Hallmarks of Cancer II (Jahn).pdf

The Hallmarks of Cancer Stephan C. Jahn, Ph.D.  The Hallmarks of Cancer Hanahan, D. and Weinberg, R. The Hallmarks of Cancer, Cell (2000) 100, p. 57-70 Hanahan, D. and Weinberg, R. Hallmarks of Cancer: The Next Generation, Cell (2011) 144, p. 646-674 Hallmark #3: Unstable DNA This is an...

The Hallmarks of Cancer Stephan C. Jahn, Ph.D.  The Hallmarks of Cancer Hanahan, D. and Weinberg, R. The Hallmarks of Cancer, Cell (2000) 100, p. 57-70 Hanahan, D. and Weinberg, R. Hallmarks of Cancer: The Next Generation, Cell (2011) 144, p. 646-674 Hallmark #3: Unstable DNA This is an “enabling” hallmark  Required for tumor progression  Can lead to drug resistance  If DNA became stable, the tumor would survive Two main forms of DNA instability  Genetic Instability  Chromosomal Instability Types of Genetic Instability Gene Amplification Probing for Gene Copy Number IrinaPav [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons Chromosomal Instability Gain or loss of whole chromosomes  Normal human cell has 46  Can get small changes  Can get genome doubling, quadrupling Can cause gain of pro-growth/invasive genes Can cause loss of growth inhibitory genes Mechanisms of Chromosomal Instability Endoreduplication Failed Cytokinesis Multipolar Spindles Monopolar Spindle Lagging Chromosomes Hallmark #4: Metastasis The transmission of cancer cells from the original site to one or more sites elsewhere in the body by the way of blood vessels or lymphatics Metastasis  Cause of 90% of deaths from solid tumors  30-40% patients with newly diagnosed cancer have clinically detectable metastases  20-30% of the remaining patients that are clinically free of metastases actually harbor hidden metastases Metastatic Cascade WassermanLab [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons  Hallmark #5: Evasion of Apoptosis Apoptosis is a cell SUICIDE mechanism. Its hallmarks are:  Cell volume loss  Membrane blebbing and formation of  apoptotic bodies  DNA fragmentation and condensation  Cytoskeleton collapse  Engulfment by immune Between 50 and 70 billion cells die cells each day due to apoptosis in the  Non-inflammatory average human adult  Triggers for apoptosis INTRINSIC STIMULI EXTRINSIC STIMULUS DNA damage Lack of survival factors (hormones) Interaction of death receptor on target cell with death ligand Loss of cell – ECM contact (ANOIKIS) Expression of abnormal cell surface Radiation and increased levels of antigens oxidants Chemotherapeutic drugs etc…..  Activation of Intrinsic pathway Activation of oncogenes DNA damage Hypoxia Cell cycle abnormalities proteasome MDM2 p53 ubiquitylation p53 undergoes degradation p53 accumulates and translocates into the nucleus DNA repair genes Apoptotic genes High affinity Low affinity p53 binding p53 binding site site Strategies to escape apoptosis Increased expression of anti-apoptotic proteins Downregulation of pro-apoptotic proteins Elevated expression of death ligands on tumor cell surface Loss of damage sensor – p53 Increased expression of survival factors / insensitivity to lack of survival factors Hallmark #6: Abnormal Cellular Metabolism Most mammalian cells under normoxic conditions pursue oxidative phosphorylation of glucose. OXPHOS = 38 molecules of ATP/molecule of glucose. Cancer cells in contrast metabolize glucose through glycolysis. Glycolysis = 2 molecules of ATP/ molecule of glucose. Phenomena of aerobic glycolysis in cancer cells was first observed by Nobel Prize winner Otto Warburg Warburg Effect  How is aerobic glycolysis triggered? I) TUMOR MICROENVIRONMENT Rapid proliferation outpaces the rate at which new blood vessels form II) MITOCHONDRIAL DEFECTS Tumor cells contain small and poorly developed mitochondria Increased Glucose Consumption Glycolysis under aerobic conditions appears to be the least preferred metabolic option because: It is an energetically inefficient pathway.  Glycolysis = 2 molecules of ATP/ molecule of glucose.  OXPHOS = 38 molecules of ATP/ molecule of glucose. Lactic acid production.  Cells have the additional liability of extruding lactic acid out of the cell and development of acid resistance to withstand the now highly acidic environment. Then why does a tumor cell pursue such an inefficient way of generating ATP? Proliferative and Survival Advantages Acidosis Makes the tumor cells highly invasive Induces heterogeneity in tumor population by promoting spontaneous transformation Induces angiogenesis through acid triggered release of VEGF Metastasis Tumor cells with upregulated glycolysis can better cope up with the bouts of hypoxia and anoxia involved with metastasis Source of anabolic substrates Glycolytic intermediates serve as precursors of nucleotides, fatty acids, protein and membrane lipids for building new cells Inhibition of apoptosis Inactivation of p53 Avoidance of immune surveillance Metabolic hallmark of cancer cells - Increased glucose flux 18Fluorodeoxyglucose Positron Emission Tomography (PET) imaging of a cancer patient. 18Fluorodeoxyglucose is a radioactive glucose analog. FdG-PET is widely employed clinically for tumor imaging. FdG PET also allows quantitation of glucose uptake.