Immunoregulation and inflammation in glioblastoma: brain tumors as neuroinflammatory diseases
Inflammation is an integral component of cancer pathology, contributing to carcinogenesis and tumor progression. One common feature of GBM is tissue necrosis accompanied by microenvironment inflammation. Immunosuppressive inflammation with associated necrosis is typical of GBMs that display higher resistance to therapies and worst prognosis [16-20]. GBM cells express and secrete immune suppressive chemokines and cytokines including interleukin-6, interleukin-10, transforming growth factor (TGF)-β, galectin-1, and prostaglandin-E, which act on infiltrating immune cells to hijack them by inducing a pro-tumor cellular phenotype. Thus, a population of non-neoplastic cells consisting mostly of tumor-associated macrophages, is established in the tumor site. These immunosuppressive changes enabled by inflammatory mediators stimulate GBM cell proliferation, migration, angiogenesis, and resistance to treatment. For example, signaling mediated by CXCR3 and CCR2 receptors recruit tumor-promoting immune cells such as T cells and myeloid-derived suppressor cells [16, 21-28]. In GBM cancer stem cells (CSCs), hypoxic tissue triggers expression of genes of the inflammatory reparative response [25, 29]. Cytokines such as interleukin (IL)-1β and TGF-β cooperate to induce inflammatory gene expression and a proinflammatory phenotype in GBM CSCs, which in turn facilitates cellular proliferation and migration [30].