The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas

Abstract

The peripheral benzodiazepine receptor (PBR) is a 18 kDa molecule mainly involved in cholesterol transport through the mitochondrial membrane. In microglia, PBR is expressed from the earliest stages of activation and appears to exert a pro-inflammatory function. This molecule is commonly up-regulated in inflammatory, degenerative, infective and ischaemic lesions of the central nervous system but it has never been reported in glioma-infiltrating microglia. We examined two anaplastic astrocytomas showing minimal contrast-enhancement and therefore little damage of the blood brain barrier to minimise the presence of blood borne macrophages within tumour tissue. The two lesions were studied in vivo using positron emission tomography (PET) with the specific PBR ligand [ 11 C](R)-PK11195 and the corresponding tumour tissue was investigated with an anti-PBR antibody. Glioma-infiltrating microglia were characterised for molecules involved in antigen presentation and cytotoxic activity. As comparison, PBR was investigated in three brains with multiple sclerosis (MS) and three with Parkinson's disease (PD). The expression profile of four anaplastic astrocytomas was also exploited and results were compared to the profile of eleven samples of normal temporal lobe and nine cases of PD. PET studies showed that [ 11 C](R)-PK11195 binding was markedly lower in tumours than in the contralateral grey matter. Pathological investigation revealed that glioma-infiltrating microglia failed to express PBR and cytotoxic molecules although some cells still expressed antigen presenting molecules. PBR and cytotoxic molecules were highly represented in MS and PD. Evaluation of microarray datasets confirmed these differences. Our results demonstrated PBR suppression in glioma-infiltrating microglia and suggested that PBR may have a relevant role in modulating the anti-tumour inflammatory response in astrocytic tumours.

The 18-kDa Mitochondrial Translocator Protein in Human Gliomas: An 11C-(R)PK11195 PET Imaging and Neuropathology Study

“…This tumor was a transforming astrocytoma in which anaplastic features were limited to a small component of the lesion, and the overall TSPO expression was as low as LGAs. Our results on tissue are consistent with previous studies that used immunohistochemistry to investigate TSPO in human astrocytomas (31,32) and documented variability in TSPO expression and some degree of overlap between WHO grade II and III lesions.…”

The 18-kDa mitochondrial translocator protein in gliomas: from the bench to bedside

“…Our experiments demonstrated that GAMs contribute minimally to TSPO expression in gliomas [25]. TSPO down-regulation in GAMs is particularly interesting and seems unique to gliomas confirming the results published by Takaya et al [14]. GAMs are known to increase substantially with tumour grade in astrocytomas and their morphology to be consistent with an activate state but they switch to a M2 phenotype with impairment of their cytotoxicity, antigen presentation and phagocytosis.…”

“…Both authors suggested a correlation between TSPO expression and outcome. Previously, Takaya et al [14] combined PET-imaging and neuropathology and observed low TSPO expression in two cases of anaplastic astrocytoma (AA) but also down-regulation in gliomaassociated microglia/macrophages (GAMs). Notably, none of previous studies investigated oligodendroglial tumours.…”

The Translocator Protein Radioligand 18F-DPA-714 Monitors Antitumor Effect of Erufosine in a Rat 9L Intracranial Glioma Model

“…It is important to note that Western blot results demonstrated high TSPO levels in the rodent glioma cell line 9L and C6, whereas TSPO expression was undetectable in murine GL261 glioma cells. Although high levels of TSPO density have been extensively reported in malignant brain tumors and successfully correlated to tumor proliferation and grade, one should also consider the existence of TSPO-negative gliomas (37). The differences observed between the treated and untreated groups relate to the higher degree of infiltration of CD11b-positive immune cells and GFAP-positive astrocytes in the tumors of ErPC3-treated animals with respect to control tumors (Fig.…”