JP6523910B2 - 腫瘍幹細胞におけるeph受容体発現 - Google Patents
腫瘍幹細胞におけるeph受容体発現 Download PDFInfo
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Description
配列番号1は、エフリンA1のアミノ酸配列、アミノ酸配列 gi[333596]ref[NP_004419.2]、エフリンA1異性形、前駆体[ホモサピエンス]に合致し;
配列番号2は、エフリンA1のヌクレオチド配列、ヌクレオチド配列 gi[33359681]ref[NM_004428.2]、ホモサピエンスephrinA1(EFNA1)、転写変異体1 mRNAに合致し;
配列番号3は、EphA2のアミノ酸配列、アミノ酸配列 gi[32967311]ref[NP_004422.2]、エフリンA型受容体2前駆体[ホモサピエンス]に合致し;
配列番号4は、EphA2のヌクレオチド配列、ヌクレオチド配列 gi[296010835]ref[NM_004431.3]、ホモサピエンスEPH受容体A2(EPHA2), mRNAに合致する。
腫瘍標本は、神経外科治療室から患者の切除手術後に入手した。成人のグリア芽細胞腫(GBM)組織サンプルは、世界保健機構ガイドラインに従って入手し、分類した。各癌組織は、二つの組織片に分割した。第1のものは病理組織学的分析のために使用した:詳細には、組織を、4%パラフォルムアルデヒドに24時間浸し、次いで、パラフィン包埋し、免疫組織化学検査に供するか、若しくは、40%から始まる連続希釈濃度のスクロース液に入れて浮遊切片を得、共焦点顕微鏡検査に供した。
制御されていない又は過剰発現Eph受容体は、形質転換、腫瘍の増殖及び生存を増進する可能性がある。ヒトのGBM標本と、その中に含まれるGBM-CSCについて、新鮮単離、連続サブカルチャーの両標本において、エフリン及びエフリン認識受容体の発現と制御を調べた。
RNeasy Miniキット(Qiagen)を用いて、全体RNAを下記から抽出した:グリア芽細胞腫と診断された、様々な患者から単離されたGBM-CSC細胞系統、新鮮な一次GBM標本、非侵襲性U87細胞(市販のヒト星状細胞腫系統)、及び、正常なヒトの神経幹細胞(HNSC、我々の研究室で取得可能、13.)。
これらのcDNAは、それぞれ個別に、EphA1, EphA2, EphA3, EphA4, EphA5, EphA7, EphA8, EphA10, EphB1, EphB2, EphB3, EphB4, EphB6受容体、及び、EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3リガンドの特定のために設計されたPCRプライマーを用いて増幅した。
・ EphA1 順行: 5'- GCC TGA CAC CAC ATA CAT CG - 3'
逆行: 5'- ATA TGC GGG TGG CTA AAC TG - 3'
・ EphA2 順行: 5'- AAA GCC GGC TAC ACA GAG AA - 3'
逆行: 5'- TTG GAC AAC TCC CAG TAG GG - 3'
・ EphA3 順行: 5'- GAG TTT GCC AAG GAA TTG GA - 3'
逆行: 5'- TTG GGA TCT TCC CTC CTC TT - 3'
・ EphA4 順行: 5'- ACC AAG CAG TGC GAG AGT TT - 3'
逆行: 5'- CTC CCC GTA CGA CAT CAC TT - 3'
・ EphA5 順行: 5'- CAA GCC TAA TAT GGC GGT GT - 3'
逆行: 5'- GTG AAC TGC CCA TCG TTT TT - 3'
・ EphA7 順行: 5'- ATC ATT GGG AGA AGG CAC TG - 3'
逆行: 5'- ATG GAC AAC ATT TGG GTG GT - 3'
・ EphA8 順行: 5'- GAG AAC GGC TCT CTG GAC AC - 3'
逆行: 5'- CCT CCA CAG AGC TGA TGA CA - 3'
・ EphA10 順行: 5'- CGA CTA ATG CTC GAC TGC TG - 3'
逆行: 5'- TGA TCA AGC AAC TGC CAC TC - 3'
・ EphB1 順行: 5'- CAG GGT ACT CGG AGA AGC AG - 3'
逆行: 5'- CCA GCA TGA GCT GGT GTA GA - 3'
・ EphB2 順行: 5'- AGT TCG GCC AAA TTG TCA AC - 3'
逆行: 5'- AGG CAG GTG AAT GTC AAA CC - 3'
・ EphB3 順行: 5'- AGC AAC CTG GTC TGC AAA GT - 3'
逆行: 5'- GGA TGA GCT TGT CCA GGG TA - 3'
・ EphB4 順行: 5'- GAG AGC TGT GTG GCA ATC AA - 3'
逆行: 5'- TGT AGG TGG GAT CGG AAG AG - 3'
・ EphB6 順行: 5'- TCA TTG CAC ATG GAA AGC AT - 3'
逆行: 5'- GGG TGA GTC CAG ACA AGG AA - 3'
・ EFNA1 順行: 5'- GGT GAC TGT CAG TGG CAA AA - 3'
逆行: 5'- AGT GGA AGG AGC AGC ACAT - 3'
・ EFNA2 順行: 5'- ATC TAC TGC CCG CAC TAT GG - 3'
逆行: 5'- AGG CGT GGC AGA GAT GTA GT - 3'
・ EFNA3 順行: 5'- CAT GCG GTG TAC TGG AAC AG - 3'
逆行: 5'- GTG GAA CTC GTA GCC CAG AG - 3'
・ EFNA4 順行: 5'- ACA TTG TCT GCC CCC ACT AC - 3'
逆行: 5'- TGG GCT GAC TCA GAC TTC CT - 3'
・ EFNA5 順行: 5'- AGG ACT CCG TCC CAG AAG AT - 3'
逆行: 5'- ATC TGG GAT TGC AGA GGA GA - 3'
・ EFNB1 順行: 5'- GCC TGG AGT TCA AGA AGC AC - 3'
逆行: 5'- GAA CAA TGC CAC CTT GGA GT - 3'
・ EFNB2 順行: 5'- GTG CCA AAC CAG ACC AAG AT - 3'
逆行: 5'- GAT GTT GTT CCC CGA ATG TC - 3'
・ EFNB3 順行: 5'- AGG CAG AGG GTG GTT ATG TG - 3'
逆行: 5'- TCT CTT TCC ATG GGC ATT TC - 3'
各種GBM-CSC細胞系統におけるEph受容体発現を定量するために、細胞標本(各試験管当たり500,000個の細胞)を遠心し、0.2mLの完全培養液に再懸濁した。次に、細胞を、暗い中4℃で30分一次抗体に暴露した。U87細胞を腫瘍細胞に対する参照コントロールとして、HNSCを神経幹細胞の参照コントロールとして用いた。
・ 抗EphA1山羊ポリクロナール抗体(0.3μg, R&D)
・ 抗EphA2山羊ポリクロナール抗体(0.5μg, R&D)
・ 抗EphA3山羊ポリクロナール抗体(0.3μg, Gene Tex)
・ 抗EphA5兎ポリクロナール抗体(0.5μg, Abcam)
・ 抗EphA7兎ポリクロナール抗体(0.5μg, Abcam)
・ 抗EphA8山羊ポリクロナール抗体(0.5μg, Santa Cruz)
・ 抗EphB1兎ポリクロナール抗体(0.5μg, Abcam)
・ 抗EphB2兎ポリクロナール抗体(0.5μg, Abcam)
・ 抗EphB6兎ポリクロナール抗体(0.5μg, Santa Cruz)
・ 驢馬抗山羊Ig PE標識抗体(0.2μg, Jackson Immunoresearch)
