Original articleHigh expression of APRIL correlates with poor prognosis in clear cell renal cell carcinoma
Introduction
Renal cell carcinoma (RCC) represents, on average, over 90% of all malignancies of the kidney that occur in adults in both sexes [7]. Surgical treatment is the first choice of treatment for localized RCC, and the 5-year survival rate (5YSR) of patients with stage I RCC is 96% [4], [17]. However, it has been reported that the rate of cases that are accompanied by metastatic disease at the time of diagnosis of RCC is 25–30% [12], and the recurrence rate after surgical treatment of localized RCC is 20–40% [13], [14]. Although cytoreductive surgery is being implemented in advanced RCC, the 5YSR of patients with stage IV RCC is 23% [4], and the role of systemic therapy has been growing. Until recently, the major systemic treatment was immunotherapy, including IL-2, IFN and their combination [17]. However, there has been recent development of new drugs based on new understandings of the complex immune system and improvements in technology [6]. Targeted therapy with tyrosine kinase inhibitors targeting VEGF, PDGF, c-kit or m-TOR has recently been used as an additional treatment option [22]. Several targeted agents have shown improved therapeutic effects in some patients with advanced RCC, thus encouraging the development of new target agents [16].
TNF-alpha has been investigated as a potential therapeutic target for patients with advanced RCC [1], [10], [15]. Moreover, the members of the Tumor Necrosis Factor Superfamily (TNFSF, composed of 19 ligands and 29 receptors) have been studied in RCC and other tumors [21], [22], [23], [33]. TNFSF members are associated with various cellular activities that regulate immune function, tolerance and malignancy [25]. The PRoliferation Inducing Ligand (APRIL, TNFSF13) and B cell Activating Factor belonging to the TNF Family (BAFF) are two related members of the TNFSF. APRIL was first described in 1998, is primarily expressed in tumor tissues and can stimulate the growth of transformed cells in vitro and in vivo [9]. The gene encoding APRIL is located on chromosome 17 in humans [23], and APRIL has been known to play an important role in B-cell development, maturation and survival [25]. Several studies have reported APRIL expression in some autoimmune diseases, including systemic lupus erythematosus (SLE) [25], [26], [28], [29], and in many hematolymphoid neoplasms, including B-cell malignancy [8], [11], [23], [25]. The detection of APRIL in various solid tumors has been reported, and its expression has been shown to be associated with prognosis, suggesting that this ligand may regulate the proliferation of solid tumors as well as B-cell malignancies [8], [21], [24], [25], [27], [31]. A recent study investigated the association between the expression of several TNFSF members and their receptors, including APRIL, and the prognosis of patients with clear cell renal cell carcinoma (CCRCC) using immunohistochemistry (IHC) and quantitative RT-PCR and reported that APRIL expression was associated with poor patient prognosis [22].
In this study, we investigated APRIL expression by IHC in resected CCRCC samples and analyzed its association with the clinicopathologic characteristics and prognosis of the patients.
Section snippets
Patients and tissue microarray
We examined 206 CCRCC samples from patients who underwent radical or partial nephrectomy at Seoul National University Hospital between 1999 and 2002. Tissue microarray (TMA) blocks were made from representative tumor core sections (2 mm in diameter) from each formalin-fixed paraffin block (SuperBioChips Laboratories, Seoul, Korea). We reviewed the hematoxylin and eosin-stained slides for all samples in order to confirm the adequacy of diagnosis and re-graded tumors as grade I–IV according to the
Basic clinicopathologic characteristics
In total, 206 patients were included in this study, of which 162 (78.6%) were males and 44 (21.4%) were females. The distribution of age at diagnosis ranged from 24 to 83 years old, and the mean and median ages at diagnosis were 55.3 and 56 years, respectively. In the analysis, we divided the patients into two patient groups, 56 years of age and over and <56 years. The distribution of the Fuhrman nuclear grading was as follows: 13 cases of grade I (6.3%), 97 cases of grade II (47.1%), 75 cases
Discussion
APRIL is a type II transmembrane protein that is produced by a variety of immune cells, such as monocytes, macrophages, dendritic cells, neutrophils and T cells [9], [23], [25]. It is known to be involved in the activation and immune responses of B cells and is also associated with B cell malignancies [8], [11], [23], [25]. Additionally, APRIL is expressed in cells outside the immune system, such as epithelial cells and osteoclasts and in other solid tumor tissues [9], [23]. APRIL can function
Conclusions
We found that the high expression of APRIL in CCRCCs was correlated with high Fuhrman nuclear grade, high pathologic stage, and poor overall and cancer-specific survival of the patients, but not disease-free survival. We also showed that it was not an independent prognostic factor but had certain potential prognostic value in relation to pathologic stage or Fuhrman nuclear grade. Additionally, the results showed a potential role for APRIL, an immune related molecule, in the pathogenesis of
Acknowledgement
This work was supported by grant 03-2013-0210 from the Seoul National University Hospital Research Fund.
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