A potential role for TGFbeta in the regulation of uveal melanoma adhesive interactions with the hepatic endothelium.
OBJECTIVE
TGFbeta has been shown to have a regulatory effect on uveal melanoma invasion, but it is not known which processes are specifically influenced. The purpose of this study was to analyze the effect of TGFbeta stimulation on the adhesive interactions of uveal melanomas with the extracellular matrix (ECM) and endothelium and, in addition, its effect on the secretion of collagenases.


METHODS
Invasive and a noninvasive uveal melanoma cell lines, supported by short-term primary uveal melanoma cultures, were used to assess the effect of TGFbeta on ECM and endothelial adhesion and degradation of the ECM. Changes in cell adhesion molecule expression were assessed by flow cytometry, and conditioned media were analyzed by gelatin zymography. Assays of adhesion to ECM substrates and endothelial cells were also performed.


RESULTS
Treatment with TGFbeta increased low basal levels of adhesion molecule and latent MMP-2 expression, as well as adhesion to hepatic endothelial cells by the noninvasive cell line. Conversely, TGFbeta reduced adhesion to laminin and a laminin-binding integrin by invasive cells but had no effect on their adhesion to the endothelium.


CONCLUSIONS
In this preliminary study, TGFbeta was found to upregulate levels of MMP-2, reduce adhesion to laminin, and downregulate expression of laminin-binding integrins. Specifically, TGFbeta was found to increase adhesion of noninvasive uveal melanoma cells to the hepatic, but not the dermal, endothelium and may therefore contribute to the preferential targeting of the liver by uveal melanomas.
Woodward
Julia K L
JK
Academic Unit of Ophthalmology and Orthoptics, Division of Clinical Sciences (S), University of Sheffield, Royal Hallamshire Hospital, UK.
Rennie
Ian G
IG
Burn
J Lance
JL
Sisley
Karen
K
D030201:Activin Receptors, Type I / Q000378:metabolism; D000328:Adult; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D008099:Liver / Q000098:blood supply; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012867:Skin / Q000098:blood supply; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014604:Uveal Neoplasms / Q000378:metabolism* / Q000473:pathology
D015815:Cell Adhesion Molecules; D007797:Laminin; D011506:Proteins; D018125:Receptors, Transforming Growth Factor beta; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D020778:Matrix Metalloproteinase 2