Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL
| العنوان: | Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL |
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| المؤلفون: | Francesca Perutelli, Elia Boccellato, Claudia Voena, Rebecca Jones, Laura Godio, Chiara Riganti, Chiara Salvetti, Mario Boccadoro, Candida Vitale, Valentina Griggio, Maria Todaro, Joanna Kopecka, Marta Coscia |
| المصدر: | Cancers Volume 13 Issue 12 Cancers, Vol 13, Iss 2883, p 2883 (2021) |
| بيانات النشر: | MDPI, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Stromal cell, Chronic lymphocytic leukemia, CXCR4, Article, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, medicine, tumor microenvironment, hypoxia inducible factor-1α, Gene, RC254-282, Tumor microenvironment, drug resistance, Chemistry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, CXCL12/CXCR4 axis, Oncology, Cancer research, chronic lymphocytic leukemia, Drug resistance, Hypoxia inducible factor-1α, Bone marrow, Idelalisib, 030215 immunology |
| الوصف: | Simple Summary In chronic lymphocytic leukemia (CLL), the interplay between the neoplastic clone and the tumor microenvironment largely contributes to leukemia survival, tumor propagation and drug resistance. A better understanding of the molecular circuits sustaining the biological effects of this microenvironment-induced support is fundamental for designing targeted treatment strategies that can be beneficial, especially for high-risk patients who fail standard therapy. In our study, we show that the targeting of the transcription factor HIF-1α or its regulatory pathways disrupts the mutual interactions occurring between the tumor microenvironment and CLL cells and exerts anti-tumor effects, by acting both at the leukemic cell- and stromal cell-level. HIF-1α and its regulatory pathways possibly represent appealing targets in the quest for novel strategies to overcome microenvironment-mediated tumor support in CLL. Abstract The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::502991e67eaf995394169500f625d1d9Test http://europepmc.org/articles/PMC8229189Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....502991e67eaf995394169500f625d1d9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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