Bladder cancers arise from distinct urothelial sub-populations

Abstract

Bladder cancer is the sixth most common cancer in humans. This heterogeneous set of lesions including urothelial carcinoma (Uca) and squamous cell carcinoma (SCC) arise from the urothelium, a stratified epithelium composed of K5-expressing basal cells, intermediate cells and umbrella cells. Superficial Uca lesions are morphologically distinct and exhibit different clinical behaviours: carcinoma in situ (CIS) is a flat aggressive lesion, whereas papillary carcinomas are generally low-grade and non-invasive. Whether these distinct characteristics reflect different cell types of origin is unknown. Here we show using lineage tracing in a murine model of carcinogenesis that intermediate cells give rise primarily to papillary lesions, whereas K5-basal cells are likely progenitors of CIS, muscle-invasive lesions and SCC depending on the genetic background. Our results provide a cellular and genetic basis for the diversity in bladder cancer lesions and provide a possible explanation for their clinical and morphological differences.

Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges

“…Lineage tracing experiments in the murine model of carcinogenesis provide a cellular and genetic basis for the diversity in bladder cancer lesions which could be responsible for their clinical and morphological differences. According to the experimental results of this study, the low grade, non-invasive papillary lesions arise from intermediate cells whereas Keratin 5 expressing basal cells are likely the progenitors of flat carcinoma in situ, a flat aggressive lesion, as well as of muscleinvasive lesions depending on the genetic background [1] . A study by Dancik et al [4] screened 874 bladder cancer patients in five cohorts for the identification of UroCSCs in muscle invasive tumors and validated the hypothesis of differential origin of non-muscle invasive and muscle invasive tumors from distinct progenitor cells.…”

“…Urothelial carcinoma (UC) of the bladder, also known as transitional cell carcinoma of the bladder, is the sixth most common cause of cancer-related deaths worldwide [1] . It is the second most frequent cancer of the genitourinary tract where men are at four times greater risk than women.…”

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

“…11,12 However, the molecular pathways responsible for the evolution, outgrowth and progression of HG-NMIBC have not been subject to comprehensive study or investigation; indeed, it is currently unclear whether HG-NMIBCs arise as a discrete disease entity, whether they represent step-wise progression from low-intermediate-grade NMIBC tumors, or whether they sit at a molecular crossroads between NMIBC and MIBC. 7,11,13 This uncertainty is illustrated by the findings that high-grade tumors harbor abnormalities in common with low-intermediate-grade NMIBC, such as mutations of FGFR3 and/or rat sarcoma viral oncogene homolog (RAS) pathway genes, 14,15 but also display extensive genetic instability and compromised regulation of vital cellular processes more in keeping with MIBC. 14,16 Epigenetic modifications are frequently implicated in the development of human malignancies, and in these cases, are typically apparent as inappropriate gene promoter CpG island DNA methylation, histone tail modification(s), aberrant expression of micro-and long non-coding-RNAs and, less frequently, loss of gene body/intergenic methylation.…”

“…5,6 The majority of NMIBCs are thought to be consequent to, and represent initiation and progression from, a complex interplay between sporadic, environmental, and heritable risk factors, including those that impact upon genetic and epigenetic pathways. NMIBCs and muscle invasive bladder cancers (MIBCs) have been shown to develop independently ('the two pathway model') on the basis of gain of function fibroblast growth factor receptor 3 (FGFR3) mutations in NMIBC, and loss of function mutations in retinoblastoma 1 (RB1) and tumor protein 53 (p53) in MIBC, [7][8][9][10] and have been shown to evolve from different cell types. 11,12 However, the molecular pathways responsible for the evolution, outgrowth and progression of HG-NMIBC have not been subject to comprehensive study or investigation; indeed, it is currently unclear whether HG-NMIBCs arise as a discrete disease entity, whether they represent step-wise progression from low-intermediate-grade NMIBC tumors, or whether they sit at a molecular crossroads between NMIBC and MIBC.…”

“…NMIBCs and muscle invasive bladder cancers (MIBCs) have been shown to develop independently ('the two pathway model') on the basis of gain of function fibroblast growth factor receptor 3 (FGFR3) mutations in NMIBC, and loss of function mutations in retinoblastoma 1 (RB1) and tumor protein 53 (p53) in MIBC, [7][8][9][10] and have been shown to evolve from different cell types. 11,12 However, the molecular pathways responsible for the evolution, outgrowth and progression of HG-NMIBC have not been subject to comprehensive study or investigation; indeed, it is currently unclear whether HG-NMIBCs arise as a discrete disease entity, whether they represent step-wise progression from low-intermediate-grade NMIBC tumors, or whether they sit at a molecular crossroads between NMIBC and MIBC. 7,11,13 This uncertainty is illustrated by the findings that high-grade tumors harbor abnormalities in common with low-intermediate-grade NMIBC, such as mutations of FGFR3 and/or rat sarcoma viral oncogene homolog (RAS) pathway genes, 14,15 but also display extensive genetic instability and compromised regulation of vital cellular processes more in keeping with MIBC.…”