Platelets actively sequester angiogenesis regulators.
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 VEGF-enriched 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 cancer-bearing hosts may have implications for the diagnosis and management of many angiogenesis-related diseases and provide a guide for antiangiogenic therapies.
Klement
Giannoula Lakka
GL
Children's Hospital, Boston, MA 02115, USA. giannoula_klement@dfci.harvard.edu
Yip
Tai-Tung
TT
Cassiola
Flavia
F
Kikuchi
Lena
L
Cervi
David
D
Podust
Vladimir
V
Italiano
Joseph E
JE
Wheatley
Erin
E
Abou-Slaybi
Abdo
A
Bender
Elise
E
Almog
Nava
N
Kieran
Mark W
MW
Folkman
Judah
J
D000244:Adenosine Diphosphate / Q000494:pharmacology; D042501:Angiogenic Proteins / Q000097:blood*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000637:transplantation; D003094:Collagen; D004338:Drug Combinations; D004343:Drug Implants; D043169:Endostatins / Q000097:blood; D016222:Fibroblast Growth Factor 2 / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007797:Laminin; D008080:Liposarcoma / Q000097:blood / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000097:blood / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000097:blood*; D015539:Platelet Activation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000032:analysis; D011509:Proteoglycans; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013917:Thrombin / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
D042501:Angiogenic Proteins; D004338:Drug Combinations; D004343:Drug Implants; D043169:Endostatins; D007797:Laminin; D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D000244:Adenosine Diphosphate; D003094:Collagen; D013917:Thrombin