JP4054050B2 - 顕微鏡可視化下での細胞材料の単離 - Google Patents
顕微鏡可視化下での細胞材料の単離 Download PDFInfo
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Description
癌進行の一般的な見解は、細胞が腫瘍サプレッサー遺伝子における2種の別々の変更を得た後に形質転換され得ることを意味する。続く腫瘍は、異形性損傷から侵入性及び転移性腫瘍に段階的に進行する。現場の癌はときおり、広範囲の上皮過形成に関連して発生することが観察されており、そしてより大きな侵入性腫瘍がその腫瘍の周囲で癌の領域としばしば関連せしめられる。
本発明のもう1つの目的は、細胞組織サンプルからの特定の細胞の直接的抽出方法を提供することである。
細胞組織サンプルからの特定の細胞の直接的抽出の自動化された方法を提供することが本発明のさらなる目的である。
本発明のさらなる追加の目的は、細胞組織サンプルから純粋な細胞集団を得る方法を提供することである。
a)スライド−固定された組織サンプルを供給し;
b)顕微鏡を用いて前記組織サンプルの細胞の像視野を形成し;
c)前記細胞の像視野から注目の細胞の少なくとも1つの区画を同定し、前記注目の少なくとも1つの区画の細胞が、細胞の隣接する区画よりも細胞の異なった型を包含し;そして
d)前記組織サンプルから注目の少なくとも1つの区画の細胞を抽出する;
ことを包含する。
a)組織サンプルを供給し;
b)接着性を有する選択領域を提供するように活性化され得る選択的活性化可能表面と前記組織サンプルとを接触せしめ;
c)前記組織サンプルの抽出されるべき少なくとも1つの部分を同定し;
d)前記組織サンプルの前記少なくとも1つの部分に対応し、そしてその部分と接触して存在する移送表面の領域を選択的に活性化することにより、前記移送表面の前記活性化された領域を前記組織サンプルの前記少なくとも1つの部分に選択的に付着せしめ;そして
e)前記移送表面の前記活性化された領域と前記組織サンプルの前記少なくとも1つの部分との間の付着性を維持しながら、前記組織サンプルの前記少なくとも1つの部分が前記組織サンプルの残りの部分から抽出されるように前記組織サンプルから前記移送表面を分離する;
ことを包含する。
本発明はまた、十分に自動化されたシステムにも向けられ、それにより、組織はスクリーン上で可視化され得、その結果、注目の細胞の正確な視野がたとえば種々のラベル、組織学的染色、抗体、特により同定され、限界を示され又は他方では、それらの位置が区別され、そして次に、手動的にもしくは自動的に、又はそれらの2種の手段の組合せにより抽出され、そして分析され得る。
接着剤移送フィルムの例は、キャリヤー支持体を有するか又は有さない小片、又は接着剤フィルムの単離された部分、好ましくは等しく間隔をあけられた部分である。これに関して、テープの使用は、作動領域へのフィルムの新しい部分の移送の容易さ、及び収集又は貯蔵手段への活性化されたフィルムの除去の容易さを提供する。組織からの接着剤フィルムの除去は、支持体(たとえば、スライド)を適切な位置に維持しながら、テープを引張ることによって達成され得る。これは、圧力プレートを使用する本発明の態様においては、その圧力プレートが除去された後に達成される。これは、多くの場合、接着剤フィルムが、引張及び圧力プレート作動過程(たとえば横方向テープ輸送方向における対称の撓み)の間、テープの位置合せを維持するテープ輸送のための機械装置、及び張力下で変化しないであろう支持体に強く結合されることを必要とする。
本発明の特性及び特徴が次の例により示されるが、それらは本発明を制限するものではない。例において、百分率は、特にことわらない限り、重量によってである。
この例においては、細胞数のために適合された正常及び腫瘍組織のサンプルを個々の対象から分析した。 MMP-2のレベルをザイモグラフィーにより決定し、そして Arcusスキャナーを用いて定量化した。結果を、スチューデンドt−テストを用いて統計学的に分析した。カテプシンBレベルを、基質 Z-Arg-Arg-NHMecに対するVmax として決定した。
この例の結果は下記表1及び表2に示されており、この表においては、適合された対の侵入性結腸癌/正常上皮及び侵入性乳癌/正常上皮におけるカテプシンB活性を列挙する。活性測定値は、Vmax 、nモル/分×mgDNA として表わされる。カテプシンB活性は、結腸癌において平均 2.3倍(p<0.005)、及び乳癌において平均 6.9倍(p=0.077)、高められた。
この例においては、ポリメラーゼ鎖反応(PCR) 分析を行なった。 72KDaのタイプIVコラゲナーゼの前に報告されたcDNA配列に基づいて、センス及びアンチセンスオリゴヌクレオチドプライマーを、酵素活性化部位の増幅のために合成した(M.Onistaなど、“Reverse Transcription-Polymerase Chain Reaction Phenotyping of Metalloproteinases and Inhibitors in Tumor Matrix Invasion", Diagn.Mol.Pathol. 2(2): 74-80, 1993)、対のオリゴヌクレオチド配列は次の通りであった:5′−CAA TAC CTG AAC ACC TTC TA、3′−CTG TAT GTG ATC TGG TTC TTG。
