PDF(Pubmed)
Abstract：
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.
摘要：
结直肠癌主要转移到肝脏，也转移到肺和腹膜。肝外转移的存在限制了治愈性（手术）治疗选择，并且与非常差的生存率有关。控制多器官转移形成的机制尚未完全了解。这里,我们检验了肿瘤生长部位影响肝外转移形成的假设。为此,我们将鼠结肠癌类器官植入原发肿瘤部位(即，盲肠)并进入原发转移部位(即，免疫活性小鼠的肝脏）。与盲肠中生长的相同起源的肿瘤相比，类器官引发的肝肿瘤在种植远处转移方面的效率更高（肝内：51vs.40%,p=0.001；腹膜腔：51%vs.33%,p=0.001；肺：30%vs.7%,p=0.017)。肝肿瘤的转移能力增强与巨噬细胞包围的玻连蛋白阳性血管的“热点”形成有关。临床样本的RNA测序分析显示玻连蛋白在肝转移中高表达，以及反映缺氧的特征，血管生成,凝血,和巨噬细胞。我们得出的结论是，肝脏特异性微环境信号促进了肝转移瘤的“向前扩散”，这些信号导致巨噬细胞相关血管热点的形成。这些信号的治疗靶向可能有助于在肝脏内控制疾病并防止向前传播。
