The effect of hypoxia on epithelial-to-mesenchymal transition and microbiome composition in the invertebrate model organism Daphnia magna

Emile Clappaert
Het uitzaaien van kankercellen in het lichaam van de patiënt gaat nog steeds gepaard met een lage levensverwachting. Eén van de eerste stappen is het loskomen van de cellen uit de tumor (de epitheliale-naar-mesenchymale transitie) en wordt vaak geactiveerd door het gebrek aan zuurstof (hypoxie). Omdat een goed modelorganisme om deze transitie te bestuderen ontbreekt, introduceren we hier Daphnia magna, een invertebrate kreeftachtige, als nieuw model in kankeronderzoek.

Watervlooien als nieuwe proefdieren in de strijd tegen kanker?

‘Een wat?’ Bij de meeste mensen aan wie ik mijn thesisonderwerp uit de doeken doe, komt deze vraag als eerste naar boven. ‘Een watervlo’, vertel ik dan, ‘is een kleine kreeftachtige die in zoet water voorkomt en leeft van algen en andere voedingsstoffen die het uit het water filtert.’ Met zijn ene oog, antennen en ietwat plompe lichaamsbouw heeft het niet meteen een hoge aaibaarheidsfactor. Toch kan dit kleine waterorganisme een rol spelen in toekomstig kankeronderzoek en het gebruik van andere proefdieren zoals muizen verminderen.

Watervlooi

Uitzaaien om te overleven

Kankercellen zijn echte energieverslinders. Energie die ze nodig hebben om hun snelle celgroei te kunnen volhouden. Om in hun grote vraag naar energie te kunnen voorzien worden grote hoeveelheden zuurstof en voedingsstoffen via het bloed aangeleverd naar de tumor. Hiervoor kan de tumor zelfs zijn eigen bloedvatenstelsel vormen door bloedvatcellen aan te trekken. Deze bloedvaten zijn echter slecht gemaakt en zullen slechts een klein deel van de tumor van bloed voorzien. Daarom blijven grote delen achter zonder voldoende energietoevoer. Door de stress die dit tekort veroorzaakt zullen de kankercellen zich genoodzaakt zien de originele tumor te verlaten en zich op andere voedselrijke plaatsen in het lichaam te vestigen. Dit kolonisatieproces wordt het uitzaaien van de tumor of metastase genoemd. Dit gaat vandaag nog steeds gepaard met een lage levensverwachting voor de patiënt. Daarom is het heel belangrijk om het mechanisme achter de uitzaaiingen te begrijpen om op die manier het proces te kunnen tegenhouden.

Eén van de eerste stappen waarbij de kankercellen zich losmaken van de originele tumor is het zich omvormen van een stevig verankerde of epitheliale kankercel naar een losse, zich vrij voortbewegende of mesenchymale kankercel. Deze overgang wordt de epitheliale-naar-mesenchymale transitie (EMT) genoemd en is een geconserveerd en omkeerbaar biologisch proces. In normale omstandigheden komt dit enkel voor tijdens de ontwikkeling van het embryo om de juiste cellen op de juiste plaats in het lichaam te krijgen. Daarnaast komt het ook voor tijdens het genezen van een wonde, waarbij de omliggende cellen zich reorganiseren om de wonde te dichten. Bij kanker zal dit proces echter misbruikt worden, geactiveerd door een hele reeks factoren zoals zuurstofgebrek, toxische stoffen of groeifactoren.

Proces

Nood aan een goed proefdier

Tot op vandaag zijn de experimenten op EMT in modelorganismen (in vivo) schaars en werden ze voornamelijk uitgevoerd in celculturen (in vitro). Omdat een goed in vivo model voor EMT nog steeds ontbreekt, introduceerden we in het labo de watervlo (Daphnia magna). Dit zoetwaterschaaldier wordt al decennialang gebruikt in ecologisch onderzoek en veroverde recent ook zijn plaats in het biomedische veld. De voordelen van Daphnia, zoals hun korte levenscyclus, vele nakomelingen, ongeslachtelijke voortplanting en het ontbreken van ethische beperkingen, maken het gebruik ervan interessant in kankeronderzoek. Indien we erin slagen om Daphnia als testorganisme op de biomedische wereldkaart te zetten, zou dit kunnen leiden tot het verminderen van het gebruik van gewervelde dieren zoals muizen, ratten en konijnen.

