TY - JOUR
T1 - Origins of Bladder Cancer
AU - Czerniak, Bogdan
AU - Dinney, Colin
AU - McConkey, David
N1 - Publisher Copyright:
© 2016 by Annual Reviews. All rights reserved.
PY - 2016/5/23
Y1 - 2016/5/23
N2 - Bladder cancer, one of the most frequently occurring human cancers, develops via two tracks referred to as papillary and nonpapillary that correspond to clinically different forms of the disease. Most bladder cancers are chemically induced, with tobacco smoking being the leading risk factor. Recent advances in bladder cancer research have enhanced our understanding of the origin of this disease from urothelial progenitor cells via field effects along papillary-luminal and nonpapillary-basal pathways. Evident from the outset of the disease, the diversity of the luminal and basal pathways, together with cell lineage tracing studies, postulates the origin of molecularly distinct subtypes from different uroprogenitor cells. The molecular mechanisms initiating field effects involve a new class of genes referred to as forerunner (FR) genes that generally map around major tumor suppressors such as RB1. These genes are silenced, predominantly by hypermethylation and less frequently by mutations, and drive the expansion of intraurothelial preneoplastic cells. Different FR genes are involved in various molecular subtypes of bladder cancer and they sensitize the uroprogenitor cells to the development of luminal and basal bladder cancers in animal models. In human bladder cancer, luminal and basal forms have dissimilar clinical behavior and response to conventional and targeted chemotherapeutic manipulations. These new research developments hold the promise of expanding our armamentarium of diagnostic and treatment options for patients with bladder cancer and improving our ability to select patients most likely to respond to a specific therapy.
AB - Bladder cancer, one of the most frequently occurring human cancers, develops via two tracks referred to as papillary and nonpapillary that correspond to clinically different forms of the disease. Most bladder cancers are chemically induced, with tobacco smoking being the leading risk factor. Recent advances in bladder cancer research have enhanced our understanding of the origin of this disease from urothelial progenitor cells via field effects along papillary-luminal and nonpapillary-basal pathways. Evident from the outset of the disease, the diversity of the luminal and basal pathways, together with cell lineage tracing studies, postulates the origin of molecularly distinct subtypes from different uroprogenitor cells. The molecular mechanisms initiating field effects involve a new class of genes referred to as forerunner (FR) genes that generally map around major tumor suppressors such as RB1. These genes are silenced, predominantly by hypermethylation and less frequently by mutations, and drive the expansion of intraurothelial preneoplastic cells. Different FR genes are involved in various molecular subtypes of bladder cancer and they sensitize the uroprogenitor cells to the development of luminal and basal bladder cancers in animal models. In human bladder cancer, luminal and basal forms have dissimilar clinical behavior and response to conventional and targeted chemotherapeutic manipulations. These new research developments hold the promise of expanding our armamentarium of diagnostic and treatment options for patients with bladder cancer and improving our ability to select patients most likely to respond to a specific therapy.
KW - Epithelial-to-mesenchymal transition
KW - Field effects
KW - Genomic profile
KW - Metastasis
KW - Molecular subtypes
KW - Urothelial carcinoma
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U2 - 10.1146/annurev-pathol-012513-104703
DO - 10.1146/annurev-pathol-012513-104703
M3 - Article
C2 - 26907529
AN - SCOPUS:84971324355
SN - 1553-4006
VL - 11
SP - 149
EP - 174
JO - Annual Review of Pathology: Mechanisms of Disease
JF - Annual Review of Pathology: Mechanisms of Disease
ER -