肺癌における癌幹細胞形質マーカーおよび新規抗癌剤効果規定遺伝子の同定

• Project/Area Number: 21590997
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Hiroshima University
• Principal Investigator: 檜山 桂子 広島大学, 原爆放射線医科学研究所, 准教授 (60253069)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肺癌 / 幹細胞 / 癌幹細胞 / Cancer stem cell model / TERT / テロメラーゼ / Stochastic clonal evolution model / 悪性度 / Rb / p16経路 / p53 / コロニー形成能 / マーカー

Research Abstract

手術不能の肺癌の予後は今なお不良であるが、その主因の一つとして、現在の化学療法・放射線療法に耐性の"がん幹細胞"の存在が考えられている。しかし、がん幹細胞が肺癌すべてに存在するのか否か、どのように発生し分布するのか、明らかではない。一方、テロメラーゼが不活化されている正常体細胞ががん化し不死化がん細胞となるには、p53、p16/Rb経路の不活化が必須であると考えられている。ゆえに我々は、肺癌組織および細胞株の遺伝子変異解析より、この経路が不活化されていない不死化がん細胞はテロメラーゼ陽性正常幹細胞→がん幹細胞という経路を経たCancer stem cell modelのがんであると考え、肺腺癌にその一群がある一方、扁平上皮癌の殆どはStochastic clonal evolution modelがあてはまるという結果を得た。この結果および組織別発生頻度から、原爆被爆では前者、毒ガス被毒では後者モデルに基づく肺癌発生が誘発された可能性も示唆された。さらに、肺癌発生モデルとして正常気道上皮にテロメラーゼ遺伝子TERTおよびSV40 early antigensを遺伝子導入したin vitroトランスフォーム細胞では、増殖とともにORFが短いvariant TERT mRNA発現が誘導されて悪性度が増強してくること、Cancer stem cell model由来と推察した肺腺癌細胞株でも同様現象を認め、この誘導がテロメラーゼ陽性細胞の肺癌発癌進展過程に関わる可能性も示唆された。

Research Products

• [Journal Article] Telomerase activation without shortening of telomeric 3'-overhang is a poor prognostic factor in human colorectal cancer (2011)
  • Author(s): Kojima, K.
  • Journal Title: Cancer Science Volume: (in press)
  • Peer Reviewed
• [Journal Article] テロメラーゼ (2011)
  • Author(s): 檜山桂子
  • Journal Title: 検査と技術 Volume: (印刷中)
• [Journal Article] A robust method for estimating gene expression states using Affymetrix microarray probe level data. (2010)
  • Author(s): Ohtaki, M.
  • Journal Title: BMC Bioinfomatics Volume: 11(ePub)
  • Peer Reviewed
• [Journal Article] Carcinogenesis and cellular immortalization without persistent inactivation of p16/Rb pathway in lung cancer. (2010)
  • Author(s): Arifin, M.
  • Journal Title: Int J Oncol Volume: 36 Pages: 1217-27
  • Peer Reviewed
• [Journal Article] Carcinogenesis and cellular immortalization without persistent inactivation of p16/Rb pathway in lung cancer (2010)
  • Author(s): Arifin M.
  • Journal Title: International Journal of Oncology 36(5) Pages: 1217-1227
  • Peer Reviewed
• [Journal Article] A robust method for estimating gene expression states using Affymetrix microarray probe level data (2010)
  • Author(s): Ohtaki M.
  • Journal Title: BMC Bioinformatics (印刷中)
  • Peer Reviewed
• [Journal Article] Activation of the hypoxia-inducible factor-1 in overloaded temporomandibular joint, and induction of osteoclastogenesis (2010)
  • Author(s): Shirakura M.
  • Journal Title: Biochem Biophys Res Commun 393(4) Pages: 800-805
  • Peer Reviewed
• [Journal Article] EMP3 as a candidate tumor suppressor gene for solid tumors. Expit Opin (2009)
  • Author(s): Fumoto S.
  • Journal Title: Expert Opinion on Therapeutic Targets 13(7) Pages: 811-822
  • Peer Reviewed
• [Journal Article] Detection of Island Hypermethylation of Caspase-8 in Neuroblastoma Using an Oligonucleotide Array (2009)
  • Author(s): Kamimatsuse A.
  • Journal Title: Pediatr Blood Cancer 52(7) Pages: 777-783
  • Peer Reviewed
• [Journal Article] Evaluation of genes identified by microarray analysis in favorable neuroblastoma (2009)
  • Author(s): Kamei N.
