Yet another function for hepatocyte growth factor

Comment on Cao et al, page 3531

In addition to the primary lymphangiogenic factors VEGF-C and VEGF-D, a number of other growth factors have recently been shown to stimulate the process. In this issue of Blood, the pleiotrophic hepatocyte growth factor is reported to stimulate lymphangiogenesis, at least partially via VEGF-C/D.

In this issue of Blood, Cao and colleagues publish an interesting article showing that hepatocyte growth factor (HGF; also called scatter factor) stimulates lymphangiogenesis in the cornea and in the periphery of tumors. Despite its name, HGF is a ligand for receptors on a variety of epithelial and mesenchymal cell types, and is important in genetic programs leading to cell growth, invasion, and protection from apoptosis.¹  HGF binds to the Met receptor tyrosine kinase, which in turn functionally interacts with receptors and pathways that have been linked to cancer progression.¹  HGF has been shown to trigger mitogenic and motogenic responses in epithelial and endothelial cells leading to tubular morphogenesis.¹ FIG1 

Stimulation of hepatocytes with HGF leads to production of vascular endothelial growth factor (VEGF), while VEGF acts on liver sinusoidal endothelial cells by stimulating expression of HGF.²  Thus, at least in this system, HGF appears to have an indirect angiogenic function, promoting vessel growth via VEGF. Several other reports have shown that HGF may, in part, function as a tumor progression factor by stimulating angiogenesis.¹  The new data by Cao et al in this issue indicate that HGF can also indirectly promote lymphangiogenesis via the VEGF-C/VEGF-D/VEGFR-3 system.

The first report, by Kajiya et al,³  on HGF's lymphangiogenic property implicated HGF in direct lymphatic endothelial cell (LEC) stimulation via Met, whereas Cao et al saw little or no migration or proliferation of LECs. This discrepancy may have been caused by the different methods used to isolate the LECs, possibly yielding cells containing distinct HGF responsive and unresponsive subpopulations. Furthermore, Kajiya et al concluded that Met is induced in the growing lymphatic endothelium and during inflammation in vivo, while Cao et al observed very little or no Met expression in the lymph vessels growing in HGF-implanted corneas and in tumors, although the receptor was abundantly expressed in blood vessels. This crucial difference could be explained by tissue specificity, differences in experimental inflammatory conditions, or technical issues, such as the use of different antibodies.

The fact that HGF and Met are expressed by a wide variety of cells makes it difficult to determine how much of the effects of HGF are direct. VEGF-C is induced by a wide variety of other growth factors, oncoproteins, and cytokines in several cell types⁴  (see figure). Cytokine-induced VEGF-C may couple the lymph vasculature into an active immune response, as inhibition of the VEGFR-3 signalling pathway was able to completely inhibit reactive lymphangiogenesis in a mouse model of chronic respiratory inflammation.⁵  As an example of indirect activators of lymphangiogenesis, fibroblast growth factor-2 (FGF-2) has been shown to up-regulate lymphangiogenic factors VEGF-C and VEGF-D, which act directly.⁶  Moreover, insulin-like growth factor 1 (IGF-1) and IGF-2 induced the proliferation and migration of cultured primary lymphatic endothelial cells, as well as corneal lymphangiogenesis.⁷  VEGF-C was reported to be up-regulated after stimulation of IGF receptor-1, suggesting that this pathway could also promote lymphatic metastasis indirectly.⁸  Also, platelet-derived growth factor B (PDGF-B) was reported to stimulate lymphangiogenesis and increase the frequency of lymphatic metastasis in PDGF-B–overexpressing tumors.⁹  It should be noted, however, that PDGF has direct tumor growth–stimulating effects via PDGF receptors that are expressed in many types of tumor cells, and these effects may account for increased propensity for metastasis.

As the 2 current HGF studies show, many of the factors that stimulate lymphangiogenesis could be context dependent in their mechanisms of action. The contribution of their indirect effects on lymphangiogenesis via stromal cells, leukocytes, and the inflammatory response should therefore be carefully analyzed. ▪