Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.
Ann Surg. 2017 Nov;266(5):765-771. doi: 10.1097/SLA.0000000000002430.
To investigate the relevance of lymphangiogenic gene expression in primary and liver metastasis of colorectal cancer (CRC) and identify determinants of lymphatic invasion.
Lymphatic development promoting vascular endothelial growth factor C (VEGFC) is associated with poor outcome in primary CRC. For colorectal liver metastasis (CRLM), intrahepatic lymph invasion and lymph node metastasis are poor prognostic factors. Exact biological factors promoting lymphatic involvement remain elusive, just as the association with molecular subtypes of CRC.
We designed a lymphangiogenic gene set (VEGFC, Nrp-2, PDPN, LYVE-1, MRC1, CCL-21) and applied it to large datasets of CRC. Gene expression of the lymphangiogenic signature was assessed in resected CRLM specimens by Rt-QPCR. In vitro experiments were performed with colon cancer cell line Colo320 (high Nrp-2 expression) and human dermal microvascular lymphatic endothelial cells (LECs).
Lymphangiogenic gene expression was associated with poor prognosis in both primary and liver metastasis of CRC. CRLM with high expression of consensus molecular subtype-4 identifier genes also exhibited high lymphangiogenic gene expression. Lymph node recurrence following CRLM resection was associated with high expression of VEGFC and Nrp-2. Blocking Nrp-2 significantly reduced invasion of Colo320 cells through an LEC monolayer.
Lymphangiogenic gene expression is correlated with worse prognosis and consensus molecular subtype-4 in both primary and liver metastatic CRC. VEGFC and Nrp-2 expression may be predictive of lymph node involvement in recurrence after resection of CRLM. Nrp-2, expressed on both tumor and LECs, may have a mechanistic role in lymphatic invasion and is a potential novel target in CRC.
研究淋巴管生成基因表达在结直肠癌（CRC）原发灶和肝转移灶中的相关性，并确定淋巴管浸润的决定因素。
促进淋巴管生成的血管内皮生长因子 C（VEGFC）与 CRC 原发灶的不良预后相关。对于结直肠癌肝转移（CRLM），肝内淋巴管侵犯和淋巴结转移是不良预后因素。促进淋巴浸润的确切生物学因素仍不清楚，就像与 CRC 的分子亚型的关联一样。
我们设计了一个淋巴管生成基因集（VEGFC、Nrp-2、PDPN、LYVE-1、MRC1、CCL-21），并将其应用于 CRC 的大型数据集。通过 Rt-QPCR 评估切除的 CRLM 标本中的淋巴管生成特征基因表达。在结肠癌细胞系 Colo320（高 Nrp-2 表达）和人真皮微血管淋巴管内皮细胞（LECs）中进行了体外实验。
淋巴管生成基因表达与 CRC 原发灶和肝转移灶的不良预后相关。高共识分子亚型-4 标识符基因表达的 CRLM 也表现出高淋巴管生成基因表达。CRLM 切除后淋巴结复发与 VEGFC 和 Nrp-2 高表达相关。阻断 Nrp-2 可显著降低 Colo320 细胞穿过 LEC 单层的侵袭。
淋巴管生成基因表达与 CRC 原发灶和肝转移灶的不良预后和共识分子亚型-4 相关。VEGFC 和 Nrp-2 的表达可能是 CRLM 切除后淋巴结受累复发的预测因素。在肿瘤和 LEC 上均表达的 Nrp-2 可能在淋巴管浸润中具有机制作用，是 CRC 的一个潜在新靶点。
