Glioblastoma: Therapeutic challenges, what lies ahead

Abstract

Glioblastoma (GBM) is one of the most aggressive human cancers. Despite current advances in multimodality therapies, such as surgery, radiotherapy and chemotherapy, the outcome for patients with high grade glioma remains fatal. The knowledge of how glioma cells develop and depend on the tumor environment might open opportunities for new therapies. There is now a growing awareness that the main limitations in understanding and successfully treating GBM might be bypassed by the identification of a distinct cell type that has defining properties of somatic stem cells, as well as cancer-initiating capacity — brain tumor stem cells, which could represent a therapeutic target. In addition, experimental studies have demonstrated that the combination of antiangiogenic therapy, based on the disruption of tumor blood vessels, with conventional chemotherapy generates encouraging results. Emerging reports have also shown that microglial cells can be used as therapeutic vectors to transport genes and/or substances to the tumor site, which opens up new perspectives for the development of GBM therapies targeting microglial cells. Finally, recent studies have shown that natural toxins can be conjugated to drugs that bind to overexpressed receptors in cancer cells, generating targeted-toxins to selectively kill cancer cells. These targeted-toxins are highly effective against radiation- and chemotherapy-resistant cancer cells, making them good candidates for clinical trials in GBM patients. In this review, we discuss recent studies that reveal new possibilities of GBM treatment taking into account cancer stem cells, angiogenesis, microglial cells and drug delivery in the development of new targeted-therapies.

Introduction

Awareness of how cancer tissue emerges and evolves is essential for designing targeted anti-cancer therapies. Cancer emerges as a result of a multistep process; each step reflects a genetic alteration that drives the progressive cell transformation into cancer. According to Hanahan and Weinberg, six essential aspects in cellular physiology drive cancer: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death, limitless replication, sustained angiogenesis and tissue invasion [1]. Recently, two additional hallmarks for cancer were proposed: cellular metabolism changes to support neoplastic growth and the ability to evade immunological destruction. Moreover, two neoplasia characteristics facilitate the acquisition of all hallmarks: genomic instability and inflammation [1].

Genomic instability and inflammation are potentially interconnected, since an inflammatory microenvironment can increase spontaneous mutagenesis rates by several mechanisms. For example, activated macrophages produce reactive oxygen species that, besides directly damaging DNA, induce the failure of DNA mismatch repairs [2]. Furthermore, macrophage migration inhibitory factor (MIF) can suppress transcription of the tumor-suppressor gene TP53, resulting in defective DNA-damage repair and increased genomic instability [3]. Tumor cells also take part in inflammatory processes by activating intrinsic inflammatory mechanisms in the surrounding epithelial or stromal cells, which often show genetic and epigenetic oncogenic alterations similar to those in tumor cells [2].

Understanding cancer cell development and the dependence on the tumor environment is important for new therapies and prevention. A recent study has demonstrated that the cancer-preventive efficiency of long-term daily treatment with anti-inflammatory drugs was found to prevent many solid tumors, including colon, esophageal, lung, prostate and brain cancers [4].

Heterotypic cellular communication plays an important role in tumorigenesis. This communication can occur between cancer cells and stroma, such as inflammatory macrophages [5]. The presence of non-cancer cells that contribute to progressive malignancy by creating the tumor microenvironment opens an opportunity for therapeutic intervention [1]. In addition, some degree of heterotypic cellular communication is seen among neighboring tumor cells. For example, cancer promotion can occur due to interclonal cooperation of mutated tumor cells in the same tissue. Different mutations in distinct cells in the same epithelium collaborate for cancer development, demonstrating that cellular interactions may contribute to oncogenic cooperation and that tumor heterogeneity may be achieved at early stages of tumorigenesis [6].

In fact, recent evidence has pointed to the existence of a small fraction of cells responsible for metastasis and indiscriminate growth. In some tumors, such as malignant gliomas, a population of cancer cells expressing a stem cells marker called prominin 1, also known as CD133, has been detected [7], [8]. CD133, a cell membrane glycoprotein, was first identified on a hepatoma cell surface and is generally expressed in hematopoietic stem cells [9], endothelial precursor cells [10] and neural stem cells [11]. The function of this transmembrane protein has not yet been clearly defined. It is a 120 kDa protein, with an N-terminal extracellular domain, two large extracellular loops, which can be N-glycosylated, and an intracellular C-terminus [13]. It is highly expressed and strongly glycosylated in stem and progenitor cells, such as neural stem cells [11]. CD133⁺ tumor cells have been mentioned as presenting an advanced ability to generate tumors in xenographs [12] and, therefore, have been called cancer stem cells (CSCs). In glioblastoma (GBM), the most aggressive primary brain tumor, CD133⁺ CSC colonies showed immune suppressor properties. GBM stem cells have been shown to trigger T-cell apoptosis, inhibit T-cell proliferation and activation and induce regulatory T cells [14]. Moreover, multivariate survival analyses have shown that the proportion of CD133 ⁺ cells affects the clinical outcome in glioma patients independent of tumor grade [7]. In another study, the survival of GBM patients was significantly shorter with higher levels of CD133 mRNA [8].

Although GBMs can contain both CD133⁺ and CD133^- cell types that generate highly aggressive tumors, CD133⁺ cells are radio- and chemoresistant. This suggests that many cancer therapies, while killing the majority of tumor cells, may finally fail because they do not eliminate CSCs, which survive and generate new tumors. Therefore, CSCs are key elements in the recurrence of GBM, making them a desirable target for therapy.

In this review, we discuss recent advances in GBM biology related to CSC, angiogenesis, microglia and drug delivery that are relevant to the development of new targeted-therapies.