Mini-reviewUnderstanding the role of cytokines in Glioblastoma Multiforme pathogenesis
Introduction
Gliomas, including astrocytomas, oligodendrogliomas and ependymomas, are the most common type of primary brain tumor of the central nervous system in adults [1], [2], [3]. Gliomas originate from glia cells (astrocytes, oligodendrocytes, ependymal cells) or cancer stem cells, and are classified by the World Health Organization (WHO) into four grades based on malignancy (I, II, III, and IV). Patients inflicted with grade IV Glioblastoma Multiforme (GBM) have a median survival of about 15 months even after aggressive surgery, chemotherapy and radiotherapy [4], [5]. GBM is characterized by diffuse invasiveness, immunosuppression, aggressive proliferation, vascularization, and resistance to conventional radiotherapy and chemotherapy. The current standard of care for GBM involves initial surgical resection followed by 57–60 Gy of radiotherapy. Patients with newly diagnosed high grade glioma are treated concurrently with temozolomide (TMZ) and radiotherapy. Despite these efforts, recurrence is common and the prognosis remains poor [6].
Cytokines are a group of small molecules with diverse effects depending on the microenvironment. Cytokines are composed of glycoproteins and polypeptides that exert pro-inflammatory, anti-inflammatory or immunosuppressive effects. In addition to the tumor cells, immune cells, extracellular matrix, blood vessels, and cytokines constitute key parts of the GBM tumor microenvironment which can be favorable for tumor growth. In addition, these factors may play critical roles in contributing to the complexity and lethality of GBM. Part of the lethality stems from its proficiency in evading immune surveillance by creating an immunosuppressive tumor microenvironment. Glioma patients are commonly unable to produce a reaction against bacterial antigens, often possess decreased levels of circulating T cells, have lower in vitro proliferation of T-cells in response to mitogens, exhibit depressed antibody response and decreased antibody and T cell cytotoxicity [3], [7]. Following tumor resection, some of these peripheral dysfunctions can be partially reversed, implicating the tumor involvement in global immunosuppression [3].
There is an urgent need for a consensus view of glioma tumor microenvironments, which will ultimately assist in the creation of new therapies that target the microenvironment to interrupt or reverse the GBM progression. This review summarizes the current progress on the study of cytokine functions in GBM, and discusses potential therapeutic strategies targeting cytokines in GBM.
Section snippets
GBM pathogenesis involving key cytokines
During the GBM progression, certain transcription factors have cross signaling among different cytokines. Signal transducers and activators of transcription (STAT) transcription factors play a central role in neural stem cells (NSCs) and astrocytic development. STAT3 is constitutively active in GBM and its levels correlate with tumor grade. The upregulated STAT3 mediates interferon (IFN) and interleukin-6 (IL-6) families of cytokines. The main pathway is through Janus kinase (JAK) which
Tumor necrosis factor-α (TNF-α)
Many cells secrete tumor necrosis factor-α (TNF-α), primarily monocytes, macrophages, activated natural killer (NK) cells and T cells [10]. T cells and endothelial cells express TNF receptors [10], [11]. In normal brain, TNF-α is responsible for dendritic cell (DC) maturation [10]. In a tumor environment, its expression correlates with GBM tumor grade. 80% of anaplastic GBM tumors express TNF-α but only 17% of astrocytoma and oligoastrocytoma express TNF-α [11]. However, TNF-α does not have the
Transforming growth factor-beta (TGF-β)
Transforming growth factor has two classes, α and β. Little is known about TGF-α activity in GBM, except for a recent phase I/II dose-escalating clinical trial assessing TP-38 therapy in which a fusion protein composed of pseudomonas exotoxin (PE) and TGF-α were tested in 20 recurrent malignant glioma patients. The median survival time was 21.6 weeks and one patient survived more than 5 years from the initial diagnosis [10].
