胃黏膜相關淋巴組織淋巴癌之研究：從治療到生物特性

Study of Gastric MALT Lymphoma: From Treatment to Biology

郭頌鑫(Sung-Hsin Kuo)

指導教授 ： 鄭安理 ； 董馨蓮

國立臺灣大學/醫學院/臨床醫學研究所/博士(2005年)

https://doi.org/10.6342/NTU.2005.02373

摘要

胃黏膜相關淋巴組織 (Mucosa-Associated Lymphoid Tissue，MALT) 淋巴癌，因其高發生率及獨特的致病機轉和臨床病理特徵，最近已成為癌症研究的重點之一。胃黏膜相關淋巴組織淋巴癌依其病理特徵分為低惡性度黏膜相關淋巴組織淋巴癌和高惡性度黏膜相關淋巴組織淋巴癌。在過去幾年來，針對低惡性度胃黏膜相關淋巴組織淋巴癌之治療，學界已達共識，即以抗生素治療作為低惡性度胃黏膜相關淋巴組織淋巴癌之第一線治療。假若對抗生素治療無效之局限性低惡性度胃黏膜相關淋巴組織淋巴癌病患或全身性轉移之低惡性度胃黏膜相關淋巴組織淋巴癌病患，則可採用手術、放射線、化學治療、免疫治療，或者整合性治療等替代治療方式，來治療這群病患。

　　相對於低惡性度胃黏膜相關淋巴組織淋巴癌，高惡性度胃黏膜相關淋巴組織淋巴癌一向被認為是由高度轉型 (transformed) 的細胞組成，其生長並不需依賴幽門螺旋桿菌 (即幽門螺旋桿菌非依賴性) ，所以必須進行化學治療。然而化學治療，卻會造成一些副作用，例如白血球低下，掉髮、噁心、噁吐等。最近我們的研究團隊，已由前瞻性的臨床試驗中，證實早期高惡性度胃黏膜相關淋巴組織淋巴癌，對於抗生素治療的反應與低惡性度胃黏膜相關淋巴組織淋巴癌並無不同，故在幽門螺旋桿菌清除之後可加以治癒 （即幽門螺旋桿菌依賴性）。且在長期追蹤下，達到組織完全緩解之病患，並無復發之現象。這個研究成果有其重要性，即是大部份早期高惡性度胃黏膜相關淋巴組織淋巴癌的病患得以免除化學治療的毒性，但也產生另一個重要問題：即高惡性度胃黏膜相關淋巴組織淋巴癌，萬一未得到有效治療，其病情有可能迅速惡化。因此在臨床上，最好能在治療前預知該腫瘤是否仍具幽門螺旋桿菌依賴性或幽門螺旋桿菌非依賴性，以期能做出最好的治療選擇。 然而到目前為止，可用來預測高惡性度胃黏膜相關淋巴組織淋巴癌是否仍具幽門螺旋桿菌依賴性或幽門螺旋桿菌非依賴性之相關病理或分子表徵仍未能充份釐清。

　　我們假設幽門螺旋桿菌非依賴性之機轉在高惡性度胃黏膜相關淋巴組織淋巴癌與低惡性度胃黏膜相關淋巴組織淋巴癌是不同的。譬如基因變化t(11;18)(q21;q21) (造成 API2-MALT1 之雜合蛋白質)，常見於幽門螺旋桿菌非依賴性的低惡性度胃黏膜相關淋巴組織淋巴癌，但卻罕見於高惡性度胃黏膜相關淋巴組織淋巴癌。再者，幽門螺旋桿菌非依賴性之機轉，雖在胃低惡性度黏膜相關淋巴組織淋巴癌已被研究一段時間，但相關之病理或分子表徵仍未能充份釐清，這可能與低胃惡性度黏膜相關淋巴組織淋巴癌較難取得高純度癌細胞有關。 在這方面，高惡性度胃黏膜相關淋巴組織淋巴癌組織反而較易微截取 (microdissection) 到高純度之癌細胞。因此，我們期望以高惡性度胃黏膜相關淋巴組織淋巴癌來作為幽門螺旋桿菌非依賴性的研究模式，去釐清幽門螺旋桿菌非依賴性的機制，也可幫助學界進一步了解與幽門螺旋桿菌相關之癌症。

　　假設這些生物標記，若能找到。是否這些可預測高惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性生物標記，也可幫助我們預測低惡性度胃淋巴癌之幽門螺旋桿菌非依賴性。同時我們將繼續探討幽門螺旋桿菌非依賴性可能的機轉和生物意義，並進行幽門螺旋桿菌非依賴性有關之基因的功能性分析，藉由功能性分析，去釐清幽門螺旋桿菌非依賴性之可能機制。 同時，將進一步研究與幽門螺旋桿菌非依賴性可能有關之基因 (包括訊息傳遞因子和傳遞路徑)，去證實這些基因與造成胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性致病機轉是否有相關性。再著，高惡性度胃黏膜相關淋巴組織淋巴癌經幽門螺旋桿菌 清除治療後，臨床上也常觀察到同一病患之高惡性度與低惡性度這兩部份之黏膜相關淋巴組織淋巴癌幽門螺旋桿菌跟根除出現不同的反應。因此進一步分析，並比較同一病患之低惡性度黏膜相關淋巴組織淋巴癌部份及高惡性度黏膜相關淋巴組織淋巴癌淋巴癌部份之clonality，將有助於了解幽門螺旋桿菌非依賴性與黏膜相關淋巴組織淋巴癌從低惡性度轉向高惡性度有關基因的變化關係，也助於釐清共存於同一病患這兩種淋巴癌之交互關係。

　　雖然約60-70 % 的低惡性度胃黏膜相關淋巴組織淋巴癌病患，仍具幽門螺旋桿菌依賴性，因此在根除幽門螺旋桿菌後腫瘤會達到完全緩解，然而其它約30-40 % 幽門螺旋桿菌非依賴性之低惡性度胃黏膜相關淋巴組織淋巴癌病患，必須接受其他治療；如化學治療，放射線治療以及開刀治療等治療方式。 然而這些治療卻會影響某些胃部功能程度和無法避免之副作用，因此尋求新的靶標治療，進一步阻段幽門螺旋桿菌非依賴性有關訊息傳遞徑路之基因，因可治癒此群病患。 另一方面，胃高惡性度黏膜相關淋巴組織淋巴癌對於化療之反應也一直未有定論。 有部份專家認為胃高惡性度黏膜相關淋巴組織淋巴癌較之一般所謂胃瀰漫性大型細胞淋巴癌 (diffuse large-cell lymphoma without MALT) 抗藥性較弱。我們也針對此進行了研究分析，我們發現，胃高性度黏膜相關淋巴組織淋巴癌對於化療之反應較胃瀰漫性大型細胞淋巴癌為佳，預後也較好。這重大發現，暗示某些黏膜相關淋巴組織之生物特性，可能影響胃高惡性度淋巴瘤之化療反應性和存活率。我們將進一步釐清可能的分子機轉和生物意義。藉由這些預測生物標記，來幫助我們在面對病人時，選擇最好的治療方式。並藉著調整這些基因表現，來加強治療效果，進而改善病人的預後。

第一部分、尋求可預測高惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性之生物標記

子題 A： 尋求可預測高惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性之生物標記

　　高惡性度胃黏膜相關淋巴組織淋巴癌一向被認為是由低惡性度胃黏膜相關淋巴組織淋巴癌轉型而來，而細胞在此轉型的同時，也已轉型成幽門螺旋桿菌非依賴性。 然而我們最近已由前瞻性的臨床試驗中證實早期高惡性度胃黏膜相關淋巴組織淋巴癌，對於抗生素治療的反應與低惡性度胃黏膜相關淋巴組織淋巴癌並無不同。 在參與這項前瞻性的臨床試驗中的二十四位早期高惡性度胃黏膜相關淋巴組織淋巴癌中，有二十二位病患達到幽門螺旋桿菌根除。 而這二十二位病患中，有十四位病患達到組織學完全緩解。換句話說，約 60% 高惡性度胃黏膜相關淋巴組織淋巴癌仍具幽門螺旋桿菌依賴性。且在長時間追蹤後，這些已達組織學完全緩解的病患，並無一人有復發之現象。

　　除了t(11;18)(q21;q21)外， (1;14)(p22;q32) 也是另外一個參與低惡性度胃黏膜相關淋巴組織淋巴癌形成有關之重要染色體轉位。而BCL10係從具有t(1;14)(p22;q32) 染色體轉位之胃黏膜相關淋巴組織淋巴癌細胞中被發現。隨後， BCL10 被發現存在於正常 T 或 B 細胞之細胞質，並負責傳遞細胞表面抗原與T或B細胞受體結合所產生的訊息，最後造成NF-kB的活化。在過去的文獻報告中，已證實BCL10之核內表現與染色體t(1;14)(p22;q32) 之轉位或BCL10基因之突變，並無相關性。 最近的研究中，更證實胃黏膜相關淋巴組織淋巴癌之BCL10核內轉位，並不是完全由BCL10基因突變之機轉所造成。 同時之前的研究報告也顯示，某些低惡性度胃黏膜相關淋巴組織淋巴癌和結節外黏膜相關淋巴組織淋巴癌，本身並無上述二種之染色體轉位，也可發現BCL10之核內轉位。 於是我們推測某些因素會造成BCL10之過度強化，而發生BCL10核內轉位，進而引發NF-kB之過度活化，因此不再依賴抗原刺激而成長、生存，故對幽門螺旋桿菌非依賴性。 同時在低惡性度胃黏膜相關淋巴組織淋巴癌病患身上，其BCL10之核內表現也與API2-MALT1有無存在有相關性，同時與腫瘤之侵犯程度非常有關，尤以侵犯漿層以下為最。然而API2-MALT1本身，在高惡性度胃黏膜相關淋巴組織淋巴癌非常少見。這現象似乎意味著BCL10可能在高惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性機轉中，扮演其重要角色。

