Unique Ability of Integrin αvβ3 to Support Tumor Cell Arrest under Dynamic Flow Conditions

Shear-resistant arrest of circulating tumor cells is required for metastasis from the blood stream. Arrest during blood flow can be supported by tumor cell interaction with attached, activated platelets. This is mediated by tumor cell integrin αvβ3 and cross-linking plasma protein ligands. To analyze the mechanism of tumor cell ligand interactions under dynamic flow conditions, we used real-time video microscopy and tested human melanoma cell binding to fibrinogen, von Willebrand Factor, or fibronectin matrices in a buffer perfusion system. When perfused at venous flow, melanoma cells arrested abruptly and began to spread immediately. This was uniquely mediated by integrin αvβ3 on all tested ligands, and required αvβ3 activation and actin polymerization. Under static conditions, αvβ3 cooperated with αvβ1 and α5β1 in supporting melanoma cell adhesion to fibronectin. But even when activated, β1 integrins did not contribute to melanoma cell arrest during flow. Soluble ligand served as a cross-linker between attached and circulating tumor cells and enhanced melanoma cell arrest. Cohesion of activated melanoma cells was restricted to the matrix surface and did not occur in suspension. We conclude that the presence of αvβ3 in a functionally activated state provides a unique advantage for circulating tumor cells by promoting tumor cell arrest in the presence of flow-dependent shear forces. Shear-resistant arrest of circulating tumor cells is required for metastasis from the blood stream. Arrest during blood flow can be supported by tumor cell interaction with attached, activated platelets. This is mediated by tumor cell integrin αvβ3 and cross-linking plasma protein ligands. To analyze the mechanism of tumor cell ligand interactions under dynamic flow conditions, we used real-time video microscopy and tested human melanoma cell binding to fibrinogen, von Willebrand Factor, or fibronectin matrices in a buffer perfusion system. When perfused at venous flow, melanoma cells arrested abruptly and began to spread immediately. This was uniquely mediated by integrin αvβ3 on all tested ligands, and required αvβ3 activation and actin polymerization. Under static conditions, αvβ3 cooperated with αvβ1 and α5β1 in supporting melanoma cell adhesion to fibronectin. But even when activated, β1 integrins did not contribute to melanoma cell arrest during flow. Soluble ligand served as a cross-linker between attached and circulating tumor cells and enhanced melanoma cell arrest. Cohesion of activated melanoma cells was restricted to the matrix surface and did not occur in suspension. We conclude that the presence of αvβ3 in a functionally activated state provides a unique advantage for circulating tumor cells by promoting tumor cell arrest in the presence of flow-dependent shear forces. phosphate-buffered saline bovine serum albumin monoclonal antibody Metastasis to distant organs is a key characteristic of malignancy. This often involves the blood stream, where circulating tumor cells are exposed to flow-dependent shear forces that physically oppose tumor cell anchorage. Tumor cell arrest within the vasculature is required for intravascular growth and extravasation within target organs of metastasis (1Al Mehdi A.B. Tozawa K. Fisher A.B. Shientag L. Lee A. Muschel R.J. Nat. Med. 2000; 6: 100-102Crossref PubMed Scopus (570) Google Scholar, 2Wong C.W. Lee A. Shientag L., Yu, J. Dong Y. Kao G., Al Mehdi A.B. Bernhard E.J. Muschel R.J. Cancer Res. 2001; 61: 333-338PubMed Google Scholar, 3Chambers A.F. MacDonald I.C. Schmidt E.E. Koop S. Morris V.L. Khokha R. Groom A.C. Cancer Metastasis Rev. 1995; 14: 279-301Crossref PubMed Scopus (224) Google Scholar). Arrest at the vessel wall depends on specific adhesive mechanisms rather than passive entrapment, because tumor cell variants that differ in their adhesion receptor outfits have distinct metastatic activities, and blocking of specific adhesion receptors can inhibit metastasis (4Orr F.W. Wang H.H. Lafrenie R.M. Scherbarth S. Nance D.M. J. Pathol. 