Mechanism of progression from bronchioloalveolar carcinoma to invasive adenocarcinoma

• Project/Area Number: 21590995
• 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: Kawasaki Medical School (2011); Okayama University (2009-2010)
• Principal Investigator: TAKIGAWA Nagio 川崎医科大学, 医学部, 教授 (60325107)
• Co-Investigator(Kenkyū-buntansha): KIURA Katsuyuki 岡山大学, 大学病院, 教授 (10243502)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 肺癌 / 発癌 / EGFR / 肺腺癌 / 遺伝子変異

Research Abstract

Bronchioloalveolar carcinoma(BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors<1 cm, 1-2 cm, and≧2 cm in diameter, respectively, were analyzed. Of the 24 tumors≦2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component by immunohistochemistry, while pSTAT3 expression was reversed. In the tumors≦2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors. pSTAT3 was identified in the BAC component of 88% of the EGFR mutant(n=17) and 82% of the wild-type tumors(n=33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines(PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor(JSI-124). In conclusion, adenocarcinomas with a BAC component overexpressed pSTAT3 at the margin compared to the center of the tumor. Moreover, STAT3 inhibitors may have therapeutic potential in the inhibition of adenocarcinoma.

Research Products

• [Journal Article] STAT3 expression in activating EGFR-driven adenocarcinoma of the lung (2012)
  • Author(s): Takata Saburo, Takigawa Nagio, Segawa Yoshihiko, Kubo Toshio, Ohashi Kadoaki, Kozuki Toshiyuki, Teramoto Norihiro, Yamashita Motohiro, Toyooka Shinichi, Tanimoto Mitsune, Kiura Katsuyuki
  • Journal Title: Lung Cancer Volume: 75 Issue: 1 Pages: 24-29
  • DOI: 10.1016/j.lungcan.2011.05.015
  • Peer Reviewed
• [Journal Article] Liposomal delivery of MicroRNA-7-expressing plasmid overcomes epidermal growth factor receptor tyrosine kinase inhibitor-resistance in lung cancer cells (2011)
  • Author(s): Kammei Rai, Takigawa Nagio, Ito Sachio, Kashihara Hiromi, Ichihara Eiki, Yasuda Tatsuji, Shimizu Kenji, Tanimoto Mitsune, Kiura Katsuyuki
  • Journal Title: Molecular Cancer Therapeutics Volume: 10 Issue: 9 Pages: 1720-1727
  • DOI: 10.1158/1535-7163.mct-11-0220
  • NAID: 120005232489
  • Peer Reviewed
• [Journal Article] Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice. (2009)
  • Author(s): Ohashi K, Takigawa N, Osawa M, Ichihara E, Takeda H, Kubo T, Hirano S, Yoshino T, Takata M, Tanimoto M, Kiura K.
  • Journal Title: Cancer Research 69 Pages: 7088-7095
  • Peer Reviewed
• [Journal Article] Effects of vandetanib on lung adenocarcinoma cells harboring epidermal growth factor receptor T790M mutation in vivo. (2009)
  • Author(s): Ichihara E, Ohashi K, Takigawa N, Osawa M, Ogino A, Tanimoto M, Kiura K.
  • Journal Title: Cancer Research 69 Pages: 5091-5098
  • NAID: 130004505698
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of EGFR signaling pathways in Japanese patients with non-small cell lung cancer. (2009)
  • Author(s): Hosokawa S, Toyooka S, Fujiwara Y, Tokumo M, Soh J, Takigawa N, Hotta K, Yoshino T, Date H, Tanimoto M, Kiura K.
  • Journal Title: Lung Cancer 66 Pages: 107-113
  • Peer Reviewed
