title: Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer.
abstract: Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95% CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3% (concordance-index, 78.5% vs. 75.2%). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95% CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators.
authors.affiliation: Department of Veterans Affairs, Nashville, TN, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Shanna A
authors.initials: SA
authors.lastname: Arnold Egloff
authors.affiliation: Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Holli A
authors.initials: HA
authors.lastname: Loomans
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Starchenko
authors.affiliation: Department of Statistics, National Cheng Kung University, Taiwan.
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Su
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ketova
authors.affiliation: Meharry Medical College, Nashville, TN, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Knoll
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Urology, The Fifth People's Hospital of Shanghai, Shanghai, China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Urology, The University of Louisville, Louisville, KY, USA.|Department of Urology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Ahmed Q
authors.initials: AQ
authors.lastname: Haddad
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|University of California San Diego, La Jolla, CA, USA.
authors.forename: Oluwole
authors.initials: O
authors.lastname: Fadare
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Ingram-Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Vanderbilt Ingram-Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clark
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Ingram-Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Andries
authors.initials: A
authors.lastname: Zijlstra
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000235:genetics / Q000378:metabolism / Q000652:urine*; D000368:Aged; D014408:Biomarkers, Tumor; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods; D015653:Cystectomy / Q000379:methods; D030541:Databases, Genetic; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000401:mortality* / Q000601:surgery / Q000652:urine*
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule; D014408:Biomarkers, Tumor
keywords: ALCAM; bladder cancer; metastasis; transitional cell carcinoma; urothelial cell carcinoma