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

Abstract

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.

Glioblastoma endothelium drives bevacizumab‐induced infiltrative growth via modulation of PLXDC1

“…In addition, after bevacizumab 33.3% GBMs transitioned from proneural or proliferative to mesenchymal, whereas 25% GBMs transitioned from mesenchymal to proneural . More recently, brain invasion in U87 xenografts treated with bevacizumab was related with fibroblast growth factor 13 (FGF13) . Interestingly, though the bevacizumab‐induced tumor invasion was remarkably decreased in vivo by FGF13 shRNA, the expression level of FGF13B was not changed by bevacizumab in vitro .…”

“…Robust preclinical data support the concept of increased invasiveness of GBM after antiangiogenic treatment and its relationship with vascular structures . In orthotopic murine models of GBM treated with antiangiogenic drugs, the tumor cells invade perivascular spaces and form satellites separated from the primary tumor .…”

Annexin A2–STAT3–Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma

“…After incubation, the radius of invasion was defined as the distance farthest from the spheroid edge and was calculated using ImageJ software (http://rsb.info.nih.gov/ij/), as previously described [35,44]. The second assay was performed using Corning Bio-Coat Matrigel® Invasion Chambers (24-well format; Corning Inc.) as previously described [25]. Each chamber was randomly counted at five high-power fields to determine the mean number of invaded cells.…”

“…We previously established two novel invasive GBM cell line models, J3T-1 and J3T-2 [13,20], which imitated mimicked the angiogenic and invasive phenotypes of human GBM [22]. J3T-1 cells express high levels of ANXA2 and exhibit marked angiogenesis and invasion around the neovasculature, whereas J3T-2 cells express low ANXA2 levels and show a diffuse invasion pattern [13,25]. We also showed that silencing of ANXA2 in J3T-1 cells (J3T-1shA) caused a switch to the diffuse invasion pattern, and conversely, overexpression of ANXA2 in J3T-2 cells (J3T-2A) induced a highly angiogenic phenotype [22].…”

5‐ALA in the management of malignant glioma

“…In Germany, significant public attention has been attained by promising case reports of using methadone along with Temozolomide, but controlled clinical trials are still missing . Therapeutic concepts aiming at targeting tumor specific signaling may be promising for the future .…”