　　在本研究中，我們已找到與高惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性有關的兩種分子標記。首先我們證實細胞核內BCL10表現，在預測高惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性方面，其敏感性可達87.5%，而特異性則高達百分之百。此外，共軛焦顯微鏡也證實NF-kB常伴隨BCL10一起在核內表現。 同時，單獨細胞核內NF-kB的表現，也可預測高惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性，其敏感性可達87.5%，而特異性則達 88.2%。

　　這些發現對我們臨床上有很重大幫助，因為早期高惡性度胃黏膜相關淋巴組織淋巴癌病患，若對抗生素無效，有可能迅速惡化，因此我們可以在使用抗生素前，先偵測胃黏膜相關淋巴組織淋巴癌檢體是否有BCL10和NF-kB之核內轉位。幫助我們即早預知病人是否屬於幽門螺旋桿菌依賴性或幽門螺旋桿菌非依賴性，給予這些高惡性度胃黏膜相關淋巴組織淋巴癌病患選擇最適合的治療。 此外我們的實驗也證實， t(11;18)(q21;q21) 很少發生在高惡性度胃黏膜相關淋巴組織淋巴癌。 因此細胞核內BCL10和NF-kB的轉移，似乎是預測高惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性中最重要的獨立因子。

子題 B： 尋求可預測高惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌依賴性之免疫標記

　　黏膜相關淋巴組織淋巴癌之發展必須仰賴存在於黏膜相關淋巴組織淋巴癌細胞之特殊T細胞和樹突狀細胞 (抗原存在表現細胞) 而成長。而這些抗原存在表現細胞，則藉由存在於B細胞和T細胞之間的CD40和CD40-ligand作為橋樑，去幫忙黏膜相關淋巴組織癌細胞生長。 為了讓B細胞和T細胞這兩者之間做有效之連繫，其存在於T細胞中之CD28或CTLA-4 ligand會與B細胞中CD80和CD86等共軛刺激分子 (co-stimulatory molecules) 做連繫，並幫忙胃黏膜相關淋巴組織淋巴癌之生長。 同時高惡性度胃黏膜相關淋巴組織淋巴癌中，已證實有共軛刺激分子(包括CD80和CD86)，以及腫瘤內浸潤T細胞存在，這現象似乎意味著CD86在高惡性度胃黏膜相關淋巴組織淋巴癌中，仍可幫忙T細胞去促進黏膜相關淋巴組織之B淋巴癌細胞的生長。

　　而另外啟發一重要免疫反應之重要因子是CD56 (+) 自然殺手細胞，其角色主要是調節人體促進和細胞促進之兩者免疫反應。雖然低惡性度胃黏膜相關淋巴組織淋巴癌較高惡性度胃黏膜相關淋巴組織淋巴癌含有較多的CD56 (+)自然殺手細胞之數目，但CD56 (+)自然殺手細胞在高惡性度胃黏膜相關淋巴組織淋巴癌仍存在之事實，顯示出高惡性度胃黏膜相關淋巴組織淋巴癌之成長，可能仍經幽門螺旋桿菌所誘導之免疫反應和T細胞之幫忙。且CD56 (+)自然殺手細胞在高惡性度胃黏膜相關淋巴組織淋巴癌細胞中，因本身具調解免疫功能，會進一步限制胃黏膜相關淋巴組織淋巴癌細胞之自動自發生長。因而在根除幽門螺旋桿菌後，會造成高惡性度胃黏膜相關淋巴組織淋巴癌之緩解。
　　在本研究中，我們已找到與高惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性有關的兩種免疫細胞標記。我們發現腫瘤細胞中有CD86之表現以及CD56 (+)自然殺手細胞之浸潤增加，可能與高惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌之依賴性有關。這發現，顯示B細胞和T細胞之相互關係仍存在於高惡性度胃黏膜相關淋巴組織淋巴癌，同時也在決定幽門螺旋桿菌依賴性中，扮演著重大關鍵。因此腫瘤細胞中是否有或無CD86之表現以及是否有或無CD56 (+)自然殺手細胞之浸潤減增加，將可決定高惡性度胃黏膜相關淋巴組織淋巴癌是否在幽門螺旋桿菌根除後，腫瘤是否反應，這也解釋為何一部份高惡性度胃黏膜相關淋巴組織淋巴癌病患，在使用抗生素根除幽門螺旋桿菌後會達到組織緩解。此重要訊息，也可幫助我們在面對此類病患時，做出最適宜的處置。

　　根據這些研究成果，我們假設：若高惡性度胃黏膜相關淋巴組織淋巴癌腫瘤中，如無CD86或浸潤T細胞等存在，其腫瘤之生長可能並不須幽門螺旋桿菌所誘發之免疫反應幫忙，換句話說，即是幽門螺旋桿菌非依賴性之高惡性度胃黏膜相關淋巴組織淋巴癌。反之，若高惡性度胃黏膜相關淋巴組織淋巴癌腫瘤中，如有CD86或浸潤T細胞以及CD56 (+)自然殺手細胞等存在，代表其黏膜相關淋巴組織淋巴癌腫瘤之生長仍須幽門螺旋桿菌所誘發之免疫反應幫忙，因此在根除幽門螺旋桿菌感染後，隨之根除所有免疫反應，進而造成黏膜相關淋巴組織淋巴癌之凋零，而造成組織學完全緩解。

第二部分 預測高惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性之生物標記是否也可幫助我們預測低惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌之非依賴性

　　低惡性度胃黏膜相關淋巴組織淋巴癌通常與幽門螺旋桿菌感染有關，故臨床上以有效抗生素根除幽門螺旋桿菌感染後，約 50-70% 的病患可達到長期之腫瘤緩解，甚而痊癒，故幽門螺旋桿菌清除已是目前該病的第一線標準療法。雖然 t(11;18)(q21;q21) 染色體轉位是預測低惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性中最重要的一個分子標記。然而，卻只有百分之五十至七十的幽門螺旋桿菌非依賴性低惡性度胃黏膜相關淋巴組織淋巴癌病患，才具有此t(11;18)(q21;q21) 染色體轉位。　換句話說，約百分之三十至五十的幽門螺旋桿菌非依賴性低惡性度胃黏膜相關淋巴組織淋巴癌病患，並沒有可靠的分子標記可預測其幽門螺旋桿菌非依賴性。 因此尋求較簡易、且易偵測、及高敏感度的分子生物標記，去幫助我們預測本身並無t(11;18)(q21;q21) 染色體轉位之低惡性度胃黏膜相關淋巴組織淋巴癌病患是否是幽門螺旋桿菌非依賴性，是迫切須要的。

　　在第一部分研究中，我們已清楚證實BCL10和NF-kB之核心轉位，是決定高惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性之重要因子，且這兩個重要因子，均在核內共同表現。由於高惡性度胃黏膜相關淋巴組織淋巴癌本身很少具有t(11;18)(q21;q21)，因此預期BCL10和NF-kB之核內轉位也可預測缺乏t(11;18)(q21;q21) 的低惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性是合理的。而NF-kB活化也會造成c-Myc和survivin之過度表現，這些分子其本身也會促進淋巴癌細胞之過度增生，最後造成低惡性度胃黏膜相關淋巴組織淋巴癌的幽門螺旋桿菌非依賴性生長。因此預期c-Myc和survivin之過度表現也可預測缺乏t(11;18)(q21;q21)的低惡性度胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性也是合理的。

　　在本研究中，我們發現60位低惡性度胃黏膜相關淋巴組織淋巴癌病患中，只有13位證實有API2-MALT1之存在。而其它47位無API2-MALT1存在之病患，BCL10核內表現之比率在幽門螺旋桿菌非依賴性病患比幽門螺旋桿菌依賴性病患有明顯提高（72.3% 比8.3%，P值小於0.001）。同時NF-kB之核內表現，在幽門螺旋桿菌非依賴性病患之比率也比起幽門螺旋桿菌依賴性病患，有明顯之提高（63.6%比8.3%，P值小於0.001）。最重要的是，在47位t(11;18)(q21;q21) 陰性之病患中，其細胞核內BCL10表現，在預測低惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性方面；其敏感度為72.7%，而特異性則為91.7%。同時，細胞核內NF-kB的表現，在預測幽門螺旋桿菌非依賴性方面，其敏感度為63.6%，而特異性也為91.7%。

　　至於c-Myc和survivin之過度表現是否也與幽門螺旋桿菌非依賴性之低惡性度胃黏膜相關淋巴組織淋巴癌有關。在我們進一步分析的數據中，顯示：其細胞核內c-Myc表現，在預測胃黏膜相關淋巴組織淋巴癌 (包括高惡性度及低惡性度胃黏膜相關淋巴組織淋巴癌) 之幽門螺旋桿菌非依賴性方面：其敏感度為67.7% 而特異性則為75.0%。同時，細胞核內survivin的表現，在預測胃黏膜相關淋巴組織淋巴癌(包括高惡性度及低惡性度胃黏膜相關淋巴組織淋巴癌)之幽門螺旋桿菌非依賴性方面：其敏感度為77.4% 而特異性則為67.5%。這個重要訊息，更加證實NF-kB之訊息傳遞路徑是決定幽門螺旋桿菌非依賴性之重要關鍵。　　

