PDF(Pubmed)
Abstract：
Desmosomes are intercellular adhesion complexes providing mechanical coupling and tissue integrity. Previously, a correlation of desmosomal molecule expression with invasion and metastasis formation in several tumor entities was described together with a relevance for circulating tumor cell cluster formation. Here, we investigated the contribution of the desmosomal core adhesion molecule desmoglein-2 (DSG2) to the initial steps of liver metastasis formation by pancreatic cancer cells using a novel ex vivo liver perfusion mouse model. We applied the pancreatic ductal adenocarcinoma cell line AsPC-1 with and without a knockout (KO) of DSG2 and generated mouse lines with a hepatocyte-specific KO of the known interacting partners of DSG2 (DSG2 and desmocollin-2). Liver perfusion with DSG2 KO AsPC-1 cells led to smaller circulating cell clusters and a reduced number of cells adhering to murine livers compared to control cells. While this was independent of the expression levels of desmosomal adhesion molecules in hepatocytes, we show that increased cluster size of cancer cells, which correlates with stronger cell-cell adhesion and expression of desmosomal molecules, is a major factor contributing to the early phase of metastatic spreading. In conclusion, impaired desmosomal adhesion results in reduced circulating cell cluster size, which is relevant for seeding and attachment of metastatic cells to the liver.
摘要：
桥粒是提供机械耦合和组织完整性的细胞间粘附复合物。以前,描述了桥粒分子表达与几种肿瘤实体的侵袭和转移形成的相关性，以及与循环肿瘤细胞簇形成的相关性。这里,我们使用一种新型的离体肝灌注小鼠模型，研究了桥粒核心粘附分子desmoglein-2（DSG2）对胰腺癌细胞肝转移形成的初始步骤的贡献。我们应用了带有和不带有DSG2敲除（KO）的胰腺导管腺癌细胞系AsPC-1，并产生了具有已知的DSG2相互作用伴侣（DSG2和desmocollin-2）的肝细胞特异性KO的小鼠系。与对照细胞相比，用DSG2KOAsPC-1细胞进行肝脏灌注导致较小的循环细胞簇和粘附在鼠肝脏上的细胞数量减少。虽然这与肝细胞中桥粒粘附分子的表达水平无关，我们发现癌细胞簇的大小增加，这与更强的细胞间粘附和桥粒分子的表达相关，是导致转移扩散早期的主要因素。总之,受损的桥粒粘附导致循环细胞簇大小减少，这与转移细胞接种和附着到肝脏有关。
