Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts.
Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts.
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DOI：
10.1186/1476-4598-9-168
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发表时间：
2010-06-27
期刊：
影响因子：
37.3
通讯作者：
Aulitzky WE
中科院分区：
文献类型：
--
作者：
Haubeiss S;Schmid JO;Mürdter TE;Sonnenberg M;Friedel G;van der Kuip H;Aulitzky WE
癌症相关成纤维细胞（CAFs）在癌症的生长、侵袭和转移中起着关键作用。因此，用小分子抑制剂靶向cas可能是一种有吸引力的抗肿瘤策略。本研究旨在鉴定影响CAF生长的小分子激酶抑制剂，并表征活性化合物对肺癌原发性CAF的生物学效应。我们筛选了两种单独的CAF菌株对160种激酶抑制剂的敏感性。鉴定出五种激酶抑制剂抑制两种细胞系50%以上的生长。其中三种是纳米摩尔浓度的PDGFR抑制剂。因此，我们进一步测试了FDA批准的PDGFR抑制剂达沙替尼、尼洛替尼、索拉非尼和伊马替尼。37株CAF菌株均对临床相关浓度的达沙替尼高度敏感。伊马替尼的效果稍差，而尼罗替尼和索拉非尼的抑制作用则明显不那么明显。我们通过微阵列分析9株CAF菌株，研究了达沙替尼对CAF转录组的影响。492个基因的表达发生了至少两倍的变化。其中104个编码细胞周期相关蛋白，其中97个被达沙替尼下调。然而，大多数受调控的基因具有多种生物功能，与增殖没有直接关系。我们将这种达沙替尼表达特征与先前描述的正常组织相关成纤维细胞（NAFs）和CAFs的差异特征以及成纤维细胞血清反应的特征进行了比较。达沙替尼调控的基因与血清抑制基因之间存在明显的重叠。更重要的是，与cas相比，达沙替尼下调的313个基因中，有64个在NAFs中也减少了。此外，在179个被达沙替尼上调的基因中，26个在NAFs中也被发现比在CAFs中升高。这些数据表明，达沙替尼部分逆转caf的表型为正常的成纤维细胞样表型。这一发现进一步支持了这一点，即用预先与达沙替尼孵育的CAF的条件培养基孵育肿瘤细胞可显著降低肿瘤细胞的增殖，这表明达沙替尼部分逆转了CAF介导的促瘤作用。因此，用达沙替尼靶向CAFs是一种很有前景的治疗原则。
Cancer associated fibroblasts (CAFs) play a critical role for growth, invasion, and metastasis of cancer. Therefore, targeting CAFs with small molecule inhibitors may be an attractive anti-tumor strategy. The current study aims to identify small molecule kinase inhibitors affecting CAF's growth and to characterize the biological effects of active compounds on primary CAFs from lung cancer. We screened two individual CAF strains for their sensitivity to a panel of 160 kinase inhibitors. Five kinase inhibitors were identified inhibiting more than 50% of the growth of both cell lines. Three of them were inhibitors of PDGFR at nanomolar concentrations. Therefore, we further tested the FDA approved PDGFR inhibitors Dasatinib, Nilotinib, Sorafenib, and Imatinib. All 37 CAF strains investigated were highly sensitive to Dasatinib at clinically relevant concentrations. Imatinib was slightly less effective, whereas the inhibitory effects of Nilotinib and Sorafenib were significantly less pronounced. We investigated the effect of Dasatinib on the CAF transcriptome by microarray analysis of 9 individual CAF strains. 492 genes were identified whose expression was changed at least twofold. 104 of these encoded cell cycle related proteins with 97 of them being downregulated by Dasatinib. The majority of regulated genes, however, were of diverse biological functions not directly related to proliferation. We compared this Dasatinib expression signature to previously described differential signatures of normal tissue associated fibroblasts (NAFs) and CAFs and to a signature of fibroblast serum response. There was a significant overlap between genes regulated by Dasatinib and serum repression genes. More importantly, of the 313 genes downregulated by Dasatinib 64 were also reduced in NAFs compared to CAFs. Furthermore, 26 of 179 genes identified as upregulated by Dasatinib were also found to be elevated in NAFs compared to CAFs. These data demonstrate that Dasatinib partially reverses the phenotype of CAFs to a normal fibroblast like phenotype. This is further supported by the finding that incubation of tumor cells with conditioned medium from CAFs pre-incubated with Dasatinib significantly reduced tumor cell proliferation, suggesting that Dasatinib partially reverses the CAF mediated tumor promoting effect. Therefore, targeting CAFs with Dasatinib represents a promising therapeutic principle.
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