Cancer Testis Antigens and Meiosis - Literature review Example

Cancer Testis Antigens Cancer Testis Antigens and Meiosis What are cancer testis antigens? They are antigens connected with tumors. They are usually depicted and present in placenta and testis. Sertoli and Leydig cells are tubular cells which do not express CTA. An example is MAGE – A, its depiction starts in primary spermatogonia and spermatocytes. Another example is SCP- 1, its depiction starts in zygotene and diplotene spermatocytes (Pastorcic-Grgic, et al., 2010). CTA has tumor-restricted pattern of expression in male germ cells in the testis in the early phases of spermatogenesis along with their strong in vivo immunogenicity. The antigen HOM-TES-14 which is repeatedly encountered during CDNA expression library is encoded by the SCP-1 gene, which is mainly expressed during prophase of mitosis in spermatocytes and involved in homologous chromosomes pairing therefore is less restricted in its expression. CTA is expressed less in non-seminomatous germ cell tumors than seminomas germ cell tumors (Chen, et al., 2013). There are CTA that are encoded on the X-chromosome called the X-CTA genes and those that are not referred to as non-CTA genes. More than half of all CTA are X-CTA and often constitute multi-gene families organized in well-defined clusters along the X-chromosome where different members are arranged into complex direct and inverted repeats. The genes encoding non-X-CT antigens are distributed throughout the genome and are mostly single copies (Cheng, et al., 2011). The X-CTA genes are expressed basically on the spermatogonia that are proliferating germ cells while non-X-CTA are expressed in the late stages of differentiation such as spermatogenesis in the normal testis. MAGE-A3, MAGE-8, MAGE-A10, XAGE-2 and XAGE-3 have been found to be expressed in the placenta in addition to testicular expression. The CTAs have different functions as various CTAs are expressed during different stages of spermatogenesis (Fratta, et al., 2011). In tumors of diverse histotypes, CTAs are largely distributed. Among various kinds of tumors, CTA varies and is depicted by data from the evaluation of its transcripts (Fratta, et al., 2011). The division of cells resulting to nuclei whereby the total chromosome number is reduced by a half its original number is termed as meiosis. The nuclei that arise from the parent nuclei are normally same as the parent nuclei but they genetic makeup is normally different. This is because genetic diversity is permitted during reproduction. Meiosis is composed of two phases, Meiosis I and II. It is through these stages that meiosis gives rise to 4 nuclei. Each of these nuclei has one set of chromosomes that usually have not undergone replication. This is because of the division of 1 nucleus that has 2 chromosome sets (Fratta, et al., 2011). Pre-meiosis occurs before the commencement of meiosis. This interface is divided into four stages. First, the cell mass is increased in G1 phase. DNA is synthesized in the S phase, which is then followed by G2 phase then the prophase. When DNA gets replicated, nucleoli get surrounded by a clear envelop and chromosomes get duplicated to form chromatin structure. In animal cells, two pairs of centrioles are involved (Ding, et al., 2010). Meiosis I is the initial stage of prophase I. Condensation of chromosomes occurs during the leptotene stage. Homologous chromosomes organize to form tetrads during Synapsis in the pachytene stage. Sister chromatids of homologous chromosomes pair and twist around each other at the site of crossing over which is called chiasmata. In this process, DNA content is exchanged between the homologous chromosomes. Sister chromatids get attached to one another during prophase I. Prophase I is categorized into leptotene, zygotene, pachytene and diplotene. Recombination is initiated during leptotene by breaking coils of DNA strands at various sites. The homologous approach each other and attach through synapsis during the zygotene stage. Synaptonemal complex protein, which is clustered along homologs gets accumulated during the pachytene stage is involved in synapse and connects homologous chromosomes along their entire lengths. It is during diakinesis that further obstruction occurs after bivalents begin to detach during diplotene (Ding, et al., 2010). The proces of meiosis II consists of 4 steps. These steps are prophase II, metaphase II, anaphase II and telophase II. Prophase II is characterised by the vanishing of nuclei, thickening and shortening ofchromatids. Spindle fibres are formed after centrioles have moved to the end poles. In metaphase II, Kinetochores which are joined to the spindle fibres aid in arrange the centromerese in a line. In anaphase II, the aligned centromeres disengage allowing for microtubules to pull sister chromatids. During telophase II, chromosomes increase in length and unfold. Four daughter cells, each containing a haploid number of chromosomes are produced during Meiosis II (Ding, et al., 2010). Recombination allows genetic diversity in organisms with sexual reproduction. It occurs through the pairing of chromosomes and crossing over. The non-sister chromatids cross-over during diplotene phase where the chromosomes join at the chiasmata (Koszul, et al., 2012). Several stages are involved in either exchange or no exchange of flanking markers. CTA genes and Topoisomerase have a significant relation as they are expressed by germ cells. Removal of Spo11 and DNA repair executed by Mer11 enzyme and is done is after cutting 12 DNA. Mer11 complex containing the mer11 protein whose function is to checking expression recombination, regulates DNA damage. Development of cancer would be caused by mutations in the gene. Exonuclease degrades DNA strands to form 3’ single strand overhang RAD51, RAD 52, and RPA are involved in mediating the invasion of strands. The process is followed by cutting of holiday junction leading to crossover or no-crossover (Szekvolgyi & Nicolas, 2010). Double strand break (DSB) of DNA formation is important for the subsequent recombination of homologous chromosomes. Recombination between homologous chromosomes generates and heals DSBs in meiosis. DSB-dependent or DSB-independent mechanisms enable pairing and Synapsis of homologous chromosomes. DSBs are induced by Trans esterase SPO1, a CTA under regulatory control by the ATM (ataxia telangiectasia mutated) kinase. RAD51 and DMC1 initiate alignment with homologs (Cole, et al., 2012). Synaptoneal complex permits for the association of homologs. It is a protein that is made up of a multi protein structure. It enhances interaction of sister chromatids. It also enhances repairing of DSB. The synaptoneal complex is composed of various components which include, SYCP1, SYCE1 and HORMAD1. Each of these components have unique importances. SYCP1 is important for the repairing of DSB. SYCE1 is needed for the sysnthesis of synaptonemal complex while lack of HORMAD1 causes flaws in the synthesis of synapses and also in recombination. Proteins such as RAD51 are DSB repair proteins which are packed onto DNA hence enhancing repair of DSB. This process is mediated by CTA TEX15 (Whitehurst, 2014). The X chromosome holds many cancer testis genes that are utilised in immunotherapy. Cancer X genes synthesis gene families that are associated with inverted DNA repeats (Whitehurst, 2014). CTAs in cancer therapy (immunotherapy) Cytotoxic T lympocytes recognize cancer Testis antigens as immunogens. Peripheral blood of a healthy donor synthesis Sp17 specific HLA – A1 and B27 limited cytotoxic T lymphocytes. These lymphocytes are able to destroy HLA – matched myeloma cells.Cytotoxic T cell cloning identify MAGE – A1 and – A3. SSX is identified by SEREX. They alll depict directed cell and humoral mediated reactions. The screening of overlieing peptide panels with CD4+ T cells obtained from peripheral blood enables the evaluation of T – cell reactions to CT antigens (Caballero & Chen, 2009). For antigen specific immunotherapy, cancer testis antigens are usually vital antigen – specific aims. The blood testis barrier in the testis allows for therecognition of foreign and self proteins by the immune sytem during the intitialization of spermatogenesis. This indicates that sperm cells found in the testis do not start immune reactions. Antigen presenting cells in the interstitial cells are usually visible in comparison to seminiferous tubules. Hence, the testis as an organ is adavantaged in terms of immunity. Hence, testis specific genes shown in cancers may be immunogenic (Shechter, et al., 2013). CTAs do not have leukocyte antigen class I expression on the surface of germ cells. It is important in making the testis an organ that is advantaged in terms of immunity. Hence, it is usually targeted for immunotherapy purposes (Ghafouri-fared & Modarressi, 2009). For adoptive immunotherapy, HLA – restricted T – cell epitopes like MAGE – A, and SSX genes are normally vital (Ghafouri-fared & Modarressi, 2009). The suitable target antigens are important for there to be a successful development of antigen – particulate immunotherapy. The first group of antigens has been availed by discovery and characterization of CTAs. It can be utilised in several epithelial cancers (Caballero & Chen, 2009). Expression of the CTA gene is limited to gametes, cancer and trophoblastic cells. Expression of the CTA gene is normally enhanced by an inhibitor like DNA methyl – transferase 1 inhibotor and 5DC. Epigenetic and non – epigenetic mechanisms regulate expression of CTAs. CTA activity is reduced by over methylanation. De – mythelating agents enhances CTA expression. CTA is reduced by histone deacetylases. Histone deacetylas inhibotoras enhance CTA activation (Rao, et al., 2011). What do non – epigenetic mechanisms encompass? They encompass transcription factors that are sequence specific. They also include common pathways such as triggered tyrosine kinases. Further studies on CTA expression could direct the production of synergistic tactics that may help in combating residual diseases (Podberezin, et al., 2013). Cancer immunotherapy (vaccines) The ever advancing knowledge in tumor antigens has enabled production of vaccines in various kinds such as proteins, peptides or genetic constructs. This is not the case in more advanced