Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Cancer - WordPress.com
Document related concepts
Epigenetics of human development wikipedia , lookup
Cancer epigenetics wikipedia , lookup
Minimal genome wikipedia , lookup
History of genetic engineering wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Mir-92 microRNA precursor family wikipedia , lookup
Oncogenomics wikipedia , lookup
Transcript
CANCER: A GENETIC DISEASE Mutations in genes that control cell growth and division are responsible for cancer. (cell proliferation and differentiation) Carcinogens DNA mutations CANCER Cancers arise when critical genes are mutated, causing unregulated proliferation of cells. These rapidly dividing cells pile up on top of each other to form a tumor. When cells detach from the tumor and invade surrounding tissues, the tumor is malignant and may form secondary tumors at other locations in a process called metastasis. A tumor whose cells do not invade surrounding tissues is benign. Tumor – is a condition where there is abnormal cellular growth thus forming a lesion or in most cases, a lump in some part of your body. Benign tumor – grows in confined area Malignant tumor – capable of invading surrounding tissues Cancer – degenerative disease with a cellular condition where there is uncontrolled growing mass of cells capable of invading neighboring tissues and spreading via body fluids to other parts of the body. Named for site of origin Carcinomas – epithelial cells; cover external & internal body surfaces (90%) Sarcomas – supporting tissue; bone, cartilage, fat, connective tissue, pancreas, Liver. Lymphoma & leukemias – blood & lymphatic tissue (leukemia reserved for cancers that reside in bloodstream not as solid tissue) COMPARISON OF NORMAL AND TUMOR GROWTH IN THE EPITHELIUM OF THE SKIN COMPARISON OF NORMAL AND TUMOR GROWTH IN THE EPITHELIUM OF THE SKIN Location/distribution NORMAL CELLS VS. CANCER CELLS Normal cell proliferation Cancer cell proliferation Anchorage dependent Anchorage independent Density-dependent inhibition Can grow on top of one another Immortal Limited number of cell divisions Telomere shortening Proliferation dependent upon extracellular signals Checkpoints activated at appropriate times Apoptosis functional Telomere maintenance Constant signal to divide independent Loss of checkpoint Apoptosis inhibited BASIC PROPERTIES OF A CANCER CELL In culture, normal cells can be transformed by chemicals or viruses. Different types of cancer cells share a number of similarities: Aberrant chromosome numbers (aneuploidy) High metabolic requirements Unregulated growth Synthesis of unusual cell surface proteins Stages in the Process of Invasion and Metastasis Basal lamina Invasion Metastasis Matrix CELL CYCLE CHECKPOINTS Transitions between different phases of the cell cycle (G1, S, G2, and M) are regulated at checkpoints. A checkpoint is a mechanism that halts progression through the cycle until a critical process is completed. CANCER AND GENES Oncogenes are genes that, when mutated, actively promote cell proliferation. Tumor suppressor genes are genes that, when mutated, fail to repress cell division. SEVERAL MUTATED OR ALTERED GENES IN CANCER Cancer cells contain several (6-8) mutated genes. Several categories of genes 1. Oncogenes -An oncogene is a gene that when mutated or altered contributes to converting a normal cell into a cancer cell. - The term oncogene is derived from the Greek word "oncos," meaning tumor. - The cellular oncogenes in their normal form are called protooncogenes and do not cause cancer. They code for a variety of normal enzymes, growth factors and receptors that relay signals to a cell's nucleus, stimulating growth. - The activation to oncogene may result in overproduction of growth factors; flooding of the cell with replication signals; and/or unrestrained cell growth. - The activation of a proto-oncogene to oncogene can occur in several ways: -mistakes during DNA replication, ie. point mutation, chromosomal rearrangement, gene amplification -from damage to DNA cause by exposure to chemicals or radiation -from viral infection and insertion into the DNA resulting in more active production of oncogene - from other causes not yet known To other points about oncogenes: - Oncogenes act as dominants; if the cell has one normal gene at a locus and one mutated gene, the abnormal product takes control. - No single oncogene can, by itself, cause cancer. It can increase the rate of mitosis of the cell. Dividing cells are at increased risk of acquiring mutations. - Oncogenes may be transmitted from generation to generation when a proto-oncogene mutates in the germ line. This results in a dominantly inherited tumor predisposition. For example, multiple endocrine neoplasia type 11 (MEN 2) is the outcome of a germline transmission of an activated RET oncogene. 