Cancer Biology Jasmina Makarevic ATTA-UR-RAHMAN SCHOOL OF APPLIED BIOSCIENCES (ASAB) Cancer Biology Jasmina Makarevic Fall Semester 2016

Oncogenes/ Proto-Oncogenes Def.: Oncogenes: a cancer-inducing gene Proto–oncogenes: a normal cellular gene that, upon alteration by DNA-damaging agents or viral genomes, can acquire the ability to function as an oncogene. Tumor-supressor-genes: produce proteins which control the cell-cycle or lead to apoptosis (program of celullar self-destruction) loss of these genes leeds to cancer! Jasmina Makarevic

Theory of „HITS“ Knudson hypothesis (multi-hit hypothesis): cancer is the result of accumulated mutations to a cell‘s DNA (Alfred G. Knudson, 1971) e.g.: If renoblastom is inherited it occures in earlier years. When it is non-inherited at least two „hits“ to occure until it become cancer. That is why you get it in older age. (Mutations had to occure in both alleles before becoming cancer) Jasmina Makarevic

Two-Hits theoretical curve Jasmina Makarevic

Solid Cancers Colon Cancer: Five hits to achieve an invasive carcinoma Jasmina Makarevic

Chemical Carcinogenesis I First evidence from Paracelcius in 1567: „wasting deseas of the miners“ And many more after him… To better understand the connection, scientist began to induce tumors in animals with chemical substances. In 1915, Katsusaburo Yamagiwa reported the first succesful induction in a rabbits ear. Jasmina Makarevic

Chemical Carcinogenesis II Jasmina Makarevic

Chemical Carcinogenesis III Summary statistics (2012) Chemical Carcinogenesis III Covalent bond formation between an electrophilic form of the carconogen and the nucleophilic site in the proteine and nucleic acids  leeding to mutations Jasmina Makarevic

Important Experimental Proof Fruit fly genetic: 1927, Hermann Mueller induced mutations in the genom of Drosophila melanogaster by exposing these flies to x-ray. In the 1940s many other chemicals used in the World War I were also found to be mtagenic These findings caused several geneticists to speculate that cancer was a disease of mutant genes. Many other Scientists proofd this in the last 50 years. But how can we proof the relative mutagenic potencies of a chemical species? Jasmina Makarevic

The Ames Test Release ist enzymes Chemically activated , Summary statistics (2012) The Ames Test Release ist enzymes Chemically activated , mutagenic state Mutant allele, which caused this Phenotype in Salmonella was susceptible to back-mutation to a wild-type allele. Salmonella has no DNA- Recovering system smalle Lipopolysaccharids Jasmina Makarevic

Epidemiologic Studies Def.: Is the science which studies the patterns, causes and effects of healthand disease conditions in defined populations. Jasmina Makarevic

Tumor Viruses Leading their host to an uncontrolled proliferation! One of the first experiments: 1911 Peyton Rous: Jasmina Makarevic

Transformed cells forming foci Jasmina Makarevic

Transformed morphology Jasmina Makarevic

Conclusion Jasmina Makarevic

Onco-Virus Jasmina Makarevic

DNA-Virus Jasmina Makarevic

Life cycle of an RNA tumor virus like RSV Jasmina Makarevic

Structure of the Rous sarcoma virus genom Reverse Transcriptase: Enzyme makes DNA complementary copy of an RNA molecule using the RNA molecule as tamplate Integrase: Integrate e.g.: retroviral DNA genome into hostecell Chromosomal DNA Jasmina Makarevic

Making of src-specific DNA Src-gene = proto-oncogene Jasmina Makarevic

Transforming Retroviruses Jasmina Makarevic

RVS without proto- oncogene? Insertional mutagenesis ALV (avian leukosis virus) MLV (murine leukemia virus) Jasmina Makarevic

Outlook 1. Are there bacteria which causes cancer? What is about chronic inflammation? What happens in the process in cancer initiation, promotion and progression? Jasmina Makarevic

Thank You for Your Attention! Jasmina Makarevic