Exploring the role of inflammation in the malignant transformation of low-grade gliomas

Highlights

• A mechanism by which low grade gliomas malignantly transform is proposed.

• The mechanism relies on the aberrant signaling that results from inflammation.

• Mutations in LGGs (e.g. IDH1) may initiate this inflammatory cascade.

• Inflammatory cytokines polarize GIMs to the pro-tumorigenic M2 phenotype.

Abstract

Studies of inflammatory mediators have established the tumor micro-environment as a driver of oncogenesis. This inflammatory milieu often precedes cancer, however recent data also point to the ability of oncogenic changes to induce inflammatory responses that are later harnessed by the tumor to survive and proliferate. In this review, we propose that the IDH1 mutation, present in the majority of low-grade gliomas (LGGs), initiates an inflammatory cascade that is ultimately hijacked by the tumor. Glioma infiltrating macrophages and microglia (GIMs) are polarized to the M2 phenotype, subverting the host's adaptive immune response, and fostering a tumor milieu ripe for angiogenesis, migration, and metastasis. As data continue to expand the role of inflammation in low-grade gliomas, new molecular pathways may emerge as therapeutic targets that offer a window of opportunity to intervene before the malignant transformation (MT) of LGGs occurs.

Introduction

In 1863, Rudolf Virchow postulated that cancer originated at sites of chronic inflammation following his observation of leukocyte infiltration within tumors (Balkwill and Mantovani, 2001). Over the next century, these early observations were considered less important and perhaps an artifact of the host's immune response to the tumor. Recent literature (Grivennikov et al., 2010, Mantovani et al., 2008, Sowers et al., 2014, Rakoff-Nahoum, 2006) from the past decade however, points to a more complex relationship between inflammation and tumor growth. Data now support mechanisms through which an inflammatory microenvironment may drive tumorigenesis (Mantovani et al., 2008, Karin, 2006).

Models of inflammation-induced cancers of the body begin with a normal cell acquiring a mutation that confers survival advantages relative to its neighbors. The development of most cancers necessitates 4–5 mutations (Fearon and Vogelstein, 1990, Hanahan and Weinberg, 2000) in sufficiently long-lived cells that will not be eliminated before the next mutational strike or in stem cells that can transmit these mutations to subsequent generations. Reactive oxygen species (ROS) and reactive nitrogen intermediates, secreted by activated inflammatory cells or cytokines in the microenvironment, may act as the source of genomic instability/DNA damage.

Similar mechanisms have been reported in the context of gliomas, whose association with an immunosuppressive milieu is well-documented. In glioblastoma patients for example, the presence of FoxP3 + T regulatory cells – which inhibit an antitumor immune response – has been associated with a more aggressive clinical course (Sayour et al., 2015). Programmed death-ligand (PD-L1) whose function is also immunoinhibitory, dominates in the tumor milieu and is known to promote glioma infiltration (Vlahovic et al., 2015).

Particularly in the case of high-grade gliomas (i.e. brain lesions with pathologic evidence of malignancy that are mitotically active, highly invasive and proliferative, and/or contain areas of internal necrosis (Louis et al., 2007), the brain parenchyma is host to a wide variety of immune infiltrates such as macrophages, microglia, neutrophils, and eosinophils. Upon stimulation by various glioma-secreted signaling factors, glioma immune infiltrates initiate ROS and cytokine-mediated cascades of inflammation that contribute to additional DNA damage, angiogenesis, metastasis, and tumor growth/proliferation (Karin, 2006, Sowers et al., 2014). This dynamic tumor niche leads to an immunosuppressive glioma microenvironment.

As immunotherapy gains traction as a brain cancer therapeutic (Vlahovic et al., 2015), it is especially important to consider the role of inflammation in gliomagenesis. Very complex and seemingly competing mechanisms of inflammation may both suppress and stimulate a glioma's inflammatory microenvironment, the balance of which drives malignancy. Despite inflammation's dichotomous effects on gliomagenesis, the summation of evidence suggests that the net effect of an inflammatory microenvironment is immunosuppressive, a characteristic which has hampered the success of various glioma immunotherapies (Charles et al., 2011, Ha et al., 2014).

While the role of inflammation in driving the malignant progression of pre-neoplastic lesions of the body is well documented, particularly in the case of cervical carcinoma, hepatocellular carcinoma, gastric cancer, and colon cancer (Coussens and Werb, 2002, Grivennikov et al., 2010, Rakoff-Nahoum, 2006, Sowers et al., 2014, Vakkila and Lotze, 2004), a similar role has not been described at length in the context of the malignant transformation of low-grade gliomas. Notwithstanding, gliomas have been associated with an immunosuppressive niche – one that allows these immunogenic tumors to evade the host's innate immune response, and provides context for this perspective review. Additionally, emerging evidence suggests the importance of immune infiltrates in low-grade gliomas (LGGs).

In low-grade glioma patients, overall survival (OS) is associated with a number of prognostic factors, one of them being astrocytoma histology compared with oligodendroglial histology (Schomas et al., 2009). This is due in part to the increased expression of inflammation-related genes in astrocytomas compared to oligodendrogliomas (Gonda et al., 2014). In fact, specific inflammatory chemokines such as CXCL12 (Salmaggi et al., 2005) have already been associated with decreased time to tumor progression in LGG patients. These recent findings point to a potential role for immune infiltrates in the malignant transformation of low-grade gliomas.

Utilizing a well-established paradigm seen in multiple other human malignancies in which inflammatory conditions precede malignant degeneration, we hypothesize that the malignant transformation of low grade gliomas occurs within the context of a normal host defense triggering inflammation in response to genomic instability and early mutational events (Mantovani et al., 2008, Grivennikov et al., 2010, Karin, 2006).