  • Journal Title: Pediatr Surg Int 25(11) Pages: 931-937
  • Peer Reviewed
• [Journal Article] ゲノム解析の臨床と研究 これを支える体制と整備 ゲノム・遺伝子研究と倫理 (2009)
  • Author(s): 檜山桂子
  • Journal Title: 日本癌治療学会誌 44(1) Pages: 1255-1259
  • Peer Reviewed
• [Journal Article] Telomere biology in neuroblastoma : telomere binding proteins and alternative strengthening of telomeres (2009)
  • Author(s): Onitake Y
  • Journal Title: J Pediatr Surg 44(12) Pages: 2258-2266
  • Peer Reviewed
• [Presentation] Exploration of the genes possibly involved in telomerase-mediated cellular immortalization in lung cancer (2010)
  • Author(s): プトラアンディカチャンドラ
  • Organizer: 第69回日本癌学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-23
• [Presentation] 食道癌における新規予後マーカーとしてのEMX2の同定 (2010)
  • Author(s): 麓祥一
  • Organizer: 第69回日本癌学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-23
• [Presentation] Alteration of the DNA repair system in hypoxic cancer cells (2010)
  • Author(s): 谷本圭司
  • Organizer: 第69回日本癌学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] 非小細胞肺癌におけるシスプラチン/パクリタキセル併用療法の薬剤応答性バイオマーカーの探索 (2010)
  • Author(s): モハメッドアーメッド
  • Organizer: 第69回日本癌学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] がんと遺伝 (2010)
  • Author(s): 檜山桂子
  • Organizer: 一貴会定例会
  • Place of Presentation: 高知
  • Year and Date: 2010-08-10
• [Presentation] 臨床に必要な腫瘍遺伝学 (2010)
  • Author(s): 檜山桂子
  • Organizer: 第2回広島臨床遺伝セミナー
  • Place of Presentation: 広島
  • Year and Date: 2010-07-26
• [Presentation] マイクロアレイデータ解析の最近の動向について (2010)
  • Author(s): 大谷敬子
  • Organizer: 2010年度日本計量生物学会年会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] Identification of a novel prognostic maker for esophageal squamous cell carcinoma (2010)
  • Author(s): Fumoto, S.
  • Organizer: Annual Meeting of Am.Assoc.Cancer Res 2010
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2010-04-19
• [Presentation] A possible target key molecule for treatment of pancreatic cancer, screened as cancer-specific immortalization associated gene (2010)
  • Author(s): Eguchi, H.
  • Organizer: Annual Meeting of Am.Assoc.Cancer Res 2010
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2010-04-19
• [Presentation] Functional analysis of SFRS10 : A novel molecular target foranti-cancer drug (2010)
  • Author(s): Wada, S.
  • Organizer: Annual Meeting of Am.Assoc.Cancer Res 2010
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2010-04-19
• [Presentation] Analysis of HIF-1-transgenic mice (2010)
  • Author(s): 谷本圭司
  • Organizer: International Symposium on the Innovation for Health and Sustainable Life
  • Place of Presentation: Hiroshima
  • Year and Date: 2010-03-09
• [Presentation] Activation of the hypoxia-inducible factor-1 in chondrocytes (2010)
  • Author(s): 谷本圭司
  • Organizer: Keystone Symposia, Hypoxia : Molecular Mechanisms of Oxygen Sensing and Response Pathway
  • Place of Presentation: Keystone, USA
  • Year and Date: 2010-01-22
• [Presentation] がんの生物学(教育セミナー) (2009)
  • Author(s): 檜山桂子
  • Organizer: 2009年度がん治療認定医教育セミナー
  • Place of Presentation: 幕張
  • Year and Date: 2009-12-19
• [Presentation] Tumor susceptibility induced by constitutive expression of hypoxia-inducible factor-lalpha in a transgenic mouse model (2009)
  • Author(s): 末岡栄三朗
  • Organizer: 第32回日本生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-11
• [Presentation] GTSE1 : A candidate gene for a new molecular target of pancreatic cancer (2009)
  • Author(s): 江口英孝
  • Organizer: 第32回日本生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-11
• [Presentation] Molecular mechanisms of anti-cancer activity of zoledronate (2009)
  • Author(s): 谷本圭司
  • Organizer: 第32回 日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-10
• [Presentation] Zoledronate inhibits HIF-1α in cancer cells (2009)
  • Author(s): 谷本圭司
  • Organizer: 第7回 がんとハイポキシア研究会
  • Place of Presentation: 京都
  • Year and Date: 2009-12-06
• [Presentation] Tumor development in transgenic mice constitutively expressing hypoxia-inducible factor-1α (2009)
  • Author(s): 末岡栄三朗
  • Organizer: 第7回がんとハイポキシア研究会
  • Place of Presentation: 京都
  • Year and Date: 2009-12-06
• [Presentation] Lung carcinogenesis model : Increase of Malignant potential occurs in transformed bronchial epithelial cells concomitant with TERT upregulation (2009)
  • Author(s): 檜山桂子
  • Organizer: The 14^<th> Congress of the Asian Pacific Society of Respirology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-11-16
• [Presentation] High telomerase expression without p16/RB aberration in lung cancer cells may be the possible marker of cancer stem cells theoretically and experimentally (2009)
  • Author(s): Arifin M.
