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Lymphotoxin-ß Receptor Immune Interaction Promotes Tumor Growth by Inducing Angiogenesis¹

Departments of Pathology/Tumor Immunology [T. H., B. S., P. S., P. M., D. N. M.] and Surgery [G. C., M. G., M. S.], University of Regensburg, D-93042 Regensburg, Germany; Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, D-81675 Munich, Germany [K. P.]; and Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119991 Moscow, Russia [S. A. N.]

Growth of solid fibrosarcoma tumors in mice was inhibited by the release of a solublelymphotoxin-ß receptor inhibitor (LTßR-immunoglobulin fusion protein) from the tumor cells. Tumor growth arrest in mice deficient in the ligand LT₁ß₂ demonstrated the requirement for activation of the LTßR on the tumor cells by host cell-derived LT₁ß₂. Activation of the LTßR resulted in enhanced release of macrophage inflammatory protein-2. Blocked angiogenesis was revealed in LTßR inhibitor-producing tumor nodules by immunohistochemistry and in vivo microscopy. The growth arrest of LTßR inhibitor-producing fibrosarcomas was overcome by forced MIP-2 expression in the tumor cells. Thus, LTßR activation on tumor cells by activated host lymphocytes can initiate a novel proangiogenic pathway leading to organized tumor tissue development.

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