Glioma-initiating cells: A predominant role in microglia/macrophages tropism to glioma

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Abstract

The relationship between cancer-initiating cells and cancer-related inflammation is unclear. Exploring the interaction between glioma-initiating cells (GICs) and tumor-associated microglia/macrophages (TAM/Ms) may offer us an opportunity to further understand the inflammatory response in glioma and the cellular/molecular features of the GIC niche. Here,we reported a positive correlation between the infiltration of TAM/Ms and the density of GICs. The capacity of GICs to recruit TAM/Ms was stronger than that of adhesive glioma cells (AGCs) in vitro. In vivo experiments suggested that implantations formed by GICs had a higher level of TAM/M infiltration than those formed by AGCs. Our studies indicate a predominant role of GICs in microglia/macrophages tropism to glioma and a close positive correlation between the distribution of GICs and TAM/Ms. As an important part of cancer-related inflammation, TAM/Ms may participate in the architecture of the GIC niche.

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).

References (40)

  • S. Bao et al.

    Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor

    Cancer Res.

    (2006)
  • D. Battista et al.

    Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus

    Eur. J. Neurosci.

    (2006)
  • C. Ginestier et al.

    CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

    J. Clin. Invest.

    (2010)
  • M.B. Graeber et al.

    Microglia in brain tumors

    Glia

    (2002)
  • H.S. Han et al.

    The function and integrity of the neurovascular unit rests upon the integration of the vascular and inflammatory cell systems

    Curr. Neurovasc. Res.

    (2005)
  • T.M. Hong et al.

    Induced interleukin-8 expression in gliomas by tumor-associated macrophages

    J. Neurooncol.

    (2009)
  • Y. Imai et al.

    Intracellular signaling in M-CSF-induced microglia activation: role of Iba1

    Glia

    (2002)
  • B. Johnson et al.

    Physiology and therapeutics of vascular endothelial growth factor in tumor immunosuppression

    Curr. Mol. Med.

    (2009)
  • M. Kerber et al.

    Flt-1 signaling in macrophages promotes glioma growth in vivo

    Cancer Res.

    (2008)
  • C.E. Lewis et al.

    Distinct role of macrophages in different tumor microenvironments

    Cancer Res.

    (2006)
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    Liang Yi and Hualiang Xiao contributed equally to this work.

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