A rare fraction of drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumourigenic potential.
A rare fraction of drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumourigenic potential.
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DOI：
10.1111/j.1365-2141.2012.09123.x
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发表时间：
2012-07
影响因子：
6.5
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Lee CG;Das B;Lin TL;Grimes C;Zhang X;Lavezzi T;Huang L;Cole J;Yau L;Li L
滤泡性淋巴瘤（FL）占非霍奇金淋巴瘤病例的近25%，其临床特征是最初对化疗敏感，随后复发。FL间质中含有一种特殊类型的基质细胞-滤泡树突状细胞（FDC），这种细胞存在于淋巴结的生发中心。我们首先从FL细胞系FLK-1中分离出致瘤细胞，并发现表达ABCG 2的SP细胞通过化疗和放疗富集。在体外，SP细胞通过趋化因子（C-X-C基序）配体12/趋化因子（C-X-C基序）受体4（CXCL 12/CXCR 4）信号传导被FDC吸引并粘附。在体内，有限稀释试验表明，SP细胞高度富集在癌症干细胞（CSC），但需要FDC的非肥胖糖尿病/严重联合免疫缺陷小鼠的肿瘤形成。使用AMD 3100（一种特异性CXCL 12/CXCR 4抑制剂）治疗可消除肿瘤生长。然后用从FL患者的腹水中分离的FL细胞（弗拉-1）验证这些发现。最后，我们检测了FL临床标本中表达ABCG 2的淋巴瘤细胞。因此，我们发现具有CSC样活性的高度致瘤性FL细胞（FL-SC）以CXCL 12/CXCR 4依赖性方式与FDC相互作用以抵抗化疗。我们的研究结果表明FL-SC和小生境细胞信号在维持致瘤性中的重要性。这些信号代表CSC根除的新靶点。
Follicular lymphoma (FL) comprises nearly 25% of non-Hodgkin lymphoma cases and is clinically characterized by initial sensitivity to chemotherapy followed by relapse. FL stroma contains a special type of stromal cell found in germinal centre of lymph nodes—the follicular dendritic cell (FDC). We first isolated tumourigenic cells from the FL cell line FLK-1 by side population (SP) technique, and found that SP cells, which express ABCG2, were enriched by chemotherapy and radiation treatments. In vitro, SP cells were attracted by and adhered to FDCs through chemokine (C-X-C motif) ligand 12/chemokine (C-X-C motif) receptor 4 (CXCL12/CXCR4) signalling. In vivo, limiting dilution assays showed SP cells were highly enriched in cancer stem cell (CSC), but required FDC for tumour formation in non-obese diabetic/severe combined immunodeficiency mice. Treatment with AMD3100, a specific CXCL12/CXCR4 inhibitor, eliminated tumour growth. These findings were then verified with FL cells isolated from an FL patient’s ascitic fluid (FLA-1). Finally, we detected the ABCG2 expressing lymphoma cells in FL clinical specimens. Thus, we found that the highly tumourigenic FL cells having CSC-like activities (FL-SC) interact with FDCs in a CXCL12/CXCR4 dependent manner to resist chemotherapy. Our results indicate the importance of FL-SC and niche cell signalling in maintaining tumourigenicity. These signals represent novel targets for CSC eradication.
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影响因子：
20.3
作者：
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