<br>肿瘤源性层粘连蛋白 α5 (LAMA5) 促进结直肠肝转移生长、分支血管生成和 Notch 通路抑制,Cancers

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肿瘤源性层粘连蛋白 α5 (LAMA5) 促进结直肠肝转移生长、分支血管生成和 Notch 通路抑制
Cancers ( IF 4.5 ) Pub Date : 2019-05-06 , DOI: 10.3390/cancers11050630
Alex Gordon-Weeks ₁ , Su Yin Lim ₂ , Arseniy Yuzhalin ₃ , Serena Lucotti ₃ , Jenny Adriana Francisca Vermeer ₃ , Keaton Jones ₃ , Jianzhou Chen ₃ , Ruth J Muschel ₃

Affiliation

肝转移生长依赖于基质因子，包括构成细胞外基质（ECM）的基质体蛋白。层粘连蛋白是 ECM 糖蛋白，具有与肿瘤进展相关的多种功能，包括血管生成。我们研究了转移性结肠癌细胞是否产生血管基底膜组装所需的层粘连蛋白，作为促进血管生成和肝转移生长的机制。使用人类特异性引物对来自原位人类结直肠肝转移瘤的 RNA 上的层粘连蛋白链进行 qPCR。使用 shRNA 抑制结肠癌细胞中层粘连蛋白 α5 (LAMA5) 的表达。在肝转移的内皮细胞中测定Notch途径基因表达。原位肝转移表达人层粘连蛋白链α5、β1和γ1（层粘连蛋白511），所有这些都是血管基底膜组装所必需的。在几个独立的结直肠癌队列中，层粘连蛋白 511 的表达与生存率降低相关，并且血管生成特征或血管密度与 LAMA5 表达显着相关。培养中的结直肠癌细胞几乎不产生 LAMA5，但在肿瘤来源的 CD11b+ 骨髓细胞通过 TNFα/NFκB 信号通路调节的培养基中培养时，其水平会增加。癌细胞中 LAMA5 的下调会损害肝转移生长，导致肿瘤内血管分支减少，并增加转移源性内皮细胞中 Notch 通路基因的表达。该数据证明了肿瘤炎症诱导结直肠癌细胞中 LAMA5 表达的机制。 LAMA5 是肝转移瘤成功生长所必需的，它促进分支血管生成并调节 Notch 信号传导。

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Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition

Hepatic metastatic growth is dependent upon stromal factors including the matrisomal proteins that make up the extracellular matrix (ECM). Laminins are ECM glycoproteins with several functions relevant to tumour progression including angiogenesis. We investigated whether metastatic colon cancer cells produce the laminins required for vascular basement membrane assembly as a mechanism for the promotion of angiogenesis and liver metastasis growth. qPCR was performed using human-specific primers to laminin chains on RNA from orthotopic human colorectal liver metastases. Laminin α5 (LAMA5) expression was inhibited in colon cancer cells using shRNA. Notch pathway gene expression was determined in endothelia from hepatic metastases. Orthotopic hepatic metastases expressed human laminin chains α5, β1 and γ1 (laminin 511), all of which are required for vascular basement membrane assembly. The expression of Laminin 511 was associated with reduced survival in several independent colorectal cancer cohorts and angiogenesis signatures or vessel density significantly correlated with LAMA5 expression. Colorectal cancer cells in culture made little LAMA5, but its levels were increased by culture in a medium conditioned by tumour-derived CD11b+ myeloid cells through TNFα/NFκB pathway signalling. Down-regulation of LAMA5 in cancer cells impaired liver metastatic growth and resulted in reduced intra-tumoural vessel branching and increased the expression of Notch pathway genes in metastasis-derived endothelia. This data demonstrates a mechanism whereby tumour inflammation induces LAMA5 expression in colorectal cancer cells. LAMA5 is required for the successful growth of hepatic metastases where it promotes branching angiogenesis and modulates Notch signalling.

更新日期：2019-05-06

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