骨形态生成蛋白4（BMP4）诱导结肠癌肿瘤干细胞分化并提高其化疗药物敏感性

tjutiger

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& Q( D1 b# k( \" a) N, n9 T, Z1.        说明：原文来自https://gastrojournal.org/article/S0016-5085(10)01464-2/abstract 由干细胞之家新闻小组成员tjutiger翻译（转帖请注明）
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题目：骨形态生成蛋白4（BMP4）诱导结肠癌肿瘤干细胞分化并提高其化疗药物敏感性/ T) F6 N( y, f% U1 w/ B" t" |$ u
背景与目的：
3 L  Z' o# E4 X) U' D许多结肠癌患者在临床上出现对药物耐受，这可能与耐药的结肠癌肿瘤干细胞（CRC-SCs）的存在相关。骨形态生成蛋白4（BMP4）能促进正常结肠组织的干细胞分化。我们研究了BMP4能否诱导结肠癌肿瘤干细胞的分化。
+ T1 r4 [1 m0 E1 }# M- w; _方法：根据CD133的表达不同或应用选择培养基分离25个结肠癌肿瘤样本中的肿瘤干细胞。体外检测这些肿瘤干细胞的BMP的表达水平和活性。通过免疫荧光，免疫印记，和流式方法分析肿瘤干细胞增殖的后代。BMP4的治疗效果则通过向免疫缺陷的小鼠注射肿瘤干细胞，分析化疗药组（n=4）与对照组（n=2）的区别。. G4 Z* @. o7 i' l% r
结果：  E$ }: q9 g- M9 ?) j# V
肿瘤干细胞不表达BMP4，而分化的细胞则表达。15次独立重复实验有12次能出现 重组BMP4促进肿瘤干细胞的分化和凋亡。而且这种作用并不依赖于Smad4表达水平或者微卫星序列的稳定性。BMP4激活经典和非经典的BMP信号通路，包括PI3K和PKB/AKT通路。在Smad4缺陷（Smad4-defective）的肿瘤中，PI3K突变或PTEN缺失能使肿瘤干细胞对BMP4无应答。向肿瘤干细胞荷瘤小鼠中给予BMP4能增加5-氟尿嘧啶和奥沙利铂的抗肿瘤作用。" q' _* ?4 d* I  J# r# ^3 j
结论：, e7 Y* K7 w8 c+ l3 I& H
在未发生Smad4突变和PI3K通路被激活的肿瘤组织中，BMP4能促进肿瘤干细胞的终末分化、凋亡和药物敏感性。BMP4或许能被开发为针对晚期结肠癌肿瘤干细胞的治疗药物。
0 {3 y: F2 }+ X8 L5 h6 t3．原文：Bone Morphogenetic Protein 4 Induces Differentiation of Colorectal Cancer Stem Cells and Increases Their Response to Chemotherapy in Mice
/ C( g9 \. C7 p$ JBackground & Aims
+ H6 C. Y- u- G$ Q3 U! s9 SThe limited clinical response observed in many patients with colorectal cancer may be related to the presence of chemoresistant colorectal cancer stem cells (CRC-SCs). Bone morphogenetic protein 4 (BMP4) promotes the differentiation of normal colonic stem cells. We investigated whether BMP4 might be used to induce differentiation of CRC-SCs and for therapeutic purposes.
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CRC-SCs were isolated from 25 tumor samples based on expression of CD133 or using a selection culture medium. BMP4 expression and activity on CRC-SCs were evaluated in vitro; progeny of the stem cells were evaluated by immunofluorescence, immunoblot, and flow cytometry analyses. The potential therapeutic effect of BMP4 was assessed in immunocompromised mice after injection of CRC-SCs that responded to chemotherapy (n = 4) or that did not (n = 2).; J% h8 V% I( S. S. ^% @
Results
7 T5 _$ S0 l3 v' TCRC-SCs did not express BMP4 whereas differentiated cells did. Recombinant BMP4 promoted differentiation and apoptosis of CRC-SCs in 12 of 15 independent experiments; this effect did not depend on Small Mothers against decapentaplegic (Smad)4 expression level or microsatellite stability. BMP4 activated the canonical and noncanonical BMP signaling pathways, including phosphoInositide 3-kinase (PI3K) and PKB (protein kinase B)/AKT. Mutations in PI3K or loss of Phosphatase and Tensin homolog (PTEN) in Smad4-defective tumors made CRC-SCs unresponsive to BMP4. Administration of BMP4 to immunocompromised mice with tumors that arose from CRC-SCs increased the antitumor effects of 5-fluorouracil and oxaliplatin.
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BMP4 promotes terminal differentiation, apoptosis, and chemosensitization of CRC-SCs in tumors that do not have simultaneous mutations in Smad4 and constitutive activation of PI3K. BMP4 might be developed as a therapeutic agent against cancer stem cells in advanced colorectal tumors.- D* A9 r0 X, A
4.如果是文献可以上传原文附件或者下载连接https://gastrojournal.org/article/S0016-5085(10)01464-2/abstract 8 ~) O+ d7 |7 m7 y; M% e
4.备注：个人翻译，理解不准确的语句还望大家积极指出。! ]0 V& P6 Q5 N* N. o1 I1 h

tjutiger

原文因为权限无法下载，坛子里哪个高手能提供一下，谢谢！O(∩_∩)O~

yangzhong305

很好

小鲁鲁

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发错地方了，麻烦版主移动一下帖子，谢谢。