Sleeping Beauty–Mediated Somatic Mutagenesis Implicates CSF1 in the Formation of High-Grade Astrocytomas

Abstract

The Sleeping Beauty (SB) transposon system has been used as an insertional mutagenesis tool to identify novel cancer genes. To identify glioma-associated genes, we evaluated tumor formation in the brain tissue from 117 transgenic mice that had undergone constitutive SB-mediated transposition. Upon analysis, 21 samples (18%) contained neoplastic tissue with features of high-grade astrocytomas. These tumors expressed glial markers and were histologically similar to human glioma. Genomic DNA from SB-induced astrocytoma tissue was extracted and transposon insertion sites were identified. Insertions in the growth factor gene Csf1 were found in 13 of the 21 tumors (62%), clustered in introns 5 and 8. Using reverse transcription-PCR, we documented increased Csf1 RNAs in tumor versus adjacent normal tissue, with the identification of transposon-terminated Csf1 mRNAs in astrocytomas with SB insertions in intron 8. Analysis of human glioblastomas revealed increased levels of Csf1 RNA and protein. Together, these results indicate that SB-insertional mutagenesis can identify high-grade astrocytoma-associated genes and they imply an important role for CSF1 in the development of these tumors. Cancer Res; 70(9); 3557-65. ©2010 AACR.

Microglial Stimulation of Glioblastoma Invasion Involves Epidermal Growth Factor Receptor (EGFR) and Colony Stimulating Factor 1 Receptor (CSF-1R) Signaling

“…This study also demonstrated that CSF-1 expression correlated with the increased presence of macro phages bearing markers that are associated with the so-called "M2 phenotype," which are believed to be one of the critical subpopulations of macrophages involved in tumor progression (6). In addition, a recent study used the Sleeping Beauty transposon mutagenesis technique in the brains of whole animals to screen for novel genes associated with glioma oncogenesis (23). It was discovered that >60% of the highgrade astro cytoma occurrence was a result of transposon-mediated enhanced expression of the Csf-1 gene.…”

Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis

“…1B), was selected for further investigation given 1) its well suggested role in the development and progression of tumors, including glioma (24,25); 2) its influence upon survival, proliferation, and differentiation of macrophages/microglial cells, which are present in abundance in the glioma microenvironment (26,27); and 3) the expression of MCSF receptor (MCSFR) only in microglial cells and not in glioma cells (28), suggesting that glioma cell-secreted MCSF may function through stromal cells and be one key determinant of glioma-stromal cell interactions underlying glioma progression. MCSF transcript levels were up-regulated in GBM, compared with normal brain tissue samples, in our cohort and three more cohorts, namely TCGA, REMBRANDT, and GSE22866 (Fig.…”

Selective depletion of cultured macrophages by magnetite nanoparticles modified with gelatin

“…M-CSFR inhibition abrogates glioma progression by inhibiting the pro-tumor activation of TAMs (25). Although there have been a number of research studies regarding M-CSF production from glioma cells (26)(27)(28), to the best of our knowledge, there is no published research assessing M-CSFR expression in glioma cells, other than a previous study that reported the activation of M-CSFR in both glioma cells and TAMs in human glioma samples (8). The observations indicated that M-CSFR expression in cultured glioma cell lines is markedly lower than that in macrophages, and may suggest that M-CSFR expression in glioma cells may not be of particular interest for further research.…”