Abstract
BackgroundCancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development. However, little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC) progression. We aim to detect the functional contributions of CAFs to promote progression of EC.MethodsStromal fibroblasts were isolated from endometrioid adenocarcinomas and normal endometrial tissues. The conditioned media of cultured CAFs and normal fibroblasts (NFs) were collected to detect the level of stromal cell-derived factor-1alpha (SDF-1α), macrophage chemoattractant protein-1 (MCP-1), migration inhibitory factor (MIF), colony stimulating factor-1 (CSF-1), and interleukin-1 (IL-1) by ELISA. The CAFs or NFs were cocultured with EC cell lines to determine the proliferation, migration, and invasion by MTT assays and transwell chambers. Xenograft models were used to observe tumor growth. Matrix metalloproteinases (MMP)-2 and MMP-9 activity was evaluated by zymography. AMD3100 (a chemokine receptor 4 (CXCR4) antagonist) was used to block the SDF-1/CXCR4 axis. Neutralizing antibodies were used to detect PI3K/Akt and MAPK/Erk pathways by western blotting. SDF-1α and CXCR4 expressions were analyzed in xenotransplanted tumors and 348 cases by immunohistochemistry.ResultsCAFs promoted proliferation, migration, and invasion as well as in vivo tumorigenesis of admixed EC cells significantly more than NFs by secreting SDF-1α. These effects were significantly inhibited by AMD3100. CAFs promoted EC progression via the SDF-1α/CXCR4 axis to activate the PI3K/Akt and MAPK/Erk signalings in a paracrine-dependent manner or increase MMP-2 and MMP-9 secretion in an autocrine-dependent manner. SDF-1α and CXCR4 expression upregulation accompanied clinical EC development and progression. High SDF-1α expression levels were associated with deep myometrial invasion, lymph node metastasis, and poor prognosis in EC.ConclusionsOur data indicated that CAFs derived from EC tissues promoted EC progression via the SDF-1/CXCR4 axis in a paracrine- or autocrine-dependent manner. SDF-1α is a novel independent poor prognostic factor for EC patients’ survival. Targeting the SDF-1/CXCR4 axis might provide a novel therapeutic strategy for EC treatment.
Highlights
Cancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development
We found that CAF-mediated endometrial cancer (EC) progression was modulated via the SDF-1/chemokine receptor 4 (CXCR4) axis, which activated intracellular PI3K/ Akt and/or MAPK/Erk signalings and increased active matrix metalloproteinases (MMP)-2 and Matrix metalloproteinases (MMP)-9 expressions
CAFs isolated from EC tissues were negative for CK and CD31 expression, moderately positive for vimentin expression, but highly positive for alpha-smooth muscle actin (α-SMA), fibroblast-specific protein-1 (FSP-1), and fibroblastactivating protein (FAP) expression
Summary
Cancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development. Little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC) progression. Solid tumors, including EC, consist of tumor cells and various types of stromal cells; tumor progression is determined by the tumor cells themselves and by the tumor stroma. Previous studies have shown that the crosstalk between tumor cells and their surrounding stroma plays an important role in tumor development [3, 4]. Myofibroblasts in the tumor stroma, collectively called cancer-associated fibroblasts (CAFs), are large, spindle-shaped mesenchymal cells that share characteristics with smooth muscle cells that expressed both vimentin and alpha-smooth muscle actin (α-SMA) [5]. The mechanisms linking CAFs and cancer progression are not fully understood
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