Colorectal cancer metastasizes predominantly to the liver but also to the lungs and the peritoneum. The presence of extra-hepatic metastases limits curative (surgical) treatment options and is associated with very poor survival. The mechanisms governing multi-organ metastasis formation are incompletely understood. Here, we tested the hypothesis that the site of tumor growth influences extra-hepatic metastasis formation. To this end, we implanted murine colon cancer organoids into the primary tumor site (i.e., the caecum) and into the primary metastasis site (i.e., the liver) in immunocompetent mice. The organoid-initiated liver tumors were significantly more efficient in seeding distant metastases compared to tumors of the same origin growing in the caecum (intra-hepatic: 51 vs. 40%,p= 0.001; peritoneal cavity: 51% vs. 33%,p= 0.001; lungs: 30% vs. 7%,p= 0.017). The enhanced metastatic capacity of the liver tumors was associated with the formation of ‘hotspots’ of vitronectin-positive blood vessels surrounded by macrophages. RNA sequencing analysis of clinical samples showed a high expression of vitronectin in liver metastases, along with signatures reflecting hypoxia, angiogenesis, coagulation, and macrophages. We conclude that ‘onward spread’ from liver metastases is facilitated by liver-specific microenvironmental signals that cause the formation of macrophage-associated vascular hotspots. The therapeutic targeting of these signals may help to contain the disease within the liver and prevent onward spread.
结直肠癌主要转移至肝脏，同时也常转移至肺部和腹膜。肝外转移的存在限制了根治性（手术）治疗的选择，并与极差的生存率相关。目前对多器官转移形成的机制尚未完全阐明。本研究旨在验证肿瘤生长部位影响肝外转移形成的假说。为此，我们将小鼠结肠癌类器官分别植入免疫健全小鼠的原发肿瘤部位（即盲肠）和原发转移部位（即肝脏）。结果显示，与同一来源但在盲肠生长的肿瘤相比，类器官引发的肝肿瘤在远处转移播散方面显著更为高效（肝内转移：51% vs. 40%，p=0.001；腹腔转移：51% vs. 33%，p=0.001；肺转移：30% vs. 7%，p=0.017）。肝肿瘤转移能力的增强与形成由巨噬细胞环绕的玻连蛋白阳性血管"热点"相关。临床样本的RNA测序分析显示，肝转移灶中玻连蛋白高表达，同时伴有反映缺氧、血管生成、凝血和巨噬细胞活化的特征基因表达谱。我们得出结论：肝转移灶的"进一步扩散"受到肝脏特异性微环境信号的促进，这些信号导致巨噬细胞相关血管热点的形成。针对这些信号的治疗靶向干预可能有助于将疾病控制在肝脏内，防止其进一步扩散。
肿瘤(癌症)患者之家