Abstract
A cancer-associated fibroblasts (CAFs) are the most important players that modulate tumor aggressiveness. In this study, we aimed to identify CAF-related genes in ovarian serous carcinomas (OSC) that account for the high incidence and mortality of ovarian cancers (OCs) and to develop therapeutic targets for tumor microenvironment modulation. Here, we performed a microarray analysis of CAFs isolated from three metastatic and three nonmetastatic OSC tissues and compared their gene expression profiles. Among the genes increased in metastatic CAFs (mCAFs), GLIS1 (Glis Family Zinc Finger 1) showed a significant increase in both the gene mRNA and protein expression levels. Knockdown of GLIS1 in mCAFs significantly inhibited migration, invasion, and wound healing ability of OC cells. In addition, an in vivo study demonstrated that knockdown of GLIS1 in CAFs reduced peritoneal metastasis. Taken together, these results suggest that CAFs support migration and metastasis of OC cells by GLIS1 overexpression. It also indicates GLIS1 in CAFs might be a potential therapeutic target to inhibit OC metastasis.
Highlights
The tumor microenvironment (TME) is a milieu in each tumor composed of different cellular and structural factors, including blood vessels, immune cells, stromal cells, and the extracellular matrix, and is involved in either tumor promotion or regression
Cancerassociated fibroblasts (CAFs) are reportedly associated with tumor metastases and invasion [1,2], and evidence has demonstrated that CAFs represent the major players in tumor–stroma crosstalk in the TME and enhance tumor progression by promoting angiogenesis or lymphangiogenesis
To identify metastatic CAF-related genes in ovarian cancers (OCs) and to identify new therapeutic targets for this tumor, we examined the differences in gene expression profiles between and nonmetastatic CAFs in the TME of ovarian serous carcinoma (OSC), which accounts for the highest incidence and the most lethal subtype among all OCs
Summary
The tumor microenvironment (TME) is a milieu in each tumor composed of different cellular and structural factors, including blood vessels, immune cells, stromal cells, and the extracellular matrix, and is involved in either tumor promotion or regression. Cancerassociated fibroblasts (CAFs), among the stromal components, are the most important players involved in modulating the TME and influencing aggressive tumor progression [1,2,3]. CAFs are reportedly associated with tumor metastases and invasion [1,2], and evidence has demonstrated that CAFs represent the major players in tumor–stroma crosstalk in the TME and enhance tumor progression by promoting angiogenesis or lymphangiogenesis. CAFs have phenotypic and functional heterogeneity [4,5,6], indicating the existence of different subpopulations with distinct functions in the TME. Based on these findings, many investigators have sought to develop therapeutics targeting CAFs in the TME. Several reports have shown that the downregulation of CAFmediated genes decreases the metastasis and growth of various human tumors, including lung cancer, breast cancer, and ovarian cancer (OC) [7,8,9,10]
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