This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanaka, Y. Articles by Eto, S. Search for Related Content PubMed PubMed Citation Articles by Tanaka, Y. Articles by Eto, S.

Constitutive Up-Regulation of Integrin-mediated Adhesion of Tumor-infiltrating Lymphocytes to Osteoblasts and Bone Marrow-derived Stromal Cells¹

First Department of Internal Medicine [Y. T., S. M., I. M., S. E.], Second Department of Surgery [T. Ha., K. Y.] and Department of Orthopedics [T. N.], School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807 Japan; First Department of Oral Anatomy, School of Dentistry, Niigata University, Niigata 951, Japan [T. Hi., H. O.]; Department of Tumor Immunology, University Hospital Nijmegen, 6525 EX Nijmegen, the Netherlands [C. G. F., Y. v. K.].

Tumor-reactive T cells, known as tumor-infiltrating lymphocyte(TIL)s are known to infiltrate various tumors. Although TILs exert cytotoxic activities against tumor cells, only a small percentage of tumors usually contain TILs that specifically react to tumor antigens. Because the exact role of these lymphocytes is unclear, we investigated the mechanisms of migration and adhesion of TILs to bone metastatic tumors, particularly to osteoblasts and bone marrow-derived stromal cell(BMSC)s. Histopathological examination showed that most TILs in secondary bone metastatic tumors (from primary tumors in the lung or breast) were found in the supporting tissue stroma between the bone and tumor mass. Cultured TILs (obtained from breast tumors) adhered spontaneously to osteoblasts and BMSCs (obtained from patients with osteoarthritis) without exogenous stimulation. Adhesion was further enhanced by chemokines macrophage inflammatory protein (MIP)-1 and MIP-1ß. TILs highly expressed activation antigens CD25 and CD69. A spontaneous activation of an integrin, lymphocyte function-associated antigen-1 (LFA-1), was also detected on TILs. TILs produced high concentrations of MIP-1 and MIP-1ß and spontaneous polymerization of cytoskeletal F-actin was observed in these cells. Adhesion of TILs to osteoblasts and BMSCs via LFA-1 and very late antigen-4 was associated with the production of osteoclastogen interleukin 6 by the latter cells. Our results indicate that integrins on TILs are activated in an autocrine manner by MIP-1 and MIP-1ß, and that treatment with the chemokines increases the binding of TILs on osteoblasts and stromal cells via a mechanism involving intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as targets for the integrin. Our data also indicated that interactions between TILs and osteoblasts/stromal cells lead to the secretion by the latter of the osteoclastogenic cytokine interleukin 6.

¹ This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.

² To whom requests for reprints should be addressed, at First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu 807, Japan. Phone: 81-93-603-1611; Fax: 81-93-691-9334; E-mail: tanaka@med.uoeh-u.ac.jp.

Received 3/23/98. Accepted 7/16/98.

This article has been cited by other articles:

				R. S. Taichman Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche Blood, April 1, 2005; 105(7): 2631 - 2639. [Abstract] [Full Text] [PDF]

				A. M. Hanash and R. B. Levy Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation Blood, February 15, 2005; 105(4): 1828 - 1836. [Abstract] [Full Text] [PDF]

				Z. Qiuping, L. Qun, H. Chunsong, Z. Xiaolian, H. Baojun, Y. Mingzhen, L. Chengming, H. Jinshen, G. Qingping, Z. Kejian, et al. Selectively Increased Expression and Functions of Chemokine Receptor CCR9 on CD4+ T Cells from Patients with T-Cell Lineage Acute Lymphocytic Leukemia Cancer Res., October 1, 2003; 63(19): 6469 - 6477. [Abstract] [Full Text] [PDF]

				B. O. Oyajobi, G. Franchin, P. J. Williams, D. Pulkrabek, A. Gupta, S. Munoz, B. Grubbs, M. Zhao, D. Chen, B. Sherry, et al. Dual effects of macrophage inflammatory protein-1{alpha} on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease Blood, July 1, 2003; 102(1): 311 - 319. [Abstract] [Full Text] [PDF]

				M. Yasuda, M. Takenoyama, Y. Obata, M. Sugaya, T. So, T. Hanagiri, K. Sugio, and K. Yasumoto Tumor-infiltrating B Lymphocytes as a Potential Source of Identifying Tumor Antigen in Human Lung Cancer Cancer Res., March 1, 2002; 62(6): 1751 - 1756. [Abstract] [Full Text] [PDF]

				M. Kobayashi, E. Azuma, M. Ido, M. Hirayama, Q. Jiang, S. Iwamoto, T. Kumamoto, H. Yamamoto, M. Sakurai, and Y. Komada A Pivotal Role of Rho GTPase in the Regulation of Morphology and Function of Dendritic Cells J. Immunol., October 1, 2001; 167(7): 3585 - 3591. [Abstract] [Full Text] [PDF]

				M. Yasuda, Y. Tanaka, M. Tamura, K. Fujii, M. Sugaya, T. So, M. Takenoyama, and K. Yasumoto Stimulation of {beta}1 Integrin Down-Regulates ICAM-1 Expression and ICAM-1-dependent Adhesion of Lung Cancer Cells through Focal Adhesion Kinase Cancer Res., March 1, 2001; 61(5): 2022 - 2030. [Abstract] [Full Text]

				Y. Tanaka, Y. Minami, S. Mine, H. Hirano, C.-D. Hu, H. Fujimoto, K. Fujii, K. Saito, J. Tsukada, Y. van Kooyk, et al. H-Ras Signals to Cytoskeletal Machinery in Induction of Integrin-Mediated Adhesion of T Cells J. Immunol., December 1, 1999; 163(11): 6209 - 6216. [Abstract] [Full Text] [PDF]

				T. Fujisaki, Y. Tanaka, K. Fujii, S. Mine, K. Saito, S. Yamada, U. Yamashita, T. Irimura, and S. Eto CD44 Stimulation Induces Integrin-mediated Adhesion of Colon Cancer Cell Lines to Endothelial Cells by Up-Regulation of Integrins and c-Met and Activation of Integrins Cancer Res., September 1, 1999; 59(17): 4427 - 4434. [Abstract] [Full Text] [PDF]