2000; 190: 310-329Crossref PubMed Scopus (250) Google Scholar). Tumor cell arrest during blood flow can be supported by tumor cell interaction with activated platelets (5Felding-Habermann B. Habermann R. Saldivar E. Ruggeri Z.M. J. Biol. Chem. 1996; 271: 5892-5900Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 6Felding-Habermann B. O'Toole T.E. Smith J.W. Fransvea E. Ruggeri Z.M. Ginsberg M.H. Hughes P.E. Pampori N. Shattil S.J. Saven A. Mueller B.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1853-1858Crossref PubMed Scopus (481) Google Scholar, 7Nierodzik M.L. Klepfish A. Karpatkin S. Thromb. 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Biol. 2000; PubMed Scopus Google Scholar). with and arrest of cells at matrices by supporting and is that the state of tumor cell integrins is in a and the of circulating metastatic cells to arrest within the of adhesive tumor cell in a blood perfusion to distinct of tumor cell integrin αvβ3 B. O'Toole T.E. Smith J.W. Fransvea E. Ruggeri Z.M. Ginsberg M.H. Hughes P.E. Pampori N. Shattil S.J. Saven A. Mueller B.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1853-1858Crossref PubMed Scopus (481) Google Scholar). When blood tumor cells a of and interactions can because blood cells and plasma the adhesive of the tumor of and activation during blood flow are to and to the of the system. We the to mechanisms of tumor cell ligand interaction in the presence of flow shear forces. We a buffer perfusion with real-time video microscopy and adhesive interactions of human melanoma cells with matrix under a of flow We that integrin αvβ3 the unique to melanoma cell arrest during flow on matrix and β1 integrins in melanoma cell adhesion to the under conditions, to contribute to melanoma cell when the cells in To melanoma cell integrin αvβ3 to be interaction the flow of circulating melanoma and the receptor with actin to cell Soluble ligand enhanced melanoma cell arrest during flow by supporting melanoma cell at the matrix This did not occur in and did not with cell arrest at the contribute to of specific adhesive that tumor from the blocking monoclonal used to analyze the of integrins to melanoma cell Ginsberg M.H. J. Biol. Chem. Full Text PDF PubMed Google Thromb. Haemost. 2001; PubMed Scopus Google and A. J. Biol. PubMed Scopus Google Scholar). (5Felding-Habermann B. Habermann R. Saldivar E. Ruggeri Z.M. J. Biol. Chem. 1996; 271: 5892-5900Abstract Full Text Full Text PDF PubMed Scopus (140) Google K. E. R. Ruggeri Z.M. PubMed Google used to melanoma cell integrin by flow and from of was from of the and was by plasma fibronectin was from and human von Willebrand was a from Ruggeri and from and from human melanoma their J. Biol. Chem. Full Text PDF PubMed Google and the B. Mueller B.M. J. 1992; PubMed Scopus Google in bovine and in cells tested from during for the cells in with in and in for the adhesion or perfusion cell adhesion under static was in at with fibrinogen, von Willebrand Factor, or and with at and melanoma cell was in with blocking or When the cells with the for at the cell to the adhesion cells to for at and by the cell and cells by with of cells by with in as was with and the was at in cell adhesion was on than of adhesion on specific for Tumor cell arrest during flow was by real-time video microscopy as (5Felding-Habermann B. Habermann R. Saldivar E. Ruggeri Z.M. J. Biol. Chem. 1996; 271: 5892-5900Abstract Full Text Full Text PDF PubMed Scopus (140) Google with specific melanoma cells with in buffer at for and used as the of a flow and with a of fibrinogen, fibronectin or von Willebrand in at for in a the flow the with the with buffer and to a cell was to and at the perfusion the of the to as the in the cell perfused at a wall shear of the cell was by buffer the as the cell the flow. of perfusion at the wall shear was and by the flow to as the in the the perfusion and interactions and at of the tumor adhesion was by the of the to and by at the during the of the and during the of the the was at the exposed to wall shear for To cell adhesion and to the of attached or the by the of arrested cells in was at with attached with video on a microscopy was used to analyze the of integrin αvβ3 in to actin in melanoma cells arrest on a matrix during flow B. B. Ginsberg M.H. