Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer.
The role of platelets in tumor progression and metastasis has been recognized but the mechanism of their action remains unclear. Five human lung cancer cell lines (A549, CRL 2066, CRL 2062, HTB 183, HTB 177) and a murine Lewis lung carcinoma (LCC) cell line (for an in vivo model of metastasis) were used to investigate how platelet-derived microvesicles (PMV), which are circular fragments shed from the surface membranes of activated platelets, and exosomes released from platelet alpha-granules, could contribute to metastatic spread. We found that PMV transferred the platelet-derived integrin CD41 to most of the lung cancer cell lines tested and stimulated the phosphorylation of mitogen-activated protein kinase p42/44 and serine/threonine kinase as well as the expression of membrane type 1-matrix metalloproteinase (MT1-MMP). PMV chemoattracted 4 of the 5 cell lines, with the highly metastatic A549 cells exhibiting the strongest response. In A549 cells, PMV were shown to stimulate proliferation, upregulate cyclin D2 expression and increase trans-Matrigel chemoinvasion. Furthermore, in these cells, PMV stimulated mRNA expression for angiogenic factors such as MMP-9, vascular endothelial growth factor, interleukin-8 and hepatocyte growth factor, as well as adhesion to fibrinogen and human umbilical vein endothelial cells. Intravenous injection of murine PMV-covered LLC cells into syngeneic mice resulted in significantly more metastatic foci in their lungs and LLC cells in bone marrow than in control animals injected with LCC cells not covered with PMV. Based on these findings, we suggest that PMV play an important role in tumor progression/metastasis and angiogenesis in lung cancer.
Janowska-Wieczorek
Anna
A
Department of Medicine & Oncology, University of Alberta, Edmonton, Canada.
Wysoczynski
Marcin
M
Kijowski
Jacek
J
Marquez-Curtis
Leah
L
Machalinski
Bogdan
B
Ratajczak
Janina
J
Ratajczak
Mariusz Z
MZ
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000378:metabolism / Q000556:secondary*; D002448:Cell Adhesion; D049109:Cell Proliferation; D002633:Chemotaxis; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D053511:Matrix Metalloproteinase 14; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D015539:Platelet Activation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D016209:Interleukin-8; C507096:Mmp14 protein, mouse; D010980:Platelet Membrane Glycoproteins; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D005340:Fibrinogen; D020929:Mitogen-Activated Protein Kinase Kinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14