One of the best characterized cytokines in GBM is transforming growth
Interferons (IFN)
Interferons are actively involved in innate immunity, which induces the downstream transcription of genes related to anti-viral, anti-microbial and antitumor effects. Interferon-α (IFN-α) is one of three main IFN isoforms. The other different IFN types are sorted based on the amino acid sequence and the receptors they bind to. Type I interferon include 13 isoforms of IFN-α, the one and only form of IFN-β, and IFN-ω, IFN-ε, IFN-κ, IFN-τ, and IFN-ζ. Type II interferon only has one type which is
Interleukin-2 (IL-2)
Interleukin-2 (IL-2) is an immuno-activating cytokine. While it is produced predominantly by T cells, it also promotes in vitro proliferation of T cells including T helper cells, CTL and T regulatory cells [44], [45], [46]. The T cells from glioma patients produce and secrete less IL-2, which is necessary for proper T-cell proliferation and activation. The CD4+ T cells are mostly affected by the drop in IL-2 secretion [7]. This is accompanied with a decreased IL-1β secretion by monocytes within
Interleukin-4 (IL-4)
Interleukin-4 (IL-4) is produced by T cells, mast cells and basophils [50]. It plays important roles in regulating the maturation and proliferation of B cells, mast cells and T cells. IL-4 can induce a type 2 T helper (Th2) response along with IL-5, IL-6, IL-9, IL-10, and IL-13 [7], [12]. The Th2 cells are important fighters against larger pathogens such as parasites and allergens through humoral immune response and downregulated tumor-specific immunity. It works in conjunction with IL-13 and
Interleukin-6 (IL-6)
As part of the Th2 cell response, interleukin-6 (IL-6) along with its receptor is highly expressed both in GBM tumors and GBM cell lines [12], [58]. IL-6 is secreted by neurons, microglia, astrocytes and peripheral monocytes [1], [58]. It has pivotal roles in the induction and modulation of reactive astrogliosis, pathological inflammatory responses and neuro-protection. Under normal conditions, IL-6 plays a key role in B cell maturation and the induction of acute inflammatory responses [15].
Interleukin-8 (IL-8)
Interleukin-8 (IL-8) is a highly prevalent cytokine in GBM both in vivo and in vitro [16], [43], and is a potent mediator of angiogenesis. This activity is accomplished through inhibiting endothelial cell apoptosis while inducing production of metallomatrix proteins (MMPs). Endothelial cells produce MMPs which are required for angiogenesis [67]. This cytokine is best characterized by its role in leukocyte, specifically neutrophil chemotactic properties [58] along with its involvement in
Interleukin-10 (IL-10)
Interleukin-10 (IL-10) is produced by many cells as well as glioma cancer stem cells (gCSCs). Dziurzynski et al. found that gCSC, which were infected with cytomegalovirus (CMV), produced CMV IL-10 that modified the monocyte lineage. Monocytes, which are precursors to macrophages, exhibited an immune-suppressive, tumor-supporting phenotype because of the CMV IL-10 which negatively impacts attempts at cancer treatment. CMV IL-10 is significant because it can bind to human IL-10 receptors and
Interleukin-12 (IL-12)
Interleukin-12 (IL-12) is secreted by mature DC and macrophages and it enhances the cytotoxic immune cells like CTLs, NK cells, and DC [57]. IL-12 also plays roles in B cell IgG production and activation of neutrophils and DCs [10]. Matching increased IL-12 levels are increased IFN-γ levels, which induce downstream pro-inflammatory cytokine release. IL-12 also polarizes T cells towards Th1 response through differentiation of T cells [7], [43]. Upon administration of IL-12, murine models have
Interleukin-13 (IL-13)
Interleukin 13 (IL-13) has been shown to be overexpressed in a majority of glioma cell lines and GBM tumor tissues [29]. IL-13 toxin can induce a more potent cytotoxic effect in human GBM cells than in nude mice. When IL-13 was injected into immunodeficient mice with tumor xenografts of human glioma cells, the mice showed highly cytotoxic effects without adverse toxicity. A mutated human IL-13 was created in order to increase affinity to its receptor IL-13α2. The mutant IL-13 exhibited 50 times
Granulocyte–macrophage colony-stimulating factor (GM-CSF)
