The molecular profile of microglia under the influence of glioma

Abstract

Microglia, which contribute substantially to the tumor mass of glioblastoma, have been shown to play an important role in glioma growth and invasion. While a large number of experimental studies on functional attributes of microglia in glioma provide evidence for their tumor-supporting roles, there also exist hints in support of their anti-tumor properties. Microglial activities during glioma progression seem multifaceted. They have been attributed to the receptors expressed on the microglia surface, to glioma-derived molecules that have an effect on microglia, and to the molecules released by microglia in response to their environment under glioma control, which can have autocrine effects. In this paper, the microglia and glioma literature is reviewed. We provide a synopsis of the molecular profile of microglia under the influence of glioma in order to help establish a rational basis for their potential therapeutic use. The ability of microglia precursors to cross the blood-brain barrier makes them an attractive target for the development of novel cell-based treatments of malignant glioma.

Fig. 1.

Microglia in glioma are polarized. M1 (classically activated macrophages) and M2 (alternatively activated macrophages) differ with respect to activating signals, receptor expression, cytokine/chemokine production, and biological behavior. When mononuclear/phagocytic cells are stimulated by IFNγ, lipopolysaccharides, and other microbial products, they differentiate into the M1 phenotype. Microbial products are recognized by PRRs on the surface of M1, such as TLRs, and stimulate the production of pro-inflammatory cytokines as well as the expression of receptors that are involved in antigen presentation. When mononuclear/phagocytic cells are activated by IL-4, IL-13, IL-10, and M-CSF, they differentiate into the M2 phenotype. Tumor-derived molecules, such as TGF-β and M-CSF, can polarize glioma-infiltrating microglia/microphages (MMs) toward the M2 phenotype and accordingly stimulate the production of anti-inflammatory molecules. Some other glioma-derived molecules, such as MCP-1 and VEGF, can recruit myeloid cells into the tumor site.

Fig. 2.

Glioma-microglia synergies drive a self-amplifying process that spirals out of control. Glioma and microglial cells have a symbiotic relationship that becomes highly skewed in favor of the glioma. The immunosuppressive microenvironment created by molecules such as TGF-β, FasL, and IL-10 polarizes glioma-infiltrating microglia toward the M2 phenotype (cf. Fig. 1). Glioma (red) produces chemotactic factors, such as MCP-1, resulting in the recruitment of microglia. Glioma further promotes the proliferation of microglia. In turn, microglia (purple) promote glioma angiogenesis as well as glioma cell invasion. The cross talk between glioma and microglia is governed by multiple paracrine loops formed by glioma and microglia released molecules and their receptors, as indicated by superscript (P) in the figure. In addition, some of the molecules act in an autocrine fashion, as indicated by the superscript (A) and regulate either glioma or microglia behavior.