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). melanoma cells perfused at a venous wall shear of a or fibronectin the the flow was in perfusion buffer to in shear cells with with with and with a of and by and at in and at on a of the of arrested cells in of at with to or with to in the of the To analyze the of integrin αvβ3 and the specific for αvβ3 and for of and was by of and of αvβ3 and was a and the of and was and We that human tumor cells can to activated platelets during blood flow, and that plasma are required for interaction (5Felding-Habermann B. Habermann R. Saldivar E. Ruggeri Z.M. J. Biol. Chem. 1996; 271: 5892-5900Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 6Felding-Habermann B. O'Toole T.E. Smith J.W. Fransvea E. Ruggeri Z.M. Ginsberg M.H. Hughes P.E. Pampori N. Shattil S.J. Saven A. Mueller B.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1853-1858Crossref PubMed Scopus (481) Google Scholar). To analyze the mechanism of tumor cell ligand binding during flow, we a buffer perfusion and matrix to the of and interactions that can when tumor cells are in blood and to When in buffer and perfused fibrinogen, von Willebrand or fibronectin matrices at a venous wall shear of human melanoma cells arrested at of of cells was to the surface as perfusion cells that in with the matrix arrested abruptly and began to spread video of in This of the is to as the in the in and To the of melanoma cell during flow, the cell was by buffer the flow, and the wall shear was to and This of the is to as the in the in melanoma cell to of the tested matrix wall shear at This that melanoma adhesion can in matrix interaction and the flow of the matrix under flow as in the venous melanoma cell arrest during flow. or cells perfused von Willebrand or fibronectin in buffer at a venous wall shear of during flow and perfusion of or cells fibronectin. the wall shear was and the or cells perfused at in the presence or of blocking or cells are variants of in αvβ3 was by during flow, and are under This a video the for the video in the that αvβ3 cell arrest during flow on a fibronectin matrix during venous flow and that cell arrest is in the presence of wall shear to cells in the and cells in the of the of the the of the at where the cell are perfused at a wall shear of of the video where the cell by buffer the flow, and the wall shear of the video at the ligand for melanoma cell arrest during flow. cells perfused a matrix at a venous wall shear of in the presence or of the cell was by buffer the flow, and the wall shear was during flow at in or and are under This a video the for the video in the that cell arrest at a matrix during venous flow by supporting at the matrix that not is in the presence of wall shear cells perfused at in the presence or the of of the of the at where the cell perfused at a wall shear of of the video where the cell by buffer the flow, and the wall shear of the video at the We adhesion supported melanoma cell arrest on fibrinogen, von Willebrand Factor, or fibronectin matrices under dynamic flow We that integrin αvβ3 can tumor cell interaction with platelets during blood flow and tumor cell arrest. To αvβ3 can melanoma cell arrest at matrix we cells their and video from in cells arrested on of the tested matrix and the was to wall shear cells to to of the tested matrix to arrest during flow was in to αvβ3 This that integrin αvβ3 is required for melanoma cell arrest under flow This was by blocking cell arrest on of the tested matrix with a blocking cell arrest was in the presence of that the within of the tested is and to αvβ3 mediated ligand binding and cell arrest during flow than adhesion receptor that can cell to of the tested matrix J. Biol. Chem. Full Text PDF PubMed Google Scholar, B. Mueller B.M. J. 1992; PubMed Scopus Google Scholar). is by αvβ3 and von Willebrand is by and fibronectin is by αvβ1 and to αvβ3 A.C. J. Sci. 1995; Google Scholar, J. J. 1996; Full Text PDF PubMed Scopus Google Scholar). Under conditions, cells attached to and von Willebrand in a because cells to to matrix within the αvβ3 cooperated with integrins to melanoma cell adhesion under static cells and cells attached