上皮成長因子受容体変異肺癌に対するゲフィチニブ治療による肺線維症発症

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24590438
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: 松原 修 公益財団法人がん研究会, その他部局等, 研究員 (40107248)
• Co-Investigator(Kenkyū-buntansha): 石川 雄一 公益財団法人がん研究会, その他部局等, その他 (80222975)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 肺線維症 / 間質性肺炎 / 病理発生機序 / EGFR変異肺癌

Outline of Annual Research Achievements

上皮成長因子受容体変異のみられる肺癌に対して、ゲフィチニブはチロシンキナーゼを選択的に阻害する内服できる抗がん剤で、強力な腫瘍縮小効果がある。しかしゲフィチニブは副作用として、重篤な間質性肺炎・肺線維症から呼吸不全死を引き起こす。治療による肺線維症発症のリスクの予想がつくと治療を安全に行えるのではないかと考えて研究を進めた。間質性肺炎・肺線維症の病理像では、肺胞の破壊、虚脱、細気管支拡張、線維芽細胞巣であり、終末となると広範な線維化と蜂窩肺病変の拡大である。剖検で見るのは終末像が多いが、生検で見ると進展において重要な組織像は線維芽細胞巣の活性化と肺胞の破壊である。線維芽細胞巣の活性化の時に肺胞上皮の壊死、特にアポトーシス、筋線維芽細胞の出現が生じていることが分かった。線維芽細胞巣の活性化での分子的な機構、組織構築の改変を、20例の症例について検討した。材料は間質性肺炎・肺線維症と診断した症例のVATS肺生検と対照症例10例の病理材料で、E-cadherin、β-catenin、vimentin、desmin、α-smooth muscle actin、TGF-β、CTGF、Ki-67などを免疫組織学的に、またTUNNEL法とラダー法でアポトーシスを検討した。線維芽細胞巣の紡錘形細胞はα-smooth muscle actin、vimentin、desminに陽性で、肺胞上皮にアポトーシスがみられ、再生と思われる増生した肺胞上皮にはTGF-β、CTGFが陽性で、両者ともKi-67の陽性が増加していた。筋線維芽細胞の出現は肺胞上皮の壊死、再生、上皮-間葉移行によるのではないかと考えられた。健常部肺、線維化肺のプロテオーム解析を行い、annexin A3, plastin-2, Hsp 27, Hsp 70といったタンパク発現に違いがありそうな結果を得、現在再現性を検討している。

