Hypothesis: are neoplastic macrophages/microglia present in glioblastoma multiforme?

Abstract

Most malignant brain tumours contain various numbers of cells with characteristics of activated or dysmorphic macrophages/microglia. These cells are generally considered part of the tumour stroma and are often described as TAM (tumour-associated macrophages). These types of cells are thought to either enhance or inhibit brain tumour progression. Recent evidence indicates that neoplastic cells with macrophage characteristics are found in numerous metastatic cancers of non-CNS (central nervous system) origin. Evidence is presented here suggesting that subpopulations of cells within human gliomas, specifically GBM (glioblastoma multiforme), are neoplastic macrophages/microglia. These cells are thought to arise following mitochondrial damage in fusion hybrids between neoplastic stem cells and macrophages/microglia.

Figure 1. Phagocytic behaviour of malignant glioma cells

(A) Phagocytic behaviour of the VM-M2 and macrophage RAW 264.7 cell lines was assessed from merging (Merge) the fluorescence (Fl) images and the differential interference contrast images after feeding the cells florescent beads. The image indicated that the malignant VM-M2 cells were phagocytic. (B) MNGC in a human GBM containing engulfed cell debris (arrow). (A) From Huysentruyt et al. (2008), reproduced with permission from Wiley, © 2008 Wiley-Liss, Inc. (B) Provided by A. Persson.

Figure 2. Fusogenic properties of malignant glioma cells

(A) The fusion hybrid hypothesis suggests that a macrophage×tumour-cell hybrid will express genetic and functional traits of both parental cells. (B) A bi-nucleated cell in human GBM expressing the macrophage fusion protein CD98 (arrows). (C) Human PXA demonstrating double immunoreactivity of the glial marker GFAP (brown) and macrophage CD68 (red). (B) From Takeuchi et al. (2008), reproduced with permission from Wiley, © 2007 Japanese Society of Neuropathology. (C) From Matyja et al. (2003), reproduced with permission from Folia Neuropathologica © Termedia.

Figure 3. Malignant glioma cells express macrophage-specific antigens

(A) Expression of the macrophage marker CD68 (Ki-M1P) in the human GBM cell line U138 (×475). (B) CD68 expression in most tumour cells of a human GBM (×400). (C) Expression of the macrophage/microglia marker Iba1 in tumour cells of the VM-M2 tumour, a mouse model of human GBM (×630). (A) From Paulus et al. (1992), with kind permission from Springer Science+Business Media: Acta Neuropathologica, Ki-MIP as a marker for microglia and brain macrophages in routinely processed human tissues, 84, 1992, 538–544, W Paulus, W Roggendorf and T Kirchner, © Springer-Verlag, 1992. (B) From Strojnik et al. (2009), reproduced with permission from International Institute of Cancer Research. (C) From Huysentruyt et al. (2008), reproduced with permission from Wiley, © 2008 Wiley-Liss, Inc.