第三部分 進一步分析胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性有關基因之功能性，以及分子機轉和生物意義。

　　我們的研究團隊率先發現，早期的高惡性度胃黏膜相關淋巴組織淋巴癌，約百分之六十至七十仍具幽門螺旋桿菌依賴性，故在幽門螺旋桿菌清除之後可加以治癒。 最近我們更進一步發現BCL10細胞核轉位或NF-kB細胞核轉位是決定高惡性度胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性的重要關鍵分子事件。 同時這兩個預測因子，也適用於低惡性度胃黏膜相關淋巴組織淋巴癌，不論其是否具有t(11;18)(q21;q21)。這重要發現將帶動此研究領域的重大變革以及新的研究方向。然而，在胃黏膜相關淋巴組織淋巴癌中，BCL10細胞核轉位或 NF-kB細胞核轉位的分子機轉及生物意義仍待進一步釐清。

　　BCL 10本身位於細胞質內，它負責傳遞來自抗原接受體所得到的訊息，並促進NF-kB之活化，因為NF-kB之本身活化，會促進B細胞之生存，以及抗凋零之機制。因此可進一步的推論，NF-kB之上調節，是造成胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性的重要機制。 因此我們假設；造成NF-kB之持續活化可能與BCL10之核內轉位有關。在這部分研究中，我們發現TNF-a會造成一部分的BCL10蛋白進入細胞核內，這些現象可被Ak1t的化學抑制劑(LY294002) 阻止，顯示Akt1訊息傳遞有關的路徑，可能在BCL10細胞核轉位中扮演重要的角色。同時我們也剖析BCL10之基因構造，發現BCL10本身並不具有核轉位之訊息 (nuclear localization signal, NLS)。這些現象顯示BCL10可能需先與某些蛋白結合，再藉以發生細胞核轉位。而BCL-3本身具NLS且和淋巴癌發展有關。 我們的研究也指出，BCL10可被Akt1磷酸化 （BCL10被Akt1磷酸化之位置為BCL10之碳終端的Ser 218和Ser 231），進而與BCL3形成複合體， 因BCL3具有核轉位訊息，於是把BCL10帶進核內。在細胞核內之BCL10/BCL3複合體可進而影響NF-kB之活性。同時，我們也發現在BCL10基因的啟動區域存在NF-kB的結合位置。這些現象顯示， 在BCL10和NF-kB之間存有一未被發現之自動回饋的分子機制。

　　到底BCL10進入核內會發生那些作用呢？其實黏膜相關淋巴組織淋巴癌B細胞或t(1;14)(p22;q32) 陽性之黏膜相關淋巴組織淋巴癌病人，其BCL10之過度表現，反而與腫瘤之形成有莫大關係，這似乎意味BCL 10本身存有我們未知的生物功能。而本篇研究中，我們也發現BCL 10是參與TNF-a 所引發NF-kB活化之訊息傳遞路徑中所必須的，更顯示出BCL 10是參與腫瘤之形成，而不是抑制腫瘤生長。同時我們的研究也指出，若抑制BCL10或BCL-3並不會影響NF-kB之DNA結合能力，然而若BCL10的碳終端之Ser 218和Ser 231被刪除掉，則TNF-a 所促進NF-kB之轉譯能力則被抑制。在我們進一步以高惡性度胃黏膜相關淋巴組織淋巴癌及低惡性度胃黏膜相關淋巴組織淋巴癌之體內的研究中，我們發現腫瘤細胞中有BCL-3之細胞核轉位、TNF-a細胞核轉位表現，細胞質有磷酸化Akt1過度表現，可能與胃黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性有關。以上這些研究結果，可以證明BCL10之核內轉位在胃黏膜相關淋巴組織淋巴癌中，是扮演TNF-α所引發NF-kB活化之訊息傳遞路徑的重要角色。

第四部分 經由比較分析同一病人之低惡性度黏膜相關淋巴組織淋巴癌及高惡性度黏膜相關淋巴組織淋巴癌部份的來源 (Clones) 和基因圖譜，將有助於了解是否造成細胞高惡性度轉型與幽門螺旋桿菌非依賴性是分屬不同的基因變異。

　　胃高惡性度黏膜相關淋巴組織淋巴癌咸信是由低惡性度黏膜相關淋巴組織淋巴癌轉型而來，而大部份病患之胃中，仍併存這兩種組織。我們過去的研究己指出黏膜相關淋巴組織淋巴癌的高惡性轉型並不必然造成幽門螺旋桿菌非依賴性。再者，在幽門螺旋桿菌清除治療後，臨床上也常觀察到同一病患之高惡性度與低惡性度腫瘤出現不同的反應。是否有些病患之高及低惡性度腫瘤分別屬於兩個不同的clones？或是造成細胞轉型與幽門螺旋桿菌非依賴性分屬不同的基因變異？這些重要的課題值得進一步探討。

　　在之前的研究中，我們已經證實高惡性度轉型並不等於幽門螺旋桿菌非依賴性。同時在本篇研究中，我們也針對高惡性度和低惡性度這兩部份黏膜相關淋巴組織淋巴癌對幽門螺旋桿菌之根除反應是否一致或者是否相異，去分析其高惡性度黏膜相關淋巴組織淋巴癌和低惡性度黏膜相關淋巴組織淋巴癌之clonality是否相異。結果我們證實，有四位病患其低惡性度與高惡性度黏膜相關淋巴組織淋巴癌部份對幽門螺旋桿菌根除治療反應不一。其中有三位其低惡性度與高惡性度黏膜相關淋巴組織淋巴癌部份之免疫球蛋白重支鏈基因重新排列呈現不同 (clonality相異)。相對於這些病患，其他低惡性度與高惡性度黏膜相關淋巴組織淋巴癌部份對幽門螺旋桿菌根除治療反應一致的十四位病患中 (十位幽門螺旋桿菌依賴性，四位幽門螺旋桿菌非依賴性)，有十二位其低惡性度與高惡性度黏膜相關淋巴組織淋巴癌具有相同之 clonality。這結果證實高惡性度胃黏膜相關淋巴組織淋巴癌並不完全是由低惡性度黏膜相關淋巴組織淋巴癌轉變而來。

　　若從另一個角度去推敲，即不同clonality之高惡性度黏膜相關淋巴組織淋巴癌和低惡性度黏膜相關淋巴組織淋巴癌部份，是否與這兩部份之黏膜相關淋巴組織淋巴癌對幽門螺旋桿菌根除之不同反應有相關性。因此在我們的研究中，也試者去研究這兩者之間的clonality。我們發現，在5位不同clonality之病患中，有三位病人其高惡性度黏膜相關淋巴組織淋巴癌和低惡性度黏膜相關淋巴組織淋巴癌對幽門螺旋桿菌根除反應不一，而其它二位病患則對幽門螺旋桿菌根除反應相似。前者之研究結果，已清楚的證實存在於同一胃部之高惡性度黏膜相關淋巴組織淋巴癌和低惡性度黏膜相關淋巴組織淋巴癌可能同時存在，但並無相關性。例如高惡性度黏膜相關淋巴組織淋巴癌部份，可能含有過度之BCL10之核內表現，因此造成高惡性度黏膜相關淋巴組織淋巴癌部份對幽門螺旋桿菌根除反應不佳，而低惡性度黏膜相關淋巴組織淋巴癌淋巴癌部份則無BCL10和NF-kB之核內表現，因此對幽門螺旋桿菌根除有效。後來我們更證實，一位患者其高惡性度黏膜相關淋巴組織淋巴癌是幽門螺旋桿菌依賴性而低惡性度黏膜相關淋巴組織淋巴癌則是幽門螺旋桿菌非依賴性；其中低惡性度黏膜相關淋巴組織淋巴癌部份則含有t(11;18)(q21;q21) 和BCL10或NF-kB之核內表現，而高惡性度黏膜相關淋巴組織淋巴癌部份則無t(11;18)(q21;q21) 、BCL10和NF-kB之核內表現。

　　以上這些研究結果，已經清楚的證實，高惡性度黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性的高惡性度黏膜相關淋巴組織淋巴癌部份可能不是由其低惡性度黏膜相關淋巴組織淋巴癌轉變而成，而可能是原發性的。且高惡性度黏膜相關淋巴組織淋巴癌之轉型也並不代表失去幽門螺旋桿菌依賴性。因為大部份幽門螺旋桿菌依賴性之高惡性度黏膜相關淋巴組織淋巴癌部份，是由幽門螺旋桿菌依賴性之低惡性度黏膜相關淋巴組織淋巴癌轉型而成。因此，同存在於同一胃部之高惡性度黏及低惡性度這兩部份之黏膜相關淋巴組織淋巴癌，其來源可能並不盡相同，因此對幽門螺旋桿菌根除反應也不一致。

第五部分、 幽門螺旋桿菌非依賴性低惡性度胃黏膜相關淋巴組織淋巴癌治療之研究----以抑制發炎反應相關之TNF-a 或NF-kB作為治療幽門螺旋桿菌非依賴性低惡性度胃黏膜相關淋巴組織淋巴癌的策略之可行性探討

