山田健人非常勤講師グループ

疾患モデルの確立によるヒトがんの生体内での分子病理学的研究

 がん細胞の増殖・浸潤や転移の分子機構、特に細胞間あるいは細胞と細胞外基質間の相互作用の解析には、ヒトがんの病態を生体内で再現する疾患モデルの開発が必要です。わたしたちは、免疫不全マウスを用いたいろいろなヒトのがんモデルの開発を通じて、それぞれのがんの病態病理の分子レベルにおける解析と新規の分子標的療法への応用について研究しています(図1)。

 ヒト白血病細胞がマウス骨髄だけでなく脊髄へ臓器特異的に浸潤するモデルを確立しました(図2)。このモデルでは、脊髄浸潤による下半身麻痺が一定期間で再現されるために白血病細胞浸潤の評価が容易ですので、このモデルを用いることで白血病細胞浸潤の調節分子として小GTP結合蛋白Rhoとその抑制因子D4-GDIを見つけました。さらに小児の白血病細胞においてD4-GDI遺伝子の点突然変異を見出し、この変異型D4-GDI遺伝子が、dominant negative変異体として機能することで、細胞接着および細胞運動能の亢進を通じて白血病細胞浸を惹起することを明らかにしました(図3)。

 アスベストによって肺の表面に発生する悪性中皮腫については、この腫瘍にCD26分子が高い頻度で発現していることを見つけました(図4)。つぎにヒト悪性中皮腫細胞株を免疫不全マウスの胸腔の中に移植することで、より患者さんに近いヒト中皮腫モデルを作り、このモデルを用いることでCD26が中皮腫細胞の浸潤・増殖に関与していることを明らかにしました(図5, 6)。そこで、ヒト化抗CD26モノクローナル抗体の開発を行い、本抗体が生体内で中皮腫に対して抗腫瘍効果を発揮することを見つけました(図7)。

 一方、これまでのマウスを用いたヒトがんモデルでは、がん細胞はヒト由来であっても、腫瘍間質や血管はマウス由来でした。そこでヒト腫瘍細胞とともにヒト骨髄由来間質細胞・間葉系幹細胞を免疫不全マウスへ移植することで、ヒト腫瘍間質の生体内での再構成に成功しました。この系を用いたヒト神経芽腫モデルでは、骨髄由来の細胞が腫瘍血管のみならず神経芽腫特異的なシュワン性間質をも形成しうることを示しました(図8)。

 これらのヒト疾患モデルは、さまざまな生物学的特徴を有する各種のヒトがんの生体内での挙動、病態を解析する手法として有用であり、臓器・組織特異的な浸潤・転移の分子メカニズムに迫るのみならず、新たな治療法の開発や治療効果の判定にも役立つと考えられます。

 

 

 

 

 

 

 

 

 

研究成果


2015年

Sakiyama T, Kubo A, Sasaki T, Yamada T, Yabe N, Matsumoto K, Futei Y.
Recurrent gastrointestinal perforation in a patient with Ehlers-Danlos syndrome due to tenascin-X deficiency.
J Dermatol 42:1-4, 2015

Matsushita M, Ozaki Y, Hasegawa Y, Terada F, Tabata N, Shiheido H, Yanagawa H, Oikawa T, Matsuso K, Du W, Yamada T, Ichikawa D, Hattori Y.
A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts.
PLoS One. 10(1):e0116135, 2015

Otsuki N, Iwata S, Yamada T, Hosono O, Dang NH, Hatano R, Ohnuma K, Morimoto C.
Modulation of immunological responses and amelioration of collagen-induced arthritis by the novel roxithromycin derivative 5-I.
Mod Rheumatol. 24:1-9, 2015


2014年

Fujimoto N,Ohnuma K, Aoe K, Hosono, Yamada T, Kishimoto T, Morimoto C.
Clinical significance of soluble CD26 in malignant pleural mesothelioma.
PLoS One. 9(12):e115647, 2014

