Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients

Abstract

SummaryWe have compared the platelet number and the serum concentration of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and interleukin-6 (IL-6) in 80 blood samples of 50 patients with advanced cancer. We have also measured the mitogenic effect of patient sera on endothelial cells in vitro in order to estimate the biological activity of serum VEGF. Serum VEGF concentration correlated with platelet number (r = 0.61; P < 10 -4 ). Serum IL-6 levels correlated with platelet count (r = 0.36; P < 10 -3 ), with serum VEGF levels (r = 0.55; P < 10 -4 ) and with the calculated load of VEGF per platelet (r = 0.4; P = 3 × 10 -4 ). Patients with thrombocytosis had a median VEGF serum concentration which was 3.2 times higher (P < 10 -4 ) and a median IL-6 serum level which was 5.8 times higher (P = 0.03) than in other patients. Serum bFGF did not show an association with any of the other parameters. Patient sera with high VEGF and bFGF content stimulated endothelial cell proliferation significantly more than other sera (P = 4 × 10 -3 ). These results support the role of platelets in the storage of biologically active VEGF. Platelets seem to prevent circulating VEGF from inducing the development of new blood vessels except at sites where coagulation takes place. IL-6, besides its thrombopoietic effect, also seems to affect the amount of VEGF stored in the platelets. This is in accordance with the indirect angiogenic action of IL-6 reported previously. The interaction of IL-6 with the angiogenic pathways in cancer might explain the stimulation of tumour growth occasionally observed during IL-6 administration. It also conforms to the worse outcome associated with high IL-6 levels and with thrombocytosis in several tumour types and benign angiogenic diseases.

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer

“…Several groups have confirmed the role of platelets in the storage of circulating VEGF-A (Verheul et al, 1997;Banks et al, 1998;Salgado et al, 1999;Gunsilius et al, 2000;Salgado et al, 2001).…”

“…In a previous study we have shown that serum IL-6 correlates not only with the platelet count (illustrating its thrombopoietic property), with serum VEGF-A (illustrating the importance of IL-6 in the regulation of VEGF-A), but also with the VEGF-A load in platelets (Salgado et al, 1999). Since thrombopoietic cytokines, such as thrombopoietin (TPO) and interleukin-3 (IL-3), enhance VEGF-A expression in megakaryocytes, and, as is the case for TPO, in parallel with megakaryocytic differentiation, we hypothesised that IL-6 derived from primary tumour cells as well as A role for IL-6 in haemostasis and angiogenesis in cancer R Salgado et al from disseminated tumour cells might enhance VEGF-A expression in platelet progenitors much in the same manner (Imai et al, 1991;Mohle et al, 1997;Bobik et al, 1998;Salgado et al, 1999).…”

“…Serum collection and VEGF-A 165 and IL-6 measurements were performed as mentioned previously (Salgado et al, 1999). Plasma VEGF-A 165 was measured with an ELISA-kit of R&D systems (R&D systems, Minneapolis, MN, USA) on trisodium citrate-anticoagulated collected blood.…”

“…Samples were assayed in duplicate. Within assay variability has been tested before (Salgado et al, 1999).…”

“…A nearly 10-fold higher serum than plasma VEGF-A level is found in both cancer patients as in healthy persons (Banks et al, 1998), indicating that circulating VEGF-A is mainly blood cell associated, in particular in platelets (Verheul et al, 1997;Salgado et al, 1999;Gunsilius et al, 2000). High serum VEGF-A levels are frequently encountered in cancer patients, the platelets of whom indeed have a higher VEGF-A content compared with healthy individuals; a prognostic significance is attributed to these levels (Salven et al, 1999;O'Byrne et al, 2000).…”