子題a： 前驅性臨床試驗：評估thalidomide治療幽門螺旋桿菌非依賴性之低惡性度胃黏膜相關淋巴組織淋巴癌之療效

　　針對抗生素治療無效之局限性或全身性轉移之低惡性度胃黏膜相關淋巴組織淋巴癌之病患，手術、放射線、化學治療、免疫治療，或者整合性治療，都是可考慮的替代治療方式。然而，以上這些治療卻會影響胃部功能，如胃液分泌、部份胃排空能力、和不可避免之副作用。 因此發展一項新的有效且低副作用之治療處方和對策，來治癒這些病患是迫切須要的。 在之前我們的研究中，我們已證實NF-kB之核內轉位的確是幽門螺旋桿菌非依賴性的重要關鍵。同時我們的研究，也證實NF-kB之活化，在低惡性度胃黏膜相關淋巴組織淋巴癌細胞中，也會造成c-Myc和survivin之過度表現，而這些分子其本身也會促進黏膜相關淋巴組織淋巴癌細胞之過度增生。除此之外，我們的研究中，也已清楚指出TNF-a可以活化NF-kB。因此若能阻斷NF-kB之活化訊息傳遞徑路如TNF-a，應可治療幽門螺旋桿菌非依賴性之低惡性度胃黏膜相關淋巴組織淋巴癌病患。

　　Thalidomide本身是一個TNF-α 抑制劑，同時也可抑制NF-kB，且副作用也甚少，所以它是一種很適合來治療幽門螺旋桿菌非依賴性之低惡性度胃黏膜相關淋巴組織淋巴癌病人的藥物。在初步觀察臨床試驗中，我們發現一位臨床上快速惡化之第四期且幽門螺旋桿菌非依賴性之低惡性度胃黏膜相關淋巴組織淋巴癌病患，其轉移性Waldeyer’s ring淋巴癌和頸部淋巴結病變，在服用thalidomide二週後，其腫瘤快速消失，這結果令人驚喜，更證實我們的假說。 於是我們設計一項前驅性臨床試驗；即使用thalidomide來治療幽門螺旋桿菌非依賴性之低惡性度胃黏膜相關淋巴組織淋巴癌病患。從2002年1月到 2004年12月這期間，我們使用thalidomide來治療八位低惡性度黏膜相關淋巴組織淋巴癌病人 (其中一位為肺黏膜相關淋巴組織淋巴癌、另外一位為眼眶黏膜相關淋巴組織淋巴癌，而其他六位為幽門螺旋桿菌非依賴性胃黏膜相關淋巴組織淋巴癌；最重要的是，全部病患其腫瘤組織均具有BCL10和NF-kB之核內轉位)，並觀察到相當療效。 在治療過程中，我們觀察到有兩位病患達到完全緩解，三位病患達到部份緩解，而其他三位病患則病情穩定。

子題b： 長時間臨床追蹤經胃切除之低惡性度胃黏膜相關淋巴組織淋巴癌病患
的預後

　　胃黏膜相關淋巴組織淋巴癌並不像胃癌，只分布在胃部的一個區域，且通常是分布在胃部各處，因此局部胃切除或部份胃切除是否能根除胃淋巴癌，到目前為止，仍是一個爭論？大部份學者認為胃黏膜相關淋巴組織淋巴癌是一多發性的，可多處分布在幽門，以及胃體部，因此局部切除胃部，必存有殘餘黏膜相關淋巴組織淋巴癌，尤其在開刀邊緣處。因此大部份學者均主張，局部手術並不是一個適合治療胃黏膜相關淋巴組織淋巴癌的方式。 但在回溯性研究中，我們發現有一位已轉移且幽門螺旋桿菌非依賴性之低惡性度胃黏膜相關淋巴組織淋巴癌病患，在局部切除胃部和切除轉移性脾臟後，經長時間 (四年) 追蹤後，並無復發之現象。 這重大發現，更激發我們去探討是否局部胃切除或部份胃切除能根除低惡性度胃黏膜相關淋巴組織淋巴癌。

　　在這一部分研究中，我們發現八位經部份胃切除的病患在經過平均追蹤五年後，仍然存活且無復發現象。值得注意是，有一位幽門螺旋桿菌非依賴性之轉移性低惡性度胃黏膜相關淋巴組織淋巴癌之患者，在胃切除、淋巴結摘除及脾臟切除後，並無復發之現象。而且大部分病患其原發處、和其它轉移處，及邊緣癌細胞，均證實有核內BCL10表現、核內NF-kB表現、和API2-MALT1之存在。同時，API2-MALT1存在常與BCL10和NF-kB之核內共同表現且與有高度相關性。

　　為何低惡性度胃黏膜相關淋巴組織淋巴癌在局部胃切除或部份胃切除後能夠痊癒？我們推想，若能經由局部胃切除，把幽門割除，應可根除與發炎相關之生物激素，以及幽門螺旋桿菌所誘發之免疫因素，因而造成胃黏膜相關淋巴組織淋巴癌細胞之凋零，最後造成組織學完全緩解。這些推論，也經由我們進一步研究證實，即這些開刀邊緣處和原發處其clonality大致相同。換句話說這些轉移的黏膜相關淋巴組織淋巴癌細胞，仍像原發處之胃部黏膜相關淋巴組織淋巴癌細胞一樣，仍依賴幽門螺旋桿菌抗原所誘發之免疫或持續發炎所導致之NF-kB過度活化而生長。因此在局部或全胃切除後，整個胃部生態環境隨之改變，例如幽門螺旋桿菌所誘發之免疫反應，以及發炎有關之致病機轉，將會被阻斷，因而造成黏膜相關淋巴組織淋巴癌之組織學完全緩解。

第六部分、 探討高惡性度胃黏膜相關淋巴組織淋巴癌和無黏膜相關淋巴組織成分之胃瀰漫大型細胞淋巴癌之間不同之化療反應性和存活率之分子機轉及生物意義。

　　我們與其他團隊已證實單獨化學治療可治癒早期侷限性高惡性度胃淋巴癌。 雖然高惡性度胃淋巴癌病患對於化療治療的反應與淋巴結高惡性度淋巴癌並無不同，但仍有些病人雖經化療緩解，仍再復發，甚至對化療反應不佳。這重大發現，引起我們極大的興趣去進一步找出相關之生物標記，能幫助我們即早預測高惡性度胃淋巴癌病患之化療反應性和存活率。最近我們發現，組織學上具有黏膜相關淋巴組織成份 (即高惡性度黏膜相關淋巴組織淋巴癌) 相對於無黏膜相關淋巴組織成份 (瀰漫大型細胞淋巴癌) 的高惡性度胃淋巴癌病患，有較好的化學緩解率和存活率。

　　大部份高惡性度黏膜相關淋巴組織淋巴癌，一向被認為是由低惡性度黏膜相關淋巴組織淋巴癌演變而成。相對於高惡性度胃黏膜相關淋巴組織淋巴癌，瀰漫大型細胞淋巴癌只有少部份是源自於低惡性度黏膜相關淋巴組織淋巴癌、其演變過程中，慢慢失去低惡性度黏膜相關淋巴組織淋巴癌之部份。因此我們針對這二組不同腫瘤病患，再去分析其幽門螺旋桿菌感染是否有些差異，包括檢體之幽門螺旋桿菌偵測，胃病人所作之Urease檢查，胃檢體切片時之幽門螺旋桿菌培養。在本篇研究中我們發現高惡性度黏膜相關淋巴組織淋巴癌病患其幽門螺旋桿菌陽性率，較瀰漫大型細胞淋巴癌病患陽性率高出甚多，且具有明顯差異性。有趣的是，幽門螺旋桿菌陽性的病患，也較幽門螺旋桿菌陰性的病患，有較好之存活率 (三年存活率: 69% 比41%，P = 0.024)。這些現象，也證實之前我們的研究成果。

　　這發現，暗示某些黏膜相關淋巴組織之生物特性，可能影響高惡性度胃淋巴癌病患之化療反應性和存活率。 在這一部份的研究中，我們首先嘗試由病理組織的檢驗，來探討Bcl-2以及cyclin D3之不同表現，是否造成高惡性度黏膜相關淋巴組織淋巴癌和瀰漫大型細胞淋巴癌兩者之間，對化療反應性和臨床預後之相異性。我們證實cyclin D3之過度表現的確與高惡性度黏膜相關淋巴組織淋巴癌之低化療反應性和低活率有關；相對於cyclin D3，Bcl-2過度表現則是造成瀰漫大型細胞淋巴癌之低化療反應和低存率之重要因子。

　　這發現顯示，抗凋零有關之基因，以及控制細胞週期有關蛋白質可能影響胃高惡性度胃淋巴癌之化療反應性和存活率。 我們將進一步釐清可能的分子機轉和生物意義。最近淋巴結內高惡性度淋巴癌可經由cDNA 基因微陣列分析分成GCB (germinal center-B cell預後較好) 和非GCB (預後較差) 兩組，而且以組織免疫方法 (偵測CD10, BCL6,和MUM-1) 代替cDNA 基因微陣列方法其正確性也極高，可見這分子分類法對治療淋巴結內高惡性度淋巴癌病患有極重要性。因胃黏膜相關淋巴組織淋巴癌源自GCB 之記憶B 型細胞，若能偵測高惡性度胃淋巴癌之CD10, BCL6,和MUM-1 表現，並進而預測高惡性度胃淋巴癌病患之存活率是可預期的。 在本研究中，我們將進一步繼續探討高惡性度胃淋巴癌病患之基礎生物學，並藉以改善高惡性度胃淋巴癌之治療成績。

