4.6 Article

Sequential Binding of alpha(v)beta(3) and ICAM-1 Determines Fibrin-Mediated Melanoma Capture and Stable Adhesion to CD11b/CD18 on Neutrophils

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JOURNAL OF IMMUNOLOGY
卷 186, 期 1, 页码 242-254

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AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1000494

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资金

  1. National Institutes of Health [CA-127892, CA-125707]
  2. American Cancer Society [RSG-04-053-01-GMC]
  3. Foreman Foundation for Melanoma Research
  4. National Science Foundation [CBET 0729091]
  5. NATIONAL CANCER INSTITUTE [R01CA125707, R01CA127892] Funding Source: NIH RePORTER

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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 alpha(v)beta(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 alpha(v)beta(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), alpha(v)beta(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 alpha(v)beta(3) and ICAM-1 may participate in multistep fibrin(ogen)-mediated melanoma cell adhesion within the circulation. The Journal of Immunology, 2011, 186: 242-254.

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