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  • Author or Editor: Jun-ichi Kuratsu x
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Naoki Shinojima, Hideo Nakamura, Masayoshi Tasaki, Kouki Kameno, Shigeo Anai, Ken-ichi Iyama, Yukio Ando, Hiroshi Seto and Jun-ichi Kuratsu

Medulloblastoma is the most frequent malignant brain tumor of the posterior fossa in children and is considered an embryonal tumor. It has been suggested that medulloblastomas be categorized into 4 distinct molecular subgroups— WNT (DKK1), SHH (SFRP1), Group 3 (NPR3), or Group 4 (KCNA1)—since each subgroup is distinct and there is no overlap. The authors report on a 13-year-old boy with medulloblastoma. He presented with sudden-onset nausea and vomiting due to intratumoral hemorrhage. The medulloblastoma was thought to be in an early developmental stage because the tumor volume was extremely small. Immunohistochemical analysis showed that the tumor was mainly composed of DKK1- and NPR3-positive areas. The individual areas of the tumor stained only for DKK1 or NPR3, with no overlap—that is, DKK1 and NPR3 expression were mutually exclusive. Samples obtained by laser microdissection of individual areas and subjected to mass spectrometry confirmed that the expression patterns of proteins were different. Fluorescence in situ hybridization for chromosome 6 showed there were 2 distinct types of cells that exhibited monosomy or disomy of chromosome 6. These results demonstrated that distinct subtypes of medulloblastoma may be present within a single tumor, an observation that has not been previously reported. Our findings in this case indicate that early-stage medulloblastoma may include more than 1 distinct subtype and hint at factors involved in the origin and development of medulloblastomas.

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Mareina Kudo, Hirofumi Jono, Satoru Shinriki, Shigetoshi Yano, Hideo Nakamura, Keishi Makino, Takuichiro Hide, Daisuke Muta, Mitsuharu Ueda, Kazutoshi Ota, Yukio Ando and Jun-ichi Kuratsu

Object

Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates diverse physiological functions, including cell proliferation and survival. Recent studies have shown that IL-6 expression is often elevated in response to several types of glioma. Although IL-6 is said to play an important role in glioma, the involvement of IL-6 signaling has been quite controversial. The aim of this study was to evaluate the involvement of IL-6 signaling in glioma and the inhibitory effect of IL-6 signaling on glioma tumor proliferation.

Methods

The expression of IL-6 receptors (IL-6Rs) was evaluated in glioma tissues by means of immunohistochemical analysis, and the involvement of IL-6 signaling in glioblastoma multiforme (GBM) U87MG cell proliferation was also determined. In addition, to examine the inhibitory effect of IL-6 signaling on glioma cell proliferation, the authors investigated the effects of tocilizumab, the humanized anti–human IL-6R antibody in U87MG cells.

Results

Increased immunoreactivity for IL-6R was predominantly found in the cytoplasm of endothelial cells in all GBM samples. Inhibition of IL-6 signaling by both IL-6– and IL-6R–specific small interfering RNA and AG490, a specific inhibitor of JAK2 phosphorylation, suppressed glioma cell proliferation. Furthermore, tocilizumab, a clinically developed humanized anti–human IL-6R antibody, exerted an antiproliferative effect on cells from the GBM cell line U87MG via the IL-6R–dependent JAK-STAT3 pathway.

Conclusions

The IL-6 signaling pathway plays an important role in glioma cell proliferation, and tocilizumab exerts an antitumor effect in U87MG glioma cells. These results may bring new insight into the molecular pathogenesis of glioma and may lead to a new therapeutic intervention.