Kurauchi-Mito A, Ichihara A, Bokuda K, Sakoda M, Kinouchi K, Yaguchi T, Yamada T, Sun-Wada GH, Wada Y, Itoh H.
Significant roles of the (pro)rennin receptor in integrity of vascular smooth muscle cells.
Hypertens Res. 37(9):830-835, 2014

Nishida H, Suzuki H, Madokoro H, Hayashi M, Morimoto C, Sakamoto M, Yamada T.
Blockade of CD26 Signaling Inhibits Human Osteoclast Development.
J Bone Miner Res. 29(11):2439-2455, 2014

Komiya E, Yamazaki H, Ryou Hatano R, Iwata S, Okamoto T, Dang NH, Yamada T, Morimoto C.
CD26-mediated regulation of periostin expression contributes to migration and invasion of malignant pleural mesothelioma cells.
Biochem Biophys Res Commun. 447(4):609-615, 2014

Yamamoto J, Ohnuma K, Hatano R, Okamoto T, Komiya E, Yamazaki H, Iwata S, Dang NH, Aoe K, Kishimoto T, Yamada T, Morimoto C.
Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.
Br J Cancer. 110(9):2232-2245, 2014


2013年

Sasaki T, Shiohama A, Kubo A, Kawasaki H, Ishida-Yamamoto A, Yamada T, Hachiya T, Shimizu A, Okano H, Kudoh J, Amagai M.
A homozygous nonsense mutation in the gene for Tmem79, a component for lamellar granule secretory system, produces spontaneous dermatitis in matted mice.
J Allergy Clin Immunol 2013; 132(5):1111-1120

Hata T, Takahashi H, Nagao K, Yoshida K, Ohyama M, Yamada T, Asano K, Amagai M.
Ectopic expression of epidermal antigens renders the lung a target organ in paraneoplastic pemphigus.
J Immunol. 2013; Jul 1;191(1):83-90, 2013

Hattori Y, Du W, Yamada T, Ichikawa D, Matsunami S, Matsushita M.
A Myeloma Cell Line Established from a Patient Refractory to Thalidomide Therapy Revealed High-Risk Cytogenetic Abnormalities and Produced Vascular Endothelial Growth Factor.
Blood Cancer J. 2013; 3(5):e115

Kou K, Saisho Y, Satoh S, Yamada T, Itoh H.
Change in beta cell mass in Japanese nondiabetic obese individuals.
J Clin Endocrinol Metab 2013; 98(9):3724-3730

Hatano R, Ohnuma K, Yamamoto J, Dang NH, Yamada T, Morimoto C.
Prevention of acute graft-versus-host disease by humanized anti-CD26 monoclonal antibody.
Br J Haematol. 2013; 162(2):263-77

Yamada K, Hayashi M, Madokoro H, Nishida H, Du W, Ohnuma K, Sakamoto M, Morimoto C, Yamada T.
Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A
Transcription.
PLoS One. 2013; 8(4):e62304.


2012年

Takamiya Y, Oikawa Y, Yamada T, Shimada A, Itoh H.
Decrease in vascular endothelial growth factor expression area in islets may be associated with type 2 diabetes development.
Diabetology Int. 3:202-208, 2012

Shiheido H, Naito Y, Kimura H, Genma H, Takashima H, Ono T, Hirano T, Du W, Yamada T, Doi N, Iijima S, Hattori Y, Yanagawa H.
An Anilinoquinazoline Derivative Induces Apoptosis of Multiple Myeloma Cells through Interaction with hCAP-G2, a Subunit of Condensin II.
PLoS ONE 7:e44889, 2012

Kondo S, Iwata S, Yamada T, Inoue Y, Ichihara H, Kichikawa Y, Katayose T, Souta-Kuribara A, Yamazaki H, Hosono O, Kawasaki H, Tanaka H, Hayashi Y, Sakamoto M, Kamiya K, Dang NH, Morimoto C.
Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer.
Clin Cancer Res. 18:6326-6338, 2012

