Inflammatory Mediators in Glioma Microenvironment Play a Dual Role in Gliomagenesis and Mesenchymal Stem Cell Homing: Implication for Cellular Therapy

Abstract

Glioblastoma is the most aggressive malignant primary brain tumor, with a dismal prognosis and a devastating overall survival. Despite aggressive surgical resection and adjuvant treatment, average survival remains approximately 14.6 months. The brain tumor microenvironment is heterogeneous, comprising multiple populations of tumor, stromal, and immune cells. Tumor cells evade the immune system by suppressing several immune functions to enable survival. Gliomas release immunosuppressive and tumor-supportive soluble factors into the microenvironment, leading to accelerated cancer proliferation, invasion, and immune escape. Mesenchymal stem cells (MSCs) isolated from bone marrow, adipose tissue, or umbilical cord are a promising tool for cell-based therapies. One crucial mechanism mediating the therapeutic outcomes often seen in MSC application is their tropism to sites of injury. Furthermore, MSCs interact with host immune cells to regulate the inflammatory response, and data points to the possibility of using MSCs to achieve immunomodulation in solid tumors. Interleukin 1β, interleukin 6, tumor necrosis factor α, transforming growth factor β, and stromal cell-derived factor 1 are notably up-regulated in glioblastoma and dually promote immune and MSC trafficking. Mesenchymal stem cells have widely been regarded as hypoimmunogenic, enabling this cell-based administration across major histocompatibility barriers. In this review, we will highlight (1) the bidirectional communication of glioma cells and tumor-associated immune cells, (2) the inflammatory mediators enabling leukocytes and transplantable MSC migration, and (3) review preclinical and human clinical trials using MSCs as delivery vehicles. Mesenchymal stem cells possess innate abilities to migrate great distances, cross the blood-brain barrier, and communicate with surrounding cells, all of which make them desirable "Trojan horses" for brain cancer therapy.

Keywords: 5-FC, 5-fluorocytosine; AMSC, adipose tissue–derived mesenchymal stem cell; BBB, blood-brain barrier; BMSC, bone marrow–derived mesenchymal stem cell; CED, convection-enhanced delivery; DC, dendritic cell; EGFRvIII, EGFR variant III; GBM, glioblastoma; GSC, glioma stem cell; IFN, interferon; IL, interleukin; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; MSC, mesenchymal stem cell; NSC, neural stem cell; TAM, tumor-associated macrophage; TGF, transforming growth factor; TNF, tumor necrosis factor; UC-MSC, umbilical cord MSC.

Figure 1

Mode of mesenchymal stem cell (MSC) and immune cell migration and trafficking to glioblastoma (GBM). (1) Inflammatory cytokines released by GBM (2) promote extravasation of MSCs, lymphocytes, and monocytes and direct them toward tumor location. IL = interleukin; TGF = transforming growth factor; TNF = tumor necrosis factor.

Figure 2

Immunosuppressive soluble factors. ATP = adenosine triphosphate; CSF-1 = colongy stimulating factor 1; CX3CL1 = chemokine ligand 1; GDNF = glial cell line-derived neurotrophic factor; GM-CSF = granulocyte-macrophage colony stimulating factor; HGF/SF = hepatocyte growth factor/scatter factor; MCP-1 = monocyte chemoattractant protein 1; MCP-3 = monocyte chemotactic protein; SDF-1 = stromal derived factor 1; TAM = tumor-associated macrophage.