Tumor-Associated Microglia/Macrophages Enhance the Invasion of Glioma Stem-like Cells via TGF-β1 Signaling Pathway

Abstract

The invasion of malignant glioma cells into the surrounding normal brain tissues is crucial for causing the poor outcome of this tumor type. Recent studies suggest that glioma stem-like cells (GSLCs) mediate tumor invasion. However, it is not clear whether microenvironment factors, such as tumor-associated microglia/macrophages (TAM/Ms), also play important roles in promoting GSLC invasion. In this study, we found that in primary human gliomas and orthotopical transplanted syngeneic glioma, the number of TAM/Ms at the invasive front was correlated with the presence of CD133(+) GSLCs, and these TAM/Ms produced high levels of TGF-β1. CD133(+) GSLCs isolated from murine transplanted gliomas exhibited higher invasive potential after being cocultured with TAM/Ms, and the invasiveness was inhibited by neutralization of TGF-β1. We also found that human glioma-derived CD133(+) GSLCs became more invasive upon treatment with TGF-β1. In addition, compared with CD133(-) committed tumor cells, CD133(+) GSLCs expressed higher levels of type II TGF-β receptor (TGFBR2) mRNA and protein, and downregulation of TGFBR2 with short hairpin RNA inhibited the invasiveness of GSLCs. Mechanism studies revealed that TGF-β1 released by TAM/Ms promoted the expression of MMP-9 by GSLCs, and TGFBR2 knockdown reduced the invasiveness of these cells in vivo. These results demonstrate that TAM/Ms enhance the invasiveness of CD133(+) GSLCs via the release of TGF-β1, which increases the production of MMP-9 by GSLCs. Therefore, the TGF-β1 signaling pathway is a potential therapeutic target for limiting the invasiveness of GSLCs.

IQGAP1 in Podosome /Invadosome is Involved in the Progression of Glioblastoma Multiforme Depending on the Tumor Status

“…The proinflammatory phenotype of the GBM associated microglial cell seems to be suppressed within the GBM environment becoming a cell that promotes glioma cell migration, neither oligodendrocytes nor endothelial cells promoted the migration and the effects of macrophages from the periphery on glioma growth are different from those of microglia [38]. TAMs were mainly located in the marginal area (Supplemental Figure S2), close to nestin + GSCs and both around microvessels CD31 + endothelial cells ( Figure 2F-O) confirming data reported by Ye et al [40]. This fact, along with pericyte-endothelial interactions, favours pathological angiogenesis [30] exhibiting a highly invasive potential.…”

“…During tumor invasion, GBM cells from the tumor migrate towards the neighbouring normal tissue by extending their edge actin-rich cancer-specific membrane protrusions forming invadopodia with the ability to infiltrate and degrade physical barriers, such as basement membranes, extracellular matrix (ECM), and cell junctions by metalloproteinases (MMPs) [30,35,36]; podosome/invadopodia are identified for their high expression levels of F-actin and/or cortactin [46]. The role of IQGAP1 as a scaffold protein in the delivering process of MMPs has been demonstrated in cell lines and animal models, as C. elegans, zebrafish, sea squirt, mice and rat [33,40,47,48]. Figure 7 is a simplified model of some of the proteins involved in the podosome/invadopodia generation mechanism and a model of the involvement of IQGAP1 in GBM progression based on the present study.…”

IQGAP1 in Podosomes/Invadosomes Is Involved in the Progression of Glioblastoma Multiforme Depending on the Tumor Status

“…The proinflammatory phenotype of the GBM associated microglial cell seems to be suppressed within the GBM environment becoming a cell that promotes glioma cell migration, neither oligodendrocytes nor endothelial cells promoted the migration and the effects of macrophages from the periphery on glioma growth are different from those of microglia [38]. TAMs were mainly located in the marginal area (Supplementary Materials, Figure S2), close to nestin + GSCs and both around microvessels CD31 + endothelial cells (Figure 2F-O) confirming data reported by Ye et al [40]. This fact, along with pericyte-endothelial interactions, favors pathological angiogenesis [30] exhibiting a highly invasive potential.…”

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma

“…The protocol was performed as previously described. 41 Sections deparaffinized and rehydrated in graded alcohols. After antigen retrieval, sections were blocked with 2% goat serum in PBS for 1 h and then incubated overnight with antibodies to ObR (1:1000; Abcam) and CD133 (1:100; Cell Signaling Technology).…”