Fibroblast growth factor 2 orchestrates angiogenic networking in non-GIST STS patients

Abstract

Background: Non-gastrointestinal stromal tumor soft-tissue sarcomas (non-GIST STSs) constitute a heterogeneous group of tumors with poor prognosis. Fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor-1 (FGFR-1), in close interplay with platelet-derived growth factor-B (PDGF-B) and vascular endothelial growth factor receptor-3 (VEGFR-3), are strongly involved in angiogenesis. This study investigates the prognostic impact of FGF2 and FGFR-1 and explores the impact of their co-expression with PDGF-B and VEGFR-3 in widely resected tumors from non-GIST STS patients.

Methods: Tumor samples from 108 non-GIST STS patients were obtained and tissue microarrays were constructed for each specimen. Immunohistochemistry was used to evaluate the expressions of FGF-2, FGFR-1, PDGF-B and VEGFR-3.

Results: In the multivariate analysis, high expression of FGF2 (P = 0.024, HR = 2.2, 95% CI 1.1-4.4) and the co-expressions of FGF2 & PDGF-B (overall; P = 0.007, intermediate; P = 0.013, HR = 3.6, 95% CI = 1.3-9.7, high; P = 0.002, HR = 6.0, 95% CI = 2.0-18.1) and FGF2 & VEGFR-3 (overall; P = 0.050, intermediate; P = 0.058, HR = 2.0, 95% CI = 0.98-4.1, high; P = 0.028, HR = 2.6, 95% CI = 1.1-6.0) were significant independent prognostic indicators of poor disease-specific survival.

Conclusion: FGF2, alone or in co-expression with PDGF-B and VEGFR-3, is a significant independent negative prognosticator in widely resected non-GIST STS patients.

Figure 1

IHC analysis of TMA of non-gastrointestinal stromal tumor soft-tissue sarcoma representing different scores for tumor cell FGF2 and FGFR-1. (A) Tumor cell FGF2 low score in Fibrosarcoma; (B) Tumor cell FGF2 high score in undifferentiated pleomorphic sarcoma; (C) Tumor cell FGFR-1 low score in undifferentiated pleomorphic sarcoma; (D) Tumor cell FGFR-1 high score in undifferentiated pleomorphic sarcoma. Abbreviations: FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; IHC, immunohistochemistry; TMA, tissue microarray.

Figure 2

Disease-specific survival curves for (A) FGF2; (B) FGFR-1; (C) FGF2 & PDGF-B; (D) FGF2 & VEGFR-3. Abbreviations: FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; PDGF, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 3

Proposed mechanisms of stimulation of growth, angiogenesis and motility in non-gastrointestinal stroma tumor soft-tissue sarcomas expressing FGF2, PDGF-B and VEGFR-3. (A) Paracrin and/or autocrin stimulation of cancer cells leading to activation of intracellular pathways and subsequently survival benefits; (B) FGF2 stimulating angiogenesis through recruitment of endothelial cells and increasing release of MMPs and uPa leading to ECM degradation and remodeling thus enabling tumor cell expansion and motility, PDGF-B recruiting VSMCs and stimulating pericyte coverage of newly formed vessle; Abbreviations: ECM, extracellular matrix; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; MMP, matrix-metallo proteinase; uPa, urokinase-like plasminogen activator; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.