・ 驢馬抗兎Ig FITC標識抗体(0.5μg, Jackson Immunoresearch)
強化レベルのEphA2がGBM-CSC細胞系統において再現可能であることが明らかにされた後、新鮮腫瘍組織においても免疫反応性EphA2の存在が特定され、これによって、この受容体が単にインビトロで長期に培養されたために生じたものなのかもしれない、という可能性は排除された。
免疫組織化学的染色のために、一次GBM腫瘍組織を、採取後、パラフォルムアルデヒド中で24時間固定した。次に、組織を、PBSに溶解した10%、20%、及び30%スクロース液において4℃で凍結しないように冷却保存し、次いで、2:1(v/v)の20%スクロース/Tissue-Tek OCT包埋化合物混合物(embedding compound mixture)において一晩包埋工程(embedding step)処理した。クライオスタットで10ミクロン厚の連続切片に切り出し、ゼラチン被覆スライドガラスにマウントし、二重免疫標識を実行した。手短に言うと、切片を空気乾燥し、0.005% BSA及び0.1%トリトンを含む0.1M Tris-HClバッファー(pH7.6)で濯ぎ、一次抗体と、4℃で一晩インキュベートした(13.)。
前述の酵素的消化及び機械的分離の直後に、一次腫瘍標本から単離した細胞懸濁液に対し、EphA2受容体発現に関してFACS分析を行った。手短に言うと、GBM組織解離から得られる細胞をLDS 751(10ng/mL, Molecular Probes)によって室温で15分染色して無傷の有核細胞を特定した。細胞をフローサイトメータ(FACSAria, BD Biosciences)によって分析し、バックゲーティング技術(LDS751陽性細胞)を用いて、FSC対SSCドットプロットにおいて、無傷の有核細胞を特定する領域(P1)を導出した。無傷の有核生細胞を特定するために、7AAD陰性細胞を含む領域に領域(P1)を加えることによって複合ゲートを創出した。次に、陽性/死亡細胞を特定するために、GBM組織解離から得られたCSCを、山羊抗ヒトEphA2(0.5μg, R&D)及び7AAD(5μg/mL, Coulter)とインキュベートした。
リガンド誘発性受容体変性によって、EphA2発現の低下が起こることがあり、これは、細胞外基質(ECM)に対する細胞接着性の上昇、細胞転移の低下、及び悪性増殖の抑制をもたらす。従って、GBM-CSC細胞におけるこの受容体の過剰発現は、細胞の悪性行動に反映されると考えられ、ephrinA1-Fcによる該受容体への結合は、発癌性に対抗すると考えられる。
用量-反応分析のために、機械的解離の直後に、ephrinA1-Fcの存在下に(0.001, 0.01, 0.1, 0.5, 1.0μg/mL)、細胞を撒き、24時間インキュベートした。継時分析のために、細胞を、ephrinA1-Fc(1.0μg/mL)と6、24、48、72時間インキュベートした。
細胞は、Cultrex被覆12-mm直径ガラス製カバースリップ(Trevigen)に、2.5×104細胞/cm2の密度となるように、コントロールとして完全培養液にて、若しくは、ephrinA1-Fcの存在下に(0.5,1.0μg/mL)撒き、24時間インキュベートした。細胞は洗浄し、4%パラフォルムアルデヒドPBS液pH7.4中で固定し、免疫染色を実行した。カバースリップは、10%正常山羊血清(NGS)又は10%牛胎児血清(FBS)、0.3% TritonX-100、及び適当な一次抗体又は抗血清(兎抗ヒトエフリンA1,1:50 Abcam、山羊抗ヒトEphA2,1:50 R&D)を含むPBSにおいて4℃で一晩インキュベートした。それとは別に、細胞は、マウスのモノクロナールIgG1 EphA2クローンD7(1:100,Sigma)によって免疫染色した。
・ Cianine Cy2又はAlexa-Fluor 488接合山羊抗兎(1:200, Jackson Immunoresearch, 1:2000, Invitrogen)
・ Cianine Cy3又はAlexa-Fluor 546接合驢馬抗山羊(1:500, Jackson Immunoresearch, 1:2000, Invitrogen)
・ Ciannine Cy3接合山羊抗マウス(1:800, Jackson Immunoresearch)
細胞は、解離後直ぐ、ephrinA1-Fc 5.0μg/mL又はEphA2-Fc 5.0μg/mLの存在下に完全培養液に撒き、10、30、60分、及び24時間インキュベートした。細胞はさらに、Cultrex被覆(Trevigen)フラスコに撒き、その分化を、EGF/FGF2の除去及び白血病阻害因子の添加(LIF 10ng/mL)によって誘発し、7-10日間インキュベートした。次に、細胞を、再懸濁し、遠心し、分解した。分解バッファーは、1%プロテアーゼ抑制因子カクテル(Sigma)及び10%フォスファターゼ抑制因子カクテル(Roche)を添加した、50mM Tris-HCl pH7.4、1mM EDTA、及び、1% TritonX-100から構成される。細胞を収集し、PBSで洗浄し、14.460×gで遠心した。タンパクの定量は、一連のアルブミン標準使用のDC Protein Assay(Bio-Rad)によって行った。70μgの各分解産物にゲル負荷バッファーを加え、タンパクは、標準プロトコールに従って、10%ポリアクリルアミドゲルによって溶解し、Hybond ECLニトロセルロース膜(GE)上に移動させた。膜は、Trisバッファー生理的食塩水(TBS)-T(TBSプラス0.02% Tween20)及び5%ミルクでブロックし、下記の一次抗体と4℃で一晩インキュベートした:
・ IgG山羊抗ヒトEphA2(1:750, R&D)
・ IgG1マウス抗ヒトEphA2クローンD7(1:500, Sigma)
・ 驢馬抗山羊IgG(1:5000, Promega)
・ 兎抗マウスIgG(1:10,000, GE)
細胞は、ephrinA1の不在下又は存在下(1.0,5.0μg/mL)に、若しくは、マウスモノクロナールIgG1異性体コントロール(isotype control)(R&D)の不在下又は存在下に24時間育成し、次いで前述の通りに分解した。EphA2リン酸化のレベルを定量するために、100μgの総タンパクを含む細胞分解物をマウス抗ヒトEck/EphA2(1:500,Upstate)と、ゆっくりと掻き回しながら+4℃で一晩インキュベートした。メーカーの指示に従って、ビーズ(Dynal Invitrogenビーズ分離)を分解バッファーによって十分に洗浄し、免疫複合体を、2x LDSサンプルバッファー(Invitrogen)によって溶出し、煮沸し、短時間遠心した。タンパクを溶解し、マウス4G10白金抗ヒトフォスフォチロシン(1:1000, Upstate)使用のウェスタンブロットによって検出した。
EphA2の下方制御/リン酸化強化、又はその認識リガンドとの競合結合が、GBM-CSCの発癌性に影響を及ぼすかどうかを決定するために、ここでは、最重要な幹細胞のパラメータ、例えば、分裂の全体的対称性に対する、ephrin A1-Fc及びEphA2-Fcの細胞分裂抑制作用を分析した。成長の活性状態におけるGBM-CSC細胞を、可溶性ephrinA1-Fc又はEphA2-Fcに暴露し、次いで、動態からの偏差を評価した。
GBM-CSC細胞の増殖指数を分析するために、神経球懸濁液を、15mLの試験管(BD)に移し、192×gで10分遠心し機械的に細かくして、単一細胞懸濁液とした。トリパンブルー排除によって細胞をカウントし、8×103細胞/cm2の生細胞を、マウスのモノクロナールIgG1アイソタイプコントロール(R&D)、ephrinA1(0.5, 1.0, 2.0, 3.0, 又は5.0μg/mL)、又はEphA2-Fc(5.0μg/mL)の存在下に撒いた。次いで、サブカルチャー工程(0 DIV)で得られた全細胞数をプロットした。各サブカルチャー継代(4-6日置き)において、単一細胞懸濁液を得、生細胞の全数をトリパンブルー排除によってカウントした。8×103細胞/cm2の生細胞を同じ条件下に再度撒いた。これによって、動態パラメータ(kinetic parameter)(成長曲線勾配、Gritti A, 2001を参照)(7.)の定義が得られるので、CSC-HNSC拡大率、腫瘍細胞に対する参照コントロールとして使用されるU87細胞、神経幹細胞の参照コントロールとして使用されるHNSCの定量において上述の組み換えタンパクの役割の指標が得られる。
