1 Introduction
Glioblastoma multiforme (GBM) is the most malignant and lethal type of brain tumors and is classified by World Health Organization as grade IV (1, 2). The tumors are infiltrative, rapidly growing and are nourished by an abnormal tumor blood flow, thereby causing a poor prognosis for patients (3). Regardless of aggressive and multimodal treatments, including surgical resection of the tumor, followed by radio- or chemotherapy, most patients suffer recurrence of the tumor and die within 15 months (4). Glioblastomas are rare tumors with a global incidence of less than 10 in 100.00 people, although the poor prognosis makes it an important health issue (5).
Glioblastomas may arise de novo, which means they begin as a Grade IV tumor with no evidence of a precursor lesion. These primary tumors are the most common form of GBM and have a tendency to be more aggressive and tend to affect older patients. Alternatively, secondary GBMs may progress from a lower-grade astrocytic tumors (WHO grade II or grade III tumors) and evolve into Grade IV tumors over time. In general, these tumors tend to be slower growing initially, but can progressively become aggressive (6, 7, 8).
The tumors have a high intratumor heterogeneity, which makes treatment and understanding of the disease a major biomedical challenge. The aim of this paper is to provide a better understanding of the underlying mechanisms and challenges for GBM, regarding the etiology, pathophysiology, diagnosis and treatment of this disease.
2 Etiology
One of the main challenges for GBMs is their multifactorial cause. The clear majority of genetic alterations in GBM occur randomly, without any known inherited or environmental factors. Only 1-5% of GBM have a genetic predisposition (9). Studies of environmental and genetic factors contributing to GBM have so far been inconclusive or negative. The only confirmed risk factor is ionizing radiation to the head and neck region, mostly indicated for another tumor or condition (9, 10). A very small percentage of GBM are inherited as part of other syndromes, such as neurofibromatosis type 1 (11) and tuberous sclerosis (12).
The previously mentioned primary and secondary GBMS are categorized based on the patients age and genetic alterations. To start with, alterations of primary GBM may include mutations and amplifications of the epidermal growth factor receptor (EGFR) gene, leading to a gain of function of this gene. Other hallmark alterations present overexpression of mouse double minute 2 (MDM2), deletion of cyclin-dependent kinase Inhibitor 2A (CDKN2A) and loss of heterozygosity (LOH) in chromosome 10q, where phosphatase and tensin homolog (PTEN) and telomerase reverse transcriptase (TERT) promoter are located.
In addition, characteristic features of secondary GBMs mostly include overexpression of platelet-derived growth factor A and platelet-derived growth factor receptor alpha (PDGFA/PDGFRa), retinoblastoma (RB), LOH of chromosome 19q and mutations of TP53 and isocitrate dehydrogenase 1 (IDH1) (13, 14, 15).
3 Molecular mechanisms
The pathogenesis of GMBs is a result from the sequential accumulation of genetic alterations leading to abnormal regulation of growth factor signaling pathways. The previously mentioned mutations and amplifications of several genes mainly lead to dysregulation of three oncogenic pathways (16).
The EGFR protein is a receptor tyrosine kinase that stimulates cell division, survival and invasion by activating oncogenic pathways. It is an inducer of the Ras and potentially the PI3K/Akt pathway. The Ras pathway controls processes as cell proliferation, cell differentiation and apoptosis and is often deregulated in cancers. The PI3/Akt pathway is activated by several mutations in various cancer types and regulates translation and cell growth. The PI3K/Akt and Ras pathway can corporate to attain potent effects. Dysregulation of both pathways is sufficient to induce malignant cancers. The pathways are also activated by deletion of the tumor suppressor gene PTEN and overexpression of PDGFA/PDGFRa (14, 17, 18).
Another pathway involved in the development of GBM is the p53 pathway. The TP53 gene is mutated or deleted, leading to a decrease in the p53 protein. This protein acts both as a transcription factor and drives apoptosis or senescence in damaged cells. Mutation of the TP53 gene, therefore leads to tumorigenesis. The p53 pathway is stimulated by CDKN2A, a gene that encodes for two proteins; p14 and p16. The p14 protein downregulates MDM2, an inhibitor of the p53 pathway. Deletion of CDKN2A thus leads to a suppression of p53. In roughly 10% of GBMs, MDM2 is mutated itself, also leading to less inhibition of the p53 pathway. The p16 protein is an inhibitor of the RB protein, a protein that stimulates cell proliferation. Deletion of p16 therefore leads to increased cell proliferation (14, 17, 18).