Watervlooien op hoogtestage

In mijn masterthesis werden twee experimenten uitgevoerd om EMT uit te lokken in Daphnia. In het eerste stelden we de watervlooien bloot aan een laag zuurstofgehalte om de zuurstofarme situatie in de tumor na te bootsen. Deze blootstelling leidde tot de productie van hemoglobine, een molecule dat de zuurstofopname verhoogt, waardoor onze watervlooien rood kleurden. Dit is vergelijkbaar met de verhoogde aanmaak van rode bloedcellen tijdens hoogtestages van topsporters, waar er ook minder zuurstof beschikbaar is. Tijdens het tweede experiment testten we de effecten van toxische stoffen op het activeren van EMT in Daphnia. Hiervoor voegden we toxische ééncellige algen toe, Microcystis aeruginosa. Deze algen produceren een krachtig gif, microcystine, dat al eerder in celculturen EMT heeft kunnen uitlokken.

Op vaste tijdstippen werd nagegaan of bepaalde EMT-gelinkte genen meer of minder werden geactiveerd in Daphnia. Een éénduidig resultaat werd hiervoor niet gevonden maar het lijkt erop te wijzen dat EMT niet voorkomt in Daphnia noch onder invloed van zuurstofgebrek noch door het toxische microcystine. Om die reden introduceren we de hypothese dat deze zoetwaterorganismen waarschijnlijk een beschermingsmechanisme hebben ontwikkeld dat EMT tegengaat. Dit kan te wijten zijn aan het feit dat de watervlooien ook in de natuur aan beide omstandigheden worden blootgesteld. Evolutionair gezien zou het best kunnen dat er een mechanisme is ontstaan dat de watervlooien beschermt tegen de schadelijke effecten die door deze condities worden uitgelokt. Verder onderzoek zal moeten uitwijzen op welke manier de watervlooien zich beschermen tegen het voorkomen van EMT. Dit zou zelfs kunnen leiden tot bevindingen die ons verder kunnen helpen in het ontwikkelen van therapieën tegen EMT en kankeruitzaaiingen. Dat is echter nog verre toekomstmuziek.

Hulp uit onverwachte hoek?

Ten slotte voerden we ook een kleinschalig experiment uit om de invloed van zuurstofgebrek op de samenstelling van de darmbacteriën of het microbioom in de Daphnia te onderzoeken. Darmbacteriën zijn vandaag een 'hot topic' in de geneeskunde en het is mogelijk dat het microbioom een rol speelde in de waargenomen bescherming tegen zuurstofgebrek in de watervlo. Na twee weken blootstelling aan lage zuurstofgehaltes werd er een duidelijke verschuiving waargenomen in de soortensamenstelling van de verzameling bacteriën in de darmen van de Daphnia. Een grootschalige studie op langere termijn is echter vereist om meer resultaten te krijgen van de invloed van de lage zuurstofgehaltes op de samenstelling van de bacteriën.

Hoe Daphnia zich kan wapenen tegen de activatie van EMT onder invloed van zuurstofgebrek en het toxische microcystine, is de vraag waarmee ik mijn thesis afsluit. Toekomstig onderzoek, waarbij een eventuele rol van de darmbacteriën wordt overwogen, zal hopelijk meer uitsluitsel brengen omtrent deze interessante observatie. Hoewel er zich nog veel vragen aandienen en nog veel verder onderzoek vereist is, kan er toch worden geconcludeerd dat de kleine Daphnia magna een rol kan spelen in toekomstig kankeronderzoek.

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Universiteit of Hogeschool
Biologie
Publicatiejaar
2017
Promotor(en)
Ellen Decaestecker
Kernwoorden
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