この研究は、KI67分析(1.)による増殖指数の定義によって補完した。手短に言うと、細胞を、EGF/FGF2の存在下に、Cultrex被覆(Trevigen)ガラス製カバースリップに撒き、ephrinA1-Fc(0.5,1.0μg/mL)に24時間暴露した。増殖細胞は、IgG兎ポリクロナール抗Ki67(1:1000,Novocastra)による間接的免疫細胞化学法によって定量した。Cy2山羊抗兎二次抗体を上述のように使用した(1:200,Jackson Immunoresearch)。各フィールドの細胞の全数は、4,6-ジアミジン-2-フェニルインドールジヒドロクロリド(DAPI、Sigma,50g/mlのPBS溶液)によって室温で10分細胞核をカウンター染色することによって定量した。
増殖は、メーカー(Roche)によって提供された説明書に従ってBrdU比色アッセイキットを用いて監視した。手短に言うと、GBM-CSCを、96ウェルマイクロプレートに5000細胞/ウェルの密度で撒いた。この細胞を、エフリンA1(0.001, 0.01, 0.1, 0.5, 1.0μg/mL)に24時間暴露し、その後、BrdU(1:10)に24時間暴露した。細胞増殖指数は3重に評価した。
GBM-CSCの自己再生能--癌幹細胞が、自己の複数のコピーを一定時間に生産する能力と定義される--は、それらの細胞の振る舞いがどの程度活動的であるかの予測指数となる。ここでは、分裂の全体対称性を左右する重大な幹細胞パラメータ、例えば、関連自己再生活性を分析した。
単一クローンの解離によって得られたGBM-CSC系統をカウントし、1000生細胞/ウェルを、L-ポリリシン被覆(0.1mg/mL,Sigma)24ウェルプレートに撒いた。7-10日後、生成された二次球の数を評価した(7.)。細胞を、マウスのモノクロナールIgG1アイソタイプコントロール(R&D)、ephrinA1-Fc(0.5, 1.0, 2.0, 3.0, 5.0μg/mL)、又はEphA2-Fc(5.0μg/mL)の存在下に撒いた。幹細胞コントロールとしてHNSCを用いた。
2×106個のGBM-CSC細胞を遠心し、DNアーゼ(1:1000、最終濃度1μg/mL, Sigma)添加の、0.5mLの完全培養液に再懸濁した。
エフリンA1-Fc及びEphA2-Fc処理の結果が、波及的関与(wave committed)の前駆細胞ではなく、真正の幹細胞に影響を及ぼすかどうかを評価するために、ephrinA1-Fc及びEphA2-Fcの、GBM-CSC副集団(SP)に及ぼす作用を調べた。
このSP細胞は、二重波長分析のドットプロットにおいて特徴的低蛍光尾部によって特定され、研究対象とするGBM-CSC(関門通過生細胞の1.41%・対・骨髄の0.03%)において検出された。ベラパミル--Hoechst 33342排出を仲介する特異的ABCトランスポーターを抑制することが知られる薬剤--によるGBM-CSC処理は、この集団を消滅させた。細胞は、Moflo (Coulter)において、350nm UV光による励起後、二重波長分析(青、450-465nm;赤、630-730nm)を用いて分析した。細胞は、5.0μg/mLのephrinA1-Fc又はEphA2-Fcの存在下に24時間育成し、次いで、DMEM/F12、プラス、DNアーゼ(1μg/mL, Sigma)、BSA(2mg/mL, Sigma)、ヘパリン(4μg/mL, Sigma)、及びEDTA(200μg/mL, Sigma)において最終濃度が2×106/mLとなるように再懸濁した。次に、GBM-CSCを、2μg/mLのHoechst 33342染料(Invitrogen)によって、時折掻き回しながら37℃で2時間放置して標識した。抑制コントロールとして、カルシウムチャンネルブロッカー・ベラパミル(Sigma)を、Hoechst 33342による標識前に、最終濃度が50μMとなるように加え、室温で10分インキュベートした。
フローサイトメトリー分析は前述のように行った。下記の一次接合抗体を用いた。
・マウス抗CD133-PE接合(0.25μg, MACS)
・マウス抗CD44-PE接合(20μL/1x106 細胞、BD)
・マウス抗CD184-CXCR4-APC接合(20μL/1x106 細胞、BD)
・マウス抗CD81-TAPA1-FITC接合(20μL/1x106 細胞、BD)
・マウス抗CD15 SSEA1-FITC接合(20μL/1x106 細胞、BD)
・マウス抗CD117-cKit-PE接合(0.2μg, BD)
幹細胞の資格を持つためには、GBM-CSCは多能性でなければならない。そこで、ephrinA1-Fc又はEphA2-Fc処理後のGBM-CSCにおいて、より分化した表現型が獲得されるかどうかを調べるために分化実験を行った。ephrinA1-Fc又はEphA2-Fcの不在下又は存在下に育成したクローン小球において、蛍光信号強度に関して細胞蛍光測定を行った。
自己再生アッセイによって得られたクローン球に対しFACS分析を行い、神経マーカー発現を、系統特異的マーカーを用いて評価した。
細胞周期分析及びBrdU/DNA分析及び検出
細胞周期分析のために、1×106細胞/サンプルを、ephrinA1-Fc(5μg/mL)又はEphA2(5μg/mL)の存在下に6、24、48時間培養した。次に、細胞を、20μMの5-ブロモ-2-デオキシウリジン(BrdU, 1:500, Sigma)に37℃で20分暴露し、70%エタノールPBS液で固定し、4℃に維持し染色に備えた(3.)。DNAは、1 mLの3N HCl、20分RT(室温)によって変性し、得られたペレットを、1%BSA(Sigma)を含む1 mLの0.5% Tween-20(Sigma)とRTで15分インキュベートした。次に、細胞を、抗BrdUモノクロナール抗体(1:10、BD)と暗い中RTで60分インキュベートした。使用した二次抗体は、Alexa 488山羊抗マウスIgG(1:500、Invitrogen)である。次に、細胞を、2.5μg/mLのヨウ化プロピジウム(PI)のPBS液、及び7μLのRNアーゼ(3mg/mL)の水溶液に再懸濁し、暗い中4℃で一晩染色した。各サンプルで少なくとも30000個の細胞について、FACSCalibur (BD Biosciences)を用いて、2-パラメータBrdU/DNA分析を行い、データはSummit 4.3ソフトウェアを用いて分析した。
アポトーシスは、TUNELアッセイキット(Roche Diagnostics)を、2パラメータフローサイトメトリーに関するメーカーの指示に従って用いることによって測定した。分析は、FACSCalibur(BD Biosciences)で行い、データは、Summit 4.3ソフトウェア(Coulter)を用いて分析した。
EphA2の過剰発現又は活性消失は、GBM-CSC細胞浸襲においても組み込まれた介在因子であり、細胞骨格修飾又は持続的リン酸化、及びFAK及びその他の細胞内経路のキナーゼ活性を引き起こす。
GBM-CSCを、ephrinA1-Fc(5.0μg/mL)又はEphA2-Fc(5.0μg/mL)の不在下又は存在下に、Cultrex被覆ガラス製カバースリップ(12mm直径)に、2.5×104細胞/cm2の密度で撒き、5及び30分放置した。Fアクチン染色のために、細胞を、4%パラフォルムアルデヒドに20分放置して固定し、0.1%(v/v)Triton-X 100によって膜透過させ、Alexa555標識ファロイジン(1:40,Invitrogen)と室温で30分インキュベートした。
