In this issue of Blood, Klement and colleagues define a new role for platelets: to selectively sequester angiogenesis modulators in tumor-bearing animals. This may have implications for diagnosis and management of angiogenesis-related diseases.
If asked what platelets are good at, most of us would say that they plug holes in the vessel walls to prevent blood loss. They are our internal Band-Aids, momentarily releasing substances that regulate hemostasis. But they can also do other things.
About 1980 platelets were found to release, in parallel, wound-healing substances, initiating the repair of injured vessels and tissues. This is still a subject of pharmacologic explorations.1
More than a decade later, platelets were awarded a novel role: to be involved in angiogenesis by means of providing growth factors for endothelial cells, for example, vascular endothelial growth factor (VEGF). Subsequently, reports from the lab of the late Dr Judah Folkman, with partly the same authors as now, showed that thrombocytopenia conferred reduced angiogenesis,2 that angiogenesis regulating proteins were selectively pumped into the budding proplatelets from the mother megakaryocyte,3 and that platelet factor-4 is taken up by platelets in tumor-bearing animals.4 These results points to a give-and-take mode of work for a platelet.
In this issue, Klement et al expand on the “take” aspect.5 They show that the platelet concentrations of proteins that regulate angiogenesis were fairly constant in a healthy animal. However, in the presence of sponges containing either VEGF or microscopic tumors, all implanted in a mouse, blood platelets accumulated angiogenesis-regulating proteins (not only VEGF, but also platelet-derived growth factor, basic fibroblast growth factor, and endostatin). Most intriguingly, there was no change of the plasma levels of these angiogenesis-regulating proteins, meaning that this uptake was specific. Moreover, common plasma proteins, such as albumin, were not sequestered.
This discovery opens up thoughts about analyzing platelet content of selected angiogenesis factors (which has still to be determined) in order to find very small tumors before they can be detected by conventional methods. Another possibility is to follow progression or regression of tumors. This is good news since analysis of the same factors in plasma samples has not been helpful for these purposes.
As with all good research, a number of questions arise from the present results. One is where the uptake takes place. Is it when platelets pass by the tumor or does it occur in the bone marrow as part of the pumping of angiogenesis peptides from the megakaryocyte? There is evidence that certain proteins are soaked up by platelets in the liver or elsewhere in the periphery. So this is a yet unresolved question.
Do other cells also containing VEGF (for example, the neutrophils) behave in a similar way? Previous studies have suggested that higher VEGF content per platelet or neutrophil is found in malignancies than in controls.
Why do dormant tumors, without active angiogenesis, confer higher levels of certain angiogenic factors than angiogenesis active tumors, as shown in this paper? Is it just a matter of balance between pro- and antiangiogenesis (eg, endostatin) factors, as suggested by the present study?
Are the sequestered factors available for stimulating or suppressing angiogenesis at other sites? Some of the experiments presented here suggest that regular secretagogues for platelets were unable to cause release of the factors, which is, to some extent, contrary to previous reports. But that may be a matter of which secretagogue is used and the environment and engagement of specific receptors.
Is the sequestration process specific for the tumors used here or is it a universal process, independent of tumor type or localization? What about metastases?
To what extent is the same process seen in inflammatory disorders as in tumors? Can the analysis of the platelet proteome be used in inflammation where angiogenesis is part of the tissue remodeling, for example, in rheumatoid arthritis, Crohn disease, or fibrotic disorders? And can angiogenesis inhibitor therapy be steered by these findings?
The research reported here unveils a new aspect of platelet biology. Platelets not only give substances to the vicinity but also take them up, acting as selective sponges. It would be of great interest to follow the translation and capitalization of this research for human medicine.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
