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Download The Hallmarks of Cancer - Roswell Park Cancer Institute
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The Hallmarks of Cancer Daniel L. Stoler, Ph.D. Department of Head and Neck Surgery [email protected] True or False: The risk of dying of cancer is on the rise. 1971 “War on Cancer” was declared. Success is always “just around the corner”. 2012 And the war goes on and on and on….. Age-adjusted Death rates Cancer is the Result of a Multistep Process Evidence - Clinical observations of progression of: •Colon Adenoma to Carcinoma •Ductal Carcinoma in situ to Invasive Breast Cancer •Prostatic intraepithelial neoplasia to Prostate Cancer normal --> ---> early ---> mid ----> late ---> carcinoma--> mets adenoma adenoma adenoma What are the underlying events and how do they come about? ? ? ? ? normal --> ---> early ---> mid ----> late ---> carcinoma --> mets adenoma adenoma adenoma In Vitro Studies of Cancer Cell Lines Review The Hallmarks of Cancer Douglas Hanahan* and Robert A. Weinberg † Cell, Vol. 100, 57–70, January 7, 2000 Review Hallmarks of Cancer: The Next Generation Douglas Hanahan* and Robert A. Weinberg Cell, Vol. 144, 646–674, March 4, 2011 • Oncogenes – mutated forms of normal cellular genes generally involved in promoting cell proliferation. These mutations result in dominant gain of function. • Tumor Suppressor genes – genes whose normal function in regulating proliferation is to stop it. Mutation results in recessive loss of function. Carcinogenesis is the accumulation of multiple genetic alterations that drive a normal cell to malignancy. Why havenᾼt we been able to cure most adult onset cancers, if surgical resection fails? Early Molecular Model of Tumor Progression - Vogelstein MeAPC DNA k-RAS DCC SMAD4 p53 ? normal --> ---> early ---> mid ----> late ---> carcinoma --> mets adenoma adenoma adenoma Hypothesis: Mutation in one gene associated with each step in progression. Reductionist View of a Tumor Hanahan &Weinberg Cell 100:57 2000 Acquired Capabilities of a Cancer Cell Cell 100, 57–70 Normal Mitogenic Growth Stimulation Signal Transduction Proteins Transmembrane Receptor Growth Factor Nucleus Cytoplasm Strategies of Tumor Cell SelfSufficiency Insensitivity to Anti-Growth Signals Anti-Growth Signal such as TGF Smads Mad Max pRB TGFR Cell Proliferation Myc Max Regulation of Apoptosis Mitochondrion Sensor Molecules ? Fas ligand Antiapoptosis signal Proapoptosis signal Fas p53 Bcl2 Bax Effector Molecules Cell Death Telomeres Your Biological Clock is Ticking (TTAGG)nTTAGGTTAGGTTAGGTTAGGTTAGG (TTAGG)nTTAGGTTAGGTTAGGTTAGG (TTAGG)nTTAGGTTAGGTTAGG (TTAGG)nTTAGGTTAGG Angiogenesis Angiogenic Factors Antiangiogenic Factors Region of insufficent blood supply Invasion and Metastasis I Integrins Cell Adhesion Molecules (Adherens) Invasion and Metastasis II Extracellular Proteases Invasion and Metastasis III A. Epithelial-Mesenchymal Transition • Normally during embryonic morphogenesis • Epithelial cells acquire Mesenchymal traits – – – – Loss of adherens junctions Change in cellular morphology Expression of proteases Increased motility B. Collective Invasion Partial EMT? C. Amoeboid Invasion Invasion and Metastasis IV A. Epithelial-Mesenchymal Transition • Normally during embryonic morphogenesis • Epithelial cells acquire Mesenchymal traits – – – – Loss of adherens junctions Change in cellular morphology Expression of proteases Increased motility B. Collective Invasion Partial EMT? C. Amoeboid Invasion Reductionist View of a Tumor Realistic View of a Tumor The Immune System • Tumor infiltrating immune cells provide factors which: – – – – – – • Stimulate growth Inhibit cell death Promote angiogenesis Degrade extracellular matrices Induce epithelial-mesenchymal transition Damage DNA (reactive oxygen species) Immune evasion – Immune surveillance hypothesis – Some data supports: • Selective killing of highly immunogenic tumors, leaving weakly immunogenic ones • Tumors disable parts of the immune system by secreting or recruiting cells that secrete immunosuppressive factors (ex. TGF B) Tumor Cell Metabolism • Normal Cells – Glucose Pyruvate (glycolysis) CO2 (mitochondria) • Tumor Cells - Glycolytic Switch – Glucose Lactate (glycolysis) – Aerobic Glycolysis • Clinically Useful – PET Scan – Radiolabeled glucose analog – Scan for areas of the body with elevated glucose uptake Hanahan &Weinberg Cell 100:57 2000 Cancer - evolution at a vastly accelerated rate favoring the growing tumor mass over the organism. Genomic Instability introduces genomic alterations and Natural Selection chooses “the fittest” tumor to survive.