未來的研究展望

　　從過去我們在胃黏膜相關淋巴組織淋巴癌的臨床以及基礎研究的經驗，我們希望，未來能進一步開展胃淋巴癌藥物治療的研究領域以及釐清胃黏膜相關淋巴組織淋巴癌之致病機制，以及與發炎發應或免疫反應相關之幽門螺旋桿菌非依賴性真正機轉。 未來之展望，期望能朝下列方向努力：

一、進一歩釐清BCL10和NF-kB細胞核轉位之分子機轉及生物意義，以及
探討造成胃黏膜相關淋巴組織淋巴癌幽門螺旋桿菌非依賴性之關鍵基因

在初步的研究中，我們發現BAFF (B-cell activating factor of the TNF family) 之核內表現比率在幽門螺旋桿菌非依賴性之胃黏膜相關淋巴組織淋巴癌病中，比起幽門螺旋桿菌依賴性病人，高出甚多，且具有統計學意義（86.6% 比 22.2%，P值為0.003）。同時在細胞株實驗中，我們也試著在這些B淋巴癌細胞株加上BAFF去刺激NF-kB之活化，結果我們發現BAFF不僅可促進B淋巴癌細胞株之過度增生，而且也造成BCL10之核內轉位，和NF-kB之活化。總言之，BAFF在幽門螺旋桿菌非依賴性黏膜相關淋巴組織淋巴癌之致病機轉中，應扮演其重要角色。因此未來若能發展一分子靶標治療，去阻斷BAFF和其相關之分子，應可治癒此群病人。

二、進一步釐清發炎發應或免疫反應與幽門螺旋桿菌非依賴性之關係，藉此解開
這者之間的鑰匙，去進一步了解胃黏膜相關淋巴組織淋巴癌之致病機轉

進一步體外實驗中，我們也證實IL-6可促進Peiffer cell (diffuse large B cell lymphoma cell) 之NF-kB活化，以及BCL10之核內轉位，同時也證實BAFF也會隨之增加，這些現象均清楚的指出：幽門螺旋桿菌非依賴性的確與胃內之發炎和免疫反應息息相關，當淋巴癌細胞接受持續的發炎免疫反應（如TNF-a、或BAFF，以及IL-6）等刺激，進而導致NF-kB之過度活化，而後導致NF-kB之下調控基因過度表現，造成黏膜相關淋巴組織淋巴癌繼續生長和分化。同時黏膜相關淋巴組織癌細胞本身也含有IL-6以及BAFF接受體，因此本身再度接受來自NF-kB活化所產生之IL-6和BAFF刺激，繼續導致NF-kB活化，造成幽門螺旋桿菌非依賴性黏膜相關淋巴組織淋巴癌的生長。

三、進一步釐清發炎反應所造成之某些調控抗凋零及細胞週期有關基因異常，與胃黏膜相關淋巴組織淋巴癌致病機轉之相關性。

最近研究顯示，幽門螺旋桿菌感染會引發慢性發炎，經長時間後會促產生反應性氧化物質（reactive oxygen species, ROS），進而造成DNA甲基化。但為何DNA甲基化會誘使B細胞clone產生胃淋巴癌，其真正機制仍未明瞭。我們猜想，某些與細胞週期或抗凋零有關之基因出了問題。例如：DAP (death associated protein)，將抑制與凋零有關之訊息傳遞路徑 (如FAS所導致凋零之訊息傳遞)，因此導致BCL-2之過度表現，而造成黏膜相關淋巴組織淋巴癌繼續生長。再加上，抑制細胞周期有關之蛋白質p16出了問題，而讓黏膜相關淋巴組織淋巴癌形成。但在最近一篇研究報告中，曾經提及p16甲基化，在經過幽門螺旋桿菌根除後且證實為幽門螺旋桿菌依賴性之患者中，追蹤之檢體中並無p16甲基化存在。故我們推測幽門螺旋桿菌所導致之ROS，而後引發DNA甲基化之現象，是暫時性的，因此在幽門螺旋桿菌根除後，這些現象會消失。未來應朝這些與調控凋零及細胞週期有關之基因，是否與發生胃黏膜相關淋巴組織淋巴癌之真正致病機轉去努力。
四、早期高惡性度胃黏膜相關淋巴組織淋巴癌之長期追蹤：以PCR 方法偵測clonality存在和組織學染色方法偵測BCL10或NF-kB之核內表現來證實是否有殘餘之胃黏膜相關淋巴組織淋巴癌細胞

在我們之前的研究，除了使用PCR方法可以鑑別其高惡性度黏膜相關淋巴組織淋巴癌和低惡性度黏膜相關淋巴組織淋巴癌這兩部份clonality是否相異外，也清楚指出其不同clonality的高惡性度黏膜相關淋巴組織淋巴癌部份及低惡性度黏膜相關淋巴組織淋巴癌部份也有不同BCL10和NF-kB的表現。同時，我們的研究團隊以前瞻性的研究方式，已證實早期的高惡性度胃黏膜相關淋巴組織淋巴癌仍具幽門螺旋桿菌依賴性，且抗生素治療可以治癒60-70%的病人。且在長期追蹤下，達到完全緩解之病患，並無復發之現象。然而到目前為止，並無一項重要研究去證實，是否已達到組織學上之完全緩解的高惡性度胃黏膜相關淋巴組織淋巴癌病患，其clonality是否存在? 我們推測可能是clonality或BCL10和NF-kB的表現在幽門螺旋桿菌根除後無法偵測到？因此針對同一病人之一系列檢体（包括幽門螺旋桿菌根除前及幽門螺旋桿菌根除後），個別去偵測clonality和BCL10及NF-kB的表現，應可釐清上述可能之機轉。

五、進一步設計一前瞻性臨床試驗，去證實是否早期胃瀰漫性大型細胞淋巴癌仍具幽門螺旋桿菌依賴性（像高惡性度胃黏膜相關淋巴組織淋巴癌一樣）；同時尋求可能之分子靶標治療，來治療高惡性度胃淋巴癌

我們與其它國外研究團隊，均已經清楚證實，高惡性度胃黏膜相關淋巴組織淋巴癌仍對抗生素治療有效，且在長期追蹤下，達到完全緩解之病患，並無復發之現象。這發現，提供我們一個重要訊息，即證實有感染幽門螺旋桿菌之早期胃大型瀰漫性淋巴癌病患，是否像高惡性度胃黏膜相關淋巴組織淋巴癌病患一樣，仍對幽門螺旋桿菌之免疫刺激有依賴性，故在經過抗生素治療後，仍能達到完全緩解？

因此我們針對這群早期胃瀰漫性大型細胞淋巴癌病患，進行一項前瞻性臨床前實驗，即使用二週三合一抗生素治療，來根除幽門螺旋桿菌後，來治療早期胃瀰漫性大型細胞淋巴癌。從2001年至2004年之間，我們總共收集到三位早期胃大型瀰漫性淋巴癌病患，在經過抗生素投予二個月後後，胃鏡檢查及組織學證實這三位病患達到完全緩解。

針對此現象，我們提出可能之機轉：即一部份早期胃瀰漫性大型細胞淋巴癌是由其低惡性度且幽門螺旋桿菌依賴性黏膜相關淋巴組織淋巴癌轉型而成。而在轉型過程中，低惡性度胃黏膜相關淋巴組織淋巴癌部分則完全消失，而只留下瀰漫性大型細胞淋巴癌部份。因此在幽門螺旋桿菌根除後，仍能達到完全緩解。另外一個原因即此部份胃瀰漫性大型細胞淋巴癌是原發性，並不是由低惡性度胃黏膜相關淋巴組織淋巴癌轉型而成，而是原發性，但本身並不具幽門螺旋桿菌非依賴性之關鍵基因，如核內BCL10、NF-kB、survivin、和BAFF之表現。

六、以胃淋巴癌之研究模式為基礎，進一步釐清發炎反應與癌症可能發生之致病機制、分子調控訊息、傳遞。藉此調節這些分子機制，進而改善治療效果，並治癒與發炎相關之癌症病患

之前我們的研究，已經證實早期胃淋巴癌不論是否具有黏膜相關淋巴組織或無黏膜相關淋巴組織成份，均在使用抗生素根除幽門螺旋桿菌之後，達到腫瘤組織學上完全緩解。但與胃淋巴癌一樣是由幽門螺旋桿菌感染所導致之早期胃癌，為何在幽門螺旋桿菌根除之後，並無法達到痊癒，這其中所隱藏之訊息，以及幽門螺旋桿菌感染所導致這二者癌症之不同的致病機轉，更值得我們去進一步探討。 我們推測：胃癌的發生是透過許多因子、以及多步驟致癌機轉所導致的結果，但幽門螺旋桿菌可能只是其中重要的因子之一。 同時，大部分胃腺癌病人一開始大多以侵犯性和轉移性表現為主，故只能以化學治療為主。然而，大部分胃癌細胞會對化學治療產生抗藥性。 最近研究顯示，過度NF-kB之活化，可促進胃癌細胞生存，並保護胃癌細胞免於凋零，於是對化學治療產生抗藥性。 可見抑制NF-kB和TNF-a，未來在預防胃癌之形成，和促進胃癌細胞對化療藥品之敏感性和有效性，有其重要性及迫切性。
最近的研究更顯示，若NF-kB被抑制，將減少腸細胞的炎症反應，並進而減少發生腸道腫瘤之可能。從這些研究報告，更加證明NF-kB之活化是扮演發炎反應和癌症發生之間最重要的橋樑。會何NF-kB之活化會產生上數等癌症，其可能致病機轉如下：(一)持續且嚴重的發炎反應會誘發生物激素之產生，而進一步促進NF-kB之活化，最後導致癌細胞之形成。(二) 癌症本身也會產生NF-kB與發炎反應有關之生物激素，如TNF-a、 BAFF等，最後形成一自動回饋機制，造成持續的NF-kB活化，最後導致癌細胞之不斷形成和生長。