浸襲度アッセイは、Pennacchietti 2003(10.)に倣って、24ウェル・トランスウェルチェンバー(8-μmポアサイズ、6.5mm、0.33cm2、Corning Costar)において実行した。フィルターの上面にはCultrexをコートし、1×105のヒト皮膚微少血管内皮細胞(HMVEC)を、EphA2-Fc(5.0μg/mL)の不在下又は存在下に1.5 mLのDMEM/F12に撒いた。下方分画には、移動の陽性刺激として、血管内皮増殖因子(VEGF、20ng/mL)、又は、GBM-CSC細胞調整培養液(1×106細胞撒布後1日の培養液から採取した1mL)を用いた。刺激は、EphA2-Fcの不在下又は存在下に、2.6mLのDMEM/F12基礎培養液に溶解してフィルターの上面に加えた。
ephrinA1-Fc又はEphA2-Fc処理の、GBM-CSCの悪性態様に与える影響の結果を定量するために、細胞を、ephrinA1-Fc(1.0又は5.0μg/mL)又はEphA2-Fc(5.0μg/mL)の存在下に撒き、適当時間インキュベートし、次いで分解した。手順は全て前述の通りに行った。
・兎抗フォスフォ FAK (Tyr576/577, Tyr 925) (1:1000, Cell Signaling)
・兎抗ヒト全体 p42/p44 MAPK (ERK1/2) (1:1000, Cell Signaling)
・兎抗ヒトフォスフォ ERK1/2 Thr202/Tyr204) (1:1000, Cell Signaling)
・兎抗フォスフォ Akt (Ser473) (1:1000; Cell Signaling)
・兎抗フォスフォ mTOR (Ser2481) (1:1000, Cell Signaling)
・兎抗フォスフォ PI3K p85 (Tyr458)/p55 (Tyr199) (1:1000, Cell Signaling)
・兎抗ヒト E-カドヘリン (1:1000, Cell Signaling)
・マウス抗ヒトゲルソリン (1:1000, Sigma)
GBM-CSC細胞を、組み換えヒトBMP4(100ng/mL, R&D)に48時間暴露した。全体RNA及びcDNAを前述に倣って取得し、次いで、EphA2発現の定量分析を行った。定量的RT-PCR反応を、Brilliant SYBR Green QPCR Core Reagent Kit (Stratagene)を用いて3重に実施した。SYBRグリーン染料は、いずれのPCR産物にも結合するので、配列特異的プローブの使用を要しない。蛍光発光をリアルタイムで記録した(Chromo 4 Four-Color Real-Time PCR Detector, MJ)。遺伝子発現プロファイリングは、相対的定量化の比較Ct法を用いて完了した。RNAの相対量は、2つの内在コントロールであるGAPDH及び18SリボソームRNA(18S rRNA)に対して正規化した。
GBM-CSCを、ephrinA1-Fc(1.0μg/mL又は5.0μg/mL)の存在下に、および、それぞれ、BMP4(100 ng/mL, R&D)、又は白血病阻害因子(LIF, 10ng/mL, Chemicon)--ヒトCNS幹細胞継代(progeny)における神経分化の強力な調節因子--の存在下に撒いた。細胞増殖指数を上述の成長曲線分析によって評価した。
EphA2の過剰発現は腫瘍発生の原因となることが知られる。さらに、分裂の全体的対称性及び関連自己再生能などの、上に分析したGBM-CSCの幹細胞の重要なパラメータは、これらの細胞の腫瘍原発性能と直線的に相関する。ephrinA1-Fc又はEphA2-Fcによる、EphA2発現又は活性の下降作用をインビボで調べた。
・コントロール-ベヒクル:細胞移植後、100μLの生理的食塩水を腫瘍周辺部位に注入した、
・ephrinA1-Fc(同時処理群):細胞の移植と、同時に、100μLの、生理的食塩水に溶解したephrinA1-Fc液(10μg/用量)の腫瘍周辺注入が伴った。
・ephrinA2-Fc(同時処理群):細胞の移植には、100μLの、生理的食塩水に溶解したEphA2-Fc液(10μg/用量)の腫瘍周辺注入が伴った。
・EphA2-Fc(移植後処理群):細胞移植後、細胞を7-10日育成し、次いで、マウスに、100μLのEphA2-Fcの腫瘍辺縁注入を行った(移植後腫瘍形成)(10μg/用量)。
V (mm3)= π/6 x a x b x c
可溶性受容体及びリガンド分子の癌の成長における抗癌効力(EphA2による発現又は活性の低下)を評価するために、より臨床との関連性の高い同所性腫瘍モデルを用いた。
GBM-CSCを、リポーター遺伝子の蛍ルシフェラーゼによって感染させた。
新規生成レンチウィルスベクター--そこでは、二方向性合成プロモーターによって二つのmRNAの協調的転写が仲介され、効率的二遺伝子転移が可能とされる、ベクターを用いた(2.)。
Luc-GBM-CSC細胞を、ephrinA1-Fc(5μg/mL)又はEphA2-Fc(5μg/mL)の不在下又は存在下に撒き、48時間後に同所性注入した。
腫瘍の形成、拡張、及び体積は、インビボLumina分析(Xenogen)で撮影した連続画像によって、数回/週、間接的に計算し、試薬処理をしないGBM細胞を移植されたコントロール動物のものと比較した。
6週後動物を屠殺した。屠殺した動物に、100mLの0.15M NaClによって経心臓灌流/固定を行い、次いで、4% PFAを含む0.1Mリン酸カリウムバッファー(KBS)、250mLを、Watson-Marlowペリスタルティックポンプを用いて120 mmHg圧で注入した。その後、前述のように、脳を固定し冷凍保存した。
山羊抗ヒトEphA2(1:50, R&D)、モノクロナールマウスIgG1抗ヒトEphA2クローンD7(1:100, Sigma)、兎ポリクロナール抗ヒトエフリンA1(1:50, Abcam)、兎抗ヒトフォスフォ・エフリンB(Tyr324/329)(1:100, Cell Signaling)、山羊抗エフリンB2(1:10, R&D)、山羊抗ヒトエフリンB3(1:10, R&D)、兎抗フォスフォ(S339)CXCR4(1:100, Abcam)、山羊抗ヒトWnt5a(1:10, R&D)、兎抗ヒトE-カドヘリン(1:100, Cell Signaling)。
同様の方法を用いて、腫瘍成長のEphA2調節に及ぼす作用をインビボで調べた。これによって、EphA2受容体の活性化又は発現の状態と、GBM-CSCの発癌性との間に明瞭な相関を、特に、この二つのパラメータの間に逆相関を定義することが可能となるかも知れない。これによってさらに、インビボにおけるEphA2調節を、患者の腫瘍におけるhGBM-TCSCプールに対する有力な治療ツールとして使用する可能性を定めることが可能となるかも知れない。
luc-GBM-CSC同所性注入の10日後、即ち、腫瘍は実質的サイズを持つが、運動又は行動異常を引き起こすことはない時点で、ミニ浸透圧ポンプ(Alzet)の脳内カテーテルを、同じ穿頭孔からマウス線条体に挿入した。
上記説明及び前述の実施例から、本発明によって記載され、取得される産物によって実現される利点は明白である。
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SEQUENCE LISTING
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<120> EPH RECEPTOR EXPRESSION IN TUMOR STEM CELLS
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ggtcccttaa ggcacagtgg gagctgagct ggaaggggcc acgtggatgg gcaaagcttg 1080
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Tyr Met Tyr Ser Val Cys Asn Val Met Ser Gly Asp Gln Asp Asn Trp
65 70 75 80
Leu Arg Thr Asn Trp Val Tyr Arg Gly Glu Ala Glu Arg Ile Phe Ile
85 90 95
Glu Leu Lys Phe Thr Val Arg Asp Cys Asn Ser Phe Pro Gly Gly Ala
100 105 110
