Human T-cell lymphotropic virus type I-infected cells extravasate through the endothelial barrier by a local angiogenesis-like mechanism.
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.
Bazarbachi
Ali
A
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, PO Box 113-6044, Beirut, Lebanon. bazarbac@aub.edu.lb
Abou Merhi
Raghida
R
Gessain
Antoine
A
Talhouk
Rabih
R
El-Khoury
Hilda
H
Nasr
Rihab
R
Gout
Olivier
O
Sulahian
Rita
R
Homaidan
Fadia
F
de Thé
Hugues
H
Hermine
Olivier
O
El-Sabban
Marwan E
ME
D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002448:Cell Adhesion; D002450:Cell Communication; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D018031:Connexin 43 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D016355:Genes, pX; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018031:Connexin 43; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9