Kurebayashi Y, Nagai S, Ikejiri A, Ohtani M, Ichiyama K, Baba Y, Yamada T, Egami S, Hoshi T, Hirao A, Matsuda S, and Koyasu S.
PI3K-Akt-mTORC1-S6K1/2 Axis Controls Th17 Differentiation by Regulating Gfi1 Expression and Nuclear Translocation of ROR gamma.
Cell Rep. 1:360-373, 2012

Shiheido H, Terada F, Tabata N, Hayakawa I, Matsumura N, Takashima H, Ogawa Y, Du W, Yamada T, Shoji M, Sugai T, Doi N, Iijima S, Hattori Y, Yanagawa H.
A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma.
PLoS One. 2012,7(6),e38878.

Kawasaki H, Nagao K, Kubo A, Hata T, Mizuno H, Yamada T, Sasaki H, Amagai M.
Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice.
J Allergy Clin Immunol. 129:1538-1546, 2012

Yoshizawa A, Nagai S, Baba Y, Yamada T, Matsui M, Tanaka H, Miyoshi S, Amagai M, Yoshikawa T, Ogawa S, Koyasu S.
Autoimmunity against M2 muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy-like phenotype.
Eur J Immunol. 42:1152-1163, 2012

Aoe K, Amatya VJ, Fujimoto N, Hosono O, Ohnuma K, Hiraki A, Fujii M, Takeshima Y, Inai K, Kishimoto T, Yamada T, Morimoto C.
CD26 overexpression is associated with prolonged survival and enhanced chemosensitivity in malignant pleural mesothelioma.
Clin. Cancer Res. 18:1447-1456, 2012


2011年

Tada A, Shimada A, Yamada T, Oikawa Y, Yamada Y, Okubo Y, Irie J, Bluestone JA, Itoh H.
A mimic of viral dsRNA triggers fulminant type 1 diabetes-like syndrome in regulatory T cell-deficient autoimmune diabetic mouse.
J Immunol. 187:4947-4953, 2011

Takahashi H, Kouno M, Nagao K, Wada N, Hata T, Nishimoto S, Iwakura Y, Yoshimura A, Yamada T, Kuwana M, Fujii Y, Koyasu S, Amagai M.
Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice. J Clin Invest.121:3677-3688, 2011

Amatya VJ, Takeshima Y, Kushitani K, Yamada T, Morimoto C, Inai K.
Overexpression of CD26/DPPIV in Mesothelioma Tissue and Mesothelioma Cell Lines.
Oncology Reports 26:1369-75, 2011

Tsunoda K, Ota T, Saito M, Hata T, Shimizu A, Ishiko A, Yamada T, Nakagawa T, Kowalczyk AP, Amagai M.
Pathogenic relevance of IgG and IgM anitbodies against desmoglein 3 in blister formation in pemphigus vulgaris. Am J Pathol.179:795-806, 2011

Hata T, Nishifuji K, Shimoda K, Yamada T, Nishikawa T, Koyasu S, Amagai M.
Transgenic rescue of desmoglein 3 null mice with desmoglein 1 to develop a syngeneic mouse model for pemphigus vulgaris.
J Dermatol Sci. 63:33-39, 2011

Yamada T.
Therapeutic monoclonal antibodies.
Keio J Med. 60: 37-46, 2011

Yamato K, Egawa N, Endo S, Ui-Tei K, Yamada T, Saigo K, Hyodo I, Kiyono T, Nakagawa I.
Enhanced specificity of HPV16 E6E7 siRNA by RNA-DNA chimera modification.
Cancer Gene Ther. 18:587-597, 2011

Matsuki E, Miyakawa Y, Asakawa S, Tsukada Y, Yamada T, Yokoyama K, Kudoh J, Okamoto S
Identification of loss of p16 expression and upregulation of MDR-1 as genetic events resulting from two novel chromosomal translocations found in a plasmablastic lymphoma of the uterus
Clin Cancer Res. 17:2101-2109, 2011

