Platelet and osteoclast beta3 integrins are critical for bone metastasis.
Mice with a targeted deletion of beta3 integrin were used to examine the process by which tumor cells metastasize and destroy bone. Injection of B16 melanoma cells into the left cardiac ventricle resulted in osteolytic bone metastasis in 74% of beta3+/+ mice by 14 days. In contrast, only 4% of beta3-/- mice developed bone lesions. Direct intratibial inoculation of tumor resulted in marrow replacement by tumor in beta3-/- mice, but no associated trabecular bone resorption as seen inbeta3+/+ mice. Bone marrow transplantation studies showed that susceptibility to bone metastasis was conferred by a bone marrow-derived cell. To dissect the roles of osteoclast and platelet beta3 integrins in this model of bone metastasis, osteoclast-defective src-/- mice were used. Src-null mice were protected from tumor-associated bone destruction but were not protected from tumor cell metastasis to bone. In contrast, a highly specific platelet aggregation inhibitor of activated alphaIIbbeta3 prevented B16 metastases. These data demonstrate a critical role for platelet alphaIIbbeta3 in tumor entry into bone and suggest a mechanism by which antiplatelet therapy may be beneficial in preventing the metastasis of solid tumors.
Bakewell
Suzanne J
SJ
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR and Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Nestor
Patrick
P
Prasad
Srinivasa
S
Tomasson
Michael H
MH
Dowland
Nikki
N
Mehrotra
Mukund
M
Scarborough
Robert
R
Kanter
James
J
Abe
Keith
K
Phillips
David
D
Weilbaecher
Katherine N
KN
D000818:Animals; D001792:Blood Platelets / Q000276:immunology*; D016026:Bone Marrow Transplantation; D001859:Bone Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D016391:Genes, src; D039661:Integrin beta3 / Q000235:genetics / Q000502:physiology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000276:immunology* / Q000473:pathology; D010014:Osteolysis / Q000276:immunology / Q000473:pathology; D040201:Platelet Membrane Glycoprotein IIb / Q000502:physiology
D039661:Integrin beta3; D040201:Platelet Membrane Glycoprotein IIb