  • Organizer: The 14^<th> Congress of the Asian Pacific Society of Respirology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-11-16
• [Presentation] Genetic variations in detoxification enzymes and HIF1α in COPD (2009)
  • Author(s): Putra A.C.
  • Organizer: The 14^<th> Congress of the Asian Pacific Society of Respirology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-11-16
• [Presentation] Telomerase activation without P16/RB inactivation as a possible marker of stem cell origin in lung adenocarcinoma (2009)
  • Author(s): Arifin M.
  • Organizer: The 19^<th> HCS-The 3^<rd> Three Universities' Consortium International Symposium "Recent progress in carcinogenesis, progression and therapy of lung cancer"
  • Place of Presentation: Hiroshima
  • Year and Date: 2009-11-01
• [Presentation] Possible involvement of HIF-1α function-related polymorphisms in lung carcinogenesis (2009)
  • Author(s): Putra A.C.
  • Organizer: The 19^<th> HCS-The 3^<rd> Three Universities' Consortium In ternational Symposium "Recent Progress in Carcinogenes is, Progression and Therapy of Lung Cancer"
  • Place of Presentation: Hiroshima
  • Year and Date: 2009-11-01
• [Presentation] ゲノム・遺伝子研究と倫理. 教育シンポジウム2 (2009)
  • Author(s): 檜山桂子
  • Organizer: 第47回日本癌治療学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-23
• [Presentation] 卵巣癌におけるTC(paclitaxel/carboplatin)療法の抗癌剤感受性関連遺伝 (2009)
  • Author(s): 山本弥寿子
  • Organizer: 第47回日本癌治療学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-22
• [Presentation] HIF1Aトランスジェニックマウスの腫瘍原性解析 (2009)
  • Author(s): 谷本圭司
  • Organizer: 博多シンポジウム「内・外環境と生物応答」
  • Place of Presentation: 博多
  • Year and Date: 2009-10-09
• [Presentation] 食道癌においてインビトロ抗癌剤感受性と臨床的予後に対し逆の相関を示す遺伝子の解析 (2009)
  • Author(s): 麓祥一
  • Organizer: 第68回日本癌学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] 癌特異的不死化関連遺伝子GTSE1:膵癌の新たな分子標的侯補 (2009)
  • Author(s): 江口英孝
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] Intact p16/RB pathway with high telomerase activity may be the marker of stem-cell origin in lung adenocarcinoma (2009)
  • Author(s): Arifin, M.
  • Organizer: The 68th Annual Meeting of the Jpn. Cancer Assoc.
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-02
• [Presentation] A role of polymorphisms of HIF-1α in lung cancer (2009)
  • Author(s): Putra, A.C.
  • Organizer: The 68th Annual Meeting of the Jpn. Cancer Assoc
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] トランスジェニックマウスを用いたHIF-1αによる腫瘍原生の解析 (2009)
  • Author(s): 末岡栄三朗
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] 癌特異的不死化関連遺伝子SFRS10の選択的スプライシングに関わるネットワークと機能の解析 (2009)
  • Author(s): 和田智
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] Exploration of the evidence of cancer stem cells in lung cancer (2009)
  • Author(s): Arifin M.
  • Organizer: European Respiratory Society Annual Congress 2009
  • Place of Presentation: Vienna, オーストソア
  • Year and Date: 2009-09-15
• [Presentation] ゲノム情報に基づく医療の展開 (2009)
  • Author(s): 檜山桂子
  • Organizer: 日本遺伝看護学会第8回学術大会
  • Place of Presentation: 広島
  • Year and Date: 2009-09-11
• [Presentation] ビスフォスフォネート製剤の抗腫瘍効果分子機構の解明 (2009)
  • Author(s): 谷本圭司
  • Organizer: 第10回ホルモンと癌研究会
  • Place of Presentation: 仙台
  • Year and Date: 2009-07-31
• [Presentation] 新規分子標的候補遺伝子SFRS10の同定と機能解析 (2009)
  • Author(s): 和田智
  • Organizer: 第13回日本がん分子標的治療学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2009-06-26
• [Presentation] EMP3の臨床的意義とその発現制御機構:食道癌と他がん種の比較 (2009)
  • Author(s): 麓祥一
  • Organizer: 第63回日本食道学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2009-06-25
• [Presentation] がん薬物療法個人応答の予測:非仮説マーカーの同定と複数遺伝子による予測の試み (2009)
  • Author(s): Mohamed, A.E.