to fibronectin and adhesion to fibronectin not be by blocking to of But a of and cell adhesion to fibronectin by and a of and adhesion by than in α5β1 as their fibronectin adhesion to protein was by blocking or antibody This that integrin αvβ3 with integrins and β1 integrins in supporting melanoma cell adhesion to fibronectin under static of adhesion receptors was of supporting static when the receptors the of integrin α5β1 supported melanoma cell adhesion to fibronectin during with integrins in supporting static melanoma cell αvβ3 is the receptor on melanoma cells that cell arrest under dynamic flow melanoma cell adhesion to fibronectin was by activation is required for and during blood flow D.G. S. Ginsberg M.H. Thromb. Haemost. 2001; PubMed Scopus Google Scholar, B. Ruggeri Z.M. 2001; PubMed Scopus Google Scholar). We that arrest of tumor cells depends on integrin activation B. O'Toole T.E. Smith J.W. Fransvea E. Ruggeri Z.M. Ginsberg M.H. Hughes P.E. Pampori N. Shattil S.J. Saven A. Mueller B.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1853-1858Crossref PubMed Scopus (481) Google Scholar). To analyze the activation state of tumor cell integrin αvβ3 the of the receptor to cell arrest on we melanoma cells to fibrinogen, von Willebrand or fibronectin in the presence of to the tumor cell in To a activation of integrins with melanoma cell arrest in the of integrin we cells under the When perfused at a venous wall shear of melanoma cell arrest was with cells in the presence of cells arrested on of the tested matrix But cells to with tested matrix when perfused in cells not to of the tested matrices under dynamic flow conditions, of the This that integrin αvβ3 to be activated to tumor cell arrest during flow and that integrin by and cells can the not even when α5β1 is by and cells and supported cell adhesion to fibronectin under static To analyze the of α5β1 in to we tested melanoma cell adhesion during in the presence of cell adhesion to fibronectin was and the of attached cells to by of cells began to to fibronectin during the of and the of attached cells a This that the fibronectin receptor of in to because cells attached to fibronectin in than in in α5β1 activation was not to cell arrest under dynamic flow to melanoma cell adhesion in than in was with cells on all tested matrix cells did not fibrinogen, or von Willebrand as adhesive of the with the of α5β1 to melanoma cell adhesion to fibronectin was not to melanoma cell arrest during flow of tumor cells to arrest under dynamic flow is for circulating metastatic on specific mechanisms that their within the vasculature of target that integrin αvβ3 the unique to melanoma cell arrest during flow, when the receptor is in the are for because cell adhesion by the of αvβ3 for Smith J.W. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, Smith J.W. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, K. Smith J.W. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). we tested activated αvβ3 can melanoma cell arrest during flow at To we under static enhanced cell adhesion to fibrinogen, as a of integrin We the cells to to in the presence of the of cell adhesion by at was not when was Under venous flow, cell arrest on was in the presence of with perfusion cell arrest was at a did not melanoma cell arrest. on fibronectin and von Willebrand This that activated integrin αvβ3 can tumor cell arrest at matrices in the presence of as in integrin αvβ3 arrest of melanoma cells under venous flow When the the tumor cells arrested This that activated adhesion and not adhesion the tumor cells attached, melanoma cells to wall shear at This is the adhesion receptor the ligand and the interaction is the perfusion we that melanoma in with the matrix began to spread immediately. involves of the and actin Nat. Rev. Biol. 2001; PubMed Scopus Google Scholar). melanoma cells that arrested at a matrix surface during venous flow, integrin αvβ3 and actin the and at the of the where cells the matrix of actin by cell with or or melanoma cell arrest at venous flow and shear cell on the This that melanoma cell arrest activated the of adhesion the actin in and activated as the adhesion with the actin This tumor cell is required for melanoma cell arrest during flow. cells perfused a matrix at a venous wall shear of for in the presence or of or the cell was by buffer the flow, and the wall shear was during flow at in or and are under tumor cell integrin αvβ3 ligand B. O'Toole T.E. Smith J.W. Fransvea E. Ruggeri Z.M. Ginsberg M.H. Hughes P.E. Pampori N. Shattil S.J. Saven A. Mueller B.