Pro-inflammatory modification of cancer cells microsurroundings increases the survival rates for rats with low differentiated malignant glioma of brain.

Abstract

Glioblastoma multiforme (GBM) is one of the most aggressive human brain tumors. The prognosis is unfavorable with a median survival of 15 months. GBM aggressive nature is associated with a special phenotype of cancer cells that develops because of the transforming growth factor β (TGF-β). The study was aimed at providing experimental justification in vivo of a possibility to suppress TGF-β production in a tumor via pro-inflammatory modification of cancer cell microenvironment, using CD45+ mononuclear cells of the red bone marrow. The experiment used animals with transplanted C6 glioma. The animals were divided into 4 groups: (I) control (N=60); (II) group of rats (N=30) that received granulocyte colony-stimulating factor (G-CSF) to recruit CD45+ bone marrow mononuclear cells into their systemic circulation (G-CSF group); (III) group of rats (N=30) that received pro-inflammatory therapy to trigger systemic inflammatory reaction by injecting bacterial lipopolysaccharides (LPS) and interferon-γ (IFNγ); (IV) rats (N=30), stimulated with G-CSF, followed by pro-inflammatory therapy. Stereotaxic modeling of a brain tumor in experimental animals, as well as a combination of morphological, immunocytochemical analyses and immunosorbent assay were used. TGF-β1 production in the tumor tissue resulted being inversely proportional to the intensity of proliferation processes and directly proportional to the size of necrosis areas, peaking on the 28th day of the experiment. Stimulation of experimental animals with G-CSF recruits CD45+ mononuclear stem and progenitor cells into the systemic circulation of experimental animals with C6 glioma, accompanied by intensification of microglial proliferation in the tumor and infiltration of the tumor tissue with microglial cells. Pro-inflammatory therapy against G-CSF stimulation results in polarization of microglia/macrophages population together with intensified antigen presentation, lower production of TGF-β and IL10, increased synthesis of pro-inflammatory cytokines TNFα and IL1 in the tumor lesion and adjacent brain matter, remodeling of tumor matrix and higher survival rates for the experimental animals. Pro-inflammatory inflammatory modification of cancer cell microenvironment suppresses TGFβ production in a tumor and increases survival rates of the rats with transplanted poorly differentiated malignant brain glioma.