  • Organizer: 第18回日本癌病態治療研究会
  • Place of Presentation: 福島
  • Year and Date: 2009-06-16
• [Presentation] Genetic Variations in Telomerase Components and Telomere Shortening in Japanese Patients with COPD (2009)
  • Author(s): Arifin, M.
  • Organizer: The 49^<th> Annual Meeting of The Japanese Respiratory Society
  • Place of Presentation: 東京
  • Year and Date: 2009-06-13
• [Presentation] Telomere reset mechanism and efficiency in human stem cells (2009)
  • Author(s): 檜山桂子
  • Organizer: JST-CIRM (California Institute for Regenerative Medicine) Workshop
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2009-06-08
• [Presentation] DNA修復能に影響を与える生体内環境因子:低酸素環境 (2009)
  • Author(s): 谷本圭司
  • Organizer: 第50回原子爆弾後障害研究会
  • Place of Presentation: 広島
  • Year and Date: 2009-06-07
• [Presentation] 道癌における新規癌抑制遺伝子EMP3の同定と放射線感受性因子としての検討 (2009)
  • Author(s): 麓祥一
  • Organizer: 第50回原子爆弾後障害研究会
  • Place of Presentation: 広島
  • Year and Date: 2009-06-07
• [Presentation] Randomized phase II/III study of docetaxel/S-1 (DS-1) versus CDDP/5FU (FUP) in advanced or recurrent gastric cancer : Updated phase II results (2009)
  • Author(s): Ikeda R.
  • Organizer: ASCO 2009 Annual Meeting
  • Place of Presentation: Orlando, 英国
  • Year and Date: 2009-05-31
• [Presentation] 保険診療としての遺伝子検査の使い方 (2009)
  • Author(s): 檜山桂子
  • Organizer: 第二内科開業医会
  • Place of Presentation: 広島
  • Year and Date: 2009-05-11
• [Presentation] Identification of novel drug-response determinants for 5-FU and CDDP in esophageal squamous cell carcinoma(ESCC) (2009)
  • Author(s): 麓祥一
  • Organizer: Am. Assoc. Cancer Res 100^<th> Annual Meeting 2009
  • Place of Presentation: Denver, USA
  • Year and Date: 2009-04-22
• [Presentation] Molecular mechanisms of degradation of the pVHL, tumor suppressor gene product, by a novel oncogenic protein, UBE2S (2009)
  • Author(s): 谷本圭司
  • Organizer: Am. Assoc. Cancer Res 100^<th> Annual Meeting 2009
  • Place of Presentation: Denver, USA
  • Year and Date: 2009-04-21
• [Presentation] Possible drug targets screened as key genes in immortalization mechanisms specific for cancer cells (2009)
  • Author(s): 和田智
  • Organizer: Am. Assoc. Cancer Res 100^<th> Annual Meeting 2009
  • Place of Presentation: Denver, USA
  • Year and Date: 2009-04-21
• [Presentation] Selection of novel marker genes that predict a response to paclitaxel and carboplatin(TC) therapy in ovarian cancer (2009)
  • Author(s): 山本弥寿子
  • Organizer: Am. Assoc. Cancer Res 100^<th> Annual Meeting 2009
  • Place of Presentation: Denver, USA
  • Year and Date: 2009-04-19
• [Book] 遺伝カウンセリングハンドブック (2011)
  • Author(s): 檜山桂子(分担執筆)
  • Publisher: メディカル ドゥ(印刷中)
• [Book] Diagnostic and prognostic molecular markers in neuroblastoma. in Clinical application of molecular diagnosis -cancer, radiation effects, and human diseases- (2010)
  • Author(s): 檜山桂子
  • Total Pages: 220
  • Publisher: Transworld Research Network
• [Book] Clinical application of molecular diagnosis -cancer, radiation effects in Clinical application of molecular diagnosis -cancer, radiation effects, and human diseases- (2010)
  • Author(s): 檜山桂子
  • Total Pages: 220
  • Publisher: Transworld Research Network
• [Book] Individualized chemotherapy for cancer. in Clinical application of molecular diagnosis -cancer, radiation effects, and human diseases- (2010)
  • Author(s): Tanimoto K
  • Total Pages: 220
  • Publisher: Transworld Research Network
• [Book] Simple EGFR mutation screening by conventional PCR. In : Clinical application of molecular diagnosis -cancer, radiation effects, and human diseases- (2010)
  • Author(s): Arifin, M
  • Total Pages: 220
  • Publisher: Transworld Research Network
• [Book] 細胞死 ; テロメア・テロメラーゼ. In:入門腫瘍内科学 (2009)
  • Author(s): 檜山桂子
  • Total Pages: 301
  • Publisher: 篠原出版新社
• [Book] 乳癌とテロメラーゼ. In:みんなに役立つ乳癌の基礎と臨床 (2009)
  • Author(s): 檜山桂子
  • Total Pages: 1095
  • Publisher: 医薬ジャーナル社