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Human T-Cell Lymphotropic Virus Type I-Infected Cells Extravasate through the Endothelial Barrier by a Local Angiogenesis-Like Mechanism

¹ Department of Internal Medicine, ³ Department of Biology, ⁴ Department of Human Morphology, and ⁶ Department of Physiology, American University of Beirut, Lebanon; ² Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France; ⁵ Fondation Rotschild, Paris, France; ⁷ Unité Propre de Recherche 9051, Centre National de la Recherche Scientifique, Laboratoire associé No. 11 du comité de Paris de la Ligue contre le Cancer, conventionné par l’Université Paris VII, Hôpital St. Louis, Paris, France; ⁸ Department of Clinical Hematology, Necker Hospital, Paris, France

Extravasation of tumor cells through the endothelial barrier is a critical step in cancer metastasis. Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is an aggressive disease characterized by visceral invasion. We show that ATL and HTLV-I-associated myelopathy patients exhibit high plasma levels of functional vascular endothelial growth factor and basic fibroblast growth factor. The viral oncoprotein Tax transactivates the promoter of the gap-junction protein connexin-43 and enhances gap-junction-mediated heterocellular communication with endothelial cells. The interaction of HTLV-I-transformed cells with endothelial cells induces the gelatinase activity of matrix metalloproteinase (MMP)-2 and MMP-9 in endothelial cells and down-regulates the tissue inhibitor of MMP. This leads to subendothelial basement membrane degradation followed by endothelial cell retraction, allowing neoplastic lymphocyte extravasation. We propose a model that offers a mechanistic explanation for extravasation of HTLV-I-infected cells: after specific adhesion to endothelia of target organs, tumor cells induce a local and transient angiogenesis-like mechanism through paracrine stimulation and direct cell-cell communication with endothelial cells. This culminates in a breach of the endothelial barrier function, allowing cancer cell invasion. This local and transient angiogenesis-like sequence that may facilitate visceral invasion in ATL represents a potential target for ATL therapy.

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