title: Urinary oncofetal ED-A fibronectin correlates with poor prognosis in patients with bladder cancer.
abstract: The extracellular matrix protein fibronectin (FN) contributes to the structural integrity of tissues as well as the adhesive and migratory functions of cells. While FN is abundantly expressed in adult tissues, the expression of several alternatively spliced FN isoforms is restricted to embryonic development, tissue remodeling and cancer. These FN isoforms, designated ED-A and ED-B, are frequently expressed by cancer cells, tumor-associated fibroblasts and newly forming blood vessels. Using a highly sensitive collagen-based indirect ELISA, we evaluated the correlation of urinary ED-A and ED-B at time of cystectomy with overall survival in patients with high-grade bladder cancer (BCa). Detectable levels of total FN as well as ED-A and ED-B were found in urine from 85, 73 and 51 % of BCa patients, respectively. The presence of urinary ED-A was a significant independent predictor of 2-year overall survival (OS) after adjusting for age, tumor stage, lymph node stage, and urinary creatinine by multivariable Logistic Regression (p = 0.029, OR = 4.26, 95 % CI 1.16-15.71) and improved accuracy by 3.6 %. Furthermore, detection of ED-A in the urine was a significant discriminator of survival specifically in BCa patients with negative lymph node status (Log-Rank, p = 0.006; HR = 5.78, 95 % CI 1.39-24.13). Lastly, multivariable Cox proportional hazards analysis revealed that urinary ED-A was an independent prognostic indicator of 5-year OS rate for patients with BCa (p = 0.04, HR = 2.20, 95 % CI 1.04-4.69). Together, these data suggest that cancer-derived, alternatively spliced FN isoforms can act as prognostic indicators and that additional studies are warranted to assess the clinical utility of ED-A in BCa.
authors.affiliation: Department of Veterans Affairs, Nashville, TN, 37212, USA.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Shanna A
authors.initials: SA
authors.lastname: Arnold
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Holli A
authors.initials: HA
authors.lastname: Loomans
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ketova
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA.|Department of Surgery, Vanderbilt University, Nashville, TN, 37232, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 1161 21st Ave S., C-2102B Medical Center North, Nashville, TN, 37232, USA.|Epithelial Biology Center, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Andl
authors.affiliation: Department of Surgery, Vanderbilt University, Nashville, TN, 37232, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 1161 21st Ave S., C-2102B Medical Center North, Nashville, TN, 37232, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clark
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, 37232, USA. Andries.Zijlstra@Vanderbilt.Edu.|Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA. Andries.Zijlstra@Vanderbilt.Edu.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 1161 21st Ave S., C-2102B Medical Center North, Nashville, TN, 37232, USA. Andries.Zijlstra@Vanderbilt.Edu.
authors.forename: Andries
authors.identifier: http://orcid.org/0000-0001-8460-8803
authors.initials: A
authors.lastname: Zijlstra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000652:urine*; D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000473:pathology* / Q000652:urine*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005353:Fibronectins / Q000652:urine*; D005455:Fluorescent Antibody Technique; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020033:Protein Isoforms; D012372:ROC Curve; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000473:pathology* / Q000652:urine*
chemical_list: D014408:Biomarkers, Tumor; D005353:Fibronectins; D020033:Protein Isoforms; C121542:oncofetal fibronectin
keywords: Biomarker; Bladder cancer; ED-A; ED-B; Fibronectin; Oncofetal