　　若能藉發炎反應與黏膜相關淋巴組織淋巴癌之幽門螺旋桿菌非依賴性相關性的研究模式，去研究發炎反應與其他癌症之致病機轉，將可敲開發炎反應和癌細胞之間所存在之秘密，且必能釐清發炎反應與炎症反應相關之致癌機制，和發炎反應所參與之基因調控，訊息傳遞，和分子機轉。我們相信，若能釐清發炎反應與癌症之相關機制，不僅可以幫助我們，在面對病患時，選擇最好的治療方式，並可藉著調整這些基因表現，來加強治療效果，進而改善病患的預後。

關鍵字

黏膜相關淋巴組織淋巴癌 ； BCL10 ； NF-kB ； 幽門螺旋桿菌

並列摘要

Mucosa-assocaited-lymphoid tissue (MALT) lymphoma of stomach is the most common extranodal lymphomas of humans. Gastric MALT lymphoma, with its relatively high incidence of occurrence and its unique clinicopathologic features, has recently become an important target of cancer research. Gastric MALT lymphoma is classified into high-grade (HG) and low-grade (LG) subtypes by histological criteria. In the past decade, important consensus has been reached in the management of LG gastric MALT lymphoma. This includes eradication of H pylori as a first step of treatment, followed by radiotherapy, surgery, systemic chemotherapy, or immunotherapy for H pylori -independent cases.

However, the management of HG gastric MALT lymphoma is much less clear; controversies exist regarding the role of H pylori eradication and the efficacy of systemic chemotherapy. It was once a central dogma that transformation of LG MALT lymphoma into HG MALT lymphoma is associated with acquisition of H pylori-independence of MALT lymphoma cells. However, we and other investigators have provided evidence that a substantial portion of the early-stage HG gastric MALT lymphomas remain H pylori -dependent, and thus can be rendered long-term remission by H pylori eradication.

Although the tumor response to H pylori eradication is almost as good as its LG counterpart, HG gastric MALT lymphoma has carried a risk of rapid disease progression if the tumors are not responding to antibiotics. Therefore, identification of cellular or molecular markers that help predict the H pylori-independence state of HG gastric MALT lymphoma is mandatory. We hypothesized that the molecular mechanisms of H pylori-independence may be different between LG and HG gastric MALT lymphoma. For example, t(11;18) (q21;q21), one of the most important predictor of H pylori -independence in LG gastric MALT lymphoma, is rarely found in its HG counterpart. This study aims to identify molecular and cellular markers, as well as gene expression profiles, which may help predict H pylori-dependence state of HG gastric MALT lymphoma. Further clarification of the biologic significance and function of novel H pylori-independence-relevant genes will be performed.

In general, the prognosis of patients with HG gastric MALT lymphoma appears adversely correlated with the proportion of large cell component in their tumor tissues. However, how MALT origin will affect the response of the HG lymphoma to chemotherapy is largely unknown. We have reported that HG gastric lymphoma with evidence of MALT (DLBL-M) respond better to systemic chemotherapy than HG gastric lymphoma without any evidence of MALT (DLBL). This finding has strongly supports that DLBL-M and DLBL are distinct entities of lymphoma. However, whether these two types of gastric lymphomas may be of different cellular origins or different tumor biologic characteristics needs to be further clarified. In this study, we will continue our effort in identification novel biomarkers that help us actually predict the chemotherapy response and the prognosis of HG gastric lymphoma and thereby to improve the care of these patients. Further clarification of the difference of molecular mechanisms and biologic significance in the DLBL and DLBL-M of stomach will be done.

Part IA. Identification of molecular, and cellular markers that may help predicts H pylori-independence state of HG gastric MALT lymphoma.

LG gastric MALT lymphoma is characterized by its closely association with H pylori infection; and eradication of H pylori by antibiotics cures 50-70% of this tumor. Recently, we have clearly demonstrated that early-stage HG gastric MALT lymphoma is as H pylori-dependent as LG gastric MALT lymphoma. We had prospectively treated 24 patients with stage IE HG gastric MALT lymphoma. Eradication of H pylori was achieved in 22 patients and was accompanied by rapid and complete tumor regression in 14 patients. After median follow-up of more than 5 years in complete responders, all these 14 patients remained disease free. The response was not affected by the proportion of large cells in the tumor tissues, but was adversely affected by the depth of tumor invasion.

t(1;14)(p22;q32) is another genetic aberration implicated in the development of MALT lymphoma. t(1;14)(p22;q32) juxtaposes BCL10 of chromosome 1 to an immunoglobulin gene locus of chromosome 14, and results in strong expression of a truncated BCL10 protein in the nuclei and cytoplasm, in contrast to the weak cytoplasmic expression of BCL10 in normal germinal center B cells. It is noteworthy that t(1;14)(p22;q32) was detected in less than 5% of low-grade gastric MALT lymphomas, whereas moderate nuclear expression of BCL10 was found in 30% to 40% of these tumors. In contrast, BCL10 nuclear expression was found to be more closely associated with the genetic aberration t(11;18)(q21;q21) and advanced tumor stages, two of the conditions predictive of H pylori–independent status in LG gastric MALT lymphoma.

Later, BCL10 was found to express in the cytoplasm of B-lymphocytes to relay the signals from antigen receptors to NF-kB activation. As NF-kB is known to mediate cell survival and anti-apoptotic signals, it has been speculated that its upregulation of BCL10 may contribute to the malignant transformation of H pylori-independent growth of MALT lymphomas.
We hypothesized that upregulation of BCL10 may trigger a constitutive NF-kB activation signal, and therefore contribute to antigen-independent growth and the progression of the gastric MALT lymphoma. Under this condition, expression patterns of NF-kB and BCL10 may be useful markers for predicting H pylori independence of HG gastric MALT lymphoma.

In this study, we compared the expression patterns of BCL10 and NF-kB in 14 H pylori–dependent and eight H pylori–independent HG gastric MALT lymphomas. The expression of BCL10 and NF-kB in pretreatment paraffin- embedded lymphoma tissues was evaluated by immunohistochemistry and confocal immuno-fluorescence microscopy. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript. In this study, we have demonstrated that aberrant nuclear expression of BCL10 was detected in seven (87.5%) of eight H pylori–independent and in none of 14 H pylori–dependent HG gastric MALT lymphomas (P< .001). All seven patients with nuclear BCL10 expression had nuclear expression of NF-kB, compared with only two of 15 patients without nuclear BCL10 expression (P < .002). As a single variable, the frequency of nuclear expression of NF-kB was also significantly higher in H pylori–independent tumors than in H pylori–dependent tumors (seven of eight [87.5%] v two of 15 [12.3%]; P < .002). The API2-MALT1 fusion transcript was detected in only one (12.5%) of eight H pylori–independent lymphomas.

This study have demonstrated that nuclear expression of BCL10 or NF-kB is highly predictive of H pylori–independent status in HG gastric MALT lymphoma, and coexpression of these two markers in the nuclei is frequent. Although nuclear BCL10 expression is highly correlated with the presence of API2-MALT1 fusion in LG gastric MALT lymphoma, it has been shown that nuclear expression of BCL10 may also be detected in some LG gastric MALT lymphomas without t(11;18)(q21;q21). These findings suggest that the direct interaction between BCL10 and API2-MALT1 fusion protein may not occur in most MALT lymphomas.

Given that t(11;18)(q21;q21) is rarely found in HG gastric MALT lymphoma, the mechanisms and biologic significance of the aberrant nuclear expression of BCL10 in these tumors are intriguing. Furthermore, the nuclear expression of NF-kB was closely associated with the aberrant nuclear expression of BCL10. Interestingly, the nuclear expression of NF-kB was also closely associated with the H pylori–independent status of HG gastric MALT lymphomas. These findings provided evidence that nuclear translocation of BCL10 or NF-kB is the pivotal molecular determinant of H pylori-independence in gastric MALT lymphoma. However, the molecular mechanisms and the biologic significance of nuclear translocation of BCL10 and NF-kB in MALT lymphoma remain obscure. Additional investigation of the molecular interaction and biologic consequences of nuclear translocation of BCL10 and NF-kB in gastric MALT lymphoma is needed.

Part IB. In search other immunologic markers that may help predict H pylori-independence state of HG and LG gastric MALT lymphoma.

