Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis
Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis
复制标题
DOI：
10.1111/j.1432-0436.2007.00235.x
复制
发表时间：
2007-11-01
期刊：
影响因子：
2.9
通讯作者：
Fausto, Nelson
中科院分区：
文献类型：
--
作者：
Campbell, Jean S.;Johnson, Melissa M.;Fausto, Nelson
肝细胞癌（HCC）的非侵入性治疗将极大地造福于公众健康。为此，我们开发了一种血小板衍生生长因子- c （PDGF-C）转基因（Tg）小鼠模型，该模型模拟了人类肝癌发生的许多方面。具体而言，PDGF-C的过度表达导致肝纤维化，在此之前，肝星状细胞被激活和增殖，随后发生发育不良病变和血管生成，并在8月龄时进展为hcc。在这里，我们发现PDGF-C过表达诱导存在于肿瘤和邻近非肿瘤实质中的内皮样细胞的增殖。蛋白酪氨酸激酶抑制剂伊马替尼（Gleevec）在体外和体内均可降低非实质细胞（NPC）的增殖，同时抑制Akt。伊马替尼体内治疗也阻断了PDGF-C Tg小鼠中CD34的表达。鼻咽癌增殖和CD34表达的减少与活性ERK1/2和PDGF受体α (PDGFR α)总水平的降低相关。综上所述，小分子抑制剂伊马替尼可减弱pdgf - c诱导的HCC中基质细胞的增殖，同时抑制CD34和PDGFR α的表达，激活Akt。我们的研究结果表明，伊马替尼可能是有效的治疗肝癌发生，特别是当新血管的存在。
Non-invasive therapies for the treatment of hepatocellular carcinoma (HCC) would be of great benefit to public health. To this end, we have developed a platelet-derived growth factor-C (PDGF-C) transgenic (Tg) mouse model, which mimics many aspects of human liver carcinogenesis. Specifically, overexpression of PDGF-C results in liver fibrosis, which is preceded by activation and proliferation of hepatic stellate cells, and is followed by the development of dysplastic lesions and angiogenesis, and progression to HCCs by 8 months of age. Here, we show that PDGF-C overexpression induces the proliferation of endothelial-like cells that are present in tumors and adjacent non-neoplastic parenchyma. The protein tyrosine kinase inhibitor, imatinib (Gleevec), decreases the proliferation of non-parenchymal cells (NPC) in vitro and in vivo, with concomitant inhibition of Akt. In vivo treatment with imatinib also blocks the expression of CD34 in PDGF-C Tg mice. Decreased NPC proliferation and CD34 expression correlated with lower levels of active ERK1/2 and total levels of PDGF receptor alpha (PDGFR alpha). In summary, the small molecule inhibitor imatinib attenuates stromal cell proliferation in PDGF-C-induced HCC, which coincides with decreased expression of both CD34 and PDGFR alpha, and activated Akt. Our findings suggest that imatinib may be efficacious in the treatment of hepatocarcinogenesis, particularly when neovascularization is present.