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Patients with malignant glioma (MG) are often treated with corticosteroids to reduce cerebral edema, but chronic use of steroids may cause glucose intolerance and development of type 2 diabetes (Db). Individuals with Db not only have significantly higher likelihood of developing malignant tumors, but also, have a higher risk of cancer-related mortality than non-Db patients. The goal of this study was to evaluate the effect of hyperglycemia on glioma growth in mouse models. Because MG are heterogeneous tumors with both invasive and “nodular” phenotypes, two different syngeneic glioma models were examined in streptozotocin-induced Db mice. We found that in the GL261 gliomas that typically grow as “nodular” tumors, hyperglycemia activated receptor for advanced glycation endproducts (RAGE) by upregulating HMGB1 expression, and promoted tumor growth irrespective of tumor microenvironment (TME). Similarly, the K-Luc gliomas, which are invasive and elicit a robust macrophage infiltration, grew faster in subcutaneous (s.c.) location in Db mice. However, intracranial (i.c.) K-luc gliomas were smaller and less invasive in hyperglycemic mice. Our studies showed that a reduction in K-Luc growth in the brains of Db mice was mostly due to the abrogation of inflammatory responses and suppression of pro-inflammatory cytokines such as IL-1b and IL-6 in TME. We conclude that hyperglycemia may enhance glioma growth by activating the RAGE pathway and suppressing antitumor responses. But, suppression of tumor inflammation may also inhibit glioma growth by abrogating i.c. tumor invasion under hyperglycemic conditions.

Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors.

Interaction of RAGE with its ligands can promote tumor progression, invasion and angiogenesis. Although blockage of RAGE signaling has been proposed as a potential anti-cancer therapy, the contribution of RAGE expression in tumor microenvironement (TME) to tumorigenesis has not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and non-invasive glioma models, animal survival was prolonged in Rage−/- mice. This improvement in animal survival, however, was not due to changes in tumor growth rate, but a reduction in tumor-associated inflammation in Rage−/- mice. Furthermore, RAGE ablation in TME abrogated angiogenesis by downregulating the expression of pro-angiogenic factors which prevented vessel pruning, and resulted in the generation of leaky vasculature. These alterations, however, were most prominent in non-invasive gliomas where the expression of VEGF and pro-inflammatory cytokines were also lower in Rage−/- tumor-associated macrophages. Interestingly, reconstituting Rage−/- tumor macrophages with either wild-type microglia or macrophages normalized tumor vascularity. This is the first report to demonstrate the pro-angiogenic function of RAGE signaling in tumor macrophages and underscores the complex role of RAGE and its ligands in gliomagenesis.

Factors released by glioma-associated microglia/macrophages (GAMs) play an important role in the growth and infiltration of tumors. We have previously demonstrated that the co-chaperone stress-inducible protein 1 (STI1) secreted by microglia promotes proliferation and migration of human glioblastoma (GBM) cell lines in vitro. In the present study, in order to investigate the role of STI1 in a physiological context, we used a glioma model to evaluate STI1 expression in vivo. Here, we demonstrate that STI1 expression in both the tumor and in the infiltrating GAMs and lymphocytes significantly increased with tumor progression. Interestingly, high expression of STI1 was observed in macrophages and lymphocytes that infiltrated brain tumors, whereas STI1 expression in the circulating blood monocytes and lymphocytes remained unchanged. Our results correlate, for the first time, the expression of STI1 and glioma progression, and suggest that STI1 expression in GAMs and infiltrating lymphocytes is modulated by the brain tumor microenvironment.