In the early phases of this process, the proliferation response of MALT lymphoma is partly dependent on functional interactions between B and T lymphocytes. It has been demonstrated by in-vitro experiments that the growth and differentiation MALT lymphoma cells require CD-40 mediated signaling and Th-2 type cytokines. The dependence on T cells for growth of the malignant B-cell clones may explain the tendency of early-stage LG MALT lymphomoma to remain localized and to regress after H pylori eradication. Expression of co-stimulatory molecules (CD40, CD80, CD86, and their ligands) and relevant cytokines has been demonstrated in gastric MALT lymphoma cells. The presence of co-stimulatory marker CD86 (B7.2) on lymphoma cells may promote T-cell-mediated neoplastic B cell proliferation. It is speculated that loss of co-stimulatory markers might preclude this interaction and thereby facilitate the transition into the antigen-independent status of HG gastric MALT lymphoma.

CD56 (+) natural killer (NK) cells are important components of the innate immune system, and have the ability to modulate both humoral- and cell-mediated immune responses. These CD56 (+) NK cells are speculated to have the ability to limit the autonomous growth of MALT lymphoma cells, and may contribute to the remission of HG MALT lymphomas after the eradication of H pylori. This study was conducted to examine the expression of CD86 and the infiltration of CD56 (+) NK cells in 16 H pylori-dependent and 10 H pylori-independent HG gastric MALT lymphomas.

We found that CD86 expression was detected in 11 (68.8%) of 16 H pylori-dependent cases but in none of 10 H pylori-independent cases (P = 0.001). H pylori-dependent HG gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8±1.4% vs 1.10.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+) NK cells compared to CD86-negative cases (2.9±1.1% vs 1.4±1.3%; P = 0.005). These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage HG gastric MALT lymphomas.

Part II. Identification of molecular, cellular markers and immunologic markers that may help predict H pylori-independence state of LG gastric MALT lymphoma without t(11;18)(q21;q21).

Although t(11;18)(q21;q21) is one of the most important predictors of H pylori- independence in LG gastric MALT lymphomas, only 50% to 70% of H pylori- independent LG gastric MALT lymphomas harbor this genetic aberration. In other words, 30-50% of H pylori-independent LG gastric MALT lymphomas have no reliable markers to predict their H pylori-independent status. Therefore, identification of other easily detected molecular markers that can provide high sensitivity in predicting H pylori -independent status of low-grade gastric MALT lymphomas without t(11;18)(q21;q21) is mandatory.

We have clearly clarified that nuclear translocation of BCL10 or NF-kB is the pivotal molecular determinant of H pylori-independence in HG gastric MALT lymphoma and that co-expression of these two markers in the nuclei is frequent. Since t(11;18)(q21;q21) rarely occurs in HG gastric MALT lymphomas, it is reasonable to speculate that nuclear translocation of BCL10 and NF-kB may also be useful for predicting H pylori-independent status of those LG gastric MALT lymphomas which lack t(11;18)(q21;q21). Therefore, this study was aim to examine whether these two markers can also predict H pylori-independent status of LG gastric MALT lymphomas without t(11;18)(q21;q21).

Sixty patients who underwent successful H pylori eradication for LG gastric MALT lymphomas were included. There were 37 patients with H pylori-dependent and 23 patients with H pylori-independent tumors. The median duration between H pylori eradication and complete histologic remission was 2.6 months (range, 0.9 to 17 months), and 34 of 37 (91.9%) patients did so within 12 months of H pylori eradication. At a median follow-up of 69.2 months (range, 12 to 124 months), 35 patients who had achieved complete histologic remission after eradication of H pylori were alive and free of lymphoma. Two patients experienced histologic relapse. Forty-seven (78.3%) patients were negative for t(11;18)(q21;q21); among them, 36 (76.6%) were H pylori-dependent and 11 (23.4%) were H pylori– independent . Nuclear expression of BCL10 was significantly higher in H pylori-independent than in H pylori-dependent tumors (8 of 11 [72.7%] vs 3 of 36 [8.3%]; P < .001). Nuclear expression of NF-kB was also significantly higher in H pylori-independent than in H pylori-dependent tumors (7 of 11 [63.6%] vs 3 of 36 [8.3%]; P < .001). Further, nuclear translocation of BCL10 and NF-kB was observed in 12 of the 13 cases with t(11;18)(q21;q21); and all these 12 cases were H pylori-independent.

This study indicate that nuclear expression of BCL10 or NF-kB is predictive of H pylori-independent status of LG gastric MALT lymphoma with or without t(11;18)(q21;q21). This finding implies that nuclear translocation of BCL10 and NF-kB may even be more specific than t(11;18)(q21;q21) in predicting H pylori-independence for gastric MALT lymphoma. Although this study did not examine other rare genetic aberrations that may relate to nuclear BCL10 expression, several recent studies revealed that t(1;14)(p22;q32) was detected in less than 5% of LG MALT lymphomas, suggesting that the latter genetic aberration is so rare that it may not be useful as a predictor. Since immunohistochemical staining for detection of BCL10 or NF-kB nuclear expression is not only specific and sensitive in predicting H pylori-independent status but also much more feasible for the daily practice of general pathology laboratories, it is an invaluable method to help select the best first-line treatment for patients with LG gastric MALT lymphoma.

We have clearly demonstrated that nuclear translocation of NF-kB is the pivotal molecular determinant of H pylori-independence in both HG and LG gastric MALT lymphoma. We also showed that the intranuclear BCL10/BCL3 complex appears to affect the transactivating activity of NF-kB. However, whether the NF-kB-down regulated genes (c-Myc, surviving, and BAFF) also contribute to the H pylori-independence of both HG and LG gastric MALT lymphoma, remain unclear. The c-Myc proto-oncogene has a central role in regulation of lymphoma cell growth and differentiation. Recent reports suggest that constitutive c-Myc expression stimulates angiogenesis and lymphangiogenesis, which may contribute to antigen-independent growth and progression of gastric MALT lymphoma. Survivin, which is a member of the inhibitor of apoptosis protein gene family, regulates both programmed cell death and mitosis. It has been shown that survivin expression and its subcellular localization both have prognostic value for patients with malignant disease. Another interesting gene is BAFF, a TNF superfamily members, has been found to be elevated in the survival of malignant B cells. Recent studies indicate that BAFF, producing by tumor cells and microenvironments, can result in unremitting NF-kB activation by forming a positive feed-back loop pathway.

Since NF-kB can induce c-Myc and survivin gene expression and BAFF expression, detection of nuclear expression of survivin, c-Myc, or BAFF can help us clarify the precise mechanisms of H pylori-independence in gastric MALT lymphoma. Our preliminary reports demonstrated that activation of NF-kB in lymphoma cells could result in upregulation of c-Myc, survivin, and TNF superfamily members BAFF. Further, nuclear translocation of survivin, expression of BAFF, and c-Myc expression were significantly associated with the H pylori-independent status of both HG and LG gastric MALT lymphomas.

Part III Further clarification of novel H pylori–independence-relevant genes of gastric MALT Lymphoma and their functions, molecular mechanisms and biologic significance

Recently, we have further clarified that nuclear translocation of BCL10 is the pivotal molecular determinant of H pylori-independence in both HG and LG gastric MALT lymphoma. This observation is revolutional in that it may lead to new directions of research in this field. However, the molecular mechanisms and the biologic significance of nuclear translocation of BCL10 in MALT lymphoma remain obscure, and is the focus of this study.

BCL10 contains a caspase recruitment (CARD) domain, and a C-terminal serine- and threonine-rich domain. Recent evidence indicates that upregulation of B-cell antigen receptor signaling triggers the activation of protein kinase C b and thereby results in phosphorylation of CARMA1 (also known as CARD11 or BIMP1), leading to BCL10 oligomerization. BCL10 then activates NF-kB by MALT1 and ubiquitin- conjugating enzyme-dependent IkB kinase ubiquitination. As NF-kB is activated, it translocates to the nucleus and results in the production of cytokines and growth factors that are important for cellular activation, proliferation and survival of B-cells. Further, there is a theoretical basis to speculate the involvement of NF-kB in mediating the translocation. This study was to test whether activation of NF-kB can result in the nuclear translocation of BCL10.

In this study, we observed that TNF-α upregulates the expression of BCL10 and induces a fraction of BCL10 nuclear translocation in MCF7 cells. Chromatin immunoprecipitation assays and electromobility shift assays identified that a NF-kB binding site resides in BCL10 5’-untranslated region. This study also demonstrates that Akt1, activated by TNF-α, phosphorylates BCL10 on Ser218 and Ser231, and the phosphorylated BCL10 subsequently complexes with BCL3 to enter the nucleus. Either inhibition of Akt1 or depletion of BCL3 blocks BCL10 nuclear translocation. These findings characterize a molecular linkage that directs BCL10 nuclear translocation in response to TNF-αtreatment.

Given that TNF-αitself induced not only increase of BCL10 but a fraction of BCL10 nuclear translocation. However, the mechanism by which the concentration of nuclear BCL10 is controlled remains unclear. Previous studies have demonstrated that the concentration of BCL3 may determine NF-kB transcriptional activity. Therefore, it is reasonable to speculate that an increasing amount of nuclear BCL10 and BCL3 might enhance NF-kB activity. Given that various cytokines, including TNF-α, are the downstream genes of NF-kB, and NF-KB is a mediator linking inflammation and tumor formation, the elevated NF-KB activity may be responsible for inflammation-associated tumor development and extracellular stimuli-independent tumor progression.

