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Plastizität der WNT-Signalwegaktivität im Kolonkarzinom

Plasticity of WNT signaling activity in colorectal cancer

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Wiener klinisches Magazin Aims and scope

Zusammenfassung

Obwohl sich bei den meisten Kolonkarzinomen inaktivierende APC-Mutationen finden, zeigen diese Tumoren häufig eine heterogene Expression des WNT-Effektorproteins β-Catenin. Starke Expression im Zellkern findet sich hier oftmals nur an der Invasionsfront des Tumors. WNT-Reporterkonstrukte können verwendet werden, um solche Tumorzellen mit hoher WNT/β-Catenin-Aktivität, die gleichzeitig hohe Mengen putativer Tumorstammzellmarker exprimieren, aus den Karzinomen zu isolieren. Werden solche Tumorzellen jedoch in Xenotransplantationsexperimente eingesetzt, zeigen diese erstaunlicherweise keine wesentlich erhöhte Tumorigenität. Hohe WNT/β-Catenin-Aktivität ist also nicht generell mit Tumorstammzelleigenschaften gleichzusetzen. Stattdessen scheint die WNT/β-Catenin-Aktivität im Kolonkarzinom plastisch zu sein, da sowohl Tumorzellen mit hoher als auch mit niedriger WNT/β-Catenin-Aktivität neue Tumoren ausbilden können, die wiederum beide Populationen enthalten. Zudem kann die WNT/β-Catenin-Aktivität über den MAPK-Signalweg moduliert werden, was aufzeigt, wie andere Signalwege zur Plastizität der WNT-Signalwegaktivität im Kolonkarzinom beitragen können.

Abstract

Despite inactivating APC mutations, colorectal cancers express the WNT-effector protein β-catenin in a heterogeneous pattern, with strong nuclear expression confined to a fraction of tumor cells, often only at the tumor’s leading edge. WNT-reporter constructs allow separation of these tumor cells with highest WNT/β-Catenin activity, which also express high levels of several putative cancer stem cell antigens. Unexpectedly however, these cells do not show exclusive tumorigenicity in xenograft experiments, thus questioning their general stemness phenotype. Instead, there appears to be significant plasticity between both tumor cells with high and low WNT/β-Catenin activity because both cell types can form tumors which again show mixed populations. Furthermore, WNT/β-Catenin activity in colon cancer cells can be modulated by MAPK signaling thus revealing a means of how other signaling pathways contribute to WNT signaling plasticity in colon cancer.

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Danksagung

Ich danke insbesondere meinen klinisch-pathologischen und wissenschaftlichen Mentoren Herrn Prof. Dr. Thomas Kirchner, Herrn Prof. Dr. Andreas Jung und Herrn Prof. Dr. Ramesh Shivdasani für die umfassende Unterstützung meiner Arbeiten. Der Deutschen Forschungsgemeinschaft (DFG) danke ich für die finanzielle Förderung im Rahmen eines Forschungsstipendiums.

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  1. Medizinische Fakultät, Pathologisches Institut, Ludwig Maximilians Universität München, Thalkirchner Str. 36, 80337, München, Deutschland

    D. Horst

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Horst, D. Plastizität der WNT-Signalwegaktivität im Kolonkarzinom. Wien klin Mag 16, 28–31 (2013). https://doi.org/10.1007/s00740-013-0091-x

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  • DOI: https://doi.org/10.1007/s00740-013-0091-x

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