Glioma-initiating cells: A predominant role in microglia/macrophages tropism to glioma
Introduction
Glioma-initiating cells (GICs) have been proven to play key roles in growth, invasion, angiogenesis and immune evasion of glioma (Bao et al., 2006b, Stiles and Rowitch, 2008, Wei et al., 2010). They have also been identified as the sources of chemo- and radio-resistance (Bao et al., 2006a, McCord et al., 2009, Dey et al., 2010), which offers a new perspective and target to explore and treat glioma. The GIC niche determines the characteristics of GICs and controls the malignant behaviors of glioma (Calabrese et al., 2007). However, there is only limited knowledge about the composition of the GIC niche.
Inflammatory mediators and inflammatory cells are indispensable components of the neoplastic microenvironment (Mantovani et al., 2008). Cancer-related inflammation promotes tumorigenesis and progression. Ginestier et al. found that chronic inflammation can stimulate the proliferation of human breast cancer stem cells and contribute to the maintenance of their stemness (Ginestier et al., 2010). Veeravagu et al. hypothesized that inflammatory cells may be an important component of the GIC niche and modulate characteristics of GICs (Veeravagu et al., 2008). But, the relationship between GICs and inflammatory cells is unclear.
Tumor-associated microglia/macrophages (TAM/Ms), which represent the largest population of infiltrating inflammatory cells in malignant glioma (Graeber et al., 2002), promote the growth, invasion and immune evasion of glioma cells (Badie et al., 2002, Nakano et al., 2008, Hong et al., 2009). A number of tumor-derived chemoattractants are thought to ensure the TAM/Ms recruitment, including colony-stimulating factor-1 (CSF-1) (Imai and Kohsaka, 2002), the CC and CX3C chemokines (Platten et al., 2003, Okada et al., 2009, Held-Feindt et al., 2010), vascular endothelial growth factor (VEGF) (Forstreuter et al., 2002)and neurotensin (NTS) (Martin et al., 2003). The levels of many of these proteins in glioma have a positive correlation with the numbers of TAM/Ms present in those tumors. In this study, we found that TAM/M infiltration was positively correlated to the histological grade of the malignancies and the number of GICs. TAM/Ms always distributed around the GICs. GICs from human glioma tissues had a stronger potential to recruit human primary microglia than adhesive glioma cells (AGCs) and the implantations derived from GICs had a higher level of TAM/M infiltration than those derived from AGCs. Our results indicate that GICs play a predominant role in inducing the infiltration of TAM/Ms, which may then participate in the architecture of the GIC niche.
Section snippets
Case selection
Our study was approved by the Ethics Committee of Southwest Hospital, Third Military Medical University, Chongqing, PR China. 32 consecutive surgically resected astrocytomas were identified from the surgical pathology database of the Pathology Department of Daping Hospital, Third Military Medical University (Supplemental Table 1). None of the patients had undergone chemotherapy or radiotherapy before surgery except for two cases of recurrent glioblastoma. All tumors were selected and classified
TAM/M infiltration and the density of GICs in astrocytomas with different histological grades
Expression of Iba1, CD68 and CD133 was assessed by immunohistochemistry in paraffin sections of 32 gliomas with different WHO grades. With increasing malignancy, the mean proportion of Iba1+ cells in gliomas increased. The percentages of Iba1+ cells in gliomas were 9.2% in WHO grade II (Fig. 1A), 21.0% in WHO grade III (Fig. 1B) and 33.7% in WHO grade IV (Fig. 1C and D). Similarly, the expression levels of CD68, a marker well known to be expressed on TAM/Ms, also increased with malignant
Discussion
Our results confirmed that GICs play an important role in TAM/M infiltration into glioma. TAM/Ms are prominent in the stromal compartment of malignancies. Previous studies have shown that TAM/Ms account for about 5% to 30% of cells within glioma(Graeber et al., 2002, Watters et al., 2005) and produce cytokines and signals that promote glioma growth, invasion and angiogenesis(Zeisberger et al., 2006, Wesolowska et al., 2008, Hong et al., 2009). We found that TAM/M infiltration varied largely in
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
We thank technicians Wei Sun and Li-ting Wang (Central Laboratory, Third Military Medical University, Chongqing, China) for their technical assistance in laser confocal scanning microscopy. This project was supported by the National Basic Research Program of China (973 Program, No. 2010CB529403) and grants from the National Natural Science Foundation of China (NSFC, No. 30901538 and NSFC, No. 30973494).
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Liang Yi and Hualiang Xiao contributed equally to this work.