Ser Ser Cys Lys Glu Thr Phe Asn Leu Tyr Tyr Ala Glu Ser Asp Leu
115 120 125
Asp Tyr Gly Thr Asn Phe Gln Lys Arg Leu Phe Thr Lys Ile Asp Thr
130 135 140
Ile Ala Pro Asp Glu Ile Thr Val Ser Ser Asp Phe Glu Ala Arg His
145 150 155 160
Val Lys Leu Asn Val Glu Glu Arg Ser Val Gly Pro Leu Thr Arg Lys
165 170 175
Gly Phe Tyr Leu Ala Phe Gln Asp Ile Gly Ala Cys Val Ala Leu Leu
180 185 190
Ser Val Arg Val Tyr Tyr Lys Lys Cys Pro Glu Leu Leu Gln Gly Leu
195 200 205
Ala His Phe Pro Glu Thr Ile Ala Gly Ser Asp Ala Pro Ser Leu Ala
210 215 220
Thr Val Ala Gly Thr Cys Val Asp His Ala Val Val Pro Pro Gly Gly
225 230 235 240
Glu Glu Pro Arg Met His Cys Ala Val Asp Gly Glu Trp Leu Val Pro
245 250 255
Ile Gly Gln Cys Leu Cys Gln Ala Gly Tyr Glu Lys Val Glu Asp Ala
260 265 270
Cys Gln Ala Cys Ser Pro Gly Phe Phe Lys Phe Glu Ala Ser Glu Ser
275 280 285
Pro Cys Leu Glu Cys Pro Glu His Thr Leu Pro Ser Pro Glu Gly Ala
290 295 300
Thr Ser Cys Glu Cys Glu Glu Gly Phe Phe Arg Ala Pro Gln Asp Pro
305 310 315 320
Ala Ser Met Pro Cys Thr Arg Pro Pro Ser Ala Pro His Tyr Leu Thr
325 330 335
Ala Val Gly Met Gly Ala Lys Val Glu Leu Arg Trp Thr Pro Pro Gln
340 345 350
Asp Ser Gly Gly Arg Glu Asp Ile Val Tyr Ser Val Thr Cys Glu Gln
355 360 365
Cys Trp Pro Glu Ser Gly Glu Cys Gly Pro Cys Glu Ala Ser Val Arg
370 375 380
Tyr Ser Glu Pro Pro His Gly Leu Thr Arg Thr Ser Val Thr Val Ser
385 390 395 400
Asp Leu Glu Pro His Met Asn Tyr Thr Phe Thr Val Glu Ala Arg Asn
405 410 415
Gly Val Ser Gly Leu Val Thr Ser Arg Ser Phe Arg Thr Ala Ser Val
420 425 430
Ser Ile Asn Gln Thr Glu Pro Pro Lys Val Arg Leu Glu Gly Arg Ser
435 440 445
Thr Thr Ser Leu Ser Val Ser Trp Ser Ile Pro Pro Pro Gln Gln Ser
450 455 460
Arg Val Trp Lys Tyr Glu Val Thr Tyr Arg Lys Lys Gly Asp Ser Asn
465 470 475 480
Ser Tyr Asn Val Arg Arg Thr Glu Gly Phe Ser Val Thr Leu Asp Asp
485 490 495
Leu Ala Pro Asp Thr Thr Tyr Leu Val Gln Val Gln Ala Leu Thr Gln
500 505 510
Glu Gly Gln Gly Ala Gly Ser Lys Val His Glu Phe Gln Thr Leu Ser
515 520 525
Pro Glu Gly Ser Gly Asn Leu Ala Val Ile Gly Gly Val Ala Val Gly
530 535 540
Val Val Leu Leu Leu Val Leu Ala Gly Val Gly Phe Phe Ile His Arg
545 550 555 560
Arg Arg Lys Asn Gln Arg Ala Arg Gln Ser Pro Glu Asp Val Tyr Phe
565 570 575
Ser Lys Ser Glu Gln Leu Lys Pro Leu Lys Thr Tyr Val Asp Pro His
580 585 590
Thr Tyr Glu Asp Pro Asn Gln Ala Val Leu Lys Phe Thr Thr Glu Ile
595 600 605
His Pro Ser Cys Val Thr Arg Gln Lys Val Ile Gly Ala Gly Glu Phe
610 615 620
Gly Glu Val Tyr Lys Gly Met Leu Lys Thr Ser Ser Gly Lys Lys Glu
625 630 635 640
Val Pro Val Ala Ile Lys Thr Leu Lys Ala Gly Tyr Thr Glu Lys Gln
645 650 655
Arg Val Asp Phe Leu Gly Glu Ala Gly Ile Met Gly Gln Phe Ser His
660 665 670
His Asn Ile Ile Arg Leu Glu Gly Val Ile Ser Lys Tyr Lys Pro Met
675 680 685
Met Ile Ile Thr Glu Tyr Met Glu Asn Gly Ala Leu Asp Lys Phe Leu
690 695 700
Arg Glu Lys Asp Gly Glu Phe Ser Val Leu Gln Leu Val Gly Met Leu
705 710 715 720
Arg Gly Ile Ala Ala Gly Met Lys Tyr Leu Ala Asn Met Asn Tyr Val
725 730 735
His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Asn Ser Asn Leu Val
740 745 750
Cys Lys Val Ser Asp Phe Gly Leu Ser Arg Val Leu Glu Asp Asp Pro
755 760 765
Glu Ala Thr Tyr Thr Thr Ser Gly Gly Lys Ile Pro Ile Arg Trp Thr
770 775 780
Ala Pro Glu Ala Ile Ser Tyr Arg Lys Phe Thr Ser Ala Ser Asp Val
785 790 795 800
Trp Ser Phe Gly Ile Val Met Trp Glu Val Met Thr Tyr Gly Glu Arg
805 810 815
Pro Tyr Trp Glu Leu Ser Asn His Glu Val Met Lys Ala Ile Asn Asp
820 825 830
Gly Phe Arg Leu Pro Thr Pro Met Asp Cys Pro Ser Ala Ile Tyr Gln
835 840 845
Leu Met Met Gln Cys Trp Gln Gln Glu Arg Ala Arg Arg Pro Lys Phe
