Flt-1 in colorectal cancer cells is required for the tumor invasive effect of placental growth factor through a p38-MMP9 pathway

Shu-Chen Wei,Meng-Tzu Weng,Po-Nien Tsao,Zhifang Cao,Jau-Min Wong

doi:10.1186/1423-0127-20-39

Abstract

BackgroundPlacenta growth factor (PlGF), a dimeric glycoprotein with 53% homology to VEGF, binds to VEGF receptor-1 (Flt-1), but not to VEGF receptor-2 (Flk-1), and may function by modulating VEGF activity. We previously have showed that PlGF displays prognostic value in colorectal cancer (CRC) but the mechanism remains elucidated.ResultsOverexpression of PlGF increased the invasive/migration ability and decreased apoptosis in CRC cells showing Flt-1 expression. Increased migration was associated with increasing MMP9 via p38 MAPK activation. Tumors grew faster, larger; with higher vascularity from PlGF over-expression cells in xenograft assay. In two independent human CRC tissue cohorts, PlGF, MMP9, and Flt-1 expressions were higher in the advanced than the localized disease group. PlGF expression correlated with MMP9, and Flt-1 expression. CRC patients with high PlGF and high Flt-1 expression in tissue had poor prognosis.ConclusionPlGF/Flt-1 signaling plays an important role in CRC progression, blocking PlGF/Flt-1 signaling maybe an alternative therapy for CRC.

Highlights

Placenta growth factor (PlGF), a dimeric glycoprotein with 53% homology to VEGF, binds to VEGF receptor-1 (Flt-1), but not to VEGF receptor-2 (Flk-1), and may function by modulating VEGF activity
Flt-1 is required for PlGF-induced invasive/migration ability of colorectal cancer (CRC) cells exogenously added PlGF or overexpression of PlGF increased the invasive/migration ability of CRC cells expressing Flt-1 Exogenous PlGF significantly increased the invasive ability of LoVo cells, which expressed the highest Flt-1 levels of the cell lines tested by up to four fold
This data suggests that Flt-1 receptor may be critical for PlGF induced tumor cell invasion in CRC cells

Summary

Introduction

Placenta growth factor (PlGF), a dimeric glycoprotein with 53% homology to VEGF, binds to VEGF receptor-1 (Flt-1), but not to VEGF receptor-2 (Flk-1), and may function by modulating VEGF activity. We previously have showed that PlGF displays prognostic value in colorectal cancer (CRC) but the mechanism remains elucidated. The fact that tumor growth and metastasis rely on angiogenesis has been widely accepted [3]. Increased angiogenesis in the primary tumor of CRC has been associated with poor prognosis and relapse of disease [4,5]. We have demonstrated that PlGF expression was upregulated in CRC tissue. Immunohistochemical staining analysis showed that PlGF was expressed mainly in tumor cells and Flt-1 was expressed in tumor cells as well as in endothelial cells.

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