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1853-1858Crossref PubMed Scopus (481) Google Scholar, N. D.G. S. Shattil S.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (140) Google Scholar). metastatic cells are by plasma of are for We with for αvβ3 binding and with tumor cell arrest at a when the adhesion receptor is To melanoma cells perfused a matrix in the presence of Under venous flow conditions, melanoma cell arrest was not enhanced by the of fibrinogen, served as cross-linking ligand between attached and circulating tumor cells and the video for in Cohesion of activated melanoma cells was restricted to the matrix surface and did not occur in suspension. the presence of melanoma cell at the matrix surface during venous flow, when the wall shear was to But tumor cells that attached to the matrix interaction is to shear that depends on cross-linking αvβ3 ligand is that binding of ligand by activated integrin αvβ3 not with tumor cell depends on the of the activated of ligand rather tumor cell arrest by promoting at the matrix This is for the arrest of metastatic tumor cells within blood at wall shear Tumor cell arrest within the vasculature is a for metastasis from the blood stream. Tumor cells to of the vessel of to within the or the cells and to within the of their target (1Al Mehdi A.B. Tozawa K. Fisher A.B. Shientag L. Lee A. Muschel R.J. Nat. Med. 2000; 6: 100-102Crossref PubMed Scopus (570) Google Scholar, 2Wong C.W. Lee A. Shientag L., Yu, J. Dong Y. Kao G., Al Mehdi A.B. Bernhard E.J. Muschel R.J. Cancer Res. 2001; 61: 333-338PubMed Google Scholar, 3Chambers A.F. MacDonald I.C. Schmidt E.E. Koop S. Morris V.L. Khokha R. Groom A.C. Cancer Metastasis Rev. 1995; 14: 279-301Crossref PubMed Scopus (224) Google Scholar). tumor cells are exposed to shear is by blood flow and physically cell Tumor cell arrest depends on specific adhesive tumor cell (4Orr F.W. Wang H.H. Lafrenie R.M. Scherbarth S. Nance D.M. J. Pathol. 2000; 190: 310-329Crossref PubMed Scopus (250) Google and are from that tumor cell under static We that tumor cells can arrest during blood flow by binding to the surface of attached and activated platelets. This interaction plasma as cross-linking (5Felding-Habermann B. Habermann R. Saldivar E. Ruggeri Z.M. J. Biol. Chem. 1996; 271: 5892-5900Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). we the mechanism of tumor cell matrix interaction during flow in a buffer perfusion to contribute to a of tumor cell adhesive in the presence of flow-dependent shear forces. we the cells can to plasma under venous flow the tested melanoma cell arrest during flow is uniquely mediated by integrin of the tested matrix αvβ3 with integrins and with β1 integrins to melanoma cell adhesion under static conditions, αvβ3 is the receptor on melanoma cells that cell arrest during flow. αvβ3 activation is required for of melanoma cell arrest. is to melanoma cell arrest during flow. of activated αvβ3 to ligand melanoma cell arrest under dynamic flow by promoting adhesion of circulating tumor cells to matrix attached we human melanoma because are to the blood for metastatic To analyze adhesive tumor cell under flow conditions, we perfused melanoma cells matrices of fibrinogen, von Willebrand Factor, or fibronectin. plasma are because to contribute to metastasis M.L. Klepfish A. Karpatkin S. Thromb. Haemost. 1995; 74: 282-290Crossref PubMed Scopus (143) Google Scholar, A.F. 2000; PubMed Google Scholar). as adhesive when at the surface of activated or or as of the Under static human melanoma cells to αvβ3 and to von Willebrand and to fibronectin and α5β1 J. Biol. Chem. Full Text PDF PubMed Google Scholar, B. Mueller B.M. J. 1992; PubMed Scopus Google Scholar, L. Smith J.W. J. Biol. PubMed Scopus Google Scholar). Under flow conditions, cell arrest was uniquely mediated by integrin the receptors not contribute to cells not the fibronectin receptor can contribute to arrest on matrix E. R. R. J. Biol. 