Correlation between TSP-1, TGF-β and PPAR-γ expression levels and glioma microvascular density

Abstract

Gliomas are the most common type of primary tumor in the central nervous system and are characterized by abundant capillary angiogenesis. It is important to study the underlying molecular mechanisms of angiogenesis in order to aid the identification of potential therapeutic targets. The aim of the current study was to investigate the expression levels of thrombospondin-1 (TSP-1), transforming growth factor-β (TGF-β) and peroxisome proliferator-activated receptor-γ (PPAR-γ) in gliomas, and determine their relationships with angiogenesis. Immunohistochemical methods were used to detect TSP-1, TGF-β and PPAR-γ expression levels and to assess microvascular density (MVD) in 99 glioma tissue samples of various grades. The total positive expression rates of TSP-1 and PPAR-γ were 78.4 and 94.1% in low-grade gliomas and 45.8 and 39.6% in high-grade gliomas. These values suggest that their expression negatively correlated with tumor grade. However, TGF-β expression positively correlated with tumor grade; the total positive expression rate of TGF-β in high-grade gliomas (93.8%) was significantly increased compared with that in low-grade gliomas (43.1%). The MVD in the low-grade group was 28±7.2 vessels/field, which was significantly lower than in the high-grade group (45±6.2 vessels/field). TSP-1 and PPAR-γ expression levels were negatively correlated with MVD (P<0.05), while the TGF-β expression level was positively correlated with MVD (P<0.05). These results indicate that the TSP-1, TGF-β and PPAR-γ expression levels in gliomas are correlated with MVD, which suggests that these proteins may be involved in the regulation of glioma angiogenesis.

Combined therapy with thrombospondin‐1 type I repeats (3TSR) and chemotherapy induces regression and significandy improves survival in a preclinical model of advanced stage epithelial ovarian cancer

“…Thrombospondin‐1 (TSP‐1) is a large extracellular matrix glycoprotein and is the first naturally occurring anti‐angiogenic factor described, with potent antitumor effects (8). The inhibitory influence of TSP‐1 on tumor growth involves inhibition of angiogenesis as well as transforming growth factor β (TGFβ) activation (8, 9). Although native TSP‐1 has shown antitumor and anti‐angiogenic effects in vivo in preclinical models (10), its large size and complex structure reduce its applicability as a therapeutic molecule.…”

“…Thrombospondin-1 (TSP-1) is a large extracellular matrix glycoprotein and is the first naturally occurring antiangiogenic factor described, with potent antitumor Abbreviations: 3TSR, thrombospondin-1 type I repeats; ABAM, antibiotic/antimycotic; CD36, cluster of differentiation 36; EOC, epithelial ovarian cancer; mEC, murine microvascular endothelial cells; MET, metronomic chemotherapy; MTD, maximum tolerated dose; SHP-1, Src homology region 2 domain-containing phosphatase-1; TGFb, transforming growth factor b; TSP-1, thrombospondin-1; TSR2, second type 1 repeat of TSP-1 including amino acids 416 to 473; VEGFR-2, vascular endothelial growth factor receptor-2 effects (8). The inhibitory influence of TSP-1 on tumor growth involves inhibition of angiogenesis as well as transforming growth factor b (TGFb) activation (8,9). Although native TSP-1 has shown antitumor and antiangiogenic effects in vivo in preclinical models (10), its large size and complex structure reduce its applicability as a therapeutic molecule.…”

TGF-β1 EXPRESSION BY GLIOMA C6 CELLS IN VITRO

“…It is believed that TGF-β-signaling is a potential target for the therapy of cancer as the expression of TGF-β isoforms increases significantly in gliomas with high degree of malignancy [24,25,27,28,32,38], helping tumor to avoid immune recognition via various mechanisms, including inhibition of CD8 + cytotoxic lymphocytes and natural killer cells [39] and stimulation of the generation of T regulatory cells. The three levels of therapeutic strategy of TGF-βsignaling inhibition are considered: the ligand itself, the ligand -receptor interactions and the intracellular signaling cascade [32].…”

“…The antiproliferative effect of TGF-β1 on epithelial cells in the early stages and promoting effect in the later stages of tumor growth was shown [26]. It is believed that TGF-β1 signaling is a potential target for antitumor therapy, while the expression of TGF-β increases significantly in gliomas with high degree of malignancy [25,27,28]. Inhibitors of TGF-β1 signaling reduce viability and invasive properties of gliomas modeled in animals [25].…”

Targeting Glioma Stem Cells for Therapy: Perspectives and Challenges

“…Disruption of the TGF-β pathway has been implicated in GBM progression via promotion of cell proliferation, angiogenesis, tumor invasion, metastasis, and immune suppression [55]. Zhang et al found that the TGF-β expression level was positively correlated with microvascular density and angiogenesis in GBM [56]. Consistently, another study also showed TGF-β promoted angiogenesis via the c-Jun N-terminal kinase pathway and macrophage infiltration in a zebrafish GBM xenograft model [57].…”