Sequential binding of αVβ3 and ICAM-1 determines fibrin-mediated melanoma capture and stable adhesion to CD11b/CD18 on neutrophils.
Fibrin (Fn) deposition defines several type 1 immune responses, including delayed-type hypersensitivity and autoimmunity in which polymorphonuclear leukocytes (PMNs) are involved. Fn monomer and fibrinogen are multivalent ligands for a variety of cell receptors during cell adhesion. These cell receptors provide critical linkage among thrombosis, inflammation, and cancer metastasis under venous flow conditions. However, the mechanisms of Fn-mediated interactions among immune cells and circulating tumor cells remain elusive. By using a cone-plate viscometer shear assay and dual-color flow cytometry, we demonstrated that soluble fibrinogen and Fn had different abilities to enhance heterotypic aggregation between PMNs and Lu1205 melanoma cells in a shear flow, regulated by thrombin levels. In addition, the involvement of integrin α(v)β(3), ICAM-1, and CD11b/CD18 (Mac-1) in fibrin(ogen)-mediated melanoma-PMN aggregations was explored. Kinetic studies provided evidence that ICAM-1 mediated initial capture of melanoma cells by PMNs, whereas α(v)β(3) played a role in sustained adhesion of the two cell types at a shear rate of 62.5 s(-1). Quantitative analysis of the melanoma-PMN interactions conducted by a parallel-plate flow chamber assay further revealed that at a shear rate of 20 s(-1), α(v)β(3) had enough contact time to form bonds with Mac-1 via Fn, which could not otherwise occur at a shear rate higher than 62.5 s(-1). Our studies have captured a novel finding that leukocytes could be recruited to tumor cells via thrombin-mediated Fn formation within a tumor microenvironment, and α(v)β(3) and ICAM-1 may participate in multistep fibrin(ogen)-mediated melanoma cell adhesion within the circulation.
Department of Bioengineering, The Pennsylvania State University, University Park, PA 16802, USA.
Pu
P
Zhang
Tugba
T
Ozdemir
Chin-Ying
CY
Chung
Gavin P
GP
Robertson
Cheng
C
Dong
D000818:Animals; D001783:Blood Flow Velocity / Q000276:immunology; D039481:CD11b Antigen / Q000097:blood*; D018821:CD18 Antigens / Q000097:blood*; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D005337:Fibrin / Q000502:physiology*; D005340:Fibrinogen / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D039302:Integrin alphaVbeta3 / Q000378:metabolism* / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood* / Q000502:physiology; D008545:Melanoma / Q000097:blood / Q000276:immunology* / Q000556:secondary; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology*; D013927:Thrombosis / Q000097:blood / Q000276:immunology / Q000473:pathology
D039481:CD11b Antigen; D018821:CD18 Antigens; C509295:ITGAM protein, human; D018836:Inflammation Mediators; D039302:Integrin alphaVbeta3; D018799:Intercellular Adhesion Molecule-1; D005337:Fibrin; D005340:Fibrinogen