title: Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells.
abstract: Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44(+)CK5(+)CK20(-)). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e.g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% beta-catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscle-invasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.
authors: Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA 94304-5542, USA. kc1@bcm.tmc.edu
authors: Keith Syson
authors: KS
authors: Chan
authors: Inigo
authors: I
authors: Espinosa
authors: Mark
authors: M
authors: Chao
authors: David
authors: D
authors: Wong
authors: Laurie
authors: L
authors: Ailles
authors: Max
authors: M
authors: Diehn
authors: Harcharan
authors: H
authors: Gill
authors: Joseph
authors: J
authors: Presti
authors: Howard Y
authors: HY
authors: Chang
authors: Matt
authors: M
authors: van de Rijn
authors: Linda
authors: L
authors: Shortliffe
authors: Irving L
authors: IL
authors: Weissman
mesh_terms: D000818:Animals; D019070:Cell Lineage; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D053554:Keratin-20 / Q000096:biosynthesis; D053555:Keratin-5 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010587:Phagocytosis; D011379:Prognosis; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D018960:Hyaluronan Receptors; D053554:Keratin-20; D053555:Keratin-5