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

Abstract

BackgroundNon-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.MethodsTumor 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.ResultsIn 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.ConclusionFGF2, alone or in co-expression with PDGF-B and VEGFR-3, is a significant independent negative prognosticator in widely resected non-GIST STS patients.

FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro

“…In an in vivo setting also the role of FGFR signaling in angiogenesis will surely become relevant. Several FGFs are described to promote neoangiogenesis, among them FGF2 but also FGF5 and FGF18, for which an overexpression in myxoid liposarcomas was detected in this study [ 43 - 45 ]. Given the fact that myxoid liposarcomas are characterized by a typical branching capillary network, an inhibitor blocking also angiogenic pathways might be particularly effective in this entity.…”

Pazopanib in sarcomas

“…Recent investigations have also shown that PDGFR-α is a highly expressed target in dermatofibrosarcoma protuberans (DFSP), a key regulator of downstream pathways in synovial sarcomas [17 ▪ ], and possibly a marker for poor prognosis in many soft tissue sarcomas [18]. Finally, FGF and its receptors also appear to play key mechanistic and prognostic roles in soft tissue sarcomas other than GIST [19,20]. Several other subtypes of sarcomas have demonstrated promising responses to antiangiogenic therapies such as bevacizumab and cediranib, though specific targets and mechanisms remain to be elucidated.…”

Tyrosine Kinase Receptor Expression in Canine Liposarcoma

“…Interest in FGF2 expression in cancer is linked to its putative target role for therapies using thalidomide, which has been demonstrated to inhibit FGF2-induced angiogenesis 10 and to be effective in the treatment of multiple myeloma 7,44,50 and has been tested in other solid tumors in humans. 31 Nevertheless, studies evaluating the prognostic impact of FGF2 have been contradictory: some studies report high FGF2 expression in neoplastic cells associated with a high proliferation rate and negative prognosis, 8,30,39 whereas others have identified a correlation between high FGF2 plasma levels and a low risk of recurrence. 20,45 These inconsistent findings have been explained hypothesizing that tumors using the FGF2 pathway might intrinsically have a less aggressive behavior 56 and that other more efficient pathways may induce cell proliferation in cases with a low FGF2 expression.…”