Taken together, these findings have provided evidence to elucidate a TNF-α-induced pathway by which BCL10 is upregulated and translocated into the nucleus. Whether our findings may be applied to other types of cells, such as inflammation-associated tumors, should be further investigated.

Part IV. Comparison of the clones of LG and HG MALT lymphoma on a background of their individual response to H pylori-eradication therapy of the co-existing HG and LG MALT lymphoma.

It is generally believed that HG MALT lymphoma is transformed from its LG counterpart; and that most patients have in their stomach the co-existence of these two conditions. However, recent studies comparing the patterns of clonal IgH rearrangement between HG- and LG-components of the same stomach have demonstrated the lack of a clonal relationship between these two components, suggesting that HG MALT lymphoma may evolve independently from co-existing LG lymphoma.

We have demonstrated that early-stage HG gastric MALT lymphomas, as well as their low-grade counterpart, may respond to antibiotics. We also clarified that nuclear translocation and co-localization of BCL10 and NF-KB are two molecular determinants of H pylori-independence of both HG and LG gastric MALT lymphomas. Further, the differential response of the co-existing HG and LG MALT lymphoma to H pylori–eradication therapy has frequently been observed in these patients. These findings have presented a strong argument that the HG transformation of gastric MALT lymphoma may not necessary lead to H pylori-independence. However, whether these two co-existing subtypes of MALT lymphoma in the same stomach may be of different cell origins, and thus have a different tumor response to H pylori-eradication, needs to be further clarified.

Among 26 patients with HG gastric MALT lymphoma, 18 containing laser capture microdissectable HG and LG MALT lymphoma cells co-existing in the same stomach were studied. The clonality of the LG and HG MALT lymphoma cells was examined by polymerase chain reaction (PCR)-based amplification of the CDR3 region of the IgH gene. Of 4 patients whose LG and HG components responded differentially to H pylori eradication therapy , three showed a different IgH gene rearrangement and a different pattern of BCL10 and NF-KB expression in the two components. In contrast, of the 14 patients whose co-existing HG and LG MALT lymphoma responded similarly to H pylori eradication (4 H pylori–independent, 10 H pylori–dependent), 12 showed single clonality and a similar pattern of BCL10 and NF-KB expression of the two components (P < .01).

Further, an API2-MALT1 fusion transcript was detected in the H pylori-independent LG part of only one patient with a differential response to H pylori eradication. These results imply that an H pylori–independent HG component may evolve independently from co-existing LG MALT lymphoma; and that the differential response of the co-existing HG and LG MALT lymphoma to H pylori eradication is primarily due to the different clonal origin of these two components of tumors.

Part V. Study of Treatment of H pylori-independent low-grade gastric MALT lymphoma: Is Inhibition of Inflammation-reaction TNF-αor NF-KB A Feasibility Strategy for Treatment of H pylori-independent low-grade gastric MALT lymphoma

Our data strongly suggest that activation of NF-KB pathway may be involved in the H pylori -independence transformation of MALT lymphoma. Recently, we demonstrated that oral thalidomide, an NF-KB and TNF-α inhibitor, induced rapid regression of a H pylori-independent, disseminated LG gastric MALT lymphoma, which showed nuclear expression of NF-KB. Therefore, we propose a proof-of-concept pilot study to evaluate the efficacy of oral thalidomide in H pylori-independent LG MALT lymphoma of the stomach with nuclear NF-KB expression.

Six patients with H pylori-independent LG gastric MALT lymphoma, and two patients with extra-nodal MALT lymphoma who had undergone chemotherapy or anti-CD2 were treated with doses of thalidomide (100-200 mg per day) until disease progression or prohibitive toxicity was observed. We have demonstrated that one patient with evidence of LG gastric MALT lymphoma and one patient with orbital LG MALT lymphoma achieved a complete response, and 4 patients (50%) achieved partial remission. This finding suggests that thalidomide has potential single-agent activity in patients with H pylori-independent MALT lymphoma or pretreated patients with MALT lymphoma.

Hopefully, identification of the molecules both upstream and downstream of BCL10, and elucidation of the interaction between BCL10 and NF-KB will be useful in designing novel therapeutics for gastric MALT lymphoma.

Gastrectomy is another choice for treatment of H pylori-independent LG gastric MALT lymphoma. However, the finding of widespread gastric MALT lymphoma cells within the gastric mucosa may result in the local relapse of the disease in cases with histologically tumor-positive resection margins following gastrectomy. Interestingly, we recent have reported that a disseminated H pylori-independent LG gastric MALT lymphomas have enjoyed long-term disease free after total gastrectomy and splenectomy. These findings further
reinforce the suggestion that the role of surgical resection in the treatment of LG gastric MALT lymphoma should be reassessed.

To investigate the role of gastrectomy in curing of LG gastectomy following the eradication of inflammation and immune reaction triggered by stomach environment. We retrospectively analyzed 8 LG gastric MALT lymphoma patients who had undergone the subtotal gastrectomy or total gastrectomy. The clonality of the laser capture microdissectable resection-margin, metastatic organs and primary lesions was evaluated by polymerase chain reaction (PCR)-based amplification of the CDR3 region of the IgH gene. We have demonstrated that three patients with positive resection-margin have enjoyed long-term disease free. Further, the clonality of resection margin was similar to the primary lesion of MALT lymphoma. These findings provided evidence that H pylori-related inflammation and immune reaction may play a role in the determination of H pylori-independent transformation of gastric MALT lymphoma

Part VI. Clarification of the molecular mechanisms and biologic significances in the different chemoresponse and prognosis between high-grade gastric MALT lymphoma and pure gastric diffuse large cell lymphoma without MALT

Diffuse large B-cell lymphoma (DLBCL) of stomach represents the most common extranodal non-Hodgkin’s lymphomas of humans. Gastric DLBCL is classified into diffuse large cell without MALT (DLBL) or with MALT lymphoma (DLBL-M) by histological criteria. Recently, our groups and other
investigators have demonstrated that systemic chemotherapy alone is a highly effective treatment for localized primary gastric DLBCL. Therefore, it is intriguing for us to further identify whether biomarkers may be used for predicting prognosis and chemoresponse of gastric DLBCL.

Recently, we have demonstrated that patients with DLBL-M patients have a significantly better response to chemotherapy and a better prognosis than patients with DLBL. Further, we have demonstrated that expression of cyclin D3 is associated with a poor response to systemic chemotherapy and a poor survival of the DLBL-M patients. In contrast to cyclin D3, the Bcl-2 expression was only independent prognostic factor for patients of DLBL. These findings imply that the some of biologic characteristics of MALT components, apoptosis-related genes, and the cell cycle protein are involved in the drug resistance and affect the clinical outcome gastric DLBCL (manuscript submitted).

Detailed molecular mechanisms and biologic significance needs to be further explored. Recent studies using a cDNA microarray demonstrate that nodal DLBCL can be divided into germinal center B cell-like (CGB) and non-GCB subgroups. This classification scheme has prognostic significance and can be replicated using immunohistochemical detection of CD10, BCL6, and MUM-1 to define germinal center (GC). Since MALT lymphoma arises from a post GC memory B-cell, the critical evaluation of CD10, BCL6, and MUM-1 to see whether this subclassification can be useful for predicting prognosis of gastric DLBCL is needed.

In this study, we will continue our effort in identification novel biomarkers that help us actually predict the chemotherapy response and the prognosis of gastric DLBCL and thereby to improve the care of these patients. We believe these predictive biomarkers can help select patients for specific treatments, and modulation of these genes expression may be a potential therapeutic strategy to improve clinical outcome in the future.

Future Perspectives

Based on the results we have in the past few years, we will focus on future research on the following four areas: (1) Further clarification of the molecular mechanisms and biologic significance of nuclear translocation of BCL10 and NF-KB. (2) Further exploration of the difference in the genetic expression of HG-transformation and H pylori-independence transformation of gastric MALT lymphoma. (3) Further clarification of the role of inflammation and immune reaction in H pylori-independence transformation of gastric MALT lymphoma. (4) Development of a perspective clinical study to test whether H pylori eradication can cure of early-stage gastric diffuse large cell lymphomas without MALT lymphoma. (5) Seek possible molecule targets to treat gastric diffuse large cell lymphomas without MALT lymphomas that are unresponsively to chemotherapy. (6) Basing on our research model of gastric MALT lymphoma, we will further explore the relationship and possible pathogenic mechanism of inflammation and gastric cancer and gastrointestinal lymphoma.

We believe this study will lead to better care of patients with gastric MALT lymphoma and diffuse large cell lymphoma, and the molecular mechanisms it unveils will further clarify the mechanism of tumor progression of malignancies related to H pylori and cure the cancer patient related to inflammation or other infections.

並列關鍵字

MALT ； BCL10 ； NF-kB:H. pylori

參考文獻

Chan JK, Ng CS, Isaacson PG. Relationship between high-grade lymphoma and low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALToma) of the stomach. Am J Pathol 1990;136:153–64

Adams JM, Cory S: The Bcl-2 protein family: arbiters of cell survival. Science 1998;281:1322-6

Akira S, Taga, T, Kishimoto T. Interleukin-6 in biology and medicine. Advances in Immunology 1993;54:1–78.

Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503-11

Alpen B, Kuse R, Parwaresch R, et al. Ongoing monoclonal B-cell proliferation is not common in gastric B-cell lymphoma after combined radiochemotherapy. J Clin Oncol 2004;22:3039-45