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Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL
| Content Provider | MDPI |
|---|---|
| Author | Vitale, Candida Griggio, Valentina Riganti, Chiara Todaro, Maria Kopecka, Joanna Jones, Rebecca Salvetti, Chiara Boccellato, Elia Perutelli, Francesca Voena, Claudia Godio, Laura Boccadoro, Mario Coscia, Marta |
| Copyright Year | 2021 |
| Description | 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. |
| Starting Page | 2883 |
| e-ISSN | 20726694 |
| DOI | 10.3390/cancers13122883 |
| Journal | Cancers |
| Issue Number | 12 |
| Volume Number | 13 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-06-09 |
| Access Restriction | Open |
| Subject Keyword | Cancers Oncology Chronic Lymphocytic Leukemia Tumor Microenvironment Hypoxia Inducible Factor-1α Cxcl12/cxcr4 Axis Drug Resistance |
| Content Type | Text |
| Resource Type | Article |
