c-Met Is a Marker of Pancreatic Cancer Stem Cells and Therapeutic Target
c-Met Is a Marker of Pancreatic Cancer Stem Cells and Therapeutic Target
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DOI：
10.1053/j.gastro.2011.08.009
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发表时间：
2011-12-01
期刊：
影响因子：
29.4
通讯作者：
Simeone, Diane M.
中科院分区：
文献类型：
--
作者：
Li, Chenwei;Wu, Jing-Jiang;Simeone, Diane M.
背景与目的：许多不同类型肿瘤的生长需要一群自我更新的癌症干细胞（CSC）。c-Met是正常小鼠胰腺干细胞和祖细胞的标志物;我们研究了它是否也是可能作为治疗靶点开发的人类胰腺CSC的标志物。方法：我们研究了原发性人胰腺癌在NOD SCID小鼠中的生长。使用体外球体试验评估表达高水平c-Met（c-Met（高））的胰腺癌细胞的自我更新能力，并与c-Met阴性或表达低水平c-Met的胰腺癌细胞进行比较。在NOD SCID小鼠中评价c-Met（高）胰腺癌细胞的致瘤性。结果：c-Met（高）细胞容易形成球体，而c-Met阴性细胞不能。使用c-Met抑制剂XL 184或用小发夹RNA敲低c-Met显著抑制肿瘤球形成。c-Met（高）细胞在小鼠中的致瘤潜力增加;表达c-Met和CD 44的细胞（占胰腺癌细胞的0.5%-5%）具有自我更新能力，并且在所有研究的细胞群中具有最高的致瘤潜力。在NOD SCID小鼠中建立的胰腺肿瘤中，当单独给药或与吉西他滨联合给药时，c-Met抑制剂减缓了肿瘤生长并减少了CSC的数量。在心脏注射癌细胞后给予XL 184 2周可预防转移的发生。结论：c-Met是胰腺癌干细胞的一种新的标志物。它是小鼠胰腺肿瘤生长和转移所必需的，是胰腺癌的治疗靶点。
BACKGROUND & AIMS: Growth of many different tumor types requires a population of self-renewing cancer stem cells (CSCs). c-Met is a marker of normal mouse pancreatic stem and progenitor cells; we investigated whether it is also a marker of human pancreatic CSCs that might be developed as a therapeutic target. METHODS: We studied growth of primary human pancreatic adenocarcinoma in NOD SCID mice. The self-renewal capability of pancreatic cancer cells that expressed high levels of c-Met (c-Met(high)) was assessed using in vitro sphere assays and compared with those that were c-Met negative or expressed low levels of c-Met. The tumorigenicity of c-Met(high) pancreatic cancer cells was evaluated in NOD SCID mice. RESULTS: c-Met(high) cells readily formed spheres, whereas c-Met-negative cells did not. Use of the c-Met inhibitor XL184 or c-Met knockdown with small hairpin RNAs significantly inhibited tumor sphere formation. c-Met(high) cells had increased tumorigenic potential in mice; those that expressed c-Met and CD44 (0.5%-5% of the pancreatic cancer cells) had the capability for self-renewal and the highest tumorigenic potential of all cell populations studied. In pancreatic tumors established in NOD SCID mice, c-Met inhibitors slowed tumor growth and reduced the population of CSCs when given alone or in combination with gemcitabine. Administration of XL184 for 2 weeks after cardiac injection of cancer cells prevented the development of metastases. CONCLUSIONS: c-Met is a new marker for pancreatic CSCs. It is required for growth and metastasis of pancreatic tumors in mice and is a therapeutic target for pancreatic cancer.