2. Tumor Suppressor genes - Suppress tumor formation. - Their protein products act to inhibit cell growth and the division cycle. - Mutations in tumor suppressor genes cause the cell to ignore one or more of the components of the network of inhibitory signals, resulting in a higher rate of uncontrolled cell proliferation. - Tumor suppressors behave as recessives. Both normal alleles must mutate before cancerous growth begins. Examples of Tumor Suppressor genes 1. p53 -53 kD protein that prevents a cell from completing the cell cycle if its DNA is not properly replicated in S phase. It responds to cell damage. - It binds to transcription factor (E2F) and prevents E21F from binding to the promoters of the proto-oncogenes c-myc and c-fos, needed for mitosis - The p53 protein may triggers programmed cell death (apoptosis) if the damage to the cell is too great to be repaired. - Defects in the p53 gene are found in most cancers. VIRUSES ASSOCIATED WITH HUMAN CANCERS Family Virus Cancer Human papillomaviruses Genital tumors Squamous cell carcinomas Oropharyngeal carcinomas Herpesviridae Epstein-Barr virus Nasopharyngeal carcinoma African Burkitt’s lymphoma B cell lymphoma Hepadnaviridae Hepatitis B virus Hepatocellular carcinoma Retroviridae Human T lymphotrophic viruses Human immunodeficiency viruses Adult T cell leukemias AIDS-associated tumors (due to impaired T cell responses Flaviviridae Hepatitis C virus Hepatocellular carcinoma Papillomaviridae GENERAL FEATURES OF VIRAL CARCINOGENESIS Most are DNA viruses (exceptions: some retroviruses and flaviviruses) Influence the cell cycle by Encoding proteins that direct cell cycle progression Integrating near cellular genes that control cell cycle progression The Central Principle of Viral Carcinogenesis Viruses can cause cancers in humans and animals Tumor viruses frequently establish persistent infections Host susceptibility factors are important determinants Viruses are seldom carcinogenic on their own Virus infections are far more common than viral cancers Prolonged periods (years) are usually required for viral carcinogenesis Viral strains may be different in their capacity to cause cancers Cancer viruses modulate cell cycle progression Animal models can reveal mechanisms of viral carcinogenesis TUMOR-INDUCING RETROVIRUSES AND VIRAL ONCOGENES Retroviruses have an RNA genome. The Rous sarcoma virus, the first tumor-inducing virus, contains four genes gag encodes the capsid protein of the virus pol encodes the reverse transcriptase env encodes a viral envelope protein v-src encodes a protein kinase that inserts into the plasma membranes of infected cells. The v-src gene is an oncogene that is responsible for the virus’s ability to induce abnormal cell growth. © John Wiley & Sons, Inc. PROTEINS ENCODED BY VIRAL ONCOGENES Growth factors similar to those encoded by cellular genes Proteins similar to growth-factor and hormone receptors Transcription factors homologous to cellular proteins Any protein INTERACTIONS OF TUMOR VIRUSES WITH THEIR HOSTS Persistent infections All known human tumor viruses establish persistent infections Genetic differences in individuals results in differential susceptibilities Host immune response Persistent viruses must evade the host immune response Different viruses have evolved different evasion mechanisms Mechanisms of action by human cancer viruses Viral gene is able to subvert cell cycle control Viruses alter the expression of normal cell cycle progression genes Either results in cellular transformation into an oncogenic state INTERACTIONS OF TUMOR VIRUSES WITH THEIR HOSTS Cell susceptibility to virus Tumor viruses possess cell specificity and do not infect other cells EBV infects B cells HTLV infects T cells Retention of viral nucleic acid in a cell Viral genes are always present in the transformed cells RETROVIRUSES Structure and composition Diploid single-stranded RNA viruses (5-8 kb) Helical ribonucleoprotein Enveloped Genetics Only diploid viruses About 10 genes, 16 proteins reverse transcriptase protease envelope gag tax rex RETROVIRUSES Epidemiology Typical infectious viruses (exogenous) Sexual transmission IV drug abusers Other, unknown transmission mechanisms Classification Leukemia viruses Alpharetrovirus Gammaretrovirus Nontransforming retroviruses Deltaretrovirus Lentivirus MECHANISMS OF RETROVIRAL CARCINOGENESIS Infection leads to uncoating in the cytoplasm Reverse transcriptase makes a double-stranded DNA copy An RNA-dependent DNA polymerase A DNA-dependent DNA polymerase A DNA-dependent RNA polymerase The ds-DNA translocates into the nucleus where it randomly integrates in host cell chromosome This version of the viral genome is termed the provirus Two replication strategies Induce cell division - leads to copies of the viral genome in each daughter cell Productive infection - spread of virus to other cells DNA TUMOR VIRUSES Virus Viral Oncoproteins Cellular Targets Polyomavirus SV40 Large T antigen Small t antigen p53 and pRb tumor suppressor genes PP2A Human papillomavirus E6 E7 p53, DLG, MAGI-1, MUPP1 pRb Bovine papillomavirus E5 PDGFβ receptor Adenovirus E1A E1B-55k pRb p53 Adenovirus 9 E4ORF1 DLG, MAGI-1, MUPP1 Epstein-Barr virus LMP1 vIL10 BCL2 homolog TRAFs IL-10 receptor (soluble viral cytokine) Rescues cell from apoptosis DNA TUMOR VIRUSES Papillomaviruses Features Non-enveloped icosahedral (55 nm) Circular ds-DNA (8 kb) Nuclear replication Stimulate cellular DNA synthesis Highly restricted host range and tissue range Many human types Only a few are known to cause cancers Cervical cancer is the most important Vaccine is now available Cause warts (abnormal cellular proliferation)
