Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer
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Shanna A. Arnold Egloff1,2, Liping Du3, Holli A. Loomans4, Alina Starchenko5, Pei-Fang Su6, Tatiana Ketova2, Paul B. Knoll7, Jifeng Wang2,8, Ahmed Q. Haddad9,10, Oluwole Fadare2,11, Justin M. Cates2, Yair Lotan10, Yu Shyr3,12, Peter E. Clark12,13, Andries Zijlstra2,12
1Department of Veterans Affairs, Nashville, TN, USA
2Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
3Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
4Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
5Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA
6Department of Statistics, National Cheng Kung University, Taiwan
7Meharry Medical College, Nashville, TN, USA
8Department of Urology, The Fifth People’s Hospital of Shanghai, Shanghai, China
9Department of Urology, The University of Louisville, Louisville, KY, USA
10Department of Urology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
11University of California San Diego, La Jolla, CA, USA
12Vanderbilt Ingram-Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
13Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA
Andries Zijlstra, email: [email protected]
Keywords: ALCAM, bladder cancer, transitional cell carcinoma, urothelial cell carcinoma, metastasis
Received: July 06, 2016 Accepted: October 19, 2016 Published: November 24, 2016
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.
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