**2. Pathophysiology**

In the 19th century, Stephen Paget postulated the "seed and soil" hypothesis, which considers that metastatic growth depends on cancer cells (the seed) interactions with and affinity for specific distant organ tissues (the soil). Paget's assertion that a nutritional microenvironment is imperative for metastatic cells to grow in distant tissues is supported by conceptual frameworks of contemporary cancer research [9]. A more advanced understanding of the complex and multifactorial mechanisms of metastasis formation consists of three premises: first, the existence of tumor heterogeneity, including morphologically- and phenotypically-distinct profiles of cancer cells with different proliferative, angiogenic, invasive, and metastatic characteristics; second, a metastatic process that is selective for tumor cells that accomplish all the key steps of the metastatic cascade; and third, the metastatic potential of a tumor, which depends on multiple, reciprocal interactions between the primary tumor and the tumor microenvironment, as well as homeostatic mechanisms [10]. This reciprocal cross-talk determines tumor progression and the potential for metastatic growth. As in the periphery, a brain tumor's microenvironment plays a critical role in metastatic colonization of the brain; but the outgrowth of tumor cells to the brain depend on specific behaviors of the tumor cells and conditions in the brain tumor microenvironment. In the literature, at least three microenvironments have been considered involved in brain metastasis formation: the perivascular niche, the brain parenchyma, and the cerebrospinal fluid also termed the leptomeningeal niche [11]. As the brain tumor grows it creates pressure on and changes the function of surrounding cells and it leads to symptoms. Most cases of Brain Tumor travel by hematogenous spread and occur most often at the gray-white matter junction [4]. The markers involved in the brain tumor are as follows:


*An Overview of Brain Tumor DOI: http://dx.doi.org/10.5772/intechopen.100806*


Circulating tumor cells (CTCs) are cells that are shed from primary or metastatic tumors in the body fluids, including blond, cerebrospinal fluid, and urine. CTCs determine the ability of epithelial tumor cells to metastasize [12]. These different types of potential biomarkers in the blood can be present in cell-free forms, attached to lipid or protein structures, or delivered by circulating extracellular vesicles or platelets [13]. CTCs are also used in the monitoring of glioblastoma patients. The level of CTCs detected after chemotherapy is significantly lower compared to their level before the treatment, which may provide invaluable insight in differentiating tumor progression from radiation necrosis [14, 15].

B. O-6 methylguanine-DNA methyltransferase mutations (MGMT)

The gene encoding O-6-methylguanine DNA methyltransferase (MGMT) is found on chromosome 10q26 [4]. By methylating DNA base pairs, alkylating chemotherapeutic drugs such as temozolomide impair DNA replication. Active MGMT reverses the effect of temozolomide, enabling normal DNA replication to occur within a tumor [16]. O-6-methyl transferase DNA methyltransferase contributes to DNA repair by reversing DNA alkylation and eliminating the guanine-alkyl group, therefore preventing apoptosis. MGMT has recently been established as a biomarker for tumor diagnosis [17]. Methylation promotes the gene code for MGMT in glioblastoma and is the genetic fingerprint with the greatest influence on clinical practice. The presence of O-6-methylguanine-DNA methyltransferase (MGMT) suggests that the current standard of treatment, adjuvant chemoradiotherapy with the alkylating drug temozolomide, is more effective [18–20].

C. Epidermal growth factor receptor

Most signaling pathways and physiological responses, including migration, proliferation, survival, and tumor development, are activated by the epidermal growth factor receptor (EGFR). EGF, TGF-, heparin-binding epidermal growth factor-like factor (HB-EGF), amphiregulin (AR), betacellulin (BTC), neuregulins (NRGs), also known as neuregulin; neu differentiation factors; glial growth factors; acetylcholine receptor inducing activity; and epiregulin are all members of the EGF superfamily (EPR) [21, 22].

D. Isocitrate dehydrogenase

Isocitrate dehydrogenase (IDH) is a protein enzyme that encodes genes on chromosome 2, the main function of IDH in the Krebs cycle is to catalyze oxidative decarboxylation [4]. IDH has been grouped into two classes (IDH 1 and IDH 2). Mutation of isocitrate dehydrogenase 1 (IDH-1) in glioblastoma was first noted by following an integrated genomic analysis of human

glioblastoma samples [16]. The IDH-1 protein protects the cytoplasm against oxidative damage. In 12% of glioblastoma samples, a heterozygous point mutation at R132 was discovered. Glioblastomas that were known to have developed from lower-grade tumors had a considerably greater prevalence of IDH-1 mutation (83%) [23]. Grade II/III astrocytomas, oligoastrocytomas, and oligodendrogliomas all have isocitrate dehydrogenase, which can be utilized to distinguish primary from secondary glioblastomas [24, 25].
