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

Candida Vitale,Rebecca Jones,Francesca Perutelli,Mario Boccadoro,Chiara Salvetti,Elia Boccellato,Claudia Voena,Marta Coscia,Joanna Kopecka,Valentina Griggio,Laura Godio,Chiara Riganti,Maria Todaro

doi:10.3390/cancers13122883

Abstract

Simple SummaryIn 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.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.

Highlights

The hypoxia inducible factor 1 (HIF-1) transcription factor plays a pivotal role in cellular responses to hypoxia, both in normal and in neoplastic tissues, where it is often upregulated
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 chronic lymphocytic leukemia (CLL) cells and exerts anti-tumor effects, by acting both at the leukemic cell- and stromal cell-level
This finding was further corroborated by the observation that exposure to CXCL12 substantially recapitulated the stimulation exerted by stromal cells (SC) on RAS/ERK1-2 and PI3K/AKT signalling, and on HIF-1α accumulation and activity

Summary

Introduction

The hypoxia inducible factor 1 (HIF-1) transcription factor plays a pivotal role in cellular responses to hypoxia, both in normal and in neoplastic tissues, where it is often upregulated. HIF-1 supports metabolic adaptation, neoangiogenesis, cell survival and migration, with an overall disease-promoting effect [1]. In chronic lymphocytic leukemia (CLL) cells, HIF-1α is constitutively expressed compared to normal B cells [5], and it acts as an important regulator of the interplay between the neoplastic clone and the tumor microenvironment. The interaction with stromal cells (SC) induces HIF-1α in CLL cells, through an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, contributing to drug resistance mechanisms, leukemia survival and tumor propagation [6,7,8]. The underlying mechanisms have not been completely elucidated, and it is currently unknown whether SC-induced HIF-1α expression in CLL cells relies on direct cell-to-cell contact or soluble factors

Objectives

Methods

Results

Conclusion