Targeting PDGFR-β in Cholangiocarcinoma
Targeting PDGFR-β in Cholangiocarcinoma
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DOI：
10.1111/j.1478-3231.2011.02687.x
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发表时间：
2012-03-01
影响因子：
6.7
通讯作者：
Gores, Gregory J.
中科院分区：
文献类型：
--
作者：
Fingas, Christian D.;Mertens, Joachim C.;Gores, Gregory J.
背景：胆管癌（CCA）是一种高度促结缔组织增生的肿瘤，肿瘤微环境富含肌成纤维细胞（MFB）。MFB衍生的PDGF-BB存活信号传导是CCA细胞对凋亡刺激的抗性的介质。这提出了靶向PDGF-BB的同源受体PDGFR-b代表治疗人CCA的潜在策略的概念。目的：在此，我们研究了在体外和体内抑制PDGFR-β在恢复CCA细胞对凋亡刺激的敏感性中的作用。研究方法：我们采用来自41名患者的人CCA样品（19个肝内和22个肝外CCA样品）、人CCA细胞系KMCH-1和HUCCT-1以及shPDGFR-β-KMCH-1和人肌纤维母细胞LX-2细胞用于这些研究。使用同系大鼠原位CCA模型进行体内实验。结果如下：在几种MFB衍生的生长因子中，PDGF-BB和CTGF表达最丰富;然而，只有PDGF-BB减弱肿瘤坏死因子相关凋亡诱导配体（TRAIL）的细胞毒性。与单一培养条件相比，与PDGF-BB分泌型MFB共培养的CCA细胞显著降低了TRAIL诱导的CCA细胞凋亡;在酪氨酸激酶抑制剂甲磺酸伊马替尼或linifanib（抑制PDGFR-b）存在下，这种细胞保护作用被废除。与这些发现一致，当PDGFR-β被敲低时，MFB赋予的细胞保护作用也被消除，如在shPDGFR-β-KMCH-1细胞中所证明的。最后，在模拟人类疾病的啮齿动物体内CCA模型中，甲磺酸伊马替尼的施用增加了CCA细胞凋亡并减少了肿瘤生长。结论：靶向PDGFR-β使CCA细胞对凋亡刺激物敏感，并且似乎在体内具有治疗作用。
Background: Cholangiocarcinomas (CCAs) are highly desmoplastic neoplasms with a tumour microenvironment plentiful in myofibroblasts (MFBs). MFB-derived PDGF-BB survival signalling is a mediator of CCA cell resistance to apoptotic stimuli. This raises the concept that targeting PDGFR-b, a cognate receptor of PDGF-BB, represents a potential strategy for the treatment of human CCA. Aims: Herein, we examine a role for inhibiting PDGFR-beta in restoring CCA cell sensitivity to apoptotic stimuli in vitro and in vivo. Methods: We employed human CCA samples from 41 patients (19 intrahepatic and 22 extrahepatic CCA samples), the human CCA cell lines KMCH-1 and HUCCT-1 as well as shPDGFR-beta-KMCH-1 and human myofibroblastic LX-2 cells for these studies. In vivo-experiments were conducted using a syngeneic rat orthotopic CCA model. Results: Of several MFB-derived growth factors profiled, PDGF-BB and CTGF were most abundantly expressed; however, only PDGF-BB attenuated tumour necrosis factor- related apoptosis-inducing ligand (TRAIL) cytotoxicity. Co-culturing CCA cells with PDGF-BB-secreting MFBs significantly decreased TRAILinduced CCA cell apoptosis when compared with monoculture conditions; this cytoprotective effect was abrogated in the presence of the tyrosine kinase inhibitors imatinib mesylate or linifanib, which inhibit PDGFR-b. Consistent with these findings, MFB-imparted cytoprotection also was abolished when PDGFR-beta was knocked down as demonstrated in shPDGFR-beta-KMCH-1 cells. Finally, administration of imatinib mesylate increased CCA cell apoptosis and reduced tumour growth in a rodent in vivo-CCA model that mimics the human disease. Conclusions: Targeting PDGFR-beta sensitizes CCA cells to apoptotic stimuli and appears to be therapeutic in vivo.