Francesca Caccuri1, Christine Rueckert, Cinzia Giagulli, Kai Schulze, Daniele Basta, Sonia Zicari, Stefania Marsico, Edoardo Cervi, Simona Fiorentini, Mark Slevin, Carlos A Guzman, Arnaldo Caruso. 1. From the Microbiology Section, Department of Molecular and Translational Medicine (F.C., C.G., D.B., S.Z., S.F., A.C.) and Section of Vascular Surgery, Department of Medical and Surgical Sciences (E.C.), University of Brescia, Brescia, Italy; Animal Models and Retroviral Vaccine Section, National Cancer Institute, National Institutes of Health, Bethesda, MD (F.C.); Department of Vaccinology and Applied Microbiology, Helmholtz Centre of Infection Research, Braunschweig, Germany (C.R., K.S., C.A.G.); Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende (Cosenza), Italy (S.M.); and School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom (M.S.).
Abstract
OBJECTIVE: AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. APPROACH AND RESULTS: Human primary lymph node-derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node-derived lymphatic endothelial cells and activating the Akt/extracellular signal-regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node-derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. CONCLUSIONS: Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.
OBJECTIVE:AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. APPROACH AND RESULTS:Human primary lymph node-derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node-derived lymphatic endothelial cells and activating the Akt/extracellular signal-regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node-derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. CONCLUSIONS: Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.
Authors: Virginia A Carroll; Mark K Lafferty; Luigi Marchionni; Joseph L Bryant; Robert C Gallo; Alfredo Garzino-Demo Journal: Proc Natl Acad Sci U S A Date: 2016-10-31 Impact factor: 11.205
Authors: Francesca Caccuri; Serena Messali; Alberto Zani; Giovanni Campisi; Marta Giovanetti; Stefania Zanussi; Emanuela Vaccher; Silvia Fabris; Antonella Bugatti; Emanuele Focà; Francesco Castelli; Massimo Ciccozzi; Riccardo Dolcetti; Robert C Gallo; Arnaldo Caruso Journal: Proc Natl Acad Sci U S A Date: 2022-06-28 Impact factor: 12.779
Authors: Riccardo Dolcetti; Cinzia Giagulli; Wangxiao He; Marina Selleri; Francesca Caccuri; Lindsay M Eyzaguirre; Pietro Mazzuca; Silvia Corbellini; Federica Campilongo; Stefania Marsico; Emanuela Giombini; Elena Muraro; Gabriella Rozera; Paolo De Paoli; Antonino Carbone; Maria Rosaria Capobianchi; Giuseppe Ippolito; Simona Fiorentini; William A Blattner; Wuyuan Lu; Robert C Gallo; Arnaldo Caruso Journal: Proc Natl Acad Sci U S A Date: 2015-11-02 Impact factor: 11.205