Mechanisms Involved in the Promoting Activity of Fibroblasts in HTLV-1-Mediated Lymphomagenesis: Insights into the Plasticity of Lymphomatous Cells

• Published in: International journal of molecular sciences Vol. 22; no. 19; p. 10562
• Main Authors: Rigotto, Giulia, Montini, Barbara, Mattiolo, Adriana, Lazzari, Nayana, Piano, Maria Assunta, Remondini, Daniel, Marmiroli, Sandra, Bertacchini, Jessika, Chieco-Bianchi, Luigi, Calabrò, Maria Luisa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.09.2021; MDPI
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Apoptosis; Aspirin - pharmacology; Cancer; Cell Line; Cells, Cultured; Coculture Techniques; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - virology; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Human T-lymphotropic virus 1 - physiology; Humans; Infections; Jurkat Cells; Kinases; Leukemia; Lymphoma; Lymphoma - drug therapy; Lymphoma - genetics; Lymphoma - virology; Metabolism; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - virology; Phosphorylation; Principal components analysis; Proteins; Signal Transduction - drug effects; Signal Transduction - genetics; Xenograft Model Antitumor Assays - methods; plasticity; HTLV-1; cancer stem cells; lymphomagenesis; ATLL; stemness
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms221910562

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of surface and intracellular markers linked to plasticity and stemness in coculture, and in vivo experiments were performed. A transcriptomic comparison between a more lymphomagenic (C91/III) and the parental (C91/PL) cell line evidenced hyperactivation of the PI3K/Akt pathway, confirmed by phospho-ELISA and 2-DE and WB analyses. C91/III cells also showed higher expression of mesenchymal and stemness genes. Short-term coculture with human foreskin fibroblasts (HFF) induced these features in C91/PL cells, and significantly increased not only the cancer stem cells (CSCs)-supporting CD10+GPR77+ HFF subpopulation, but also the percentage of ALDH1bright C91/PL cells. A non-cytotoxic acetylsalicylic acid treatment decreased HFF-induced ALDH1bright C91/PL cells, downregulated mesenchymal and stemness genes in cocultured cells, and delayed lymphoma growth in immunosuppressed mice, thus hindering the supportive activity of HFF on CSCs. These data suggest that crosstalk with HFF significantly intensifies the aggressiveness and plasticity of C91/PL cells, leading to the enrichment in lymphoma-initiating cells. Additional research is needed to better characterize these preliminary findings.