Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 264124, 5 pages http://dx.doi.org/10.1155/2013/264124 Review Article Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies Anna Carolina Carvalho da Fonseca1 and Behnam Badie2 1 Laboratório de Morfogênese Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil 2 Division of Neurosurgery and Department of Cancer Immunotherapeutics & Tumor Immunology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA Correspondence should be addressed to Behnam Badie; Received 23 April 2013; Accepted 3 June 2013 Academic Editor: Anirban Ghosh Copyright © 2013 A. C. Carvalho da Fonseca and B. Badie. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Malignant gliomas are the most common primary brain tumors. Their deadliest manifestation, glioblastoma multiforme (GBM), accounts for 15% of all primary brain tumors and is associated with a median survival of only 15 months even after multimodal therapy. There is substantial presence of microglia and macrophages within and surrounding brain tumors. These immune cells acquire an alternatively activated phenotype with potent tumor-tropic functions that contribute to glioma growth and invasion. In this review, we briefly summarize recent data that has been reported on the interaction of microglia/macrophages with brain tumors and discuss potential application of these findings to the development of future antiglioma therapies. 1. Introduction Malignant gliomas, the most common primary brain tumors that arise from glial cells within the central nervous system (CNS), are among the most fatal human cancers [1]. Glioblastoma multiforme (GBM), the most aggressive type of malignant glioma, is highly invasive, making tumor recurrence certain even after a complete resection [2]. Besides, the presence of the blood-brain barrier (BBB) significantly limits the penetration of most chemotherapeutic agents into the CNS [3]. With a median survival of only 14.6 months even after aggressive therapy with surgery, radiation, and chemotherapy, most patients succumb to their disease within two years of the initial diagnosis [4]. Thus, there is a pressing need for discovery of more effective therapies to improve patient outcomes. Malignant gliomas are heavily infiltrated by myeloidderived cells (recently reviewed by Kushchayev et al. [5]). Among these, tumor microglia and macrophages appear to be the most common cells in brain tumors. Tumor microglia arise from resident CNS macrophages, while circulating monocytes give rise to glioma-associated macrophages. In experimental glioma models, tumor microglia and macrophages can be differentiated by FACS based on CD45 and CD11b staining characteristics [6], but in human tissue samples, such separation is not as distinct. Although both cell types can acquire M1 phenotype and are capable of releasing proinflammatory cytokines, phagocytosis, and antigen presentation [7], their effector immune function in gliomas appears to be suppressed. In fact, increasing new evidence suggests that microglia and macrophages interact with the tumor cells by promoting their growth and migration [8]. In this review, we briefly summarize recent data that has been reported on microglia/macrophages brain tumor interaction and discuss potential application of these findings to the development of future antiglioma therapies. 2. Chemoattraction Glioma-associated microglia and macrophage (collectively referred to as GAMs here) compose approximately 30% of 2 tumor inflammatory cells and are actively recruited by gliomas through secretion of a variety of factors including chemokines, cytokines, and matrix proteins [9–13]. Among chemokine pathways involved in TAM chemoattraction, CCL2 (monocyte chemotactic protein-1 (MCP-1)) was among the first identified in gliomas [14]. Although CCL2 expression can be induced by a variety of stimuli and cytokines, mechanisms responsible for its baseline expression by gliomas are being studied. Adenosine-5󸀠 -triphosphate (ATP), for example, was shown to stimulate the production of chemokines MCP-1 and interleukin-8 (IL-8) in gliomas [15]. Recently, we demonstrated that in a subgroup of gliomas, protein S100 calcium binding protein B (S100B) may also play a role in MCP-1 upregulation and GAM recruitment [16]. A direct correlation between the percentage of GAMs and MCP-3 expression levels has also been demonstrated in human gliomas, suggesting MCP-3 to also participate in microglia/macrophages chemoattraction [12]. Stromal-derived (SDF-1) factor-1 is another chemokine that has been shown to promote microglia/macrophage trafficking in gliomas [17]. Trying to recapitulate neuropathological features of human high-grade glioma, Wang et al. established a new murine brain tumor model, ALTS1C1, which expresses high levels of SDF-1. To unveil the role of SDF-1 in this tumor model, the expression of this chemokine in tumor cells was inhibited. The density of microglia/macrophages in the SDF-knockdown tumor was higher in nonhypoxic than in hypoxic regions, suggesting that SDF-1 production by tumor cells might be crucial for the accumulation of microglia/macrophages into areas of hypoxia and tumor invasiveness [13]. Glioma and GAMs participate in a number of paracrine networks that promote their coexistence. Glioma cells constitutively express colony stimulating factor-1 (CSF-1) that stimulates microglia invasion through its receptor CSF1R. Synergistically, microglia stimulate glioma cell invasion through epidermal growth factor receptor (EGFR) activation [10]. Further, in response to glioma cells, microglia express tumor necrosis factor receptor of mouse embryo (TROY) that drives microglia migration towards glioma cells [18]. Also, the chemokine CX3CL1 expressed in glioblastoma cells promotes recruitment of human microglia/macrophages through its receptor CX3CR1 and enhances the expression of matrix metalloproteases 2, 9, and 14 in these cells, possibly promoting tumor invasion [11]. Glioma-initiating and cancer stem cells also have a role in recruiting microglia/macrophages. The former promote microglia migration through chemokines CCL5, vascular endothelial growth factor (VEGF) and neurotensin (NTS) release [19], while conditioned medium from the latter was shown to induce the migration of human monocytes [20]. 3. Immunosuppression After attracting microglia/macrophages, tumor cells establish an immunosuppressed microenvironment, leading GAMs to acquire an alternatively activated (M2) phenotype that further contributes to the local immunosuppression and Clinical and Developmental Immunology supports tumor growth and invasion [8, 21 (...truncated)