Profiling of VEGFs and VEGFRs as Prognostic Factors in Soft Tissue Sarcoma: VEGFR-3 Is an Independent Predictor of Poor Prognosis

Kilvaer, Thomas K.; Valkov, Andrej; Sørbye, Sveinung Wergeland; Smeland, Eivind; Bremnes, Roy M.; Busund, Lill-Tove; Dønnem, Tom

doi:10.1371/journal.pone.0015368

Cited by 33 publications

(35 citation statements)

References 28 publications

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“…Overexpression and/or aberrant activation of VEGFR are associated with poor prognosis in sarcomas 40 . Recently, a phase II clinical trial demonstrated that bevacizumab, a humanized monoclonal antibody that targets VEGF-A, inhibited the binding of VEGFR and showed favorable activity in combination with chemotherapeutic drugs in STS 41 .…”

Section: Targeting Receptor Tyrosine Kinases (Rtks)mentioning

confidence: 99%

Targeting protein kinases to reverse multidrug resistance in sarcoma

Chen

Shen

Choy

et al. 2016

Cancer Treatment Reviews

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Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma.

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Section: Targeting Receptor Tyrosine Kinases (Rtks)mentioning

confidence: 99%

Targeting protein kinases to reverse multidrug resistance in sarcoma

Chen

Shen

Choy

et al. 2016

Cancer Treatment Reviews

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“…binding to the receptor tyrosine kinase (RTK) vascular endothelial growth factor receptor (VEGFR)-2/KDR/flk-1 and/or VEGFR-1/Flt1 expressed by endothelial cells and tumor cells [6]. Recently, the expressions of VEGF-C and VEGF-D, which are distinguished lymphangiogenic ligands of VEGFR-3/Flt4 expressed in lymphatic endothelial cells (LEC) [7][8][9], have been significantly correlated to the progression of certain types of cancer [10][11][12]. Thus, tyrosine phosphorylation of VEGFR-3 stimulates the proliferation of tumor cells [10], such as in Kaposi's sarcoma [13] and gastric cancer [14].…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 induces the transactivation of vascular endothelial growth factor receptor-3 and modulates cell migration and vasculogenic mimicry in melanoma cells

Spinella¹,

Caprara²,

Castro³

et al. 2012

J Mol Med

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Endothelin receptor B (ET(B)R) is a G-protein-coupled receptor overexpressed in melanoma, blood, and lymphatic endothelial cells. Given that aberrant signal transduction can be mediated through cross talk between receptors, here, we explore the functional relationship between ET(B)R and the vascular endothelial growth factor receptor (VEGFR)-3 system and how this cross talk might influence the aggressive behavior of melanoma cells. The expression of VEGFR-3 and its ligands, VEGF-C and VEGF-D, significantly increased after activating ET(B)R by ET-1 in primary and metastatic melanoma cell lines. These effects, similarly to those induced by hypoxia, were mediated by hypoxia-inducible factor (HIF)-1α and HIF-2α. ET-1 caused the phosphorylation of VEGFR-3, which was accompanied by the activation of the downstream signaling molecules, such as MAPK and AKT. Inhibition of c-Src activity or silencing of the scaffold protein β-arrestin-1 reduced ET-1-induced VEGFR-3 phosphorylation, demonstrating that, upon ET-1 stimulus, β-arrestin-1 is involved with c-Src in the ET(B)R-mediated VEGFR-3 transactivation. Moreover, ET-1 in combination with VEGF-C further increased VEGFR-3, MAPK, and AKT phosphorylation and markedly promoted cell migration and vasculogenic mimicry. Dual inhibition of ET(B)R and VEGFR-3 was required for the effective inhibition of these effects, as well as for VEGFR-3 phosphorylation, demonstrating that ET(B)R cross talk with VEGFR-3 enhances cell plasticity and motility. Finally, in melanoma xenografts, ET(B)R antagonist inhibited tumor growth and the activation of the VEGF-C/VEGFR-3 axis, indicating that targeting ET(B)R may improve melanoma treatment acting directly or indirectly by impairing ET(B)R cross talk with VEGFR-3.

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“…The detailed methodology has previously been reported and cut-off values chosen were the same as in our previous studies [14-16]. High expression in tumor cells were defined as ≥ 1 (VEGF-C), ≥ 1.5 (PDGF-A, PDGF-C, PDGF-B, VEGF-A, VEGF-D, VEGFR-1-2 and -3) and ≥ 2 (PDGF-D, PDGFR-α, PDGFR-β, FGF2 and FGFR-1).…”

Section: Methodsmentioning

confidence: 99%

The VEGF- and PDGF-family of angiogenic markers have prognostic impact in soft tissue sarcomas arising in the extremities and trunk

et al. 2014

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BackgroundSoft-tissue sarcomas are rare malignant tumors of mesenchymal lineage that can arise in any part of the body. Prognosis, and hence also treatment may vary according to histologic subtype and localization. Angiogenesis is the process of forming new blood vessels from pre-existing ones. The deregulation of this process is thought to be an important step in malignant transformation. This study investigates the prognostic impact of platelet derived growth factor- (PDGF), vascular endothelial growth factor- (VEGF) and fibroblast growth factor (FGF) families in soft-tissue sarcomas of the extremities & trunk (ET) and visceral & retroperitoneal (VR) locations.MethodsTumor samples from 181 patients (115 ET and 66 VR) with resected soft tissue sarcomas were collected and tissue microarrays were constructed. Immunohistochemistry was used to evaluate angiogenic marker expression. Recurrence-free survival (RFS), metastasis-free survival (MFS) and disease-specific survival (DSS) were used as endpoints in prognostic impact assessment.ResultsIn univariate analyses, almost all investigated angiogenic markers had prognostic impact in the ET group. In contrast, only FGFR-1 showed any significant prognostic impact in the VR group. In the multivariate analyses, PDGF-D (HR = 1.863, 95% CI = 1.057-3.283, P = 0.031), VEGFR-1 (HR = 2.106, 95% CI = 1.038-4.272, P = 0.039) and VEGF-A (HR 2.095, 95% CI 1.028-4.271, P = 0.042) were independent negative prognosticators for DSS, MFS and RFS, respectively, in the ET group. FGFR-1 was an independent positive prognosticator for DSS (HR = 0.243, 95% CI = 0.095-0.618, P = 0.003) in the VR group.ConclusionsAngiogenic molecules from the PDGF and VEGF families have prognostic impact in soft-tissue sarcomas arising in the ET, but not in VR locations. In the latter histological grade and resection margins are the most important prognostic factors.

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Profiling of VEGFs and VEGFRs as Prognostic Factors in Soft Tissue Sarcoma: VEGFR-3 Is an Independent Predictor of Poor Prognosis

Cited by 33 publications

References 28 publications

Targeting protein kinases to reverse multidrug resistance in sarcoma

Targeting protein kinases to reverse multidrug resistance in sarcoma

Endothelin-1 induces the transactivation of vascular endothelial growth factor receptor-3 and modulates cell migration and vasculogenic mimicry in melanoma cells

The VEGF- and PDGF-family of angiogenic markers have prognostic impact in soft tissue sarcomas arising in the extremities and trunk

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