PMID- 34207596
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210705
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 13
IP  - 12
DP  - 2021 Jun 9
TI  - Targeting HIF-1alpha Regulatory Pathways as a Strategy to Hamper 
      Tumor-Microenvironment Interactions in CLL.
LID - 10.3390/cancers13122883 [doi]
LID - 2883
AB  - 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 alpha subunit of HIF-1 (HIF-1alpha) 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-1alpha 
      upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. 
      HIF-1alpha 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-1alpha was also observed in idelalisib-treated patients, who 
      showed, along with a downregulation of HIF-1alpha 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-1alpha 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.
FAU - Vitale, Candida
AU  - Vitale C
AUID- ORCID: 0000-0002-2592-8724
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Griggio, Valentina
AU  - Griggio V
AUID- ORCID: 0000-0003-1589-1195
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Riganti, Chiara
AU  - Riganti C
AUID- ORCID: 0000-0001-9787-4836
AD  - Department of Oncology, University of Torino, via Santena 5, 10126 Torino, Italy.
FAU - Todaro, Maria
AU  - Todaro M
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Kopecka, Joanna
AU  - Kopecka J
AUID- ORCID: 0000-0003-3612-3953
AD  - Department of Oncology, University of Torino, via Santena 5, 10126 Torino, Italy.
FAU - Jones, Rebecca
AU  - Jones R
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Salvetti, Chiara
AU  - Salvetti C
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Boccellato, Elia
AU  - Boccellato E
AUID- ORCID: 0000-0001-5202-2621
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Perutelli, Francesca
AU  - Perutelli F
AUID- ORCID: 0000-0002-7538-9626
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Voena, Claudia
AU  - Voena C
AUID- ORCID: 0000-0002-1324-1431
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Godio, Laura
AU  - Godio L
AD  - Division of Pathology, A.O.U. Citta della Salute e della Scienza di Torino, via 
      Santena 5, 10126 Torino, Italy.
FAU - Boccadoro, Mario
AU  - Boccadoro M
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
FAU - Coscia, Marta
AU  - Coscia M
AUID- ORCID: 0000-0003-2123-7675
AD  - University Division of Hematology, A.O.U. Citta della Salute e della Scienza di 
      Torino, via Genova 3, 10126 Torino, Italy.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Torino, 
      via Nizza 52, 10126 Torino, Italy.
LA  - eng
GR  - Local funds (ex 60%)/Universita degli Studi di Torino/
GR  - IG15232/Associazione Italiana per la Ricerca sul Cancro/
GR  - IG21408/Associazione Italiana per la Ricerca sul Cancro/
PT  - Journal Article
DEP - 20210609
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC8229189
OTO - NOTNLM
OT  - CXCL12/CXCR4 axis
OT  - chronic lymphocytic leukemia
OT  - drug resistance
OT  - hypoxia inducible factor-1alpha
OT  - tumor microenvironment
COIS- C.V. (Candida Vitale) has received consultancy fees from Janssen. M.B. has 
      received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers 
      Squibb and AbbVie; has served on the advisory boards for Janssen and GSK; has 
      received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, 
      Bristol-Myers Squibb and Mundipharma. M.C. received honoraria from Janssen, 
      Gilead, Abbvie, Shire and research support from Janssen and Karyopharm 
      Therapeutics. The remaining authors declare no conflicts of interest.
EDAT- 2021/07/03 06:00
MHDA- 2021/07/03 06:01
PMCR- 2021/06/09
CRDT- 2021/07/02 01:32
PHST- 2021/04/29 00:00 [received]
PHST- 2021/05/26 00:00 [revised]
PHST- 2021/06/04 00:00 [accepted]
PHST- 2021/07/02 01:32 [entrez]
PHST- 2021/07/03 06:00 [pubmed]
PHST- 2021/07/03 06:01 [medline]
PHST- 2021/06/09 00:00 [pmc-release]
AID - cancers13122883 [pii]
AID - cancers-13-02883 [pii]
AID - 10.3390/cancers13122883 [doi]
PST - epublish
SO  - Cancers (Basel). 2021 Jun 9;13(12):2883. doi: 10.3390/cancers13122883.