Unveiling the characteristics of cancer-testis antigen MAGEA10
Date
2024-01-16
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Abstract
Vähk on tänapäeval üks juhtivatest surmapõhjustest ning seetõttu otsitakse pidevalt efektiivsemaid ja kahjutumaid viise selle raviks. Praegu laialdaselt kasutusel olevad ravimeetodid ei erista vähkkasvajat ümbritsevatest kudedest ning seetõttu kannatavad patsiendid raskete kõrvalmõjude all. Järjest enam proovitakse leida raviviise, mis mõjuksid vaid vähirakkudele, vähendades seega oluliselt ravi kõrvalmõjusid. Immunoteraapia on üks paljulubavamaid uusi lähenemisi vähiravis ning selle juures on oluline koht vähi-testise antigeenidel. Vähi-testise antigeenid on valgud, mida kodeerivad geenid on enamikes normaalsetes kudedes vaigistatud, kuid vähirakkudes lülitatakse nende valkude tootmine taas sisse. Lisaks on vähi-testise antigeenid võimelised kehas esile kutsuma immuunvastuseid ning seega on tegemist väga heade immunoteraapia sihtmärkide kandidaatidega. Üks tuntumaid vähi-testise antigeenide perekondi on MAGEA (melanoomi-seoseline antigeen A), mille mitmed liikmed kutsuvad esile tugevaid immuunvastuseid ning mida leidub paljudes erinevates vähkkasvajates. Antud doktoritöö fookuses on valk MAGEA10, mille puhul on eelnevalt täheldatud väga tugevaid immuunvastuseid, mille tõttu saaks seda valku kasutada immunoteraapias. Uuriti lähemalt valgu erinevaid osi, mõistmaks, millised regioonid mõjutavad eri omadusi. Kinnitati, et järjestus, mis suunab valgu rakutuuma, sisaldub MAGEA10 esimeses 14-s aminohappejäägis ning esimesed 120 aminohappejääki sisaldavad endas põhjust, miks valgu arvutuslik ja katseline suurus ei ühti. Lisaks kinnitati, et MAGEA10 ja teine perekonnaliige MAGEA4 väljuvad rakust ekstratsellulaarsete vesiikulite (EV) koosseisus, kinnitudes sealjuures tugevalt osakeste pinnale. See tähendab, et MAGEA valgud saavad rakust väljudes interakteeruda rakuvälise keskkonnaga ning seetõttu saaks neid kasutada ka vähi diagnostikas. Kokkuvõttes, antud doktoritöö aitab paremini mõista MAGEA10 omadusi, lihtsustamaks selle kasutamist vähi diagnostikas ja ravis.
Cancer is one of the leading causes of death in the modern world and thus a search for more effective and less harmful treatments is constantly ongoing. The therapeutic approaches widely used do not differentiate between cancerous and normal tissues and therefore patients suffer a myriad of side effects. Therapeutic approaches, such as immunotherapy, which specifically target cancer cells are being developed constantly to minimise the possibilities of adverse side effects. An important part of these new treatment options is finding tumour-specific targets, such as cancer-testis antigens (CTA). CTAs are proteins which are not produced in most normal tissues but reemerge in cancer cells. As well as being cancer-specific, CTAs are also able to induce immune responses in patients. These qualities make CTAs perfect candidates for usage as diagnostic markers and immunotherapeutic targets. A well-known group of CTAs is the MAGEA (melanoma-associated antigen A) family. Multiple MAGEA proteins are present in a wide array of cancers and elicit immune responses in patients. This dissertation focuses on the MAGEA10 protein, which is known for evoking very strong immune responses and can therefore be highly useful in cancer immunotherapy. Different regions of MAGEA10 were studied to find out, which parts may be responsible for its many characteristics. It was determined that the sequence directing the protein into the cell nucleus resides within the first 14 amino acid residues and that the first 120 residues are responsible for the fact that MAGEA10’s computational and experimental weights do not align. It was also determined that MAGEA10 and MAGEA4, another family member exit cells via extracellular vesicles (EVs) and strongly attach to the particles’ surface. This suggests that MAGEA proteins are able to interact with the extracellular environment after leaving the cell, implying a possibility for using them in diagnostics. In conclusion, this dissertation helps to understand the characteristics of MAGEA10, so that it could be utilised in cancer diagnostics and treatment.
Cancer is one of the leading causes of death in the modern world and thus a search for more effective and less harmful treatments is constantly ongoing. The therapeutic approaches widely used do not differentiate between cancerous and normal tissues and therefore patients suffer a myriad of side effects. Therapeutic approaches, such as immunotherapy, which specifically target cancer cells are being developed constantly to minimise the possibilities of adverse side effects. An important part of these new treatment options is finding tumour-specific targets, such as cancer-testis antigens (CTA). CTAs are proteins which are not produced in most normal tissues but reemerge in cancer cells. As well as being cancer-specific, CTAs are also able to induce immune responses in patients. These qualities make CTAs perfect candidates for usage as diagnostic markers and immunotherapeutic targets. A well-known group of CTAs is the MAGEA (melanoma-associated antigen A) family. Multiple MAGEA proteins are present in a wide array of cancers and elicit immune responses in patients. This dissertation focuses on the MAGEA10 protein, which is known for evoking very strong immune responses and can therefore be highly useful in cancer immunotherapy. Different regions of MAGEA10 were studied to find out, which parts may be responsible for its many characteristics. It was determined that the sequence directing the protein into the cell nucleus resides within the first 14 amino acid residues and that the first 120 residues are responsible for the fact that MAGEA10’s computational and experimental weights do not align. It was also determined that MAGEA10 and MAGEA4, another family member exit cells via extracellular vesicles (EVs) and strongly attach to the particles’ surface. This suggests that MAGEA proteins are able to interact with the extracellular environment after leaving the cell, implying a possibility for using them in diagnostics. In conclusion, this dissertation helps to understand the characteristics of MAGEA10, so that it could be utilised in cancer diagnostics and treatment.
Description
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Keywords
vähk (meditsiin), rakuvälised vesiikulid, immuunvastus, biomarkerid, immuunravi, molekulaarne biotehnoloogia, cancer (medicine), extracellular vesicles, immune response, biochemical markers, immunotherapy, molecular biotechnology