Abstract
Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. >0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox’s regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.
Highlights
Urothelial bladder cancer (BCa) accounts for approximately 3% of global cancer diagnoses and 2.1% of cancer-related deaths worldwide [1]
We were interested in potential biomarkers for bladder cancer that are expressed in TCs as well as in immune cells (ICs) cells to gain more insight into the interaction of tumor cells and the tumor microenvironment
A well-recognized marker expressed in TCs and ICs in bladder cancer is PD-L1, which has already been utilized for therapy stratification of checkpoint inhibitor therapies [12,13,14]
Summary
Urothelial bladder cancer (BCa) accounts for approximately 3% of global cancer diagnoses and 2.1% of cancer-related deaths worldwide [1]. We found that the expression of the immune cell marker chemokine CC motif ligand 2 (CCL2) was differentially associated with prognosis, depending on whether it was expressed in tumor cells (poor prognosis) or in immune cells (good prognosis) of bladder cancer patients [15]. Another candidate could be progranulin (GP88; synonymous: granulin–epithelin precursor; proepithelin; PC cell-derived growth factor; acrogranin) as it is expressed in bladder cancer cells [16] and is expected to be expressed in immune cells. None of the studies reported its presence, in immune cells, in the context of tumors
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