Abstract
Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors whose classification and treatment is complicated by molecular heterogeneity within the histological subtypes and by the lack of prognostic/therapeutic biomarkers. This study analyses expression of target proteins involved in insulin-like growth factor pathway (IGF1Rβ, IRS1 S612 and IGFBP7) in high-grade STS to stratify patients with the worst prognosis. Tissue microarray analysis performed on 145 high-grade STS samples revealed a uniform expression of IGF1Rβ and IRS1 S612, while IGFBP7 was more strongly expressed in metastatic than in metastasis-free patients. This was confirmed by multivariate regression analysis that demonstrated the independent poor prognostic role of IGFBP7 overexpression with a significant increase of risk of metastasis (HR = 6.358, 95% CI = 2.946-13.721; P < 0.0005). Given the evidence that circulating protein may generate from tissue tumor cells, in 59/145 patients who had available serum we measured IGFBP7 concentration. The ELISA assay revealed significantly higher levels in tumor patients than in the control with a possible threshold value of 25 ng/ml. Differentiating sera according to primary tumor histotype, significantly higher IGFBP7 concentration was found in synovial sarcoma and liposarcoma than in other STS histotypes. This study revealed that tissue expression of IGFBP7, considered a tumor stroma marker in mesenchymal derived cells, was highly prognostic in poor metastasis-free survival. In parallel, the determination of serum protein levels might contribute to STS diagnosis. Subsequent analyses will be crucial to understand the clinical relevance of IGFBP7 protein in STS.