forms of melanomas where no efficient antigen particulate cancer vaccine has been made. Cancer limited arrangement of tissue allotment, availability for vaccine formulation and immunogenicity determine the selection of an antigen for a vaccine. CTAs are limited to the organization and disrtribution of tisseus which is restricted to cancerous tissue and the placenta (Cebon, 2010). Because of the immunogenecity of CTAs, manufacture of vaccines for haematological malignancies is now acheivable. Cytotoxic T lymphocytes like NY – ESO – 1 and Sp17 are some of the kind of lymphocytes that CTAs are immunogenic to. These lymphocytes can destroy autologous tumuor cells (Aruga, et al., 2013). The precedence list of targets for cancer vaccines includes many CTAs like SSX1, NY – ESO1 and MAGEA1. Encoded antigens like NY – ESO – 1 and MAGEA3 are the main targets of clinical trials. MAGRIT has been clinically tried. Its starting trials have shjown that its vaccine, MAGEA3, is well put up with. It stimulated a certain T cell reaction and hindered growth of tumors in several patients. Clinical trials of NY – ESO1 show that the vaccine is also tolerated (Whitehurst, 2014). A form of vaccination that showed good toleration and several clinical advantages to several patients in biliary tract cancer is the four – peptide vaccination (Whitehurst, 2014). Deterioration of independent tumor nodules have resulted from the administration of both peptide vaccines. This is inclusive of instantaneous deterioration in melanoma patients. Wider spectrums are of CD4+ and CD8+ responses from the immune system are as a result of recombinant protein vaccines. These vacceine types are appropriate for large population of patients due to their unrestrictivity. They are unrestrictive to HLA patient types (Ferrucci, et al., 2012). Various forms of the NY – ESO – 1 proein vaccines like ISCOMATRIX are some of the vaccines that are being evaluated. ISCOMATRIX is a combination of NY – ESO -1 and cholesterol- bearing hydrophobised pullulan. Utilization of bacterial vectors or naked plasmids has enabled the evaluation of chances of generating NY – ESO – 1 protein in vivo through the use of DNA vaccine constructs (Caballero & Chen, 2009). The CTAs are able to elicit cellular and humoral responses therefore leading directly to the of antigen specific cancer vaccines development. NY-ESO-1 peptide, protein and pox-NY-ESO-1 vaccines can induce strong NY-ESO-1 humoral and cellular responses in patients with no pre-existing NY-ESO-1 immunity. The field of developing antigen-specific cancer vaccine is in early steps (Karbach, et al., 2010). Future aspects of cancer testis antigen Findings indicate that expression of CTAs often depict marked specificity for tumor cells. For early detection and target specific gene therapy or treatment of cancer, the tumor markers are used to target tumors. Immune privilege of testis and concept of testis specific genes, which are expressed in various cancers, can provide leads to further development of tumor vaccines (Ghafouri-fared & Modarressi, 2009). In the near future, active immunotherapy will become available. Presently, development of active immunotherapy is still in a pre-clinical and clinical trial phase. To provide tools for active immunotherapy, knowledge in CTAs should be encouraged and their ability to elicit cellular and humoral responses. On development of vaccine-based clinical trials, cancer-testis antigens are targets for cancer immunotherapy. In addition, future fights against cancer will depend on applications of the review of immunological aspects of conventional cancer treatments (Ghafouri-fared & Modarressi, 2009). DNA/RNA analyses can fail to detect changes in the tumoral cells that are caused by post-translational modifications. Studies based on proteomics are underway and new biomarkers for cancers can be identified through detection of any modifications of CTAs at the protein level in the cells with tumors when compared with normal cells. This will be an important future aspect of cancer testis antigens (Ghafouri-fared & Modarressi, 2009). In the future, the role of CTAs will be explored as it has proven to be important in adoptive T-cell transfer approaches and in immunotherapeutic approach that are non-specific, aimed to explore CTLA-4 checkpoint (Caballero & Chen, 2009). To evolve cancer treatment strategies CTAs with potent activity in tumor cells need to be identified and methods to exploit these dependencies developed. Exploration of the currently known role and potential of CTAs in lung cancer would help improve the cure, rate of this tumor (Chiriva-Internati, et al., 2012). References Aruga, A. et al., 2013. 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Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nature Reviews Immunology , Volume 13, pp. 206-218. Szekvolgyi, L. & Nicolas, A., 2010. From meiosis to postmeiotic events: Homologous recombination is obligatory but flexible. FEBS Journal, 277(3), pp. 571-589. Whitehurst, A. W., 2014. Cause and Consequence of Cancer/Testis Antigen Activation in Cancer. Annual Review of Pharmacology and Toxicology, Volume 54, pp. 251-272. Read More