oxygen, VEGF and start secreting VEGF to signal EC to grow towards them! VHL (von Hippel Lindau) – binds hydroxylated HIF and gets degraded College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Process of Angiogenic Sprouting 12 Tumor VEGF binding induces formation of an endothelial cell “tip cell” at forefront of sprout. VEGF Behind the tip cell, proliferating stalk cells extend the sprouting vessel. Tip cell Growing sprout moves along a VEGF gradient. When two tip cells meet they fuse and allow for a connected lumen, allowing Blood Vessel blood to flow. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Angiogenesis in Cancer 13 Vasculature in cancer is unlike normal angiogenesis. Leaky Tortuous Disorganized (i.e. haphazardly constructed) Inadequate flow Provides direct entry, allowing cells easy access to the circulation. Jain 2005 Science College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Angiogenesis In Cancer 14 How do cancer cells induce angiogenesis? 1) Cells growing too fast, make a larger mass, and create areas of hypoxia. 2) Oncogene Activation: EGFR (epidermal growth factor receptor), Src, and Ras all activate VEGF: 3) Loss of Tumor Suppressors: VHL (von Hippel Lindau) loss in cancer causes increased HIF-1a activity. p53 normally induces Thrombospondin, which is an angiogenesis inhibitor; so, loss of p53 means no TSP, so loss of inhibitor of angiogenesis. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Other Angiogenic Mechanisms 15 Vascular mimicry Tumor cells organize themselves to form vessel like channels. Or leaky vessels just flow through matrix of tumor bed. Operativeneurosurgery.com College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Other Angiogenic Mechanisms 16 Vasculogenesis Recruitment of endothelial progenitor cells from the bone marrow. After reaching the tumor, they differentiate and contribute to the tumor neovasculature (new blood vessels). 40% of tumor endothelial cells are from circulating endothelial progenitor cells from bone marrow! College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Outline Part II 17 I. Hallmarks – Angiogenesis I. Definitions II. Angiogenic Switch III. Angiogenesis and Cancer IV. Other Methods of Angiogenesis II. Hallmarks – Metastasis I. Definitions II. Seed and Soil Hypothesis III. Metastatic Cascade College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Hallmark – Invasion and Metastasis 18 Activating Invasion and Metastasis Escaping the primary mass, migrating to distant site, and starting second tumor mass. Primary cause of cancer mortality. Hanahan and Weinberg 2011 Cell College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Metastasis 19 Metastasis = the ability to dissociate, disseminate, and colonize discontinuous secondary sites. Metastasis remains the cause of 90% of deaths from solid tumors. Cure more likely for cancers when diagnosis occurs before cells have spread beyond the tissue of origin. cancer.gov College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Metastasis 20 First recorded 1580s. Greek = “meta” – change, alteration, result of change and “stasis” – state of equilibrium. Also = “beyond stillness” Refers to the process and the outcome. This is critical part of cancer, since it is usually the secondary mass that causes the most clinical problem and or mortality. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Metastasis 21 Metastatic cells are behaviorally, genetically, and biochemically distinct from the cells still at the primary site. Metastasis is accomplished through entire series of sequential steps, called the metastatic cascade. Metastasis occurs not only through bloodstream, but also along nerves, along basal (under) side of endothelial cells (blood vessels), lymphatic system, and interstitium and peritoneal cavity. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Metastasis 22 1889 Stephen Paget proposed the “seed and soil” hypothesis to explain the organs that are afflicted with disseminated cancer. Seed = Cancer Cells Soil = organ/site and environment 1975 Irwin Bross proposed the metastatic cascade to define the sequential events needed for metastasis success. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Metastasis – Seed and Soil 23 Seed and Soil Hypothesis Seed = Cancer Cells Soil = other organs and environments Not all cancer cells that escape the primary mass will form tumors. Not all sites will foster growth of escaped cancer cells. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Metastasis - Seed and Soil 24 Certain cancers have a predisposition to metastasize to certain organs. Metastasis is not random. For example: Melanoma, Breast and Lung cancers tend to metastasize to the Brain. Bone most common site for breast and prostate cancers. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Metastatic Cascade 25 1. Developing a Metastatic Cell 2. Motility and Invasion 3. Intravasation 4. Dissemination and Transport 5. Cellular Arrest, Vascular Adhesion, and Extravasation 6. Colonization Know these numbers/steps! Fidler Nature Reviews Cancer 2003 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Metastatic Cascade 26 1. Developing a Metastatic Cell The cell acquires more malignant oncogene activation, changing the behavior. Fidler Nature Reviews Cancer 2003 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Metastatic Cascade 27 2. Motility and Invasion The cell acquires the means to break down the basement membrane (e.g. collagen) and begins to migrate. EMT = epithelial to mesenchymal transition. Fidler Nature Reviews Cancer 2003 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Metastatic Cascade 28 2. Motility and Invasion Migration = movement/motility Invasion = breaks down, destroys, or digests the basement membrane to pave the path through. Fidler Nature Reviews Cancer 2003 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Metastatic Cascade 29 3. Intravasation The cell intravasates (invades/enters) into the blood supply, lymphatic supply or other means to escape the primary mass. Fidler Nature Reviews Cancer 2003 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Metastatic Cascade 30 4. Dissemination and Transport The cell has entered the circulation (or other) and has to survive interactions with other cells and a new environment. Single cells that have entered the vasculature typically roll along the endothelium Fidler Nature Reviews Cancer 2003 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Metastatic Cascade 31 5. Cellular Arrest, Vascular Adhesion, and Extravasation The cell has reached a stopping point, adheres to the vessel wall, and extravasates (exits) into the new tissue. Fidler Nature Reviews Cancer 2003 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. The Metastatic Cascade 32 6. Colonization The cell interacts with premetastatic niches that are permissive for proliferation and colonization of secondary sites. Colonization is dependent upon a combination of tumor cell and tissue-specific factors. Fidler Nature Reviews Cancer 2003 College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Metastasis Hallmarks 33 Hurst and Welch. 2011. Cancer Research College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Metastasis Hallmarks 34 Hurst and Welch. 2011. Cancer Research College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Conclusions 35 Tumors have acquired mechanisms to recruit their own blood supply termed angiogenesis. VEGF is the key activator for angiogenesis. Other mechanisms include vascular mimicry and vasculogenesis, recruiting cells from the bone marrow, to form new vessels. Metastasis is the major cause of clinical mortality for cancer patients. Metastasis behavior is described by the seed and soil hypothesis. Metastasis is a complex process of several steps (metastatic cascade) that facilitates successful colonization and growth of the metastatic tumor. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. Summary Hallmarks Angiogenesis and Metastasis 36 Keywords Angiogenesis VEGF Angiostatin HIF1a Vasculogenesis Metastasis Seed and Soil Stephen Paget Metastatic cascade EMT College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved. References 37 Emperor of All Maladies: A Biography of Cancer. Siddhartha Mukerjee Molecular Biology of Cancer: Mechanisms, Targets, and Therapeutics. Lauren Pecorino 4th edition. Additional references included on corresponding slides. Cancer.gov Hurst and Welch. 2011. The Hallmarks of Metastasis. Cancer Research. College of Arts and Sciences and Heersink School of Medicine © UAB. All Rights Reserved.