Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL

Cancers

Claudia Voena¹  Chiara Riganti²  Joanna Kopecka²  Laura Godio³  Mario Boccadoro⁴  Francesca Perutelli⁴  Marta Coscia⁴  Candida Vitale⁴  Valentina Griggio⁴  Maria Todaro⁴  Chiara Salvetti⁴  Elia Boccellato⁴  Rebecca Jones⁴ 

[1] Department of Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, 10126 Torino, Italy;Department of Oncology, University of Torino, via Santena 5, 10126 Torino, Italy;Division of Pathology, A.O.U. Città della Salute e della Scienza di Torino, via Santena 5, 10126 Torino, Italy;University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, via Genova 3, 10126 Torino, Italy;

关键词: chronic lymphocytic leukemia;    tumor microenvironment;    hypoxia inducible factor-1α;    CXCL12/CXCR4 axis;    drug resistance;   

DOI  :  10.3390/cancers13122883

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown