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Prognostische Biomarker für das metastasierte kolorektale Karzinom

Prognostic biomarkers for metastatic colorectal cancer

  • Hauptreferate: Aktuelle Habilitationen
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Zusammenfassung

Fernmetastasen bestimmen beim kolorektalen Karzinom (KRK) wesentlich das Gesamtüberleben und die Prognose. Biomarker, die mit dem Auftreten von Fernmetastasen korrelieren, sind somit von großer klinischer Bedeutung für die Risikostratifizierung und die klinische Therapieentscheidung. Im Rahmen des Habilitationsprojekts wurden verschiedene prognostische Biomarker untersucht und mit dem Auftreten von Fernmetastasen sowie verschiedenen Mustern der Fernmetastasierung beim KRK korreliert.

Es konnte gezeigt werden, dass KRK mit Mikrosatelliteninstabilität (MSI), nachweisbar durch einen Verlust der hMLH1-Proteinexpression, ein sehr niedriges Fernmetastasierungsrisiko aufweisen. Im Gegenzug wiesen mikrosatellitenstabile (MSS) KRK (mit positiver hMLH1-Expression), Aktivierung des Wnt/β-catenin-Signalwegs und starker Expression des Krebsstammzellmarkers CD133 ein sehr hohes Risiko für Lebermetastasen auf. Aus diesen Beobachtungen konnte ein 2‑stufiger, auf 3 immunhistochemischen Färbungen basierender Algorithmus abgeleitet werden, mit dessen Hilfe KRK entsprechend ihres Fernmetastasierungsrisikos klassifiziert werden können. In weiteren Studien ließ sich nachweisen, dass eine Deregulation des Wnt/β-catenin-Signalwegs und die Expression von Krebsstammzellmarkern wie CD133 und CD44 mit einer hämatogenen Metastasierung in die Leber, aber nicht mit einer Peritonealkarzinose oder einer hämatogenen Metastasierung in das ZNS korrelieren. Bei KRK-Patienten mit ZNS-Metastasen fanden sich vermehrt Mutationen im MAPK-Pathway (KRAS- oder BRAF-Mutation) in Kombination mit einer niedrigen β‑catenin-Expression. Aus den Ergebnissen lässt sich schlussfolgern, dass beim KRK für die verschiedenen Muster der Fernmetastasierung unterschiedliche molekulare Mechanismen eine Rolle spielen müssen.

Abstract

In colorectal cancer (CRC) distant metastases essentially determine the overall survival and prognosis. Biomarkers that correlate with the presence of distant metastases are therefore of great clinical importance for risk stratification and clinical treatment decisions. As part of the habilitation project various prognostic biomarkers were analyzed and correlated with the occurrence of distant metastases and different patterns of distant spread in CRC. It could be demonstrated that CRC with microsatellite instability (MSI), as detected by a loss of hMLH1 protein expression, have a very low risk of distant metastases. In contrast, microsatellite stable (MSS) CRC (with positive hMLH1 expression) with concurrent activation of the Wnt-beta catenin signaling pathway and strong expression of the cancer stem cell marker CD133, exhibit a very high risk for liver metastases. From these observations a two-step immunohistochemical algorithm based on three immunohistochemical stains could be derived, allowing CRC to be classified according to the risk of distant metastases. Further studies demonstrated that a deregulation of the Wnt-beta catenin signaling pathway and the expression of cancer stem cell markers, such as CD133 and CD44 correlated with hematogenous metastasis to the liver but not with peritoneal carcinomatosis or hematogenous metastasis to the central nervous system (CNS). Finally, in CRC patients with CNS metastases, increased rates of mutations in the mitogen-activated protein kinases (MAPK) pathway (KRAS and BRAF mutations) in combination with a low beta catenin expression could be detected. It can be concluded from these results that for CRC with different patterns of distant spread alternative molecular mechanisms must play a role.

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Danksagung

Ich möchte mich bei meinem Mentor Prof. Dr. Thomas Kirchner für die kontinuierliche Förderung und Unterstützung während des Habilitationsprojekts herzlich bedanken. Zudem gilt mein Dank Prof. Dr. David Horst und Prof. Dr. Andreas Jung sowie meinen klinischen Kooperationspartnern Prof. Dr. Martin Angele, Prof. Dr. Jutta Engel, Prof. Dr. Volker Heinemann, Prof. Dr. Frank Kolligs und Dr. Marlies Michl für die stetige gute Zusammenarbeit.

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  1. Pathologisches Institut, Ludwig-Maximilians-Universität München, Thalkirchner Straße 36, 80337, München, Deutschland

    J. H. L. Neumann

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J. H. L. Neumann gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine vom Autor durchgeführten Studien an Menschen oder Tieren.

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Neumann, J.H.L. Prognostische Biomarker für das metastasierte kolorektale Karzinom. Pathologe 37 (Suppl 2), 180–185 (2016). https://doi.org/10.1007/s00292-016-0204-6

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