図6bは、侵入性乳癌の5人の症例における MMP-2の発現を示す。棒グラフは、酵素の 72KDaの前形において3倍の適切な上昇率(p<0.05)及び酵素の 62KDaの活性形において10倍の適切な上昇率(p<0.05)を示す。
この例においては、鎖コンホメーション多型現象(SSCP)分析を行なった。ラベルされ、増幅された DNAを、等体積のホルムアミド充填染料(95%のホルムアミド;20mMのEDTA;0.05%のブロモフェノールブルー;及び0.05%キシレンシアノール)と共に混合した。サンプルを、95℃で5分間、変性し、そして6%アクリルアミド(49:1のアクリルアミド:ビス)、5%グリセロール及び 0.6×TBE から成るゲル上に負荷した。サンプルを8Wで室温で、一晩、電気泳動した。ゲルを3mmの Whatman紙に移し、乾燥せしめ、そしてオートラジオグラフィーをKodak X-OMATフィルムにより行なった。
一般的な方法によれば、接着剤表面が細胞又は組織の表面と接触して配置され、そして接着力が注目の細胞材料を接着剤表面に結合する。工具又は針の先端であり得る接着剤表面がその材料を獲得し、そしてそれを液体分析反応混合物に移送するために使用される。接着剤表面の例は、工具の先端上の接着剤被膜、又はその先端と細胞材料の表面との間の静電力の使用を包含する。
図8a〜8dは、本発明の1つの態様に従っての接着剤移送方法の連続的段階の図示である。
活性化可能接着剤層32は、組織に対して局部的に付着性になるよう電磁線により刺激される(活性化される)その能力により特徴づけられる。選択的に活性化可能接着剤層32を活性化するためには、1又は複数の化学成分が層中に組込まれ、そこで前記化学成分が電磁エネルギーの選択的吸収を引き起こす。好ましくは、そのような化学成分は、たとえばレーザーダイオードと共に使用するのに適切なIR−吸収性染料である。
図8bに示されるように、移送表面30は、細胞材料サンプル33と接触せしめられる。活性化可能接着剤層32は好ましくは、続いて獲得のために選択される細胞材料サンプルの小区域よりも大きな領域を有することが注目される。
隣接するヘマトキシリン及びエオシン断片を用いて、微小切除の最適領域、すなわち興味ある特定の小細胞集団の局在化、有意な炎症を含む領域の排除、等について組織断片を評価した。
ヒト前立腺癌は、明白な侵入性癌に進行する前、前立腺上皮内腫瘍(PIN) と呼ばれる現場腫瘍相を通して進行することがわかっている。 PIN病巣は、時おり、前立腺癌に関連することが見出されており、そして組織学的に、PION病巣における細胞は侵入性前立腺癌細胞の特徴に類似するいくつかの特徴を有する。これまでの報告は、 PIN病巣が時おり、異数性であることを示している。しかしながら、 PINと侵入性癌との間の正確な関係は不明確のまま存続している。
D8S136との反応を次のようにして行なった: 950℃で2分間、続いて次のようなサイクルで40サイクル: 950℃で30秒間、 550℃で30秒間、 720℃で30秒間、続いて 720℃で最後の2分間のインキュベーション。
発生期の現場乳癌は時おり、広範囲の上皮過形成及び侵入性癌に関連して発生することが観察されている。病理学者は、存在物間の関係についての形跡として、異型過形成、現場癌及び侵入性癌の共通する関連性を組織学的に解釈して来た。
ホルマリン又はアルコール固定された、パラフィン包埋された保管組織サンプルからの標準の6μm断片を、被覆れていないガラススライド上に調製した。断片を、パラフィン除去し、ヘマトキシリン及びエオシンにより染色し、水中、3%グリセロールにより1分間、処理し、そしてレーザー捕獲微小切除(LCM) の前、空気乾燥せしめた。新鮮な組織は、使用される場合、手術の直後、−70℃で急激に凍結された。6μmの低温保持断片を、標準の組織学的ガラススライド上の標準ガラス上で調製した。組織断片をホルマリン又はアルコールにおいて固定し、そしてヘマトキシリン及びエオシンにより染色した(Lerner Laboratories, Pittsburgh, PA) 。断片をアルコールにおいて脱水し、そして LCM移送の前、5分間、空気乾燥せしめた。
cDNAライブラリーを、レーザー捕獲微小切除により単離された材料を用いて生成した。二本鎖cDNAを、RNアーゼH−介入された第二鎖置換方法に基づいて約5μgの完全な細胞 RNAから調製した。逆転写第一鎖合成を、約50ng/μLのオリゴ(dT)によりプライムした。反応を約45℃で15分間、実施した。第二鎖置換及びEcoRIリンカーの付加を、製造業者(Superscript Choice System, Life Technologies Inc., Gaithersburg, MD) により示されている通りに行なった。第二鎖合成の後、反応生成物を電気泳動し、そして約 0.3kb〜約2kbのフラグメントを、β−アガロース(New England Biolabs, Beverly, MA)を用いて、1%の低融点アガロースからゲル単離した。cDNAペレットを、20μlのトリス−EDTAに再懸濁し、そして−20℃で貯蔵した。
