SDC-1 is expressed mainly in epithelial tissues, hence, studies aiming to address its role in malignancies have focused on carcinoma. In a number of malignancies, the expression of SDC-1 correlates with tumor stage and grade [15–18], but the association between SDC-1 status and BCa has not been extensively studied. Other investigators have reported a positive correlation of SDC-1 with fibroblast growth factors (FGFRs) in bladder tumors, these factors are thought to be key molecules in low-grade BCa . Only Shimada et al., have investigated the biologic role of SDC-1 in human BCa cells. In their study, the BCa cell lines, UMUC2 and UMUC3 had SDC-1 expression silenced by siRNA transfection, which led to an induction of apoptosis in vitro and a reduction in mouse orthotopic bladder tumor growth .
To our knowledge, our study is the largest study to date to evaluate SDC-1 in human bladder tumors both in voided urine and in tumor sections. We used two complimentary approaches to classify SDC-1 expression in human bladder tumors. First, urinary SDC-1 levels were monitored by ELISA in a cohort of 308 subjects. While there was no difference in urinary SDC-1 levels between BCa-bearing subjects and non-BCa bearing subjects (p = 0.23), lower urinary levels of SDC-1 were associated with the presence of high-grade tumors and/or MIBC. The prognostic capability of SDC-1 in predicting higher grade and higher stage disease prior to patients undergoing cystoscopy and transurethral resection of bladder tumor has the potential to improve patients’ outcomes. Second, we determined the expression pattern of SDC-1 protein in a cohort of 193 bladder tissue specimens. Though a difference in SDC-1 expression pattern was not seen between bladder tumors and benign bladder histology, possibly due to the small sample size of the benign cohort, a significant shift in cellular localization of SDC-1 was associated with high-grade tumors and MIBC. These tumors tended to lose the distinct membranous staining observed in normal urothelia. The two complimentary approaches utilized in the current study yielded similar inferences, i.e., more aggressive or more advance BCa has less membrane bound SDC-1. If less membrane bound SDC-1 is present in a tumor mass, then it might be expected that less shed or released SDC-1 would be present in the soluble fraction of voided urine from patients with more aggressive or advanced BCa.
Shifts in SDC-1 expression patterns have been alluded to in previous reports, but none in BCa. A study by Mennerich et al., described a shift of SDC-1 expression from the epithelial component to the stromal component in solid tumors . An observed overall increase in tumor SDC-1 mRNA was demonstrated by in situ hybridization and protein levels confirmed by immunohistochemistry in tumor-associated stromal cells in breast, lung and colon carcinoma. We did not observe this phenomenon in our study, the majority of SDC-1 expression was in the epithelial component of the bladder tumors. The expression pattern shift that our analyses revealed was from distinctly membranous to diffusely cytoplasmic in high-grade and high-stage bladder tumors. This association with disease progression suggests that the loss of SDC-1 function at the cell-surface or cell membrane and thus may facilitate cancer progression and the development of invasive and metastatic disease. Several studies have shown the involvement of cell-surface SDC-1 in cell-cell and cell-matrix adhesion, possibly through the regulation of integrin activities . The loss of SDC-1 at the cell surface by extracellular cleavage can decrease the strength of tumor cell adhesion within the tissue architecture, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues as well as distant sites . The loss of SDC-1 at the cell-surface could also occur through a switch to translation of alternative, non-membranous isoforms, or by aberrant processing in an advanced tumor. This concept exists for the well-known tumor suppressor gene E-cadherin. Similar to SDC-1, cell-surface E-cadherin assists in cell adhesion and loss of E-cadherin is associated with more aggressive BCa that possess a greater potential to invade and metastasize [22, 23]. Though the present studies are quite intriguing, they only elude to a biologic phenomenon which now must be further explored to a) report associated cellular and molecular changes, b) confirm the ELISA and immunohistochemistry results in a large cohort, c) determine which domain (cytoplasmic, transmembrane or extracellular) is shed in voided urine and d) determine in addition to changes in location in expression if there are changes in the quantity of SDC-1 expression between the various disease states. Furthermore, the preliminary nature of our immunohistochemical results should be confirmed in a larger cohort.