Masahito Nagata

GLI2 is a novel therapeutic target for metastasis of osteosarcoma.

Aberrant activation of the Hedgehog (Hh) pathway has been reported in several malignancies. We previously demonstrated that knockdown of GLI2 inhibited proliferation of osteosarcoma cells through regulation of the cell cycle. In this study, we analyzed the function of GLI2 in the pathogenesis of osteosarcoma metastasis. Immunohistochemical studies showed that GLI2 was overexpressed in patient osteosarcoma specimens. Knockdown of GLI2 inhibited migration and invasion of osteosarcoma cells. In contrast, the forced expression of constitutively active GLI2 in mesenchymal stem cells promoted invasion. In addition, xenograft models showed that knockdown of GLI2 decreased lung metastasis of osteosarcomas. To examine clinical applications, we evaluated the efficacy of arsenic trioxide (ATO), which is a Food and Drug Administration‐approved antitumor drug, on osteosarcoma cells. ATO treatment suppressed the invasiveness of osteosarcoma cells by inhibiting the transcriptional activity of GLI2. In addition, the combination of Hh inhibitors including ATO, vismodegib and GANT61 prevented migration and metastasis of osteosarcoma cells. Consequently, our findings suggested that GLI2 regulated metastasis as well as the progression of osteosarcomas. Inhibition of the GLI2 transcription may be an effective therapeutic method for preventing osteosarcoma metastasis.

Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion

It has been reported that GLI2 promotes proliferation, migration, and invasion of mesenchymal stem cell and osteosarcoma cells. To examine the molecular mechanisms of GLI2-mediated osteosarcoma metastasis, we performed a microarray analysis. The gene encoding ribosomal protein S3 (RPS3) was identified as a target of GLI2. Real-time PCR revealed that RPS3 was upregulated in osteosarcoma cell lines compared with normal osteoblast cells. Knockdown of GLI2 decreased RPS3 expression, whereas forced expression of a constitutively active form of GLI2 upregulated the expression of RPS3. RPS3 knockdown by siRNA decreased the migration and invasion of osteosarcoma cells. Although forced expression of constitutively active GLI2 increased the migration of human mesenchymal stem cells, knockdown of RPS3 reduced the up-regulated migration. In contrast, forced expression of RPS3 increased migration and invasion of osteosarcoma cells. Moreover, reduction of migration by GLI2 knockdown was rescued by forced expression of RPS3. Immunohistochemical analysis showed that RPS3 expression was increased in primary osteosarcoma lesions with lung metastases compared with those without. These findings indicate that GLI2-RPS3 signaling may be a marker of invasive osteosarcoma and a therapeutic target for patients with osteosarcoma.

Surgical Results of Lumber Fusion in Hemodialysis Patients

今回，透析患者に対する腰椎固定手術についてその手術成績と問題点について検討した．対象は，2002～2008年に手術を行った30例（男性15例，女性15例）であった．手術時年齢は52～72歳（平均61.8歳），透析歴は6ヶ月～31年（平均13年6ヶ月）であった．術前診断は，破壊性脊椎関節症（DSA）12例，腰椎変性すべり症10例，腰部脊柱管狭窄症4例，腰椎椎間板ヘルニア3例，分離すべり症1例であった．手術方法はPLF 24例，PLF+PLIF 4例，前方固定術2例であった．結果，JOAスコアの改善率50％以上が22例（73.3％）であったが，合併症による死亡が2例（6.7％）あった．透析患者に対する腰椎固定手術は合併症が多く，透析医，麻酔医との連携と十分なインフォームドコンセントが重要である．

Lateral Approach to C2 Root Schwannoma Located Ventral to the Spinal Cord: A Case Report

脊髄腹側にあるC2前根糸由来の神経症腫に対し側方進入にて手術施行したので報告する．（症例）31歳男性．2003年2月上位頚椎のdumb-bell腫瘍に対し，後方進入にて環椎後弓切除・腫瘍摘出術施行．病理はschwannomaであった．myelopathyは軽快するも，MRI上脊柱管内に腫瘍は遺残．2004年9月左上肢の筋力低下出現．手術目的にて2005年6月入院．四肢DTRの亢進，左上下肢の筋力低下を認め，JOA scoreは11/17．脊髄は環椎レベルで腹側から著明に圧迫されており，側方進入摘出術を施行．胸鎖乳突筋後方より進入，腫瘍を内減圧し骨削除は行わずに全摘し得た．腫瘍はC2神経根前根と連続していた．術後大後頭神経領域の知覚低下出現するもmyelopathyは軽快した．（考察）上位頚椎部の脊髄腫瘍は呼吸麻痺や重篤な麻痺を来しうるため，特に良性の場合全摘が望ましい．腫瘍が脊髄腹側に存在する場合，側方進入摘出術は有用な方法と考える．