Presence of multidrug resistance and ER stress in a mouse model of hepatocellular carcinoma

Yves-Paul Vandewynckel Hans Van Vlierberghe Isabelle Colle
Persbericht

Presence of multidrug resistance and ER stress in a mouse model of hepatocellular carcinoma

Achilleshiel van tumoren ontdekt in leverkanker

Iedereen kent wel iemand in zijn omgeving die getroffen werd door kanker. Momenteel wordt voor de behandeling van kanker vooral chemotherapie gebruikt. Dit heeft echter vele bijwerkingen zoals haaruitval en misselijkheid. Ook is de verbetering van de levensverwachting door de huidige chemotherapie slechts beperkt. In een muismodel voor leverkanker is een nieuwe universele strategie ontdekt die de weg opent naar een innovatieve vorm van kankerbehandeling voor dit type, maar ook voor alle andere tumoren. Deze ondervinden door hun snelle groei een gebrek aan voedingstoffen en zuurstof. Ons mechanisme zorgt ervoor dat de tumorcellen zich kunnen aanpassen aan de stressvolle omstandigheden waarin ze moeten opgroeien. Wanneer we medicamenteus dit aanpassingsvermogen van de tumorcellen kunnen verminderen zullen specifiek de tumorcellen die deze stress ondervinden afsterven. Onafhankelijk van het kankertype en zelfs bij uitgezaaide kankers kan deze strategie soelaas bieden voor deze vreselijke ziekte.

Kanker is en blijft een zware diagnose. Iedereen kent wel iemand in zijn nabije omgeving die met deze verwoestende ziekte in contact is gekomen. Samen met de patiënten en hun familie blijven we hopen op een significante doorbraak. Kanker ontstaat door de ongebreidelde groei van cellen die op deze manier een gezwel vormen. Dit kan in bijna alle weefsels van het lichaam voorkomen. Sinds enkele jaren weten we dat tijdens de groei van een tumor de bestaande bloedvaten tekortschieten en de tumor via loslating van groeifactoren nieuwe bloedvaten probeert aan te leggen. (Fig. 1)  Deze zijn echter van mindere kwaliteit zijn als de bestaande en dit veroorzaakt een tekort aan zuurstof en suiker in de kern van de tumor. Het gezwel zal hierdoor stress ondervinden op celniveau. Niet de psychologische stress die eenieder onder ons wel eens ondervindt, maar wel een verstoring van de normale processen binnenin de cel, in dit geval een tumorcel.

Om te overleven moeten cellen eiwitten kunnen produceren. Dit productieproces bestaat uit verschillende stappen. Een belangrijke stap hierin is de opvouwing van de eiwitketens in de juiste vorm. In stressvolle omstandigheden zal het opvouwen moeizaam verlopen en ontstaan er meer onopgevouwen eiwitten. Ons lichaam probeert steeds het gezond evenwicht te herstellen. Ook op celniveau heeft de cel herstelmechanismen ontwikkeld om deze slechte eiwitten te verwijderen. Als de hoeveelheid aan schade echter te groot is om te herstellen, zal de cel beslissen om gecontroleerd in celdood te gaan, de  cel pleegt als het ware zelfmoord.

Door versterking van dit herstelmechanisme heeft de tumorcel zich echter gewapend om in deze stressvolle omstandigheden toch te kunnen overleven. Wanneer we medicamenteus dit herstel verminderen, kunnen we specifiek de cellen in ons lichaam die ernstige stress ondervinden doen afsterven. Men kan dit zien als een directe aanval op de Achilleshiel van de tumor. In een gezonde mens ondervinden de cellen geen ernstige stress en krijgen alle weefsels voldoende zuurstof en energie. Bij een kankerpatiënt zullen enkel de cellen in de gezwellen deze stress ondervinden en dit geeft ons een manier om alleen de kankercellen te behandelen zonder alle andere cellen schade te berokkenen zoals nu gebeurt met de huidige chemotherapie.

Onderzoek naar kanker kan meestal niet gebeuren op de patiënten zelf. Daarvoor gebruiken we muizen met bepaalde kankers. (Fig. 2) Leverkanker is wereldwijd het 3de belangrijkste type qua kankergerelateerde sterfte. In ons labo onderzoeken we muizen met leverkanker. Dit stelt ons in staat om theorieën en geneesmiddelen te testen op een ethisch verantwoorde manier. In dit onderzoek werd de theorie bevestigd dat onopgevouwen eiwitten aanwezig zijn in de levertumoren van de muizen. Ook werd er aangetoond dat de bovenvermelde herstelmechanismen geactiveerd zijn in de tumoren. Dit vormt de basis voor verder onderzoek naar een nieuwe behandeling via onderdrukking van deze mechanismen. Hierbij is het belangrijk te vermelden dat dit principe in feite niet alleen op levertumoren, maar op alle tumoren die snel groeien van toepassing is. Deze universele strategie biedt hoop aan het onderzoek naar kankerbehandelingen die de laatste decennia ondanks aanzienlijke budgetten slechts een beperkte toename aan levensverwachting heeft opgeleverd.

Het onderzoeksproject omvatte ook een luik om de aanwezigheid van resistentie in het diermodel aan te tonen. Resistentie aan chemotherapie is een majeur probleem in de kankerbehandeling, zeker in het geval van de levertumoren. Hierbij zag men onverwachts dat de muizen geen resistentiegenen vertoonden terwijl deze toch belangrijke rol spelen in de resistentie van leverkanker bij mensen.

Het slotstuk van het onderzoek was de innovatieve beeldvorming van de levertumoren in de muizen. Dit is tot stand gekomen door zelf specifieke antilichamen te merken met radioactiviteit en hiermee welbepaalde scans te doen. Dit is wereldwijd nog nooit gebeurd met dergelijke antilichamen. Deze spelen een rol in de bloedvatvorming en in het beschermingsmechanisme van de tumorcellen zoals hierboven beschreven. De resultaten hiervan worden momenteel door een team van experts verder geanalyseerd en zal later dit jaar worden gepubliceerd.

We kunnen concluderen dat dit resultaat hoop biedt aan de onderzoekers op dit vakgebied om eindelijk een nieuwe universele strategie voor kankerbehandeling te ontwikkelen. Het herstelmechanisme is enkel geactiveerd in de tumorcellen die door hun groei onder stress moeten overleven en dit maakt dat de gezonde cellen onbehandeld blijven waardoor de bijwerkingen van deze strategie waarschijnlijk beperkt zullen zijn. Deze theorie moet, zoals bij elk onderzoek, nog bevestigd worden in de praktijk, maar het snel stijgend aantal onderzoeksprojecten rond dit mechanisme zal dit proces zeker versnellen.

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Universiteit of Hogeschool
Geneeskunde - Inwendige ziekten
Publicatiejaar
2012
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