Hypoxia-Driven M2-Polarized Macrophages Facilitate Cancer Aggressiveness and Temozolomide Resistance in Glioblastoma

Abstract

Hypoxia-induced M2 phenotypes of tumor associated macrophages (TAMs) promote the development and chemoresistance of multiple types of cancers, including glioblastoma (GBM). However, the detailed molecular mechanisms have not been fully understood. In this study, we firstly reported that hypoxic pressure promoted M2 macrophage generation, which further promoted cancer progression and temozolomide (TMZ) resistance in GBM through secreting vascular endothelial growth factor (VEGF). Specifically, the clinical data suggested that M2 macrophages were significantly enriched in GBM tissues compared with the adjacent normal tissues, and the following in vitro experiments validated that hypoxic pressure promoted M2-polarized macrophages through upregulating hypoxia-inducible factor-1α (HIF-1α). In addition, hypoxic M2 macrophages VEGF-dependently promoted cell proliferation, epithelial-mesenchymal transition (EMT), glioblastoma stem cell (GSC) properties, and TMZ resistance in GBM cells through activating the PI3K/Akt/Nrf2 pathway. Also, M2 macrophages secreted VEGF to accelerate angiogenesis in human umbilical vein endothelial cells (HUVECs) through interacting with its receptor VEGFR. In general, we concluded that hypoxic M2 macrophages contributed to cancer progression, stemness, drug resistance, and angiogenesis in GBM through secreting VEGF, and our data supported the notion that targeting hypoxia-associated M2 macrophages might be an effective treatment strategy for GBM in clinical practices.

Glioma-associated microglia/macrophages (GAMs) in glioblastoma: Immune function in the tumor microenvironment and implications for immunotherapy

“…For instance, specific GAMs that are absent in normal brain tissue were directly detected in the perivascular niche (merged with CD31 + vessels) ( 89 ). Furthermore, studies have not only verified the direct contact effect of GAMs with blood vessels around and inside the tumor using allografted mice but have also detected elevated levels of various angiogenesis-inducing factors, such as VEGF, VEGFR1, CCR2, CXCR4, CCL2/5, and CXCL2/10/14 ( 14 , 90 – 93 ). Recent research has confirmed the strong correlation between GAMs and tumor blood vessels in GBM patients and observed the restructuring of the blood vessel architecture, indicating the potential of anti-angiogenic therapy in the treatment of GBM ( 88 ).…”

Exploring Monocytes-Macrophages in Immune Microenvironment of Glioblastoma for the Design of Novel Therapeutic Strategies

“…However, long-term administration of TMZ generally generates resistance, limiting its efficacy. The contribution of macrophages to the therapeutic resistance of TMZ was also reported [ 99 ].…”

Temozolomide Resistance in Glioblastoma by NRF2: Protecting the Evil

“…Once active, AKT can regulate several downstream target genes related to glucose metabolism, apoptosis, and cell cycle progression [ 71 ]. A study observed that by secreting VEGF, hypoxic M2 macrophages were able to promote the activation of the PI3K/AKT/NRF2 pathway to enable TMZ resistance, as well as cancer aggressiveness and stemness in GBM cells [ 72 ].…”