期刊
INTERNATIONAL JOURNAL OF CANCER
卷 137, 期 2, 页码 289-298出版社
WILEY
DOI: 10.1002/ijc.29385
关键词
hepatocyte growth factor; ovarian cancer; ascites; mesothelial cells; cMet; Akt; ERK1/2
类别
资金
- Canadian Institute for Health Research [MOP-244194-CPT-CFDA-48852]
- Centre de Recherche Clinique Etienne-Lebel du Centre Hospitalier Universitaire de Sherbrooke
Ovarian cancer ascites consist of a proinflammatory environment that is characterized by the presence of abundant human peritoneal mesothelial cells (HPMCs). Cytokines and growth factors in ascites modulate cell activities of tumor cells. The expression of proinflammatory cytokines in ascites is associated with a more aggressive tumor phenotype. The effect of ascites on HPMCs is for the most part unknown but this interplay is thought to be important for epithelial ovarian cancer (EOC) progression. Here, we examine the components of ascites, which stimulate patient-derived HPMC migration, from women with advanced EOC. We show that ovarian cancer ascites enhanced the migration of HPMCs. This effect was inhibited by heat treatment, hepatocyte growth factor (HGF) blocking antibodies and a HGF receptor (cMet) inhibitor. In ovarian cancer ascites, HGF is present at high concentration compared to benign fluids. Ascites-mediated activation of cMet was associated with Akt and EKR1/2 phosphorylation. This response was partly inhibited by heat treatment and cMet inhibitor. Ascites-induced migration and a cMet phosphorylation were strongly inhibited by epidermal growth factor receptor (EGFR) inhibitor PD153035, suggesting the transactivation of cMet by EGFR. Our study suggests that HGF and ligands of EGFR are factors that mediate ovarian cancer ascites-mediated migration of HPMCs by activating cMet and possibly downstream ERK1/2 and Akt pathways. The study provides evidence for the first time that ascites not only support tumor growth but also enhance the migratory potential of cancer-associated mesothelial cells, which in turn may support cancer progression. What's new? The majority of patients with epithelial ovarian cancer present with ascites and advanced disease with peritoneal dissemination. Ovarian cancer ascites are an accumulation of fluid in the peritoneal cavity that represents a pro-inflammatory environment and contains abundant human peritoneal mesothelial cells. This study provides first evidence that ascites not only support tumor growth but also enhance the migratory potential of cancer-associated mesothelial cells, which may in turn support cancer progression. Ascites thus constitute a complex regulatory network of soluble factors, including hepatocyte growth factor (HGF), that confer to patient-derived mesothelial cells a migratory phenotype through the activation of cMet receptor.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据