Shift in the balance between circulating thrombospondin-1 and vascular endothelial growth factor in cancer patients: Relationship to platelet a-granule content and primary activation

Abstract

Tumoral angiogenesis is regulated by the balance between factors that activate and inhibit angiogenesis. Elevated levels of activators have been associated with a poor prognosis in cancer patients, but little is known about the net balance between circulating activators and inhibitors in these patients. This study was designed to determine whether the balance between circulating concentrations of the angiogenesis inhibitor TSP-1 and the activator VEGF differs from that in healthy persons, and to shed light on the possible role of platelets in this balance. Twenty-five cancer patients and 18 healthy subjects were included. Serum and plasma concentrations of VEGF, TSP-1 and PF4 were measured by ELISA. Our results showed that in healthy subjects the balance between the TSP-1 and VEGF concentrations in serum and in serum minus plasma was twice to three times as high as in cancer patients (p<0.05). The theoretical TSP-1 content per platelet was greater in healthy subjects than in patients (94 vs. 53.6 ng/mL, p<0.05), and platelet activation (determined indirectly as the plasma concentration of PF4) was greater in cancer patients (129 vs. 48 IU/mL, p<0.01). Platelet activation correlated significantly with serum concentration of TSP-1 (r=0.470, p=0.018) and showed a tendency toward correlation with plasma concentration of TSP-1 (r=0.382, p=0.059). Our findings show that the circulating TSP-1/VEGF balance is diminished in cancer patients. Platelet activation may play an important role in this decrease and may ultimately lead to increased angiogenic activity in these patients. (Int J Biol Markers 2004; 19: 221-8).

Blood platelets contain tumor-derived RNA biomarkers

“…Interest in platelets and their ability to interact with intravascular components have enticed several groups to pursue the use of platelets as a protein source for cancer biomarkers and investigating their function in disease. [18][19][20][21][22] Several platelet proteins were identified as potential cancer biomarkers, including PF4 23 and thrombospondin-1. 24 Interestingly, thrombospondin-1 was shown to be a negative regulator of angiogenesis and affects plateletmediated recruitment of bone marrow-derived cells to sites of tumor angiogenesis.…”

Differential changes in platelet VEGF, Tsp, CXCL12, and CXCL4 in patients with metastatic cancer

“…As previously described, the platelet contents (per 10 6 platelets) of the above-mentioned factors were estimated by subtracting plasma VEGF/ CXCL12/TSP1/CXCL4 levels from serum levels [18]. However, hematocrits between cancer patients and healthy controls were significantly different.…”

“…In fact, the knock-out of tsp-1 and -2 resulted in complex changes of platelet function, including increased secretion of MMP9 and CXCL12 [15]. Platelets derived from a small sample of cancer patients were found to display a ''pro-angiogenic shift'' with relatively decreased contents of tsp-1 and relatively increased VEGF [18]. Nevertheless, platelets may influence malignant disease not only by modulating angiogenesis, but also by interference with anti-tumor immunity: the above-mentioned inhibition of metastasis in thrombocytopenic mice can be completely reversed by additional depletion of NK cells.…”

VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients

“…We have previously demonstrated [7] that the levels of angiogenesis regulatory proteins in circulating platelets of mice bearing human tumor xenografts change in tumor growth and can be used as markers of disease. Earlier studies have reported higher levels of vascular endothelial growth factor (VEGF) in platelets of patients with cancer [8,9]. However, they did not report on the coincident concentration of other angiogenesis regulators in platelets of patients with cancer.…”