The angiogenic responses induced by release of angiogenic proteins from tumor cell‐activated platelets are regulated by distinct molecular pathways

Abstract

There is mounting evidence that tumor angiogenesis can be regulated by platelets (Plts), which serve as major sources and delivery vehicles of many proangiogenic cytokines including transforming growth factor-b and vascular endothelial growth factor. Although considerable progress has been made in understanding the role for Plt secretion in tumor angiogenesis, very little is known about the precise mechanisms underlying cancer cell induction of Plt granule release. Here, we demonstrated that nonsmall cell lung cancer (NSCLC) cells directly induced Plt secretion of several angiogenic regulatory cytokines that promoted angiogenesis in concert. Moreover, we discovered that these Plt-derived angiogenesis modulators were regulated by different molecular pathways and could be largely inhibited by combination of multiple signaling inhibitors. Our present studies indicated that manipulation of Plt secretion of angiogenic cytokines without compromising hemostatic functions could provide a novel option for management of tumor angiogenesis and metastasis in NSCLC patients with thrombocytosis. V C 2015 IUBMB Life, 67(8):626-633, 2015

Targeting Platelets for the Treatment of Cancer

“…In addition to their ability to release angiogenic factors upon activation, platelets can also sequester VEGF, as evidenced by the preferential accumulation of VEGF in platelets compared to plasma or other cells after subcutaneous injection of radiolabeled VEGF into mice [ 69 , 70 ]. Wu et al, have recently demonstrated that non-small cell lung cancer (A549)-activated platelet releasate can stimulate angiogenesis even in the presence of VEGF neutralising antibody [ 71 ]. Therefore, platelet-derived VEGF contributes to tumour angiogenesis but is not essential as activated platelets can also release microvesicles and exosomes to induce expression of angiogenic factors in cancer cells [ 11 ].…”

Integrin β3/Akt signaling contributes to platelet-induced hemangioendothelioma growth

“…There is accumulating evidence indicating that platelets are activated to release pro-angiogenic factors in response to neighbor cells, including tumor cells 23, 29–31 . This may account for the observed platelet-induced increases in EOMA cell proliferation.…”

“…Wu et al . reported that lung cancer cells could induce platelets to release several pro-angiogenic factors, including IL-1α, GM-CSF, MMP-1 and VEGF, resulting in enhanced endothelial cell migration and capillary tube formation 23 . However, when we evaluated CD62P surface levels we did not observe significant activation by EOMA cells.…”

“…Activated platelets released several trophic factors from specialized intracellular granules, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet-derived endothelial cell growth factor (PDGF), to support the survival and growth of endothelial cells 19–21 . Tumor cells can induce the activation of platelets, resulting in the promotion of tumor angiogenesis and the facilitation of cancer progression 22, 23 . Additionally, integrin β3, an abundant glycoprotein on the platelet plasma membrane, plays an important role in hypoxia-induced retinal angiogenesis and fetal angiogenesis, suggesting direct platelet-endothelium contact can mediate endothelial cell proliferation 24, 25 .…”

Resveratrol inhibits VEGF‐induced angiogenesis in human endothelial cells associated with suppression of aerobic glycolysis via modulation of PKM2 nuclear translocation

“…Capillary tube formation was performed as we described previously . Briefly, Matrigel was added into 24‐well plates (100 μL/well) and solidified in a 37°C incubator.…”