Hepatocyte growth factor promotes lymphatic vessel formation and function

Abstract

The lymphatic vascular system plays a pivotal role in mediating tissue fluid homeostasis and cancer metastasis, but the molecular mechanisms that regulate its formation and function remain poorly characterized. A comparative analysis of the gene expression of purified lymphatic endothelial cells (LEC) versus blood vascular endothelial cells (BVEC) revealed that LEC express significantly higher levels of hepatocyte growth factor receptor (HGF-R). Whereas little or no HGF-R expression was detected by lymphatic vessels of normal tissues, HGF-R was strongly expressed by regenerating lymphatic endothelium during tissue repair and by activated lymphatic vessels in inflamed skin. Treatment of cultured LEC with HGF promoted LEC proliferation, migration and tube formation. HGF-induced proliferation of LEC did not require vascular endothelial growth factor receptor-3 activation, and HGFinduced cell migration was partially mediated via integrin alpha-9. Transgenic or subcutaneous delivery of HGF promoted lymphatic vessel formation in mice, whereas systemic blockade of HGF-R inhibited lymphatic function. These results identify HGF as a novel, potent lymphangiogenesis factor, and also indicate that HGF-R might serve as a new target for inhibiting pathological lymphangiogenesis.

Pathways Targeting Tumor Lymphangiogenesis

“…Treatment with soluble VEGFR-3 inhibited the effects of virally delivered angiopoietin-1 in mice, indicating that angiopoietin-1 also acts indirectly via the VEGFR-3 pathway (24). Hepatocyte growth factor was recently identified as a potent lymphangiogenesis factor, as overexpression of hepatocyte growth factor in transgenic mice and its intradermal delivery resulted in lymphatic vessel hyperplasia (25). These effects were not inhibited by a VEGFR-3 blocking antibody, indicating that hepatocyte growth factor might directly promote lymphangiogenesis.…”

Interaction of tumor cells and lymphatic vessels in cancer progression

“…57 A complex of NRP-2 and VEGFR-3 may include integrin b1 and possibly simultaneously interact with semaphorin 3 components for correct lymphangiogenic signaling. 33,60 A continuously growing number of additional factors are studied as potential modulators of lymphangiogenesis, including integrin a9 expressed specifically by lymphatic valve endothelial cells, hepatocyte growth factor, 61 the Tie-2 --angiopoietin signaling system, 27 fibroblast growth factor 2 62 and platelet-derived growth factor BB. 63 The selection of the most promising anti-lymphangiogenic targets is based on previous experiences of, for example, blocking tumor angiogenesis.…”

Developmental and pathological lymphangiogenesis: from models to human disease

“…Several other growth factors with lymphangiogenic function have been proposed, including Wbroblast growth factor-2 (FGF-2), platelet-derived growth factors (PDGFs), insulinlike growth factors (IGFs), hepatocyte growth factor (HGF) and growth hormone (GH) (Banziger-Tobler et al 2008;Björndahl et al 2005;Cao et al 2004Cao et al , 2006Chang et al 2004;Kajiya et al 2005;Kubo et al 2002;Saito et al 2006;Shin et al 2006). While all of them are capable of stimulating the proliferation of lymphatic endothelial cells in vitro or sometimes upon overexpression in vivo, their deWnitive role in developmental or pathological lymphangiogenesis via loss-of-function analysis remains to be established.…”