title: Fluorescent imaging of high-grade bladder cancer using a specific antagonist for chemokine receptor CXCR4.
abstract: We previously reported that the expression of CXC chemokine receptor-4 (CXCR4) was upregulated in invasive bladder cancers and that the small peptide T140 was a highly sensitive antagonist for CXCR4. In this study, we identified that CXCR4 expression was induced in high-grade superficial bladder tumors, including carcinoma in situ and invasive bladder tumors. To visualize the bladder cancer cells using urinary sediments from the patients and chemically induced mouse bladder cancer model, a novel fluorescent CXCR4 antagonist TY14003 was developed, that is a T140 derivative. TY14003 could label bladder cancer cell lines expressing CXCR4, whereas negative-control fluorescent peptides did not label them. When labeling urinary sediments from patients with invasive bladder cancer, positive-stained cells were identified in all patients with bladder cancer and positive urine cytology but not in controls. Although white blood cells in urine were also labeled with TY14003, they could be easily discriminated from urothelial cells by their shape and size. Finally, intravesical instillation of TY14003 into mouse bladder, using N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer model, demonstrated that fluorescent signals were detected in the focal areas of bladder of all mice examined at 12 weeks of BBN drinking by confocal microscopy and fluorescent endoscopy. On the contrary, all the normal bladders were found to be negative for TY14003 staining. In conclusion, these results indicate that TY14003 is a promising diagnostic tool to visualize small or flat high-grade superficial bladder cancer.
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nishizawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishiyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Noriko
authors.initials: N
authors.lastname: Tanahara
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kotani
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Mikami
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Toda
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Evans
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Saito
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity; D002278:Carcinoma in Situ / Q000139:chemically induced / Q000175:diagnosis* / Q000378:metabolism; D003952:Diagnostic Imaging; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000175:diagnosis* / Q000378:metabolism; D014556:Urine / Q000737:chemistry / Q000166:cytology
chemical_list: C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D010446:Peptide Fragments; D019718:Receptors, CXCR4; D002085:Butylhydroxybutylnitrosamine