850 855 860
Ala Asp Ile Val Ser Ile Leu Asp Lys Leu Ile Arg Ala Pro Asp Ser
865 870 875 880
Leu Lys Thr Leu Ala Asp Phe Asp Pro Arg Val Ser Ile Arg Leu Pro
885 890 895
Ser Thr Ser Gly Ser Glu Gly Val Pro Phe Arg Thr Val Ser Glu Trp
900 905 910
Leu Glu Ser Ile Lys Met Gln Gln Tyr Thr Glu His Phe Met Ala Ala
915 920 925
Gly Tyr Thr Ala Ile Glu Lys Val Val Gln Met Thr Asn Asp Asp Ile
930 935 940
Lys Arg Ile Gly Val Arg Leu Pro Gly His Gln Lys Arg Ile Ala Tyr
945 950 955 960
Ser Leu Leu Gly Leu Lys Asp Gln Val Asn Thr Val Gly Ile Pro Ile
965 970 975
<210> 4
<211> 3970
<212> DNA
<213> Homo sapiens
<400> 4
ggttctcacc caacttccat taaggactcg gggcaggagg ggcagaagtt gcgcgcaggc 60
cggcgggcgg gagcggacac cgaggccggc gtgcaggcgt gcgggtgtgc gggagccggg 120
ctcgggggga tcggaccgag agcgagaagc gcggcatgga gctccaggca gcccgcgcct 180
gcttcgccct gctgtggggc tgtgcgctgg ccgcggccgc ggcggcgcag ggcaaggaag 240
tggtactgct ggactttgct gcagctggag gggagctcgg ctggctcaca cacccgtatg 300
gcaaagggtg ggacctgatg cagaacatca tgaatgacat gccgatctac atgtactccg 360
tgtgcaacgt gatgtctggc gaccaggaca actggctccg caccaactgg gtgtaccgag 420
gagaggctga gcgtatcttc attgagctca agtttactgt acgtgactgc aacagcttcc 480
ctggtggcgc cagctcctgc aaggagactt tcaacctcta ctatgccgag tcggacctgg 540
actacggcac caacttccag aagcgcctgt tcaccaagat tgacaccatt gcgcccgatg 600
agatcaccgt cagcagcgac ttcgaggcac gccacgtgaa gctgaacgtg gaggagcgct 660
ccgtggggcc gctcacccgc aaaggcttct acctggcctt ccaggatatc ggtgcctgtg 720
tggcgctgct ctccgtccgt gtctactaca agaagtgccc cgagctgctg cagggcctgg 780
cccacttccc tgagaccatc gccggctctg atgcaccttc cctggccact gtggccggca 840
cctgtgtgga ccatgccgtg gtgccaccgg ggggtgaaga gccccgtatg cactgtgcag 900
tggatggcga gtggctggtg cccattgggc agtgcctgtg ccaggcaggc tacgagaagg 960
tggaggatgc ctgccaggcc tgctcgcctg gattttttaa gtttgaggca tctgagagcc 1020
cctgcttgga gtgccctgag cacacgctgc catcccctga gggtgccacc tcctgcgagt 1080
gtgaggaagg cttcttccgg gcacctcagg acccagcgtc gatgccttgc acacgacccc 1140
cctccgcccc acactacctc acagccgtgg gcatgggtgc caaggtggag ctgcgctgga 1200
cgccccctca ggacagcggg ggccgcgagg acattgtcta cagcgtcacc tgcgaacagt 1260
gctggcccga gtctggggaa tgcgggccgt gtgaggccag tgtgcgctac tcggagcctc 1320
ctcacggact gacccgcacc agtgtgacag tgagcgacct ggagccccac atgaactaca 1380
ccttcaccgt ggaggcccgc aatggcgtct caggcctggt aaccagccgc agcttccgta 1440
ctgccagtgt cagcatcaac cagacagagc cccccaaggt gaggctggag ggccgcagca 1500
ccacctcgct tagcgtctcc tggagcatcc ccccgccgca gcagagccga gtgtggaagt 1560
acgaggtcac ttaccgcaag aagggagact ccaacagcta caatgtgcgc cgcaccgagg 1620
gtttctccgt gaccctggac gacctggccc cagacaccac ctacctggtc caggtgcagg 1680
cactgacgca ggagggccag ggggccggca gcaaggtgca cgaattccag acgctgtccc 1740
cggagggatc tggcaacttg gcggtgattg gcggcgtggc tgtcggtgtg gtcctgcttc 1800
tggtgctggc aggagttggc ttctttatcc accgcaggag gaagaaccag cgtgcccgcc 1860
agtccccgga ggacgtttac ttctccaagt cagaacaact gaagcccctg aagacatacg 1920
tggaccccca cacatatgag gaccccaacc aggctgtgtt gaagttcact accgagatcc 1980
atccatcctg tgtcactcgg cagaaggtga tcggagcagg agagtttggg gaggtgtaca 2040
agggcatgct gaagacatcc tcggggaaga aggaggtgcc ggtggccatc aagacgctga 2100
aagccggcta cacagagaag cagcgagtgg acttcctcgg cgaggccggc atcatgggcc 2160
agttcagcca ccacaacatc atccgcctag agggcgtcat ctccaaatac aagcccatga 2220
tgatcatcac tgagtacatg gagaatgggg ccctggacaa gttccttcgg gagaaggatg 2280
gcgagttcag cgtgctgcag ctggtgggca tgctgcgggg catcgcagct ggcatgaagt 2340
acctggccaa catgaactat gtgcaccgtg acctggctgc ccgcaacatc ctcgtcaaca 2400
gcaacctggt ctgcaaggtg tctgactttg gcctgtcccg cgtgctggag gacgaccccg 2460
aggccaccta caccaccagt ggcggcaaga tccccatccg ctggaccgcc ccggaggcca 2520
