Abstract
Mammary carcinoma cells produce pro-angiogenic factors to stimulate angiogenesis and tumor growth. Trefoil factor-3 (TFF3) is an oncogene secreted from mammary carcinoma cells and associated with poor prognosis. Herein, we demonstrate that TFF3 produced in mammary carcinoma cells functions as a promoter of tumor angiogenesis. Forced expression of TFF3 in mammary carcinoma cells promoted proliferation, survival, invasion and in vitro tubule formation of human umbilical vein endothelial cells (HUVEC). MCF7-TFF3 cells with forced expression of TFF3 generated tumors with enhanced microvessel density as compared to tumors formed by vector control cells. Depletion of TFF3 in mammary carcinoma cells by siRNA concordantly decreased the angiogenic behavior of HUVEC. Forced expression of TFF3 in mammary carcinoma cells stimulated IL-8 transcription and subsequently enhanced IL-8 expression in both mammary carcinoma cells and HUVEC. Depletion of IL-8 in mammary carcinoma cells with forced expression of TFF3, or antibody inhibition of IL-8, partially abrogated mammary carcinoma cell TFF3-stimulated HUVEC angiogenic behavior in vitro, as did inhibition of the IL-8 receptor, CXCR2. Depletion of STAT3 by siRNA in MCF-7 cells with forced expression of TFF3 partially diminished the angiogenic capability of TFF3 on stimulation of cellular processes of HUVEC. Exogenous recombinant hTFF3 also directly promoted the angiogenic behavior of HUVEC. Hence, TFF3 is a potent angiogenic factor and functions as a promoter of de novo angiogenesis in mammary carcinoma, which may co-coordinate with the growth promoting and metastatic actions of TFF3 in mammary carcinoma to enhance tumor progression.
Highlights
Angiogenesis is required for expansion and metastatic progression of mammary carcinoma [1, 2]
To determine the effect of Trefoil factor-3 (TFF3) secreted from mammary carcinoma cells on the angiogenic behavior of Human umbilical vein endothelial cells (HUVEC), MCF-7 and T47D cells were stably transfected with a pIRESneo3 expression vector containing TFF3 cDNA or a pIRESneo3 empty vector [19]
The expression of TFF3 in these new set of stable cell lines were again validated by semi-quantitative RT-PCR and Western blot analyses, which were consistent with our previous studies [16, 19]
Summary
Angiogenesis is required for expansion and metastatic progression of mammary carcinoma [1, 2]. Increased microvessel density and the presence of tumor metastases in lymph nodes predicts poor survival outcome in patients with mammary carcinoma [2,3,4,5]. Forced expression of TFF3 in mammary carcinoma cells has been demonstrated to promote oncogenicity, cellular invasion and resistance to apoptosis [12, 16, 17]. TFF3 expression is associated with poor survival outcome in patients with ER+ mammary carcinoma [19]. TFF3 has recently been demonstrated to stimulate cellular invasion and metastasis of ER+ mammary carcinoma cells in a Src-STAT3 dependent manner [19]. TFF3 expression is associated with increased microvessel density, both in gastric [21] and mammary carcinoma [18]. A functional role for TFF3 in tumor angiogenesis has not been determined
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