Tumorigenesis from a pathological perspective : Tumor spread and epigenetically regulated genes in bladder cancer

Abstract

The article describes the tumorigenesis of bladder cancer from apathological 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 asingle tumor focus in nearly 2/3of 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 aclonal 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 aclonal relationship in bladder tumors remained inconclusive. We found indications for both theories but intraurothelial migration/seeding was more prominent.Afurther 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 aputative tumor suppressive role. Thus, epigenetic gene silencing is an additional mechanism of tumorigenesis especially in tumor progression.