Kaneko H, Fukao T, Kasahara K, Yamada T, Kondo N.
Augmented cell death with human and mouse Bloom syndrome helicase deficiency.
Mol. Med. Reports 4: 607-609, 2011

Ghani FI, Yamazaki H, Iwata S, Okamoto T, Aoe, Okabe K, Mimura Y, Fujimoto N, Kishimoto T, Yamada T, Xu CW, Morimoto C.
Identification of cancer stem cell markers in human malignant mesothelioma cells.
Biochem Biophys Res Commun. 404:735-742, 2011

Hattori Y, Miyakawa Y, Yokoyama K, Yamada T, Du W, Jinzaki M, Shinmoto H, Okamoto S.
Prospective Study of Combination Therapy with Low-Dose Thalidomide plus Prednisolone Ameliorating Cytopenia in Primary Myelofibrosis.
Int. J Hematol 93:129-131, 2011

Wada N, Nishifuji K, Yamada T, Kudoh J, Shimizu N, Matsumoto M, Peltonen L, Nagafuchi S, Amagai M.
Aire-dependent thymic expression of desmoglein 3, the autoantigen in pemphigus vulgaris, and its role in T cell tolerance.
J Invest Dermatol 131:410-407, 2011


2010年

Uchida H, Yamazaki K, Fukuma M, Yamada T, Hayashida T, Hasegawa H, Kitajima M, Kitagawa Y, Sakamoto M
Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in colorectal cancer.
Cancer Science 10:1731-1737, 2010

Inamasu J, Nakatsukasa M, Kuramae T, Masuda Y, Tomiyasu K, Yamada T.
Gliomatosis cerebri mimicking chemotherapy-induced leukoencephalopathy in a patient with non-Hodgkin's lymphoma.
Intern Med. 49:701-705. 2010

Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, Furusawa J, Ohtani M, Fujii H, Koyasu S
Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells.
Nature 463;540-544, 2010

Uchida R, Masugi Y, Nishizawa T, Kimura T, Yamada T.
Extensive endobronchial growth of metastatic hepatocellular carcinoma resulting in respiratory failure: A case report
Pathol. Res. Pract.206:116-120, 2010


2009年

Isobe T, Oda H, Takayanagi N, Kunisue T, Komori H, Arita N, Ueda N, Nose M, Yamada T, Takahashi S, Tanabe S
Hexabromocyclododecanes in human adipose tissue from Japan.
Environ. Chem. 6: 328-333, 2009

Tanese K, Ishiko A, Hayase K, Yoshida T, Kishi K, Yamada T
Immunolocalization of Epstein-Barr virus-related antigens in a case of sweat gland adenocarcinoma.
Br J Dermatol 161: 694-697, 2009

Yamada K, Hayashi M, Du W , Ohnuma K, Sakamoto M , Morimoto C, Yamada T
Localization of CD26/DPPIV in nucleus and its nuclear translocation enhanced by anti-CD26 monoclonal antibody with anti-tumor effect.
Cancer Cell Int 9:17, 2009

Nishida H, Yamazaki H, Yamada T, Iwata S, Dang NH, Inukai T, Sugita K, Ikeda Y, Morimoto C
CD9 correlates with cancer stem cell potentials in human B-acute lymphoblastic leukemia cells.
Biochem Biophys Res Commun. 382:57-62, 2009

Hibi T, Mori T, Fukuma M, Yamazaki K, Hashiguchi A, Yamada T, Tanabe M, Aiura K, Kawakami T, Ogiwara A, Kosuge T, Kitajima M, Kitagawa Y, Sakamoto M.
Synuclein-gamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer.
Clin Cancer Res. 15:2864-2871, 2009

Vishwa Jeet Amatya, Yukio Takeshima, Hidekazu, Kohno, Kei Kushitani, Taketo Yamada, Chikao Morimoto, Kouki Inai
Caveolin-1 expression differentiates epithelioid mesothelioma from lung adenocarcinoma.
Histopathology 55;10-19, 2009