MODULE II CANCER 12 09 2012 BIG CONCEPTS What is cancer Who has it o 44 of men will develop it prob prostate 23 will die o 38 of women will develop it prob tit 20 will die o largely a disease of the old when nothing else gets you cancer does Why don t people in Mozambique die of cancer How s It different from other diseases o Body cant fight cancer like other diseases o Cant develop resistance immunity and pass it to next generation What is it at a cellular level o Uncontrolled cellular growth o Loss of tissue architecture and function o Connective tissue hijacked from normal function o Cells within a tissue obtaining new phenotype What is it at an organismal level What are the various types of cancer o Carcinomas cancers of epithelial tissues Breast prostate colon lung bladder liver skin o Sarcomas cancers of mesenchymal tissues o Leukemias cancers of blood or bone marrow Arise in bone marrow or in circulation o Lymphoma arise in lymphatic system o Myelomas arise from plasma cells in bone marrow o CNS cancers brain What is the relationship between developmental bio and cancer How does cancer arise and spread o ALTERED GENE EXPRESSION o Caused by changes to the DNA Mutations base changes epigenetics change in gene structure leads to hyperplasia dysplasia anaplasia etc dedifferentiation reactivation of developmental processes EMT proliferation of undifferentiated cells What are the stages of cancer progression 6 steps o 1 Genetically altered cell some cell within a normal population sustains a genetic mutation that increases it propensity to proliferate when it would normally rests o 2 Hyperplasia the altered cell and its descendants continue to look normal but still reproduce too much after years 1 million of these cells suffers another mutation that further loosens control on cell growth o 3 Dysplasia while proliferating excessively the offspring of the cells appear abnormal in shape and orientation dysplasia after time another rare mutation occurs altering cell behavior o 4 In situ cancer the affected cells become still more abnormal in appearance and growth if the tumor has yet to break the boundaries between tissues it is in situ cancer This tumor may remain contained indefinitely but eventually some cell acquires a new mutation o Can take years from initial mutation to in situ cancer o 5 Invasive cancer if the genetic changes allows the allowing it to invade other underlying tissues and to shed cells into the lymph or blood stream malignant in other parts of the body o eventually becomes lethal by disrupting vital organs CANCER IS A GENETIC DISEASE Cancer is caused by genetic alterations in somatic tissues o Inherited cancer causing mutations o Inherited cancer predisposing mutations o Non inherited somatic mutations o Spontaneous or induced o Non mutation based genetic mutations Spontaneous or Inherited Mutations What kinds of genes are affected in cancer Oncogenes Tumor suppressors How can they be affected genes whose products promotes cell growth genes whose products retard ell growth Positive and negative signals control cell growth o Oncogenes control positive signals o Tumor suppressors control negative signals Proto oncogenes can be affected by increased expression levels mutations o Ex Cmyc o Overamplification activates pro growth gene represses antigrowth sgenes o Protooncongenes can also promote cell death Are mutations the only way to affect cancer genes Cancer and Stem Cells All tissues have stem cells o Non specialized self renewing cells o Division produces unequal daughter cells o One remains a self renewing stem cells one becomes a differentiating cell Prominent theory cancer arises from transformation of stem cells would cause proliferation and under differentiation In terms of causation WHAT IS THE ROOT CAUSE OF CANCER Mutations Epigenetics aneuploidy some viruses express oncoproteins changes in the amount of DNA What kinds of events can produce this cause What causes mutagens o Carcinogens compounds associated with cancer Typically cause cancer by changing DNA sequence Chemical modification of DNA Misincorporation of bases during DNA replication ionizing radiation charged energetic particles certain electromagnetic radiation some viruses o Mutations vs carcinogens NOT THE SAME Mutations explicitly cause dna damage Carcinogens can promote cancer without causing mutations How to know AMES TEST Epigenetics o Viruses o Cause cancer by 2 ways Expression of oncoproteins RNA tumor viruses capture host oncoproteins DNA tumor viruses inactivate tumor suppressors oncoproteins in these typically don t have cellular counterparts Insertional Mutagenesis Insertion of viral genome into host genome Can inactivate tumor suppressors and activate Aneuploidy oncogenes o Changes in the amount of DNA o Majority of human tumors of aneuploid 1 State of Altered chromosomal structure 2 State of Altered chromosomal complement 3 process of Changing chromosome structure 4 process of Changing chromosome complement Cell become aneuploidy through errors in o DNA replication o DNA repair o Chromosome segregation o Checkpoint function History it aneuploidy chromosomes necessary for development Cells with extra centrosomes can arise through cytokinesis failures MUTATION VS CARCINOGEN HOW DO YOU ENCOUNTER THESE EVENTS Environmental factors pollutants radiation genetics HOW CAN DIET INFLUENCE CANCER Mutations carcinogens and oxidants Epigenetics alteration of DNA Methylation Antioxidants YOU DON T INHERIT CANCER YOU INHERIT A RISK FOR CANCER PRESDISPOTION Chrosomal Chaos article 6 features of cancer that cannot be explained by mutations Cancer risk increases with age Carcinogens take a long time to cause cancer Carcinogens induce aneuploidy Patterns of aneuploidy can be observed Gratuitous traits do not contribute to cancer Cancer cells morph faster than genes Key vocab Metaplasia change in cell shape and cell type re differentiation Hyperplasia excessive growth with no loss of differentiation can be normal Neoplasia new growth typically abnormal and unregulated Dysplasia loss of differentiation not necessarily associated with growth Anaplasia lack of differentiation no identifiable tissue character Lack of differentiation is considered a hallmark of aggressive malignancies Malignancies o is the tendency of a medical condition especially tumors to become progressively worse and to potentially result in death o cancers is characterized by anaplasia invasiveness and metastasis HALLMARKS OF