Vascular endothelial growth factor receptor‐1 promotes migration and invasion in pancreatic carcinoma cell lines

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Abstract
BACKGROUND Vascular endothelial growth factor receptor‐1 (VEGFR‐1) is one of three receptor tyrosine kinases for VEGF, a key regulator of angiogenesis in cancer. Although VEGFRs initially were believed to be expressed exclusively on endothelial cells (ECs), recent studies have demonstrated the presence of VEGFR‐1 on non‐EC types. The authors hypothesized that VEGFR‐1 is present and functional in pancreatic carcinoma cells, contributing to the malignant phenotype. METHODS The authors assessed the expression of VEGFR‐1 and its ligands in 11 pancreatic carcinoma cell lines by reverse‐transcriptase–polymerase chain reaction, enzyme‐linked immunosorbent assay, and/or Western blot analysis. The function of VEGFR‐1 was evaluated by treating two representative cell lines with VEGF‐B, a selective ligand for VEGFR‐1, and/or a specific anti‐VEGFR‐1 antibody and assessing the effects on signaling, migration, invasion, and proliferation. RESULTS All 11 pancreatic carcinoma cell lines expressed VEGFR‐1 mRNA and protein, as well as the VEGFR‐1 ligands VEGF‐A and VEGF‐B. Two representative cell lines (L3.6 and Panc‐1) exhibited VEGF‐B‐induced mitogen‐activated protein kinase signaling. A VEGFR‐1 neutralizing antibody abrogated signaling, confirming that the ligand effect was mediated through VEGFR‐1. VEGFR‐1 stimulation by VEGF‐A or VEGF‐B was found to promote migration in both cell lines. Panc‐1 cells also demonstrated enhanced Matrigel invasion after VEGFR‐1 stimulation. VEGFR‐1‐dependent migration and invasion were blocked by the VEGFR‐1 neutralizing antibody. VEGFR‐1 activation did not appear to enhance cell proliferation. CONCLUSIONS VEGFR‐1 appears to be expressed ubiquitously in pancreatic carcinoma cell lines, in which it induces signaling and promotes migration and invasion. Overexpression of VEGF in tumors may activate tumor cells bearing VEGFR‐1 via an autocrine pathway. Agents targeting VEGF or its receptors may have a dual inhibitory effect on tumor growth by suppressing both angiogenesis and tumor cell function. Cancer 2005. © 2005 American Cancer Society.