GM-CSF modulates granulocytes and macrophages in their mature forms. This glycoprotein stimulates colony formation among granulocytes and macrophages and also helps with DCs antigen presentation. GM-CSF often leads to inflammation when overexpressed by T cells, fibroblasts, endothelial cells, macrophages and stroma cells. IL-1 and IL-2 can augment GM-CSF production while other pro-inflammatory cytokines like IL-1 and TNF can induce it through NF-κB transcription factor. IL-4, IL-13 and
Vascular endothelial growth factor (VEGF)
VEGF is a well characterized cytokine that causes neovascularization and acceleration of vascular permeability [87]. Its tumorigenic effects include enhanced migration and proliferation and reversing senescence of endothelial cells [88], [89]. The mRNA level of VEGF is higher in GBM especially in hypoxic areas of the tumor. NF-κB and STAT3 transcription factors both upregulate VEGF expression in malignant glioma. VEGF can also be induced by hypoxia-inducible factor-1 (HIF-1) to promote
Chemokines
Within the family of cytokines, there is a group of cytokines that have chemotaxis functions called chemokines. Chemokines function primarily by binding to G-coupled protein receptors to induce cell trafficking, activation and differentiation. CXCL12 chemokine and its respective receptor, CXCR4, play an important role in stem cell trafficking, angiogenesis and vasculature development in glioma tumors. CXCL12, also known as SDF-1, is overexpressed in necrotic and hypoxic regions of GBM. CXCL8
Cancer stem cells
Cancer stem cells (CSCs) have a high prevalence among high grade neural primary tumors such as gliomas and medulloblastomas. CSCs, also known as tumor initiating cells (TICs), have the capability to initiate tumor growth and are resistant to conventional chemo and radiation therapies. CSCs are often found in the perivascular spaces at the invasive lining of the tumor. The perivascular region is a unique environment for brain tumor cells to thrive because of the increased angiogenesis induced by
Comprehensive therapy
Within the brain tumor microenvironment, there is a large heterogeneity and so is the variety of cytokine function (Fig. 1). Developing a comprehensive standard on cytokine function to which researchers and clinicians can agree upon is crucial towards developing effective therapies for GBM patients. A larger scope of understanding cytokine function may yield multiple cytokine-targeted therapies towards GBM which could prove more fruitful than any single therapy alone.
Current GBM therapy
Perspectives
Of the clinical trials investigating possible cytotoxin therapies against GBM, the three most promising therapeutic targets are IL4-PE, TP-38 and IL13-PE. They all have shown acceptable dosage toxicities and safety in phase I and II clinical trials in addition to effective tumor responses [112]. There are some drawbacks to the immunotherapy approach to GBM. Targeting one type of receptor has limited effectiveness due to the cross-communication that cytokines and other ligands have with each
Acknowledgements
This work was supported in part by the William and Ella Owens Medical Research Foundation, Dr. Marnie Rose Foundation (M. Li), and the Vivian L. Smith Department of Neurosurgery at the University of Texas Health Science Center at Houston, Medical School.
References (112)
- et al.
Challenges in clinical design of immunotherapy trials for malignant glioma
Neuro. Clin. North Am.
(2010) - et al.
Immunotherapy of surgical malignancies
Curr. Probl. Surg.
(2004) - et al.
Challenges in clinical design of immunotherapy trials for malignant glioma
Neurosurg. Clin. North Am.
(2010) - et al.
Therapeutic targets in malignant glioblastoma microenvironment
Sem. Radiat. Oncol.
(2009) - et al.
Targeted tumor therapy with the TGF-β2 antisense compound AP 12009
Cytok. Growth Factor Rev.
(2006) - et al.
The failure of current immunotherapy for malignant glioma. Tumor-derived TGF-beta, T-cell apoptosis, and the immune privilege of the brain
Brain Res. Brain Res. Rev.
(1995) - et al.
A phase I trial of Ad.hIFN-beta gene therapy for glioma
Mol. Ther.
(2008) - et al.
Interferon-gamma in brain tumor immunotherapy
Neurosurg. Clin. North Am.
(2010) Interleukin-4: a prototypic immunoregulatory lymphokine
Blood
(1991)- et al.
Analysis of interleukin (IL)-8 expression in human astrocytomas: associations with IL-6, cyclooxygenase-2, vascular endothelial growth factor, and microvessel morphometry
Hum. Immunol.
(2009)