tttcctaccg gaagttcacc tctgccagcg acgtgtggag ctttggcatt gtcatgtggg 2580
aggtgatgac ctatggcgag cggccctact gggagttgtc caaccacgag gtgatgaaag 2640
ccatcaatga tggcttccgg ctccccacac ccatggactg cccctccgcc atctaccagc 2700
tcatgatgca gtgctggcag caggagcgtg cccgccgccc caagttcgct gacatcgtca 2760
gcatcctgga caagctcatt cgtgcccctg actccctcaa gaccctggct gactttgacc 2820
cccgcgtgtc tatccggctc cccagcacga gcggctcgga gggggtgccc ttccgcacgg 2880
tgtccgagtg gctggagtcc atcaagatgc agcagtatac ggagcacttc atggcggccg 2940
gctacactgc catcgagaag gtggtgcaga tgaccaacga cgacatcaag aggattgggg 3000
tgcggctgcc cggccaccag aagcgcatcg cctacagcct gctgggactc aaggaccagg 3060
tgaacactgt ggggatcccc atctgagcct cgacagggcc tggagcccca tcggccaaga 3120
atacttgaag aaacagagtg gcctccctgc tgtgccatgc tgggccactg gggactttat 3180
ttatttctag ttctttcctc cccctgcaac ttccgctgag gggtctcgga tgacaccctg 3240
gcctgaactg aggagatgac cagggatgct gggctgggcc ctctttccct gcgagacgca 3300
cacagctgag cacttagcag gcaccgccac gtcccagcat ccctggagca ggagccccgc 3360
cacagccttc ggacagacat atgggatatt cccaagccga ccttccctcc gccttctccc 3420
acatgaggcc atctcaggag atggagggct tggcccagcg ccaagtaaac agggtacctc 3480
aagccccatt tcctcacact aagagggcag actgtgaact tgactgggtg agacccaaag 3540
cggtccctgt ccctctagtg ccttctttag accctcgggc cccatcctca tccctgactg 3600
gccaaaccct tgctttcctg ggcctttgca agatgcttgg ttgtgttgag gtttttaaat 3660
atatattttg tactttgtgg agagaatgtg tgtgtgtggc agggggcccc gccagggctg 3720
gggacagagg gtgtcaaaca ttcgtgagct ggggactcag ggaccggtgc tgcaggagtg 3780
tcctgcccat gccccagtcg gccccatctc tcatcctttt ggataagttt ctattctgtc 3840
agtgttaaag attttgtttt gttggacatt tttttcgaat cttaatttat tatttttttt 3900
atatttattg ttagaaaatg acttatttct gctctggaat aaagttgcag atgattcaaa 3960
ccgaaaaaaa 3970
<210> 5
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA1 forward
<400> 5
gcctgacacc acatacatcg 20
<210> 6
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA1 reverse
<400> 6
atatgcgggt ggctaaactg 20
<210> 7
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA2 forward
<400> 7
aaagccggct acacagagaa 20
<210> 8
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA2 reverse
<400> 8
ttggacaact cccagtaggg 20
<210> 9
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA3 forward
<400> 9
gagtttgcca aggaattgga 20
<210> 10
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA3 reverse
<400> 10
ttgggatctt ccctcctctt 20
<210> 11
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA4 forward
<400> 11
accaagcagt gcgagagttt 20
<210> 12
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA4 reverse
<400> 12
ctccccgtac gacatcactt 20
<210> 13
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA5 forward
<400> 13
caagcctaat atggcggtgt 20
<210> 14
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA5 reverse
<400> 14
gtgaactgcc catcgttttt 20
<210> 15
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA7 forward
<400> 15
atcattggga gaaggcactg 20
<210> 16
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA7 reverse
<400> 16
atggacaaca tttgggtggt 20
<210> 17
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA8 forward
<400> 17
gagaacggct ctctggacac 20
<210> 18
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA8 reverse
<400> 18
cctccacaga gctgatgaca 20
<210> 19
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA10 forward
<400> 19
cgactaatgc tcgactgctg 20
<210> 20
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphA10 reverse
<400> 20
tgatcaagca actgccactc 20
<210> 21
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB1 forward
<400> 21
cagggtactc ggagaagcag 20
<210> 22
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB1 reverse
