Circulating markers of angiogenesis, inflammation, and coagulation in patients with glioblastoma

Abstract

Inflammation, angiogenesis, and coagulation are linked to the development of cancer. In glioblastoma, microvascular proliferation is a hallmark, and lymphocytic infiltration is a common finding. Thromboses are frequent in patients with glioblastoma. The objective of this study was to assess presurgical levels of circulating markers of inflammation, angiogenesis, and coagulation in a prospective series of patients with glioblastoma, and to explore their correlations and possible associations with clinical findings. Angiogenesis markers included were vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor-receptor 1 (sVEGFR-1), and thrombospondin-1 (TSP-1). Inflammatory markers included were C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and sialic acid (SA). Coagulation markers included were fibrinogen (Fg), endogen thrombin generation (ETG), prothrombin fragments 1 + 2 (F1 + 2), and tissue factor (TF). Forty-seven patients and 60 healthy subjects were included in the study. Signs of tumor necrosis in presurgical MRI were associated with shorter survival (P < 0.01). All inflammation markers, F1 + 2, ETG, VEGF and sVEGFR-1, were significantly elevated in glioblastoma patients. Correlations were found between ETG and Fg (r = 0.44, P < 0.01). Sialic acid correlated with Fg (r = 0.63, P < 0,001); CPR correlated with SA (r = 0.60, P < 0.001), Fg (r = 0.76, P < 0.001), TNFα (r = 0.56, P < 0.001), and IL-6 (r = 0.65, P < 0.001); and IL-6 also correlated positively with TNFα (r = 0.40, P < 0.02) and Fg (r = 0.45, P < 0.01). Vascular endothelial growth factor inversely correlated with sVEGFR-1 (r = -0.35, P < 0.02). No associations were found between marker levels and survival or progression-free survival.

Serum albumin and survival in glioblastoma multiforme

“…Albumin is a recognized 'negative' acute phase protein with serum levels inversely related to the magnitude of the systemic inflammatory response as a consequence of increased catabolism and downregulation of hepatic synthesis, primarily by the cytokines TNFa and IL-6 [19]. Patients with GBM have significantly higher levels of circulating IL-6 compared with normal controls [20]. Moreover, amplified IL-6 gene expression has been confirmed in glioblastoma tumour cells [21], and has been shown to correlate inversely with survival [22].…”

Type I IFNs signaling and apoptosis resistance in glioblastoma cells

“…IRF-1 was the third hit of the list. In general, there were several correlations with genes of the IFN response (USP18, ISG20, ISG15) thus possibly indicating that in the selected tumors an inflammatory response was engaged [25].…”

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

“…We recently developed specific ELISAs for OPN-R and OPN-L and demonstrated that these cleaved OPN forms are markedly elevated in the synovial fluid of patients with rheumatoid arthritis but not osteoarthritis or psoriatic arthritis, validating its significance in vivo (25). Thrombin activation is increased in patients with GBM as shown by the elevation of prothrombin fragment F1 ϩ 2 in their plasma (27), and intravascular thrombosis has been suggested to be involved in progression of astrocytomas to GBMs (28).…”