Differential Expression of Axl and Gas6 in Renal Cell Carcinoma Reflecting Tumor Advancement and Survival

Abstract

Purpose: Overexpression of the receptor tyrosine kinase Axl is implicated in several cancers.Therefore, we conducted this study to determine the expression of Axl and its ligand Gas6 in various renal cell carcinoma (RCC) types and in oncocytoma. Experimental Design: Real-time quantitative reverse transcription-PCR was used to quantify tumor mRNA levels for Axl and Gas6 in a cohort (n = 221) of RCC patients. Serum levels of soluble sAxl and Gas6 proteins were measured using specific ELISA assays (n = 282). The presence of Axl protein in tumor tissue was evaluated by immunohistochemistry (n = 294). Results were correlated to tumor-associated variables, clinical biochemical tests, and patient survival. Results: Tumor Axl mRNA levels correlated independently to survival when assessed against tumor stage and grade. In the study group, the median cancer-specific survival of all RCC patients during 307 months of follow-up was 55 months (confidence interval, F40.4). The 25% of patients with lowest tumor Axl mRNA levels had significantly better survival than the rest (P = 0.0005), with 70% of the patients still alive at the end of follow-up. In contrast, in patients with medium-high Axl mRNA, only 25% were alive at the end of follow-up. Tumor Gas6 mRNA levels correlated to survival, tumor-associated variables, and disease severity as did serum levels of soluble sAxl and Gas6 protein. However, no correlation between Axl protein in tumor tissue and survival was found. Conclusions: Axl and Gas6 expression in RCC are associated with tumor advancement and patient survival. In particular, low tumorAxl mRNA levels independently correlated with improved survival.Renal cell carcinoma (RCC) represents f2% to 3% of all human cancers (1), being the most common cancer of the adult kidney (2). The prevalence is skewed between men and women (1.5:1), and RCC incidence peaks at 60 to 70 years of age (3). The only curative treatment of RCC is surgery (4). Today, smaller and less advanced RCC tumors are detected by imaging techniques, such as ultrasound and computed tomography, and nephron-sparing surgery of tumors <4 cm in diameter is an alternative that provides recurrence-free and long-term survival rates (5). However, the outcome of metastatic RCC is poor and mortality remains very high with a median cancer-specific survival of 21 months (6, 7). Treatment of metastatic RCC, in addition to removal of primary tumor and resection of metastases, is palliative and includes systemic therapies, such as immunotherapy (e.g., IFNa). Recently, a number of promising tyrosine kinase inhibitors are approved both in the United States and Europe for treatment of metastatic RCC (5).RCC is composed of different tumor types, including conventional or clear cell RCC (cRCC; representing the majority of RCCs, 75-85%), papillary RCC (pRCC; 10-15%), chromophobe RCC (chRCC; 4-5%), collecting duct carcinoma (<1%), and unclassified RCC (5%; ref. 8). In f4% to 5% of the cases, benign oncocytoma is diagnosed when RCC is suspected (9). The more aggressive ...

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