Podoplanin-Positive Fibroblasts Enhance Lung Adenocarcinoma Tumor Formation: Podoplanin in Fibroblast Functions for Tumor Progression
Podoplanin-Positive Fibroblasts Enhance Lung Adenocarcinoma Tumor Formation: Podoplanin in Fibroblast Functions for Tumor Progression
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DOI：
10.1158/0008-5472.can-10-3228
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发表时间：
2011-07-15
期刊：
影响因子：
11.2
通讯作者：
Ochiai, Atsushi
中科院分区：
文献类型：
--
作者：
Hoshino, Ayuko;Ishii, Genichiro;Ochiai, Atsushi
在转移过程中，癌细胞与血管外膜成纤维细胞（VAF）相互作用，VAF是血管最外层结缔组织层的主要成分。这种活性表明在血管周围区域存在特定的肿瘤微环境。南卡罗来纳共注射人肺腺癌细胞系（A549、PC-14和CRL-5807）和人VAF（hVAF）导致高的肿瘤形成率，与共注射这些细胞系和人肺组织来源的成纤维细胞（hLF）相比。cDNA微阵列分析显示，podoplanin在hVAFs中的表达水平高于hLFs（4.7倍）。流式细胞术分析还显示hVAF中podoplanin的表达水平（43% +/-17.5%）高于hLF（16% +/-10.3%）。与分选的podoplanin阴性hVAF相比，分选的podoplanin阳性hVAF显示增强的肿瘤形成、淋巴结转移和A549的肺转移。hVAFs中podoplanin的敲低降低了肿瘤形成和体外集落形成的增强效应。与对照hVAFs相比，hVAFs中podoplanin的过表达加速了A549的肿瘤形成。此外，对小型人肺腺癌（n = 112）的分析显示，癌症相关成纤维细胞阳性的podoplan患者的淋巴结转移率显著较高，复发风险较高。这些结果表明由podoplanin介导的hVAFs对癌症进展的促进作用，并表明血管周围环境可能构成肿瘤进展的特定生态位。Cancer Res; 71（14）; 4769-79. (C)2011年AACR。
During the metastatic process, cancer cells interact with vascular adventitial fibroblasts (VAF), which are the main components of the outermost connective tissue layer of blood vessels. This activity suggests the presence of a specific tumor microenvironment in the perivascular area. The s.c. coinjection of human lung adenocarcinoma cell lines (A549, PC-14, and CRL-5807) and human VAF (hVAF) resulted in a high rate of tumor formation, compared with the coinjection of these cell lines and human lung tissue-derived fibroblasts (hLF). A cDNA microarray analysis revealed a higher expression level of podoplanin in hVAFs than in hLFs (4.7-fold). Flow cytometry analysis also showed a higher expression level of podoplanin in hVAFs (43% +/- 17.5%) than in hLFs (16% +/- 10.3%). Sorted podoplanin-positive hVAFs displayed enhanced tumor formation, lymph node metastasis, and lung metastasis of A549 compared to sorted podoplanin-negative hVAFs. Knockdown of podoplanin in hVAFs decreased the augmenting effect of tumor formation and in vitro colony formation. The overexpression of podoplanin in hVAFs hastened the tumor formation of A549, compared with control hVAFs. Furthermore, the analysis of small-sized human lung adenocarcinoma (n = 112) revealed that patients with podoplan in positive cancer-associated fibroblasts had a significantly higher rate of lymph node metastasis and a high risk of recurrence. These results indicate a promotive effect of hVAFs mediated by podoplanin on cancer progression and suggest that the perivascular environment may constitute a specific niche for tumor progression. Cancer Res; 71(14); 4769-79. (C) 2011 AACR.