Besides the most important genes that were mentioned, many other genes and proteins are involved in the development of GBMs. The genetic heterogeneity of the tumor makes it difficult to classify the tumors and to find specific targets for treatment. Upon treatment, the tumors can switch their genetic make-up and change to another subtype, which makes tumor or patient-specific treatment challenging.
4 Progression and Symptoms
Grade IV GBM are proliferative, functionally malignant and necrosis-prone tumors. Usually, the presentation of GBM in patients comes with a short clinical history, ranging between 3-6 months. Although, if the tumor develops from a low-grade precursor, the clinical history can span over several years (19).
The symptoms that occur in patients may be different. Symptoms can arise directly as a result of necrosis that gives rise to cognitive impairments and focal neurological sign. Depending on the location of the tumor, these symptoms may differ. For example, patients with a tumor located in the frontal lobe may experience a personality change, while patients with a tumor located in the temporal lobe might have difficulties with hearing and visualizing. Depending on the location of the tumor, patients can also suffer from seizures. In addition, secondary effects may include headaches and vomiting, due to and increased intracranial pressure as a consequence of the tumor growth (19).
5 Diagnosis
Upon suspicion of a brain tumor, the patient will be referred to a neurologist who will take a neurological exam. During this exam, the vision, hearing, balance, coordination, strength and reflexes are tested. Further diagnosis will include imaging techniques and a definite diagnosis is given by a histopathological examination of the tumors after surgical removal (20).
The primary imaging technique used to diagnose GBM is magnetic resonance imaging (MRI) scans. This method is the gold standard for diagnosing brain tumors, due to the exceptional contrast in soft tissue, allowing complexity and heterogeneity of the tumor to be well-visualized. Often, CT or PET scans are advised when a patient is not able to undergo MR scan (20, 21).
While the diagnosis for GBM is easily done, the challenge remains in diagnosing the tumor earlier in the development of the disease. Timely diagnosis of the tumor may result in a longer life expectancy.
6 Treatment
In contempt of the aggressive and multimodal efforts, GBM treatment is still one of the most challenging tasks in oncology. Standard treatment consists of maximal surgical resection, followed by radiotherapy and complementary chemotherapy, often with temozolomide (22, 23).
In most cases of GBM, surgery is the first step of treatment. The goal is to reach maximal safe resection, to minimalize the chance of leaving tumor in the brain. This is done with the help of intraoperative imaging or fluorescence-guided visualization of the tumor tissue. The main challenge for surgery lies with the location of the tumor and its heterogeneous and complex development. Tumor cells tend to infiltrate extensively into surrounding brain tissue, making it difficult to distinguish tumor from normal tissue during surgical treatment. Surgical resection is often followed by external beam irradiation for up to six weeks, as well as daily oral intake of temozolomide. Temozolomide is a relatively new agent that induces cell cycle arrest and apoptosis of tumor cells. The goal of these chemo- and radiotherapy is to destroy the remaining tumor cells. However, despite these invasive therapies most tumors will recur within 7 months of the initial diagnosis, which makes treatment of this disease a major challenge (22, 23).
7 Future research
In addition to the standard care, ongoing research for new treatment focusses on both additional measures to improve local control of the tumor, as well as systemic treatments to address infiltrative cells distant from the main tumor. This remains a huge challenge, considering that analyses to find molecular features that predict the response of GBMs to drugs is a major thrust. Furthermore, future research focusses more on personalized medicine to prevent the unnecessary expense and toxicity of agents for patients and to target the tumor more specifically.
8 Conclusion
Due to its heterogeneity, glioblastoma is one of the most challenging diseases in oncology. Despite ongoing, rapidly evolving research, scientists have not been able to overcome the challenges and the disease remains incurable. New discoveries on the field of genetics might provide novel targets and improved treatment for GBMs to provide a better prognosis for patients.