Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer
Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer
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DOI：
10.1158/1535-7163.mct-07-0483
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发表时间：
2008-02-01
影响因子：
5.7
通讯作者：
Yao, Qizhi
中科院分区：
文献类型：
--
作者：
Li, Min;Bharadwaj, Uddalak;Yao, Qizhi
鉴于胰腺癌的高死亡率，迫切需要对这种毁灭性疾病进行有效治疗。我们已经表明，间皮素的表达在人胰腺癌细胞中高于在人胰腺导管上皮细胞中，并且与周围正常组织相比，间皮素mRNA在21例临床胰腺癌标本中的18例（86%）中显著过表达。然而，间皮素在肿瘤进展中的生物学功能尚不清楚。在此，我们研究了间皮素过表达在体外胰腺癌细胞增殖和迁移以及体内胰腺癌进展中的作用。我们发现，与载体对照细胞系相比，在裸鼠异种移植模型中，间皮素的强制表达分别显著增加了90%和300%的肿瘤细胞增殖和迁移，并使肿瘤体积增加了4倍。沉默间皮素抑制胰腺癌细胞的细胞增殖和迁移，并在体内消除肿瘤进展。用含有人间皮素的嵌合病毒样颗粒进行疫苗接种基本上抑制了C57 BL/6 J小鼠中的肿瘤进展。间皮素特异性抗体和CTL活性的增加以及调节性T细胞的减少与肿瘤进展减少和生存期延长相关。这项研究揭示了间皮素的新功能，并提出了一种新的治疗性疫苗策略，即靶向间皮素以控制胰腺癌进展。
Given the high fatality rate of pancreatic cancer, an effective treatment for this devastating disease is urgently needed. We have shown that mesothelin expression was higher in human pancreatic cancer cells than in human pancreatic duct epithelial cells, and mesothelin mRNA was substantially overexpressed in 18 of 21 (86%) clinical pancreatic adenocarcinoma specimens when compared with the surrounding normal tissues. However, the biological functions of mesothelin in tumor progression are not clearly understood. Here we studied the effects of mesothelin overexpression in pancreatic cancer cell proliferation and migration in vitro and pancreatic cancer progression in vivo. We found that forced expression of mesothelin significantly increased tumor cell proliferation and migration by 90% and 300%, respectively, and increased tumor volume by 4-fold in the nude mice xenograft model when compared with the vector control cell line. Silencing of mesothelin inhibited cell proliferation and migration in pancreatic cancer cells and ablated tumor progression in vivo. Vaccination with chimeric virus-like particles that contain human mesothelin substantially inhibited tumor progression in C57BL/6J mice. The increases in mesothelin-specific antibodies and CTL activity and the decrease in regulatory T cells correlated with reduced tumor progression and prolonged survival. This study revealed novel functions of mesothelin and suggested a new therapeutic vaccine strategy whereby mesothelin is targeted to control pancreatic cancer progression.