<400> 22
ccagcatgag ctggtgtaga 20
<210> 23
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB2 forward
<400> 23
agttcggcca aattgtcaac 20
<210> 24
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB2 reverse
<400> 24
aggcaggtga atgtcaaacc 20
<210> 25
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB3 forward
<400> 25
agcaacctgg tctgcaaagt 20
<210> 26
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB3 reverse
<400> 26
ggatgagctt gtccagggta 20
<210> 27
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB4 forward
<400> 27
gagagctgtg tggcaatcaa 20
<210> 28
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB4 reverse
<400> 28
tgtaggtggg atcggaagag 20
<210> 29
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB6 forward
<400> 29
tcattgcaca tggaaagcat 20
<210> 30
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EphB6 reverse
<400> 30
gggtgagtcc agacaaggaa 20
<210> 31
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA1 forward
<400> 31
ggtgactgtc agtggcaaaa 20
<210> 32
<211> 19
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(19)
<223> EFNA1 reverse
<400> 32
agtggaagga gcagcacat 19
<210> 33
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA2 forward
<400> 33
atctactgcc cgcactatgg 20
<210> 34
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA2 reverse
<400> 34
aggcgtggca gagatgtagt 20
<210> 35
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA3 forward
<400> 35
catgcggtgt actggaacag 20
<210> 36
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA3 reverse
<400> 36
gtggaactcg tagcccagag 20
<210> 37
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA4 forward
<400> 37
acattgtctg cccccactac 20
<210> 38
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA4 reverse
<400> 38
tgggctgact cagacttcct 20
<210> 39
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA5 forward
<400> 39
aggactccgt cccagaagat 20
<210> 40
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNA5 reverse
<400> 40
atctgggatt gcagaggaga 20
<210> 41
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNB1 forward
<400> 41
gcctggagtt caagaagcac 20
<210> 42
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNB1 reverse
<400> 42
gaacaatgcc accttggagt 20
<210> 43
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNB2 forward
<400> 43
gtgccaaacc agaccaagat 20
<210> 44
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNB2 reverse
<400> 44
gatgttgttc cccgaatgtc 20
<210> 45
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNB3 forward
<400> 45
aggcagaggg tggttatgtg 20
<210> 46
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> primer_bind
<222> (1)..(20)
<223> EFNB3 reverse
<400> 46
tctctttcca tgggcatttc 20
Claims (9)
- エフリンA型受容体2(EphA2)の細胞外リガンド結合ドメインを含む、癌幹細胞の集団を含むグリオーマ脳腫瘍を治療することに用いるための医薬であって、EphA2の細胞外リガンド結合ドメインがグリオーマ脳腫瘍の癌幹細胞増殖及び/又は移動を阻害することによりグリオーマ脳腫瘍が治療され、EphA2の細胞外リガンド結合ドメインは配列番号3に示すEphA2前駆体のアミノ酸位置28から201に位置する、医薬。
- 前記癌幹細胞増殖及び/又は移動の阻害が、癌幹細胞により生じる手術後の脳腫瘍再発の治療に効果がある、請求項1に記載の医薬。
- 前記癌幹細胞増殖及び/又は移動の阻害が、癌幹細胞により生じる手術後の脳腫瘍再発の予防処置に効果がある、請求項1に記載の医薬。
- 癌幹細胞が、グリア芽細胞腫細胞の癌幹細胞であるか、又は多形性グリア芽細胞腫細胞の癌幹細胞である、請求項1〜3のいずれか一項に記載の医薬。
- エフリンA型受容体2(EphA2)の細胞外リガンド結合ドメインを含む、グリオーマ脳腫瘍の癌幹細胞増殖及び/又は移動を阻害するための薬剤であって、グリオーマ脳腫瘍は癌幹細胞の集団を含み、EphA2の細胞外リガンド結合ドメインがグリオーマ脳腫瘍の癌幹細胞増殖及び/又は移動を阻害することによりグリオーマ脳腫瘍が治療され、EphA2の細胞外リガンド結合ドメインは配列番号3に示すEphA2前駆体のアミノ酸位置28から201に位置する、薬剤。
- 前記癌幹細胞増殖及び/又は移動の阻害が、癌幹細胞により生じる手術後の脳腫瘍再発の治療に効果がある、請求項5に記載の薬剤。
- 前記癌幹細胞増殖及び/又は移動の阻害が、癌幹細胞により生じる手術後の脳腫瘍再発の予防処置に効果がある、請求項5に記載の薬剤。
- 癌幹細胞がグリア芽細胞腫細胞の癌幹細胞である、請求項5〜7のいずれか一項に記載の薬剤。
- グリア芽細胞腫細胞の癌幹細胞が多形性グリア芽細胞腫細胞の癌幹細胞である、請求項8に記載の薬剤。
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