Differential expression of insulin like growth factor binding protein-4 (IGFBP4) in melanoma progression

Abstract

8557 Background: Members of the IGFBP family are thought to regulate tumor progression through both IGF-dependent and independent mechanisms. Moreover, IGFBPs may exhibit distinct functions depending on whether they are present locally in tissue or systemically. Our preclinical data suggest that IGFBP4 serves as an endogenous inhibitor of angiogenesis and melanoma tumor growth. To examine the clinical validity of our observations, we compared IGFBP4 expression in tissue and sera in primary melanoma patients with a low risk of metastases versus patients with established metastatic disease. Methods: Eighty-nine melanoma patients (primary stage IA, n=57; metastatic, n=32; 44 M, 45 F; Median Age=56) prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the NYU School of Medicine were studied. IGFBP4 protein expression in tumors was assessed in 83 patients using goat anti-human IGFBP4 antibody (R&D Systems) in an immunohistochemical assay. For each case, the percentage of tumor cells that stained positively was estimated. IGFBP4 concentration in the serum was measured in 64 patients by an ELISA assay (Diagnostic Systems Laboratories, Inc.). Fifty-eight patients had both sera and tumor specimens available for correlation. Results: The median IGFBP4 expression in tumor specimens from primary patients was 70% compared to 5% in metastatic patients (P=0.002, Wilcoxon rank-sum test). The median concentration of IGFBP4 in sera was 43.8 ng/ul in primary patients versus 41.0 ng/ul in metastatic patients (P=0.83). A weak association between IGFBP4 expression in tissue and IGFBP4 shedding in sera was observed (Spearman correlation coefficient=0.16, P=0.24) in the 58 cases with both sera and tissue available. Conclusions: Our data demonstrate that IGFBP4 expression in melanoma clinical specimens decreases in the progression from primary to metastatic melanoma, consistent with its potential role as an inhibitor of angiogenesis. Data also suggest that IGFBP4 tissue expression may be more clinically relevant than its sera shedding. Future studies using a larger sample size and extended follow up are needed to further define the role of IGFBP4 in melanoma progression. No significant financial relationships to disclose.