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Biol. 2000; PubMed Scopus Google Scholar, D.G. S. Ginsberg M.H. Thromb. Haemost. 2001; PubMed Scopus Google Scholar). We that tumor cell integrin be activated to arrest of human cells B. O'Toole T.E. Smith J.W. Fransvea E. Ruggeri Z.M. Ginsberg M.H. Hughes P.E. Pampori N. Shattil S.J. Saven A. Mueller B.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1853-1858Crossref PubMed Scopus (481) Google Scholar). cells can αvβ3 in activated and the cells are metastatic the activated receptor B. O'Toole T.E. Smith J.W. Fransvea E. Ruggeri Z.M. Ginsberg M.H. Hughes P.E. Pampori N. Shattil S.J. Saven A. Mueller B.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1853-1858Crossref PubMed Scopus (481) Google Scholar). melanoma cells can arrest during blood flow interaction with platelets (5Felding-Habermann B. Habermann R. Saldivar E. Ruggeri Z.M. J. Biol. Chem. 1996; 271: 5892-5900Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). This that at a of cells αvβ3 in activated or in a state in αvβ3 activated during blood flow the buffer perfusion melanoma cell αvβ3 to be activated with to melanoma cell arrest at This to that αvβ3 activation was required for of melanoma cell arrest during flow, activation of integrins as by adhesion during was not to contribute to matrix interaction during flow. that the buffer perfusion provides a for the activation state of αvβ3 to analyze that or tumor cell integrin αvβ3 of αvβ3 activation the adhesive of tumor cells in the of blood flow and metastasis B. O'Toole T.E. Smith J.W. Fransvea E. Ruggeri Z.M. Ginsberg M.H. Hughes P.E. Pampori N. Shattil S.J. Saven A. Mueller B.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1853-1858Crossref PubMed Scopus (481) Google Scholar). state of integrin adhesion receptors is by integrin receptor within the plasma and to the integrin and receptor Y. Biol. 2000; PubMed Scopus Google Scholar, D.G. S. Ginsberg M.H. Thromb. Haemost. 2001; PubMed Scopus Google Scholar). be by to cell adhesion in the presence of flow-dependent shear forces. that of the melanoma cell integrins that the tested ligands, specific cells that in with of the tested matrices during flow arrested and began to spread This was by of the of the cell surface and of the adhesion receptor with of actin melanoma cell arrest. of αvβ3 within the involves of actin as for adhesion J. E.J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google as as of actin and of that the integrin to the A. Shattil S.J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S.J. Thromb. Haemost. PubMed Scopus Google Scholar). was that activated αvβ3 is to the of cells Shattil S.J. Pampori N. Nat. Biol. 2001; PubMed Scopus Google Scholar). with that activated not αvβ3 tumor cell arrest under flow, that the activated receptor specific that dynamic matrix interactions and mechanisms that the receptor to of of integrin activation is the to We that activated melanoma cell integrin αvβ3 fibrinogen, and in to that of in with that or plasma protein of tumor cell with platelets during blood flow (5Felding-Habermann B. Habermann R. Saldivar E. Ruggeri Z.M. J. Biol. Chem. 1996; 271: 5892-5900Abstract Full Text Full Text PDF PubMed Scopus (140) Google we in the buffer perfusion that supported of circulating melanoma cells to cells attached to the matrix did not of melanoma adhesion and of circulating tumor cells to a mechanism to that for growth B. Ruggeri Z.M. 2001; PubMed Scopus Google Scholar). that circulating tumor cells of activation a adhesion integrin to tumor cell arrest at a matrix or on ligand at the surface of arrest that the receptor to activated of the adhesion receptor or enhanced as and are of tumor cell arrest. the of activated integrin to activation provides a unique advantage for circulating tumor cells by promoting tumor cell arrest in the presence of flow-dependent shear forces. This be during metastasis from the and tumor cells that can in the metastatic We Ruggeri of for to the video microscopy and for with