Abstract:
In gastric cancer (GC), the liver is a common organ for distant metastasis, and patients with gastric cancer with liver metastasis (GCLM) generally have poor prognosis. The mechanism of GCLM is unclear. Invadopodia are special membrane protrusions formed by tumor cells that can degrade the basement membrane and ECM. Herein, we investigated the role of invadopodia in GCLM. We found that the levels of invadopodia-associated proteins were significantly higher in liver metastasis than in the primary tumors of patients with GCLM. Furthermore, GC cells could activate hepatic stellate cells (HSCs) within the tumor microenvironment of liver metastases through the secretion of platelet-derived growth factor subunit B (PDGFB). Activated HSCs secreted hepatocyte growth factor (HGF), which activated the MET proto-oncogene, MET receptor of GC cells, thereby promoting invadopodia formation through the PI3K/AKT pathway and subsequently enhancing the invasion and metastasis of GC cells. Therefore, cross-talk between GC cells and HSCs by PDGFB/platelet derived growth factor receptor beta (PDGFRβ) and the HGF/MET axis might represent potential therapeutic targets to treat GCLM.
摘要:
在胃癌(GC)中,肝脏是远处转移的常见器官,胃癌肝转移(GCLM)患者一般预后较差。GCLM的机制尚不清楚。Invadopodia是由肿瘤细胞形成的特殊的膜突起,可以降解基底膜和ECM。在这里,我们研究了invadopodia在GCLM中的作用。我们发现,肝转移患者的侵袭足病相关蛋白水平明显高于GCLM患者的原发性肿瘤。此外,GC细胞可通过分泌血小板源性生长因子亚基B(PDGFB)激活肝转移瘤微环境中的肝星状细胞(HSC)。活化的HSC分泌肝细胞生长因子(HGF),激活了MET原癌基因,GC细胞的MET受体,从而通过PI3K/AKT途径促进侵袭性足足的形成,并随后增强GC细胞的侵袭和转移。因此,通过PDGFB/血小板衍生生长因子受体β(PDGFRβ)和HGF/MET轴在GC细胞和HSCs之间的交叉可能代表治疗GCLM的潜在治疗靶点。