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Tumorgenese aus pathologischer Sicht

Tumorausbreitung und epigenetisch regulierte Gene beim Harnblasenkarzinom

Tumorigenesis from a pathological perspective

Tumor spread and epigenetically regulated genes in bladder cancer

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Zusammenfassung

Die vorliegende Arbeit betrachtet die Tumorgenese des Harnblasenkarzinoms auf drei dem Pathologen zugänglichen Ebenen: morphologisch, molekular- und epigenetisch. „Feldkanzerisierung“ und intraurotheliale Migration/Tumorzellseeding sind die wissenschaftlichen Haupthypothesen, welche das syn- und metachrone Auftreten multipler Tumoren im gesamten Harntrakt erklären sollen. In ausführlichen Zystektomiekartierungsstudien fanden wir in fast zwei Drittel aller Präparate ein unifokales Tumorgeschehen umgeben von einem tumornahen präinvasiven Carcinoma in situ. Weitere Untersuchungen mithilfe der TP53-Mutations- und Loss-of-heterozygosity-Analyse an ausgewählten Fällen sprechen für eine klonale Verwandtschaft der Tumorläsionen. In-situ-lineage-tracing via Cytochrom-C-Oxidase/Succinatdehydrogenase-Enzymhistochemie mit nachgeschalteter mitochondrialer DNA-Mutationsanalyse zum definitiven Klonalitätsnachweis blieb bei Harnblasentumoren inkonklusiv. Insgesamt fanden sich Hinweise auf beide Ausbreitungstheorien, wobei jedoch die intraurotheliale Migration/Tumorzellseeding den mengenmäßig größeren Anteil darstellt.

Ein weiterer Tumorgenesemechanismus ist die Inaktivierung von Genen durch epigenetische DNA-Methylierung. Wir analysierten die DNA-Methylierung von verschiedenen Genen, welche in RNA-Expressionsanalysen des Harnblasenkarzinoms herabreguliert waren. Dabei war insbesondere epigenetisch inaktiviertes ITIH5 mit einem frühen Rezidiv in pT1 High grade-Tumoren vergesellschaftet und zeigte funktionell einen forcierten invasiv-metastatischen Phänotyp, was eine initial tumorsuppressive Rolle nahelegt. Die epigenetische Gen-Inaktivierung stellt damit einen weiteren Tumorgenesemechanismus v. a. in der Progression der Erkrankung dar.

Abstract

The article describes the tumorigenesis of bladder cancer from a pathological perspective in three dimensions: morphology, genetics and epigenetics. Field cancerization and tumor cell migration/seeding are the two main hypotheses used for explaining synchronous and metachronous tumors in the urinary tract. By detailed histological mapping of completely embedded cystectomy specimens we found a single tumor focus in nearly 2/3 of the bladders accompanied by surrounding preinvasive carcinoma in situ. We substantiated our findings by studies analyzing TP53 mutations and loss of heterozygosity in various tumor sites. Identical TP53 mutations suggested a clonal relationship of the tumor foci. In situ lineage tracing via cytochrome C oxidase and succinate dehydrogenase enzyme histochemistry and subsequent mitochondrial DNA mutation analysis for definitive evidence of a clonal relationship in bladder tumors remained inconclusive. We found indications for both theories but intraurothelial migration/seeding was more prominent.

A further mechanism in tumorigenesis is gene inactivation by epigenetic DNA methylation. We analyzed DNA methylation of various genes, which had previously been found by RNA expression analysis to be downregulated in bladder cancer. Most importantly, epigenetically silenced ITIH5 was associated with early relapse in pT1 high grade tumors and functionally showed an enhanced invasive metastatic phenotype in tumor cells, suggesting a putative tumor suppressive role. Thus, epigenetic gene silencing is an additional mechanism of tumorigenesis especially in tumor progression.

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Danksagung

Besonderer Dank gilt Dr. rer. nat. Michael Rose, der die zahlreichen Experimente zur DNA-Methylierung im Rahmen seiner Promotion durchgeführt hat. Weiterhin bedanke ich mich bei Frau Prof. Knüchel-Clarke für die Förderung und Möglichkeit zur Habilitation sowie bei Prof. Dr. rer. nat. Dahl (AG Molekulare Onkologie, Institut für Pathologie RWTH Aachen) für die Unterstützung. Zudem danke ich allen Mitarbeiter(-innen) und Kooperationspartnern, die an den zahlreichen Experimenten beteiligt waren.

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  1. Institut für Pathologie, Uniklinik RWTH Aachen, Pauwelsstr. 30, 52074, Aachen, Deutschland

    N. T. Gaisa

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N.T. Gaisa gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren. Es wurde anonymisiert retrospektiv menschliches Gewebe untersucht, welches im Rahmen von Routinehistologischen Untersuchungen oder im Rahmen des Biobankings archiviert wurde. Positive Stellungnahmen der Ethikkommission zu den einzelnen Projekten liegen vor (RWTH EK 122/04, 173/06, 206/09, 76/10).

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Gaisa, N.T. Tumorgenese aus pathologischer Sicht. Pathologe 37 (Suppl 2), 196–203 (2016). https://doi.org/10.1007/s00292-016-0207-3

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