EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation
| Autor: | Francisco José Ortuño, Miguel A. Flores, Gloria Soler, Dolores García, Luis Miguel Alonso-Colmenar, Paula Fortea, Eva M. Trinidad, Agustín G. Zapata |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Integrin alpha4 Apoptosis Mice 0302 clinical medicine immune system diseases hemic and lymphatic diseases Tumor Cells Cultured Protein Isoforms Medicine CD11a Antigen RNA Small Interfering Cells Cultured Aged 80 and over B-Lymphocytes Mice Inbred BALB C biology leukemia Middle Aged Ephrin-A4 Extravasation ephrin Specific Pathogen-Free Organisms Leukemia medicine.anatomical_structure Oncology Lymphatic Metastasis 030220 oncology & carcinogenesis Female RNA Interference Tumor necrosis factor alpha Research Paper Endothelium integrin Cell Survival High endothelial venules Integrin Inmunología Context (language use) 03 medical and health sciences Human Umbilical Vein Endothelial Cells Animals Humans Hematología Aged Biología celular Tumor Necrosis Factor-alpha business.industry Transendothelial and Transepithelial Migration medicine.disease Leukemia Lymphocytic Chronic B-Cell Xenograft Model Antitumor Assays Coculture Techniques 030104 developmental biology Immunology Cancer research biology.protein Lymph Nodes business extravasation |
| Zdroj: | E-Prints Complutense. Archivo Institucional de la UCM instname Oncotarget E-Prints Complutense: Archivo Institucional de la UCM Universidad Complutense de Madrid |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.10311 |
| Popis: | A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival. |
| Databáze: | OpenAIRE |
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