Research Products

• [Journal Article] The clinicopathological features associated with skip N2 metastases in patients with clinical stage IA non-small-cell lung cancer (2015)
  • Author(s): Gorai A, Sakao Y, Kuroda H, Uehara H, Mun M, Ishikawa Y, Nakagawa K, Masuda M, Okumura S
  • Journal Title: Eur J Cardiothorac Surg Volume: 47(4) Pages: 653-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SEVERAL TOPICS OF PULMONARY VASCULITIS AND PULMONARY HEMORRHAGE SYNDROMES (2014)
  • Author(s): Matsubara O
  • Journal Title: Pathology Volume: Suppl 2 Pages: S38
  • Peer Reviewed
• [Journal Article] Community-acquired lobar pneumonia caused by Pseudomonas aeruginosa infection in Japan: a case report with histological and immunohistochemical examination (2014)
  • Author(s): Takajo D, Iwaya K, Katsurada Y, Miyai K, Takasu A, Matsubara O, Sakamoto T, Tamai S, Tsuda H
  • Journal Title: Pathol Int Volume: 64(5) Pages: 224-30
  • Peer Reviewed / Open Access
• [Journal Article] The expression and clinical significance of connective tissue growth factor in advanced head and neck squamous cell cancer (2014)
  • Author(s): Kikuchi R, Kikuchi Y, Tsuda H, Maekawa H, Kozaki K, Imoto I, Tamai S, Shiotani A, Iwaya K, Sakamoto M, Sekiya T, Matsubara O
  • Journal Title: Hum Cell Volume: 27(3) Pages: 121-8
  • Peer Reviewed / Open Access
• [Journal Article] Pleuroparenchymal fibroelastosis as a series of airway complications associated with chronic graft-versus-host disease following allogeneic bone marrow transplantation (2014)
  • Author(s): Fujikura Y, Kanoh S, Kouzaki Y, Hara Y, Matsubara O, Kawana A
  • Journal Title: Intern Med Volume: 53(1) Pages: 43-6
  • Peer Reviewed / Open Access
• [Journal Article] Wide local extension and higher proliferation indices are characteristic features of symptomatic lobular neoplasias (LNs) and LNs with an early invasive component (2014)
  • Author(s): Katsurada Y, Yoshida M, Maeshima AM, Ikeda K, Shibata T, Kinoshita T, Matsubara O, Tsuda H
  • Journal Title: Histopathology Volume: 64(7 Pages: 994-1003
  • Peer Reviewed / Open Access
• [Journal Article] Fatty acid synthase overexpression in adult testicular germ cell tumors: potential role in the progression of non-seminomatous germ cell tumors (2014)
  • Author(s): Miyai K, Iwaya K, Asano T, Tamai S, Matsubara O, Tsuda H
  • Journal Title: Virchows Arch Volume: 464(2) Pages: 221-8
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Mechanism of EML4-ALK Rearrangement Mediated by Chromothripsis in a Patient-Derived Cell Line (2014)
  • Author(s): Kodama T, Motoi N, Ninomiya H, Sakamoto H, Kitada K, Tsukaguchi T, Satoh Y, Nomura K, Nagano H, Ishii N, Terui Y, Hatake K, Ishikawa Y
  • Journal Title: J Thorac Oncol Volume: 9(11) Pages: 1638-46
  • Peer Reviewed / Open Access
• [Journal Article] Combined effects of asbestos and cigarette smoke on the development of lung adenocarcinoma: different carcinogens may cause different genomic changes (2014)
  • Author(s): Inamura K, Ninomiya H, Nomura K, Tsuchiya E, Satoh Y, Okumura S, Nakagawa K, Takata A, Kohyama N, Ishikawa Y
  • Journal Title: Oncol Rep Volume: 32(2) Pages: 475-82
  • Peer Reviewed / Open Access
• [Journal Article] A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high-grade pulmonary neuroendocrine carcinoma (large cell neuroendocrine carcinoma and small cell lung cancer) (2014)
  • Author(s): Kenmotsu H, Niho S, Ito T, Ishikawa Y, Noguchi M, Tada H, Sekine I, Watanabe S, Yoshimura M, Yamamoto N, Oshita F, Kubota K, Nagai K
  • Journal Title: Lung Cancer Volume: 84(3) Pages: 254-8
  • DOI: 10.1016/j.lungcan.2014.03.007. Epub 2014 Mar 13
  • Peer Reviewed / Open Access
• [Journal Article] Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer (2014)
  • Author(s): Ono H, Motoi N, Nagano H, Miyauchi E, Ushijima M, Matsuura M, Okumura S, Nishio M, Hirose T, Inase N, Ishikawa Y
  • Journal Title: Cancer Med Volume: 3(3) Pages: 632-42
  • DOI: 10.1002/cam4.220. Epub 2014 Mar 3
  • Peer Reviewed / Open Access
• [Journal Article] Reproducibility of histopathological diagnosis in poorly differentiated NSCLC: an international multiobserver study (2014)
  • Author(s): Thunnissen E, Noguchi M, Aisner S, Beasley MB, Brambilla E, Chirieac LR, Chung JH, Dacic S, Geisinger KR, Hirsch FR, Ishikawa Y, Kerr KM, Lantejoul S, Matsuno Y, Minami Y, Moreira AL, Pelosi G, Petersen I, Roggli V, Travis WD, Wistuba I, Yatabe Y, Dziadziuszko R, Witte B, Tsao MS, Nicholson AG
  • Journal Title: J Thorac Oncol Volume: 9(9) Pages: 1354-62
  • Peer Reviewed / Open Access
• [Journal Article] A subset of small cell lung cancer with low neuroendocrine expression and good prognosis: a comparison study of surgical and inoperable cases with biopsy (2014)
  • Author(s): Hamanaka W, Motoi N, Ishikawa S, Ushijima M, Inamura K, Hatano S, Uehara H, Okumura S, Nakagawa K, Nishio M, Horai T, Aburatani H, Matsuura M, Iwasaki A, Ishikawa Y
  • Journal Title: Hum Pathol Volume: 45(5) Pages: 1045-56
  • DOI: 10.1016/j.humpath.2014.01.001.
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary tumor thrombotic microangiopathy with circulatory failure treated with imatinib (2014)
  • Author(s): Ogawa A, Yamadori I, Matsubara O, Matsubara H
  • Journal Title: Intern Med Volume: 52(17) Pages: 1927-30
  • Peer Reviewed / Open Access
• [Presentation] Adenocarcinoma in situ of the lung (2015)
  • Author(s): Matsubara O
  • Organizer: 10th Asia Pacific IAP Congress
  • Place of Presentation: Brisbane, Australia
  • Year and Date: 2015-06-04 – 2015-06-07
  • Invited
• [Presentation] Several topics of lung pathology (2015)
  • Author(s): Matsubara O
  • Organizer: 3rd Pacific Pathology Workshop
  • Place of Presentation: Suva, Fiji
  • Year and Date: 2015-05-08 – 2015-05-09
  • Invited
• [Presentation] Pathological role of fibroblastic foci and bronchiolar epithelial proliferation in IPF/UIP (2015)
  • Author(s): Matsubara O
  • Organizer: 104th US and Canadian Academy of Pathology
  • Place of Presentation: Boston, USA
  • Year and Date: 2015-03-22 – 2015-03-27
• [Presentation] Pulmonary neuroendocrine tumors (2014)
  • Author(s): Matsubara O
  • Organizer: 9th Asia Pacific Society for Molecular Immunohistology
  • Place of Presentation: Cebu, Phillipines
  • Year and Date: 2014-11-27 – 2014-11-28
  • Invited
• [Presentation] Pathology of pulmonary vasculitis (2014)
  • Author(s): Matsubara O
  • Organizer: International Congress of IAP
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2014-10-05 – 2014-10-10
  • Invited
• [Book] 20 HHV-8 related lung neoplastic and nonneoplastic diseases. In: Fraire AE et al.ed. Viruses and the LUng (2014)
  • Author(s): Matsubara O, Mark EJ
  • Total Pages: 177-190
  • Publisher: Springer