New Material DNA Replica on Cell Cycle Cancer Cancer Tumors Grow from Single Cells X chromosome inactivation is random in normal tissue but not in tumor Shows monoclonal origin or tumor Tumors large enough to detect are very advanced at the cellular level Early detection is VERY important Tumors Grow from Single Cells X chromosome inac va on random in normal ssue but not in tumor shows monoclonal origin Tumors Grow from Single Cells of tumor tumors large enough to detect very advanced X chromosome inactivation is random in normal tissue but not in tumor cellular level Shows monoclonal origin or tumor early detec on VERY Tumors large enough to detect are very advanced at the cellular level Early detection is VERY important important Cancer Ini0a0on Progression Mul0HStep Process Cancer Initiation and Progression is a Cancer Initiation and Progression is a Multi Step Process Multi Step Process bladder cancer in chemical workers aver exposure colon cancer in English women Colon cancer in English women Bladder cancer in chemical workers Colon cancer in English women Bladder cancer in chemical workers after exposure to 2 napthylamine after exposure to 2 napthylamine Cancer General Features Cancer General Features that tell them to grow or not grow classi ca on sarcoma carcinoma lymphoma autonomous growth Classification grow on own Sarcoma become resistant to signals Carcinoma Lymphoma benign or malignant Autonomous Growth metastasis in malignant Benign or Malignant spread invade Metastasis grow enter leave circula on Grow Enter and Leave since they move to new Circulation environment survive in new site w o signals from similar cells Spread and invade Survive in new site Changes in Cancer Cells Changes in Cancer Cells autonomous growth grow on own w o signals round cells Autonomous Growth Round Cells Dedifferentiation Changes in surface molecules No contact inhibition of growth No contact inhibition of movement No anchorage requirement Disregard proliferation cues Avoid programmed cell death Avoid differentiation Genetically unstable Metastasis can grow on top of each other NO contact inhibi on of movement change in surface molecules NO contact inhibi on of growth become metasta c NO anchorage requirement de di eren a on don t need a at surface to grow on disregard prolifera on cues avoid programmed cell death avoid di eren a on gene cally unstable cancer cells have muta ons get more muta ons metastasis Proposed Causes of Cancer Muta0ons Viruses Inherited Condi0ons Proposed Causes of Cancer Proposed Causes of Cancer slide 1 of 2 Mutations Viruses Inherited Condition Mutations Viruses Inherited Condition soma c muta on Somatic Mutation Somatic Mutation Ames Test Ames Test point muta on can get Carcinogens are Ames test Carcinogens are A atoxin Mutagens reversion to WT Mutagens ER liver in agar ER liver in agar Ames test measures how Detoxification likely this is to happen Detoxification Cytochrome P450 carcinogens mutagens Cytochrome P450 Normal clearance ER liver in agar Normal clearance mechanism can mechanism can detoxi ca0on get rid of convert a non convert a non mutagenic toxins via urine mutagenic molecule to a cytochrome P450 molecule to a carcinogen detoxi ca on occurs in carcinogen aflatoxin b1 smooth ER aflatoxin b1 Virus Virus normal clearance DNA Virus SV40 DNA Virus SV40 mechanism can convert RNA Retroviruses non mutagenic molecule to RNA Retroviruses Genetic Predisposition carcinogen Genetic Predisposition Tumor Suppressor Gene A atoxin B1 Tumor Suppressor Gene Ames test Proposed Causes of Cancer Muta0ons Viruses Inherited Condi0ons slide 2 of 2 virus DNA virus SV40 RNA retroviruses gene c predisposi on tumor suppressor gene Mul0ple Muta0ons Must Occur to Generate Malignant Cancer most tumors cell clones mul ple muta ons required to Multiple Mutations Must Occur to Generate Malignant Cancer transform growth selec on favors fast dividing cells tumor cells gene cally unstable accumulate muta ons tumor promoters aid tumor forma on phorbol esters ac vate PKC Most tumors are cell clones Multiple mutations required to transform Growth and selection favors fast dividing cells Tumor cells are genetically unstable and accumulate mutations Tumor promoters aid tumor formation Phorbol esters activate PKC 1016 divisions during a human life 10 6 mutations per gene per division 1010 mutations per gene during life Why not more cancer Oncogenes Tumor Suppressor Genes Oncogenes and Tumor Suppressor Genes overac vity muta on oncogene turned ON oncogene must be ac vated to Oncogene transform dominant Must be activated to transform Dominant 1 copy can transform cell One copy can transform cell point muta on transloca on ampli ca on Point Mutation Translocation Amplification gives posi ve growth signal Tumor Suppressor Gene tumor suppressor gene Must be inactivated Recessive must be inac vated recessive Loss of both copies Genetic predisposition loss of BOTH copies gene c predisposi on can inherit 1 bad copy very strong predisposi on b c then only have to mutate 1 copy underac vity muta on tumor suppressor gene turned OFF Discovery of Oncogenes Discovery of Oncogenes Oncogenes Derived from proto oncogenes Proteins involved in regulation of growth Our genomes carry genes that can cause cancer Mutagens induce specific changes in specific genes RNA Tumor Virus DNA Rearrangement EXAMPLE Src non receptor tyrosine kinase Example Myc transcription factor Sequence is identical to host sequence Gene Transfer Example ras small GTP binding protein oncogenes derived from protoHoncogenes proteins involved in growth genome carries cancer causing regula on genes mutagens induce speci c changes in speci c genes RNA tumor virus EX SRC non receptor tyrosine kinase DNA rearrangement EX Myc transcrip on factor sequence is iden cal to host sequence gene transfer EX Ras small GTP binding protein Oncogene Ac0va0on Oncogene Activation Abl Oncogene Activation by Chromosomal Translocation fusion of Abl gene w oncogene Abl Oncogene Activation by Chromosomal Translocation CML chronic myelogenous leukemia Abl is a non receptor Tyrosine Kinase Cousin of Src Gleevec is a Drug that inhibis Abl Gleevec cures leukemia if given early Later stage tumor cells have increased genetic instability and mutate so rapidly that they develop resistance before they die Abl Oncogene Ac0va0on via Chromosomal Transloca0on Abl non receptor tyrosine kinase cousin of SRC Abl gene fuses oncogene Gleevac drug that inhibits Abl cures leukemia if