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Hepatocyte Growth Factor Promotes Cancer Cell Migration and Angiogenic Factors Expression: A Prognostic Marker of Human Esophageal Squamous Cell Carcinomas

Authors' Affiliations: ¹ Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, PR China and ² Van Andel Research Institute, Grand Rapids, Michigan

Requests for reprints: Yi Ren, Center for Drug Discovery and Development/R40, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH 44195. Phone: 216-445-0417; Fax: 216-636-2498; E-mail: reny{at}ccf.org or Simon Law, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, PR China. Phone: 852-285-54774; Fax: 852-281-94221; E-mail: slaw{at}hku.hk.

Purpose: Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, play important roles in tumor development and progression. In this study, we measured the serum HGF levels in patients with esophageal squamous cell carcinoma (ESCC) to evaluate its relationships with clinicopathologic features and the role of HGF in ESCC.

Experimental Design: One hundred and forty-nine patients with ESCC were studied. Pretherapy serum was collected and ELISA was used to detect the concentrations of HGF, vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8). The function of HGF was shown by invasion chamber assay.

Results: Pretherapy serum HGF was found to be significantly higher in patients with ESCC than in control subjects. The levels of HGF correlated significantly with advanced tumor metastasis stage and survival. Multivariate analyses showed that serum HGF level in cell migration was an independent prognostic factor. Increased HGF serum levels correlated positively with serum levels of VEGF and IL-8. Our results also showed that HGF was overexpressed in ESCC tissues and cell lines. In vitro study showed that HGF could stimulate ESCC cell to express VEGF and IL-8 and markedly enhance invasion and migration of ESCC cells. Furthermore, HGF-induced IL-8 and VEGF expression was dependent on extracellular signal-regulated kinase signaling pathways. The inhibition of extracellular signal-regulated kinase activation reduced HGF-mediated IL-8 and VEGF expression.

Conclusions: Our results suggest that serum HGF may be a useful biomarker of tumor progression and a valuable independent prognostic factor in patients with ESCC. HGF may be involved in the progression of ESCC as an autocrine/paracrine factor via enhancing angiogenesis and tumor cell invasion and migration.

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