Human T-cell lymphotropic virus type 1–transformed cells induce angiogenesis and establish functional gap junctions with endothelial cells

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

“…Coculture experiments between leukemic cells and the endothelium revealed that HTLV-I-transformed cells adhere and communicate with endothelial cells, in agreement with our previous report (25). Coculture of HAECs with calceinlabeled HuT-102 cells produced a progressive transfer of fluorescence from the leukemic cells to the HAECs (Fig.…”

“…3D) and a significant increase in VEGF secretion in Tax-transfected HeLa cells (Fig. 3E), confirming our previous findings that HTLV-I-positive cells synthesize and secrete VEGF, presumably as a result of Tax-induced transcriptional activation of the VEGF gene (25).…”

“…The invasive nature of HTLV-I-associated diseases strongly suggests a possible interaction between HTLV-I-infected cells and endothelial cells. In that sense, we have recently shown that HTLV-I-positive cells communicate with endothelial cells through both paracrine stimulation and direct gap-junction-mediated heterocellular communication (25). Indeed, ATL-derived cells specifically secrete high levels of the angiogenic factors VEGF and bFGF, induce endothelial tube formation in vitro, and establish functional gap-junction-mediated communication with endothelial cells.…”

Loss of the ex vivo but not the reinducible CD8+ T-cell response to Tax in human T-cell leukemia virus type 1-infected patients with adult T-cell leukemia/lymphoma

“…That no ex vivo response was found in two patients with acute leukemia, but not in a patient with a chronic form suggests that the CD8 þ T cell priming defect might be linked to the degree of expansion of ATLL cells in vivo. Indeed, since ATLL cells have been shown to constitutively produce cytokines with immunosuppressive properties such as TGF-b, 26 IL-10, 25 and VEGF, 27 their massive proliferation in vivo could strongly impair the processes of CD8 þ T-cell proliferation and differentiation. Reduced priming of CD8 þ T cells could also be related to mechanism of immune escape developed in ATLL cells such as extinction of Tax expression [28][29][30] and/or decreased recognition of Tax epitopes due to downregulation of MHC-I expression 31 or mutations into immunodominant Tax epitopes.…”

Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-κB pathway

“…Tax also influences the microenvironment: it induces the synthesis of TGF-b, inhibits TGF-b signal transduction in infected cells, 21 induces angiogenesis, metalloproteinases and gap junction-mediated communication between infected cells and endothelial cells, 22 hence contributing to the extravasation and invasiveness of ATL cells. 23 Therefore, Tax is at the root of several aspects of the malignant transformation such as proliferation, growth factor independence, inactivation of tumor suppressors, resistance to apoptosis, genetic instability, tumor dissemination, immune escape and chemotherapy resistance.…”