CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors.
CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors.
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DOI：
10.1038/srep46662
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发表时间：
2017-04-21
影响因子：
4.6
通讯作者：
Ishii G
中科院分区：
文献类型：
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作者：
Ishibashi M;Neri S;Hashimoto H;Miyashita T;Yoshida T;Nakamura Y;Udagawa H;Kirita K;Matsumoto S;Umemura S;Yoh K;Niho S;Tsuboi M;Masutomi K;Goto K;Ochiai A;Ishii G
肿瘤相关成纤维细胞（CAFs）在肿瘤化疗过程中起重要作用，尤其是通过影响肿瘤细胞对分子靶向治疗的耐药性。在这里，我们报告了一个特殊的患者特异性CAFs亚群的存在，增加EGFR基因突变阳性肺癌的EGFR酪氨酸激酶抑制剂（EGFR-TKI），吉非替尼的敏感性。当与EGFR突变阳性的肺癌细胞共培养时，这些CAF增加了吉非替尼对癌细胞的杀伤作用，而在没有吉非替尼的情况下，它们不影响癌细胞的活力。使用不同的单细胞衍生克隆的测定证明了上述致敏能力是克隆特异性的。微阵列分析显示，CD 200在该CAFs中以高得多的水平表达。敲低CD 200表达剥夺了CAFs的致敏潜力，表明CD 200是负责该效应的功能分子。对接受术后吉非替尼治疗的患者样本的免疫组化分析显示，切除的肺腺癌含有CD 200阳性CAF的个体在术后复发时倾向于具有更长的吉非替尼无进展生存期。这些结果表明，CD 200阳性CAFs可以增加对EGFR-TKI的敏感性，并可能在EGFR-TKI的治疗用途中具有深远的应用。
Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability. The assay using different single cell-derived clones demonstrated that the aforementioned sensitizing ability is clone-specific. Microarray analysis revealed that CD200 was expressed at much higher levels in this CAFs. Knocking down of CD200 expression deprived CAFs of their sensitizing potential, suggesting that CD200 is the functional molecule responsible for the effect. Immunohistochemical analysis of samples from patients receiving postoperative gefitinib treatment revealed that the individuals whose resected lung adenocarcinomas contained CD200-positive CAFs tended to have longer progression free survival of gefitinib when they recurred after surgery. These results suggest that CD200-positive CAFs can augment the sensitivity to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.