Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion

• Published in: Oncogene 2018-02, Vol.37 (6), p.777-786
• Main Authors: Otani, Y, Ichikawa, T, Kurozumi, K, Inoue, S, Ishida, J, Oka, T, Shimizu, T, Tomita, Y, Hattori, Y, Uneda, A, Matsumoto, Y, Michiue, H, Date, I
• Format: Article
• Language: English
• Subjects: 101/1; 13/106; 13/109; 13/51; 14/1; 45/61; 45/77; 631/67/1922; 64/60; 692/53/2421; 82/51; Angiogenesis; Animals; Apoptosis; Astrocytes; Bevacizumab; Bevacizumab - pharmacology; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Care and treatment; Cell Biology; Cell Movement; Cell Proliferation; Cytoplasm; Development and progression; Female; Fibroblast growth factors; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblasts; Follow-Up Studies; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioma; Glioma cells; Gliomas; Growth factors; Health aspects; Human Genetics; Humans; Hypoxia; Immunotherapy; Internal Medicine; Intracellular; Medical prognosis; Medicine; Medicine & Public Health; Metastases; Mice; Mice, SCID; Monoclonal antibodies; Neoplasm Invasiveness; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; original-article; Parenchyma; Patient outcomes; Prognosis; Ribonucleic acid; RNA; Stem cells; Targeted cancer therapy; Tubulin; Tumor cells; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.373

Glioblastoma has the poorest prognosis, and is characterized by excessive invasion and angiogenesis. To determine the invasive mechanisms, we previously used two glioma cell lines (J3T-1 and J3T-2) with different invasive phenotypes. The J3T-1 showed abundant angiogenesis and tumor cell invasion around neovasculature, while J3T-2 showed diffuse cell infiltration into surrounding healthy parenchyma. Microarray analyses were used to identify invasion-related genes in J3T-2 cells, and the expressed genes and their intracellular and intratumoral distribution patterns were evaluated in J3T-2 cell lines, human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens. To determine the role of the invasion-related genes, invasive activities were evaluated in vitro and in vivo . Fibroblast growth factor 13 (FGF13) was overexpressed in J3T-2 cells compared to J3T-1 cells, and in human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens, when compared to that of normal human astrocytes. Immunohistochemical staining and the RNA-seq (sequencing) data from the IVY Glioblastoma Atlas Project showed FGF13 expression in glioma cells in the invasive edges of tumor specimens. Also, the intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 decreased glioma invasion both in vitro and in vivo and prolonged overall survival of several xenograft models. FGF13 was negatively regulated by hypoxic condition. Silencing of FGF13 also decreased in vivo bevacizumab-induced glioma invasion. In conclusion, FGF13 regulated glioma cell invasion and bevacizumab-induced glioma invasion, and could be a novel target for glioma treatment.