title: Activated tumor cell integrin αvβ3 cooperates with platelets to promote extravasation and metastasis from the blood stream.
abstract: Metastasis is the main cause of death in cancer patients, and understanding mechanisms that control tumor cell dissemination may lead to improved therapy. Tumor cell adhesion receptors contribute to cancer spreading. We noted earlier that tumor cells can expressing the adhesion receptor integrin αvβ3 in distinct states of activation, and found that cells which metastasize from the blood stream express it in a constitutively high affinity form. Here, we analyzed steps of the metastatic cascade in vivo and asked, when and how the affinity state of integrin αvβ3 confers a critical advantage to cancer spreading. Following tumor cells by real time PCR, non-invasive bioluminescence imaging, intravital microscopy and histology allowed us to identify tumor cell extravasation from the blood stream as a rate-limiting step supported by high affinity αvβ3. Successful transendothelial migration depended on cooperation between tumor cells and platelets involving the high affinity tumor cell integrin and release of platelet granules. Thus, this study identifies the high affinity conformer of integrin αvβ3 and its interaction with platelets as critical for early steps during hematogenous metastasis and target for prevention of metastatic disease.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weber
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Zuka
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Lorger
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Tschan
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Torbett
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Andries
authors.initials: A
authors.lastname: Zijlstra
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Quigley
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Staflin
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, CA 92103, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Eliceiri
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Krueger
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Marchese
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Zaverio M
authors.initials: ZM
authors.lastname: Ruggeri
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA. Electronic address: brunie@scripps.edu.
authors.forename: Brunhilde H
authors.initials: BH
authors.lastname: Felding
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis / Q000378:metabolism*; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*
chemical_list: D039302:Integrin alphaVbeta3
keywords: Blood stream; Extravasation; Integrin activation; Metastasis; Platelets