Hepatocyte growth factor/Scatter factor in the eye

doi:10.1016/S1350-9462(00)00015-X

Progress in Retinal and Eye Research

Volume 19, Issue 6, November 2000, Pages 779-802

https://doi.org/10.1016/S1350-9462(00)00015-X Get rights and content

Abstract

Hepatocyte growth factor, also known as scatter factor (HGF/SF) is a multipotential cytokine which can produce a range of responses in target cells and its influence in the eye in health and disease is just beginning to be appreciated. Usually HGF/SF is synthesised by mesenchymally derived cells and targets and signals epithelial cells in a paracrine manner via their c-Met surface receptor. However, there is growing evidence for the existence of autocrine loops in a number of cell systems prominent among which are ocular cells such as the corneal endothelium, the lens epithelium, the retinal pigment epithelium (RPE) and others. Marked cellular proliferation is stimulated when activated HGF/SF is exposed to hepatocytes, renal epithelium, melanocytes and vascular endothelial cells but it is often a poor mitogen for other cell types. In target cells the cytokine promotes other bioactions such as junctional breakdown, shape change, cell scattering, directional and nondirectional migration, cell survival, invasive behaviour and/or tubule formation. These activities seem to depend on HGF/SF linking with the c-Met receptor and pathways to stimulate the various types of cytokine/receptor response are being unravelled at the present time. In corneal wound healing, HGF/SF is produced by stromal keratocytes and targets the repairing epithelium. HGF/SF is a constituent of tears, aqueous humour and vitreous humour at levels above that found in plasma although it is not clear how much is activated. Aqueous HGF/SF may well influence lens epithelial, corneal endothelial and trabecular meshwork cell survival. Vitreous levels of HGF/SF are elevated in proliferative vitreoretinopathy (PVR), where a target cell is the RPE and in proliferative diabetic retinopathy (PDR) where HGF/SF has been shown to be a major angiogenesis factor. Finally HGF/SF may be involved in the metastatic spread of tumour cells from uveal melanomata and in the formation of vascular channels in these tumours.

Introduction

We know that cytokines in general, and growth factors in particular, have a far wider range of bioactivity than simply causing target cells to proliferate. Settlement, survival, adhesion, synthesis, motility, invasiveness, cytostasis, induction of tubule formation and phenotypic alteration are among the many behavioural features which are modulated by growth factors and other cytokines. One growth factor which is better known for its motility and shape-change stimulating functions than for its proliferative action is hepatocyte growth factor or scatter factor (HGF/SF). HGF/SF has been recognized for some time as a factor of considerable importance to cell and tissue function and is now beginning to be appreciated for its role within the eye in health and disease.

Section snippets

The factor

Stoker and Perryman (1985) found that cultured 3T3 fibroblasts secreted a substance that had a marked effect on Madin-Darby canine kidney (MDCK) epithelium. MDCK cells form compact colonies after plating in tissue culture and the fibroblast-derived factor has the intriguing effect of causing the tightly packed colonies to break up by inducing each individual cell to spread out (Fig. 1). The fibroblast-derived substance was called scatter factor and subsequently it was shown to be secreted by a

The cornea

Over the years research into bioactive agents which are relevant to the cornea has focused on a number of growth factors including EGF, members of the FGF family, TGFβ and others (Kitazawa et al., 1990, Schultz et al., 1994, Wilson et al., 1994, Honma et al., 1997, Andresen and Ehlers, 1998). Each group in turn has had its period of intense research but it is only in recent times that the possible significance of HGF/SF to corneal welfare has started to be appreciated.

Corneal stromal

Vitreous humour

The vitreous content of soluble protein is low and has been estimated to be around 0.01% of the fluid compartment (Swann and Constable, 1972) which compares poorly with a soluble protein value of 7.0% for blood. Even although the overall protein concentration is low, the vitreous is still thought to act as a reservoir (Bito, 1977) or holding pen for some key substances like peptide growth factors. In times of crisis for adjacent tissues like the retina and lens, the vitreous can provide a

Future directions

HGF/SF produces a range of biological effects in target cells and it is to be found at various sites within the eye. The research conducted on the activities of this cytokine on ocular cells and tissues still is limited but it will be the subject of considerable ocular research interest in the near future. HGF/SF may have a key role in such diverse activities as ocular development, the regulation of normal adult tissue and it may be involved in pathologies ranging from to PDR to the development

Acknowledgements

The authors acknowledge the support of the Sir Jules Thorn Charitable Trust, Guide Dogs for the Blind Association, The Dunhill Medical Trust and The Foundation for Prevention of Blindness.

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Hepatocyte growth factor/Scatter factor in the eye

Abstract

Introduction

Section snippets

The factor

The cornea

Vitreous humour

Future directions

Acknowledgements

Exp. Eye Res.

Ophthalmology

Jap. J. Ophthalmol.

Exp. Eye Res.

Lancet

FEBS Lett.

Neuron

J. Biol. Chem.

Cell. Biol. Int. Rep.

Prog. Ret. Eye Res.

Bioch. Biophys. Res. Com.

Cytokine Growth Factor Rev.

Exp. Eye Res.

Biochem. Biophys. Res. Com.

Biochem. Biophys. Res. Com.

Am. J. Ophthalmol.

J. Biol. Chem.

Biochem. Biophys. Res. Com.

J. Biol. Chem.

Biochem. Biophys. Res. Com.

Cell

Surg. Oncol.

J. Biol. Chem.

Biochem. Biophys. Res. Com.

Prog. Growth Factor Res.

Biochem. Biophys. Res. Com.

J. Biol. Chem.

Exp. Cell. Res.

Am. J. Ophthalmol.

Cell

Adv. Cancer Res.

Dev. Biol.

Chemotaxis of human keratocytes is increased by platelet-derived growth factor-BB, epidermal growth factor, transforming growth factor-alpha, acidic fibroblast growth factor, insulin-like growth factor-I, and transforming growth factor-beta

Curr. Eye Res.

Scatter factor and hepatocyte growth factor: activities, properties and mechanism

Cell. Growth Differen.

Essential role for the c-Met receptor in the migration of myogenic precursor cells to the limb bud

Nature

Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product

Science

A role for hepatocyte growth factor in diabetic retinopathy

Br. J. Ophthalmol.

Scatter factor: a possible role in proliferative vitreoretinal disease

Invest. Ophthalmol. Vis. Sci.

Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth

J. Cell. Biol.

Insulin-like growth factor (IGF-1) in aqueous humour. Study in non diabetic and diabetic patients

Invest. Ophthalmol. Vis. Sci.

Expression of the Met/HGF receptor in normal and neoplastic human tissues

Oncogene

Circular ruffle formation and closure lead to macropinocytosis in hepatocyte growth factor/scatter factor-treated cells

Eur. J. Cell. Biol.

The role of the microtubular system in the cell response to HGF/SF

J. Cell. Sci.

Expression of growth control and differentiation genes in human lens epithelial cells with extended life span

IOVS

Regional localisation of the hepatocyte growth factor (HGF) gene to human chromosome 7 band q21.1

Genomics

Comparison of biological and immunochemical properties indicates that scatter factor and hepatocyte growth factor are indistinguishable

J. Cell. Sci.

Purification of scatter factor, a fibroblast-derived basic protein that modulates epithelial interactions and movement

Proc, Natl. Acad. Sci. USA

Expression of c-met is a strong independent prognostic factor in breast carcinoma

Cancer

Different point mutations in the met oncogene elicit distinct biological properties

FASEB J.