C5a receptor expression is associated with poor prognosis in urothelial cell carcinoma patients treated with radical cystectomy or nephroureterectomy

Abstract

Abstract.Patients with aggressive urothelial cell carcinoma (UCC) that undergo radical cystectomy or nephroureterectomy exhibit markedly high rates of disease recurrence and mortality. To select appropriate adjuvant thxerapies in addition to radical surgery, the identification of predictive prognostic markers for UCC patients is required. The aim of the present study was to identify such markers, by evaluating the association of UCC complement component 5 (C5) fragment a (C5a) receptor (C5aR) expression, detected using immunohistochemistry, with clinicopathological parameters and survival outcomes of UCC patients. The results revealed that C5aR was expressed in cancer cells, particularly at the invasive front, but not in noncancerous urothelial cells or adjacent cells. The UCC C5aR-positive rate of patients treated with radical surgeries was 73% (38/52) and the rate was 83% (20/24) at stages I-II of disease. No correlation between C5aR expression and any of clinicopathological parameters, which included gender, tumor location, World Health Organization grade, T stage, vessel invasion and stage of disease, was identified. However, univariate and multivariate analyses revealed that C5aR-positive UCC patients exhibited significantly lower overall survival rates [hazard ratio (HR), 3.14; 95% confidence interval (CI), 1.03-9.60; P=0.035 and HR, 3.92; 95% CI, 1.15-13.4; P=0.029, respectively] and 5-year survival rates (0.42 vs. 0.83) compared with C5aR-negative UCC patients. Furthermore, 5-year survival and disease-specific survival rates were lower in patients with C5aR-positive UCC (0.51; 95% CI, 0.30-0.71) than patients with C5aR-negative UCC (0.83; 95% CI, 0.62-1.00). These results indicate that UCC C5aR expression is predictive of poor patient outcomes and thus may lead to the appropriate selection of adjuvant therapies at earlier UCC stages, which could improve patient prognosis. IntroductionUrothelial cell carcinoma (UCC) is one of the most common types of cancer in the USA, accounting for ~4.5% of all newly diagnosed cancer cases and 2.8% of all cancer-associated mortalities in 2013 (1). In the USA, the most common site of UCC is the bladder, and bladder UCC is the fourth most common type of cancer and the sixth leading cause of cancer-associated mortality in males (1). Bladder UCC may be classified into two subtypes at diagnosis, non-muscle and muscle-invasive, which exhibit distinct clinical features (2). The non-muscle-invasive subtype commonly recurs in the bladder cavity and accounts for 70-80% of cases of bladder UCC, with muscle invasion present in only 10-20% of cases. The 5-year survival rate of the non-muscle-invasive subtype of UCC is >90%. By contrast, muscle-invasive bladder UCC, which accounts for ~20% of bladder UCC cases, exhibits a poor prognosis with a 5-year survival rate of <50%. Carcinoma in situ (CIS), which is classified into the non-muscle invasive aggressive subtype, is localized to the epithelium and exhibits invasive and metastatic potential. In patients with aggressive bladder UCC (...

Enhancement of cancer invasion and growth via the C5a‑C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion

“…In clinically obtained tissue samples, C5aR was expressed in urothelial carcinoma cells at the invasive front rather than the surface layer in the epithelium and in almost all the cells in the deeper invasion site (18), which, together with high C5aR expression in gastric cancer cells invading the adjacent blood vessels (20,21), implies the involvement of the C5a-C5aR system in human cancer invasion. However, C5a-C5aR-mediated cancer invasion has not been fully elucidated in cancer patients.…”

“…Moreover, human cancer cells release C5a from human C5 and plasma via a serine protease on the cell membrane (15). The survival rates of patients with C5aR-positive or highly expressing non-small cell lung (16), breast (17), urothelial (18), clear cell renal (19), and gastric cancers (20,21) are lower than those of patients with the corresponding C5aR-negative cancers. It is likely that the C5a-C5aR system promotes human cancer.…”

Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis by CXCL16-mediated Effects

“…All these studies underscore the emerging role played by C5a/C5aR1 signaling in the tumor microenvironment, but the role of C5aR1 in tumor cells is poorly understood despite the fact that its expression has been associated with poor prognosis in a variety of human cancers (7,(14)(15)(16). Some reports have indicated that C5aR1 enhances motility and invasiveness but its contribution to metastatic spread remains mostly unknown (15,(17)(18)(19).…”

Complement in Metastasis: A Comp in the Camp

“…Elevation of C5a or C5aR1 levels has been observed in solid tumors including lung (50, 53), gastric (56), ovarian (57), breast (58), urothelial (59), and clear cell renal cancers (60).…”