Discuss malignant transformation by chemical and viral induction in terms of tumor antigens and the effect of antigenic modulation on tumor evasion.
Malignant transformation is the process of carcinogenesis. Malignant transformations arise from mutations. Mutations are caused by genetics, radiations, chemical agents and viruses. Chemicals cause malignant transformation following a cascade of events. the initiation phase comes first and it is dose and time dependent in this phase mutation of DNA HAPPENS and the process is irreversible. There are two types of initiators .directly acting initiators which cause direct mutations. The direct initiators are highly active electrophiles, that is; they are electron deficient. They form covalent bonds with the nucleotides in the human DNA. Indirectly acting initiators require metabolic activation to affect the human cells. They are also called pro carcinogens. Most of them are metabolised by CYP450monooxygenases in the liver. There is gene polymorphism in inheritance of this enzyme. Activity of this enzyme therefore relies on the type of isoenzyme. For example; the Chinese have enzymes which are defective in adduct metabolism and detoxification and are prone to developing hepatocellular carcinoma. Cigarretes have benzopyrene which is metabolized by CYP1A1 to active adducts. A small percentage of the white population has a highly inducible form and this increases chances of carcinogenesis. Next is the promotion phase, it does not involve the DNA and changes that happen are reversible. .To initiate carcinogenesis with chemicals, the cells are exposed to carcinogenic chemical. The cells then mutate and this is where the DNA mutates. The chemical carcinogen can be direct action or indirect acting .In the DNA mutation happens at Tp53 responsible for tumor suppression or target RAS. Promoters such as hormones snd certain drugs can also augment carcinogenicity of some chemicals which on their own are not carcinogenic.
Viruses induce carcinogenesis. There are oncogenic RNA viruses and DNA viruses. Human T cell leukaemia virus type one for example causes adult T-cell leukaemia or lymphoma a tumour endemic in parts like the carribean.it is a retrovirus with affinity for CD4 cells. The infection is by transmission of infected T cells during sexual intercourse, blood transfusion or breast feeding. The virus genome contains gag, pol, env but it also has tax. Tax codes for proteins essential for viral replication but it also contributes to acquisition of cancer hallmarks. It causes increased pro-growth signalling and cell survival. It also increases genomic instability. There are oncogenic DNA viruses, five are known to cause human cancer. They include; human papilloma virus, Epstein Barrs virus, HBV, kaposi’s sarcoma virus and merkel cell polyoma virus. HPV is integrated in the cancers cells. The integration interfere with viral DNA within E1/E2open reading frame.E2 iral repressor is lost oncoprotein E6 and E7 overexpressed.E6 protein binds and mediates degradation of p53 and stimulates expression TERT the catalytic site of telomerase.E7 activity complements those of E6 .It functions to speed up cells going through G1 cell cycle checkpoint. It binds to RB proteins and displace E2F transcription factors promoting progression of the cell cycle. EBV infects the B cell lymphocytes. The viruses use CD21 complement receptor to attach to B cells and infect them. The infection is latent and the cells are not killed by the virus, however, cells infected express viral proteins which make them immortal. Latent membrane protein -1 act a CD40 receptor .It activates NF-Kb and JAK/STAT signalling pathways promoting cell survival and proliferation. It also prevents apoptosis by activating BCL2.The two are just examples which illustrate malignant transformation which is virus induced.
Cancer cells develop by a number of mechanisms which include; growth suppressors inhibition, mutation of genes that regulate apoptosis and activation of growth promoting antigens. When multiple genes are deregulated malignant tumors fully develop. Cancer cells are different, they allow for rapid growth, escape normal cell regulations invade tissues metastasise and also evades immune system. Tumors are recognised by the immune system that they are foreign. All components of the immune system respond to tumors and they include the specific and non-specific together with humoral and cellular immunity. In the body immune surveillance goes on and this is the process of recognizing and destroying foreign tumor cells.Tumor surveillance is mediated by natural killer cells,CD8 cell mediated cytotoxicity, macrophage cell attack and the antibody dependent cell mediated toxicity. When cancer occurs it is an indication that the immune response has failed to eliminate all of the foreign cells. The tumors act as antigens in the body hence the name tumor antigens. There were two types of tumor antigens initially; the tumor specific and tumor associated antigens. Examples of tumor associated antigens are; human chorionic gonadotropin, alpha fetoprotein and Prostate specific antigen. The classification was found to be faulty because some antigens which were thought to be expressed by tumors were found to be secreted by normal cells. With advanced immunologic techniques, tumor antigens are now identified using cytotoxic T Lymphocytes(CTLs) .CTLs are responsible for immune defence agains tumors and they identify proteins from class 1 major histocompatibility complex. CLASSES OF TUMOR ANTIGENS.MECHANISMS OF MENTIONED ATT ACTIVITY .Tumors can activate or suppress the immune system. They activate immune response by for example expressing foreign antigen with MHC .They suppress immune response by for instance activating T regulatory cells which release IL-10 and TGF B. The balance between activation and suppression indicate if a cancer has become clinically relevant. Presence of tumor cells and antigens initiate cytokine release such as interferon alpha. It consequently activates and stimulate maturation of dendritic cells which present the tumors to CD8 and CD4 cells. Under normal conditions T cytotoxic cells should destroy the tumor. Natural killer cells recognize oxygen reactive species produced by tumour cells. Cancer occurs because the tumor cells evade the immune surveillance and response. Tumors escape by induction of lymphocyte apoptosis, immune suppression by T regulatory cells, low immunogenicity and antigen modulation? Defects I mhc1 production mechanism makes cancer cells invisible to CD8 cells. The tumours can also escape immune response by selecting the resistant clones that have occurred due to genetic mutation.