Background-Tyrosine kinase inhibitors (TKIs) have advanced cancer treatment. Sunitinib, a recently-approved, multi-targeted TKI, prolongs survival for patients with metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST), but concerns about cardiac safety have arisen with this agent.

Clinical trials with antiangiogenic agents have not been able to validate plasma or serum levels of angiogenesis regulators as reliable markers of cancer presence or therapeutic response. We recently reported that platelets contain numerous proteins that regulate angiogenesis. We now show that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in platelets from non-tumor-bearing animals. This process is selective, as platelets do not take up a proportional amount of other plasma proteins (eg, albumin), even though these may be present at higher concentrations. We also find that VEGFenriched Matrigel pellets implanted subcutaneously into mice or the minute quantities of VEGF secreted by microscopic subcutaneous tumors (0.5-1 mm 3 ) result in an elevation of VEGF levels in platelets, without any changes in its plasma levels. The profile of other angiogenesis regulatory proteins (eg, platelet-derived growth factor, basic fibroblast growth factor) sequestered by platelets also reflects the presence of tumors in vivo before they can be macroscopically evident. The ability of platelets to selectively take up angiogenesis regulators in cancerbearing hosts may have implications for the diagnosis and management of many angiogenesis-related diseases and provide a guide for antiangiogenic therapies. IntroductionPlatelets play a major role in hemostasis, as well as in tissue repair, maintenance of endothelium, and vascular tone. They may also facilitate delivery of angiogenesis regulators and other growth factors to sites of pathologic angiogenesis. 1,2 Correlative studies suggest that increasing platelet counts may be linked to tumor progression. 3,4 We and others have reported previously that platelets contain several proteins that regulate angiogenesis. [5][6][7][8] We have now discovered that the platelet concentrations of angiogenesis regulatory proteins, although relatively constant and stable under physiologic conditions, are modified by and reflect the presence of a tumor. In the presence of microscopic (Ͻ 1.0 mm) tumors in a mouse, circulating platelets sequester increased concentrations of angiogenesis regulatory proteins, without a corresponding elevation in their plasma levels. The uptake of angiogenesis regulatory proteins is selective, as platelets do not take up other plasma proteins. For example, although albumin is present in plasma at much higher concentrations than, for example, vascular endothelial growth factor (VEGF), albumin levels in platelets do not differ in the presence or absence of tumors.In this study, we used a high-throughput surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry (SELDIToF MS), which permitted a rapid analysis of a large number of samples in a highly efficient and reproducible manner. 9,10 In this open-ended proteomic comparison of platelets from tumor-bearing and non-tumor-bearing animals, the majority of identified differentiall...

Complex cell behaviours are triggered by chemical ligands that bind to membrane receptors and alter intracellular signal transduction. However, future biosensors, medical devices and other microtechnologies that incorporate living cells as system components will require actuation mechanisms that are much more rapid, robust, non-invasive and easily integrated with solid-state interfaces. Here we describe a magnetic nanotechnology that activates a biochemical signalling mechanism normally switched on by binding of multivalent chemical ligands. Superparamagnetic 30-nm beads, coated with monovalent ligands and bound to transmembrane receptors, magnetize when exposed to magnetic fields, and aggregate owing to bead-bead attraction in the plane of the membrane. Associated clustering of the bound receptors acts as a nanomagnetic cellular switch that directly transduces magnetic inputs into physiological cellular outputs, with rapid system responsiveness and non-invasive dynamic control. This technique may represent a new actuator mechanism for cell-based microtechnologies and man-machine interfaces.