Claims (6)
- 癌、感染性疾患又は他の病理学的過程に関連する注目の細胞材料を収集するための診断キットであって、
細胞材料に適用され、前記注目の細胞材料を他の細胞材料から区別するマーカー、
選択的に活性化されうる移送表面、及び
前記選択的に活性化されうる移送表面に適用される熱又は他の電磁エネルギーの源であって、当該選択的に活性化されうる移送表面を前記注目の細胞材料に付着させる当該熱又は他の電磁エネルギーの源、
を有するキット。 - 基材から注目の細胞材料を選択するために装置であって、
選択的に活性化されうる移送表面、及び
熱又は他の電磁エネルギーが前記選択的に活性化されうる移送表面に適用される際に当該選択的に活性化されうる移送表面を注目の細胞材料に接着させる当該熱又は他の電磁エネルギーの源、
を有する装置。 - 前記熱源又は他の電磁エネルギー源がレーザーに由来する、請求項2に記載の装置。
- 前記レーザーが紫外線レーザーである、請求項3に記載の装置。
- 前記選択的に活性化されうる移送表面が熱可塑性材料から構成される、請求項2〜4のいずれか1項に記載の装置。
- 前記注目の細胞材料が、細胞材料の混合物を含むサンプルに由来する、請求項2〜5のいずれか1項に記載の装置。
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1995
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1996
- 1996-10-09 JP JP51529097A patent/JP3958366B2/ja not_active Expired - Fee Related
- 1996-10-09 AU AU76633/96A patent/AU716979B2/en not_active Ceased
- 1996-10-09 DE DE69633248T patent/DE69633248T2/de not_active Expired - Lifetime
- 1996-10-09 EP EP96939463A patent/EP0862612B1/en not_active Expired - Lifetime
- 1996-10-09 ES ES96939463T patent/ES2225898T3/es not_active Expired - Lifetime
- 1996-10-09 AT AT96939463T patent/ATE274572T1/de not_active IP Right Cessation
- 1996-10-09 CA CA002233614A patent/CA2233614C/en not_active Expired - Fee Related
- 1996-10-09 WO PCT/US1996/016517 patent/WO1997013838A1/en active IP Right Grant
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ATE274572T1 (de) | 2004-09-15 |
AU716979B2 (en) | 2000-03-16 |
CA2233614C (en) | 2008-02-19 |
DE69633248T2 (de) | 2005-11-17 |
JP3958366B2 (ja) | 2007-08-15 |
EP0862612A1 (en) | 1998-09-09 |
US6010888A (en) | 2000-01-04 |
US5843657A (en) | 1998-12-01 |
AU7663396A (en) | 1997-04-30 |
US6569639B2 (en) | 2003-05-27 |
JP2006345868A (ja) | 2006-12-28 |
JP2000500325A (ja) | 2000-01-18 |
US20010031481A1 (en) | 2001-10-18 |
US6204030B1 (en) | 2001-03-20 |
ES2225898T3 (es) | 2005-03-16 |
WO1997013838A1 (en) | 1997-04-17 |
DE69633248D1 (de) | 2004-09-30 |
CA2233614A1 (en) | 1997-04-17 |
EP0862612B1 (en) | 2004-08-25 |
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