Abstract
PurposeEmerging evidence has shown that macrophages (Mφs) at different tumor sites have diverse clinical attributes. Stabilin-1 is a multi-functional scavenger marker for specialized tumor-associated Mφs. This study investigates the relationship between the density and microlocalization of stabilin-1+ Mφs within tumors and the clinical outcomes of patients with urothelial carcinoma of the bladder (UCB).MethodsIn this retrospective study, 283 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry and immunofluorescence analyses were used to colocalize the expression of stabilin-1 with other markers for Mφs (CD14, CD68, CD163, and CD206). Kaplan–Meier analysis and Cox proportional hazards regression models were applied to estimate overall survival (OS) and recurrence-free survival (RFS).ResultsIn UCB tissues, stabilin-1 was primarily expressed on Mφs, as evident from triple immunofluorescence staining for stabilin-1 and Mφ markers. Stabilin-1+ Mφs were often more prominent in stromal regions rather than intratumoral regions in UCB tissues (P < 0.0001). After dichotomization at the median cell density for stabilin-1+ Mφs, only intratumoral stabilin-1+ Mφ density was a predictor of poor OS (P < 0.001) and RFS (P = 0.026). Moreover, intratumoral stabilin-1+ Mφ density was positively associated with tumor stage (P < 0.01) and histological grade (P < 0.01), and emerged as an independent prognostic factor for OS (HR 2.371; P < 0.0001), but not for RFS (HR 1.491; P = 0.061).ConclusionsOur findings indicate that intratumoral stabilin-1+ Mφs could potentially be used as a pro-tumoral prognostic marker for UCB patients.
Highlights
Urothelial carcinoma of the bladder (UCB) is the most common type of urological tumor in China [1]
Stabilin-1 was primarily expressed on Mφs, which was demonstrated by co-expression of stabilin-1 and other markers of Mφs (CD14, CD68, CD163, and CD206) in triple-color immunofluorescence stains (Fig. 1a–c)
Stabilin-1 was expressed on some endothelium cells and/ or lymphatic vessels in several UCB tissues, but these cells are excluded based on morphology (Supplementary Fig. 1; Fig. 1d)
Summary
Urothelial carcinoma of the bladder (UCB) is the most common type of urological tumor in China [1]. (NMIBC) and muscle-invasive bladder cancer (MIBC) [2]. Recent studies have highlightened the importance of the inflammation, which provides important pro-tumoral function and affects the prognosis of bladder patients [6]. Different subsets of tumor-associated Mφs (TAMs) are involved in stimulating angiogenesis/lymphangiogenesis, suppressing antitumor immunity and enhancing tumor cell invasion and metastasis [11]. CD14 and CD68 are considered as pan markers of Mφ, but they cannot be used to identify the phenotype or functional status of Mφs [13]. A recent study showed that cells with a mature TAM phenotype expressed combinations of previously classified pro-tumorigenic (CD163 and CD206) and anti-tumorigenic (CD169 and CD38) markers in renal cell carcinoma [15]. A more detailed understanding of TAM phenotypes in the tumor microenvironment would be useful for investigating and therapeutically targeting these cells
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