Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells.
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.
Chan
Keith Syson
KS
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
Espinosa
Inigo
I
Chao
Mark
M
Wong
David
D
Ailles
Laurie
L
Diehn
Max
M
Gill
Harcharan
H
Presti
Joseph
J
Chang
Howard Y
HY
van de Rijn
Matt
M
Shortliffe
Linda
L
Weissman
Irving L
IL
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*
D018960:Hyaluronan Receptors; D053554:Keratin-20; D053555:Keratin-5