Cong Fengyun, Huang Jiahao, Wu Changtao, Zhong Huage, Qiu Guanhua, Luo Tao, Tang Weizhong
Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China.
Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, China.
J Cancer Res Ther. 2024 Dec 1;20(7):2082-2093. doi: 10.4103/jcrt.jcrt_230_24. Epub 2025 Jan 10.
Colorectal cancer (CRC) is one of the most common cancers worldwide. The mechanisms underlying metastasis, which contributes to poor outcomes, remain elusive.
We used the Cancer Genome Atlas dataset to compare mRNA expression patterns of integrin α6 (ITGA6) and integrin β4 (ITGB4) in patients with CRC. We measured ITGA6 and ITGB4 expression levels in highly metastatic (i.e., HCT116 and SW620) and lowly metastatic (i.e., SW480 and Caco2) CRC cell lines. Exosomes were isolated from cell culture media and characterized using western blotting and nanoparticle analyses. The role of exosomes in lung metastasis was investigated using xenograft experiments in mice models, which received CRC cell injection and were treated with exosomes.
ITGA6 and ITGB4 were significantly overexpressed in CRC tissues, and ITGA6 was associated with the American Joint Committee on Cancer (AJCC) stage and outcome. ITGA6 and ITGB4, as well as exosomal ITGA6 and ITGB4, were significantly more highly expressed in HCT116 and SW620 cells than in SW480 and Caco2 cells. The proliferation and tubulogenesis of vascular endothelial cells were markedly decreased by disruption of ITGA6 and ITGB4 but were markedly increased by ectopic expression of ITGA6 and ITGB4. Exosomal ITGA6 and ITGB4 promoted CRC metastasis to the lung in vivo.
Taken together, our findings suggested that exosomal ITGA6 and ITGB4 displayed organotropism to the lung and upregulated proliferation and tubulogenic capacities, which might help reduce lung metastasis from CRC. These findings provided new insights into the mechanisms of CRC metastasis and provided novel potential therapeutic targets.
结直肠癌（CRC）是全球最常见的癌症之一。导致预后不良的转移机制仍不清楚。
我们使用癌症基因组图谱数据集比较结直肠癌患者中整合素α6（ITGA6）和整合素β4（ITGB4）的mRNA表达模式。我们测量了高转移性（即HCT116和SW620）和低转移性（即SW480和Caco2）结直肠癌细胞系中ITGA6和ITGB4的表达水平。从细胞培养基中分离出外泌体，并通过蛋白质印迹和纳米颗粒分析进行表征。使用小鼠模型的异种移植实验研究外泌体在肺转移中的作用，该模型接受结直肠癌细胞注射并接受外泌体治疗。
ITGA6和ITGB4在结直肠癌组织中显著过表达，并且ITGA6与美国癌症联合委员会（AJCC）分期和预后相关。ITGA6和ITGB4以及外泌体ITGA6和ITGB4在HCT116和SW620细胞中的表达明显高于SW480和Caco2细胞。ITGA6和ITGB4的破坏显著降低了血管内皮细胞的增殖和管状形成，但ITGA6和ITGB4的异位表达显著增加了这些过程。外泌体ITGA6和ITGB4在体内促进了结直肠癌向肺的转移。
综上所述，我们的研究结果表明，外泌体ITGA6和ITGB4对肺具有器官趋向性，并上调了增殖和管状形成能力，这可能有助于减少结直肠癌的肺转移。这些发现为结直肠癌转移机制提供了新的见解，并提供了新的潜在治疗靶点。
