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Transcript
Inflammation & Cancer 1 Chronic Inflammation 2 3 Ulcerative Colitis 4 5 6 Why would chronic inflammation lead to cancer? • The pathogen (e.g., virus) carries an oncogene that is inappropriately expressed. • Infection leads to cell death that requires rapid proliferation that is associated with an accumulation of replication-induced mutations. • In its effort to clear the infectious agent, the immune system causes some undesirable side-effects. 7 Inactive Trypsin 8 9 Why would chronic inflammation lead to cancer? • The pathogen (e.g., virus) carries an oncogene that is inappropriately expressed. • Not all chronic inflammation is due to an infectious agent. For those that are, no oncogenes have been identified. • Infection leads to cell death that requires rapid proliferation that is associated with an accumulation of replication-induced mutations. • The rate of replication-induced mutations is 1:109, assuming the repair mechanisms are working properly. • In its effort to clear the infectious agent, the immune system causes some undesirable side-effects. 10 11 NSAID Use 12 75 mg aspirin/day for 10 years 13 14 15 16 17 Mouse Models 18 19 20 21 Target Genes of NF-kB Cytokines/Chemokines and their Modulators Immunoreceptors Proteins Involved in Antigen Presentation Cell Adhesion Molecules Acute Phase Proteins Stress Response Genes Cell Surface Receptors (-) Regulators of Apoptosis Growth Factors, Ligands and their Modulators Early Response Genes Transcription Factors Enzymes 22 23 Autocrine signaling Autocrine signaling through PGE2 cox2 ROS/RNS? 24 Paracrine signaling 25 Autocrine signaling Autocrine signaling through PGE2 cox2 NSAIDs 26 Paracrine signaling MAPKKK Pathway 27 TumorInfiltrating Lymphocytes (TILs) 28 29 Macrophages 30 TumorAssociated Macrophages (TAMs) 31 - - - CSF-1 = M-CSF 32 - - 33 CSF-1 - CSF-1 - - 34 CSF-1/M-CSF MCP-1/CCL2 RANTES/CCL5 VEGF PDGF CSF-1 35 MIP-1g 36 37 TNF-a Growth Survival More inflammatory cells COX-2/PGE2 38 Matrix Metalloproteinases (MMPs) 39 - - - 40 41 42 43 44 45 - 46 - Lack paracrine support Hydrodynamic sheer forces 47 48 49