Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
Biochem Biophys Res Commun. 2013 Sep 27;439(3):378-83. doi: 10.1016/j.bbrc.2013.08.073. Epub 2013 Aug 29.
Peritoneal dissemination (PD) is the most frequent metastatic pattern of advanced gastric cancer (GC) and the main cause of death in GC patients. Human peritoneal mesothelial cell (HPMC) injury induced by gastric cancer cells (GCCs) and GCC outgrowths supported by peritoneal milky spot macrophages (PMSMs) are the key events during gastric cancer peritoneal dissemination (GCPD). In this study, we investigated whether PMSMs remodeled by GCC can induce HPMC injury and create a favorable microenvironment for GCPD. We established a tumor-associated macrophage (TAM) model using in vitro cell coculture. Normal macrophages cocultured with GCCs down-regulated expression of antigen-presenting surface molecules CD80, CD86, and MHC-II, but, notably, they up-regulated expression of phagocytic scavenger receptor CD206, which is similar to the M2 macrophage phenotype. In further experiments, various experimental methods were applied to detect the injurious effect of TAMs on HPMCs in another TAM-HPMC coculture. Our results showed that GCCs can induce HPMC apoptosis by unregulated apoptosis associated with cleaved caspase3, cleaved caspase9, and p21 proteins. HPMC growth ceased, and both early- and late-stage apoptosis were observed. Additionally, GCCs can induce HPMC fibrosis via increased expression of epithelial cell marker E-cadherin and decreased expression of mesenchymal cell marker α-SMA. Our results demonstrate that, in the GCPD process, PMSMs were remodeled by GCCs, resulting in phenotypic and functional transformation. In turn, this transformation induced HPMC injury and provided a favorable microenvironment for GCC anchorage and growth. These results may provide new insight into the mechanisms of GCPD.
腹膜转移（PD）是晚期胃癌（GC）最常见的转移模式，也是 GC 患者死亡的主要原因。胃癌细胞（GCCs）诱导的人腹膜间皮细胞（HPMC）损伤和腹膜乳斑巨噬细胞（PMSMs）支持的 GCC 外生是胃癌腹膜转移（GCPD）过程中的关键事件。在本研究中，我们研究了由 GCC 重塑的 PMSM 是否会诱导 HPMC 损伤并为 GCPD 创造有利的微环境。我们通过体外细胞共培养建立了肿瘤相关巨噬细胞（TAM）模型。正常巨噬细胞与 GCC 共培养后，其抗原呈递表面分子 CD80、CD86 和 MHC-II 的表达下调，但值得注意的是，它们上调了吞噬性清道夫受体 CD206 的表达，类似于 M2 巨噬细胞表型。在进一步的实验中，应用各种实验方法在另一个 TAM-HPMC 共培养中检测 TAM 对 HPMC 的损伤作用。我们的结果表明，GCC 可以通过与 cleaved caspase3、cleaved caspase9 和 p21 蛋白相关的不受调节的细胞凋亡诱导 HPMC 凋亡。HPMC 生长停止，并观察到早期和晚期凋亡。此外，GCC 可以通过增加上皮细胞标志物 E-钙粘蛋白的表达和降低间充质细胞标志物 α-SMA 的表达诱导 HPMC 纤维化。我们的结果表明，在 GCPD 过程中，GCC 重塑了 PMSM，导致其表型和功能发生转化。反过来，这种转化诱导了 HPMC 损伤，并为 GCC 锚定和生长提供了有利的微环境。这些结果可能为 GCPD 的机制提供新的见解。