• [Presentation] エクソン19欠失EGFR遺伝子変異陽性肺癌モデルに対するアファチニブの効果 (2011)
  • Author(s): 二宮崇, 瀧川奈義夫, 村上斗司, 本多宣裕, 南大輔, 越智宣昭, 八杉昌幸, 久保寿夫, 市原英基, 谷本光音, 木浦勝行
  • Organizer: 第52回日本肺癌学会総会
  • Place of Presentation: 大阪市
  • Year and Date: 2011-11-04
• [Presentation] エクソン19欠失EGFR遺伝子変異陽性肺癌モデルに対するアファチニブの効果 (2011)
  • Author(s): 二宮崇, 瀧川奈義夫, 村上斗司, 本多宣裕, 南大輔, 越智宣昭, 八杉昌幸, 久保寿夫, 市原英基, 谷本光音, 木浦勝行
  • Organizer: 第52回日本肺癌学会総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2011-11-04
• [Presentation] Effect of everolimus on lung tumorigenesis in transgenic mice carrying activating EGFR mutation (2011)
  • Author(s): Yasugi Masayuki, Takigawa Nagio, Ochi Nobuaki, Ichihara Eiki, Hisamoto Akiko, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2011-10-03
• [Presentation] ERK reactivation mediated by SRC in acquired resistance to gefitinib in non-small cell lung cancer with EGFR mutation (2011)
  • Author(s): Ochi Nobuaki, Takigawa Nagio, Yasugi Masayuki, Ichihara Eiki, Hisamoto Akiko, Hotta Katsuyuki, Tabata Masahiro, Tanimoto Mitsune, Kiura Katsuyuki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2011-10-03
• [Presentation] Effect of everolimus on lung tumorigenesis in transgenic mice carrying activating EGFR mutation (2011)
  • Author(s): Yasugi Masayuki, Takigawa Nagio, Ochi Nobuaki, Ichihara Eiki, Hisamoto Akiko, Hotta Katsuyuki, Tabata Masahiro, Tanimoto Mitsune, Kiura Katsuyuki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2011-10-03
• [Presentation] ERK reactivation mediated by SRC in acquired resistance to gefitinib in non-small cell lung cancer with EGFR mutation (2011)
  • Author(s): Ochi Nobuaki, Takigawa Nagio, Yasugi Masayuki, Ichihara Eiki, Hisamoto Akiko, Hotta Katsuyuki, Tabata Masahiro, Tanimoto Mitsune, Kiura Katsuyuki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2011-10-03
• [Presentation] Multiple molecular targeting effects by miR-7 in EGFR tyrosine kinase inhibitor-resistant lung cancer xenograft models (2011)
  • Author(s): Kammei Rai, Takigawa Nagio, Ito Sachio, Kiura Katsuyuki, Yasuda Tatsuji, Shimizu Kenji, Tanimoto Mitsune
  • Organizer: 102nd Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Orlando, USA
  • Year and Date: 2011-04-04
• [Presentation] JAK2/STAT3 induces erlotinib-resistance in lung cancer cells harboring EGFR-activating mutations (2011)
  • Author(s): Harada Daijiro, Takigawa Nagio, Ohashi Kadoaki, Ichihara Eiki, Kubo Toshio, Takeda Hiromasa, Kashihara Hiromi, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki
  • Organizer: 102nd Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Orlando, USA
  • Year and Date: 2011-04-03
• [Presentation] Lipofection of the designed plasmid expressing microRNA-7 has antitumor effect in gefitinib-resistant lung adenocarcinoma in vivo. (2010)
  • Author(s): Rai K, Takigawa N, Ito S, Kashihara H, Ichihara E, Kiura K, Yasuda T, Shimizu K, Tanimoto M.
  • Organizer: 米国癌学会
  • Place of Presentation: ワシントンDC
  • Year and Date: 2010-04-20
• [Presentation] The role of STAT3 in the progression of lung adenocarcinoma (2009)
  • Author(s): Takata S, Takigawa N, Kiura K, et al.
  • Organizer: 第68回日本癌学会総会
  • Place of Presentation: 横浜市
  • Year and Date: 2009-10-02