Lecture 25. Transformation and Oncogenesis. Flint et al, Chapter 18Some cancer terms (Box 18.1)Types of cancersTransformed cells (Table 18.1)Sensing the environment: (Fig. 18.3)The cell cycle (Fig. 18.4)Cell cycle control (Fig. 18.5)Oncogenic VirusesOncogenic Viruses: a Genetic Paradigm for Cancer (Fig. 18.6)HistoryOncogenic viruses and cancer (Table 18.2)Insertional mutagenesisViral transforming genesViral transforming genes v-oncogenes (see Table 18.6, Figs. 18.7. 18.8)Viral proteins that alter cellular signaling pathways (Fig. 18.13, Table 18.8)Viral adapter proteins that alter cellular signaling pathwaysCell cycle Regulation by the Rb proteinTransformation via cell cycle control pathwaysTransformation via cell cycle control pathwaysInhibition of p53 functions (Fig. 18.20, 21)p53 regulation (Fig. 18.20)Inhibition of p53 functions (Fig. 18.21)Oncogenesis by hepatitis viruses (Fig. 18.22)Slide 24Lecture 25. Transformation and Oncogenesis. Flint et al, Chapter 18•Cancer: a genetic disease•Results from growth of successive populations of cells in which mutations have accumulated•Alteration of steps in regulatory pathways that control cell communication and proliferation•Uncontrolled growth  Cellular disorganization  Cancer•Approx. 20% of all human cancers are of viral origin.•Viruses are major causes of liver and cervical cancers•Malignancy can result as a consequence of a side effect of viral infection or of host response to virus.Some cancer terms (Box 18.1)•Neoplasm: an abnormal new growth•Benign: a growth that does not infiltrate into surrounding tissues.•Malignant: Any disease of a progressive, fatal nature•Tumor: swelling; caused by abnormal cell growth not from inflammation; can be benign or malignant.•Cancer: A malignant tumor; growth not encapsulated; infiltrates into surrounding tissues; spread by lymphatic vessels to other parts of body; death caused by destruction of other organs, by extreme debility and anemia or by hemorrhage.•Carcinogenesis: Complex multistage process by which cancer develops.•Oncogenic: causing a tumor•Metastases: Secondary tumors derived from cells of primary tumor that disseminated to other parts of the body.Types of cancersCancers get their names based on the tissue of origin•Adenoma: A cancer of hormone secreting cells. Many cancers of reproductive tracts.•Carcinoma: cancer of epithelioid tissue•Fibroblast: tissue derived from connective tissue•Fibropapilloma: Solid tumor of cells derived from connective tissue•Hepatocellular carcinoma: a cancer of liver epithelial cells•Endothelioma: any tumor, particularly a benign one, arising from the endothelial lining of blood vessels•Leukemia: A cancer of white blood cells•Lymphoma: a cancer of lymphoid tissue•Retinoblastoma: Cancer of retinal cells•Sarcoma: A cancer of fibroblastsTransformed cells (Table 18.1)Much of what we know about cancer is derived from studies of Transformed CellsThese have abnormal growth parameters and behaviors:•Immortality: can grow indefinitely•Reduced requirement for serum growth factors•Loss of capacity for growth arrest upon nutrient deprivation•High saturation densities•Loss of contact inhibition•Anchorage independent (can grow in soft agar)•Altered morphology (rounded and refractile)•Tumorogenic: can cause tumors when transplanted into animalsSensing the environment: (Fig. 18.3) •Cells must sense what is going on around them•Cell surface receptors interact with ligands•Signal transduction cascades •Second messengers•Activation and repression of genesThe cell cycle (Fig. 18.4) •Cell growth regulated by an internal timer: cell cycle•Divided into 4 phases•G1: cell growth, restriction point•S: DNA synthesis•G2: preparation for cell division•M: MitosisCell cycle control (Fig. 18.5)•Rb protein: phosphorylation status of Rb used to control cell cycle–Rb phosphorylation: allows passage of G1 restriction point, entry into S-phase–Rb dephosphorylation: signals end of M phase.•Cell cycle is controlled by the cyclin-Cdk machinery•Different cyclins and cyclin dependent kinases expressed at different stages of the cell cycle.Oncogenic Viruses•Cause cancer by inducing changes that affect cell proliferation•Approx 20% of all human cancers causes by one of 5 viruses”–1. Epstein-Barr virus–2. Hepatitis B–3. Hepatitis C,–4. HTLV I–5. Hum. PapillomavirusesOncogenic Viruses: a Genetic Paradigm for Cancer (Fig. 18.6) •Study of viral transformation of cells laid the foundations for our current understanding of cancer.•Enabled identification of Oncogenes and Tumor Suppressor genes•Foundation for the genetic paradigm of cancerHistory•1908: Ellerman and Bang show that avain leukemia could be transmitted through filtered extracts or serum from infected birds.•1911: Rous showed that solid tumors could be produced in chickens by using cell-free extracts from a transplantable tumor (Rouse Sarcoma Virus: the first discovered retrovirus)•1933: Shope isolates papillomavirus from warts•1978: Bishop and Varmus define oncogeneOncogenic viruses and cancer (Table 18.2)Family Associated Cancer(s)RNA viruses Flaviriridae Hepatitis C virus Hepatocellular carcinoma Retroviridae Haemopoetic cancers, sarcomas, carcinomasDNA viruses Adenoviridae Various solid tumors Hepadnaviridae Hepatocellular carcinoma Herpesviridae Lymphomas, carcinomas, sarcomas Papillomaviridae Papillomas and carcinomas Polyomaviridae Various solid tumors Poxviridae Myxomas and fibromasInsertional mutagenesis •Integration of retroviral progenomes mutates the genome of a cell.•Proviral promoters can activate transcription of nearby genes.•Transformation can occur if the nearby gene is an oncogene.–e.g. c-myc•Transformation can also occur if insertion disrupts tumor suppressor genes.Viral transforming genes •2 general strategies–Permanent activation of cellular signal transduction cascades–Disruption of cell cycle regulationViral transforming genesv-oncogenes (see Table 18.6, Figs. 18.7. 18.8) •Characteristic of transforming viruses•Cellular origin (Bishop and Varmus, Nobel Prize 1989)•Picked up by retroviruses•Typically fusions of viral + cellular genes•Viral sequences alter expression, regulation and localization of gene products–e.g. overexpression of myc is sufficient to inducetransformation–e.g. v-erbB is a truncated form