Growth factors regulate the expression profile of their syndecan co-receptors and the differentiation of mesothelioma cells.
BACKGROUND
Diffuse malignant pleural mesotheliomas are locally aggressive and highly lethal tumors that are becoming more common. The tumor derives from pluripotential mesothelial stem cells, which differentiate into epithelial or mesenchymal elements. Tumors with a predominantly epithelial growth pattern have a better prognosis than the sarcomatous and mixed types, the phenotype being important for the biology of the tumor. We have previously shown that mesotheliomas express a wide range of cell surface heparan sulfate proteoglycans (HSPGs), particularly syndecans, which interact with growth factors and matrix components.


METHODS
This study was undertaken to examine the epithelial-mesenchymal transition of mesothelioma cells by exposing epithelially-differentiated cells to an array of growth factors. Following substitution with TGF-beta 2, EGF, FGF-2, IGF-I and PDGF-BB, the expression levels of syndecans-1, -2 and -4 were monitored at selected times (30 minutes, 6 hours and 18 hours) by semi-quantitative RT-PCR and FACS analysis. The morphological appearance and proliferation rate of the treated cells was correlated to the PG profile obtained and to the subcellular compartmentalization of PGs.


RESULTS
An early response was obtained only for syndecan-4. Changes in the differentiation pattern appeared later. Exposure to EGF and IGF-I induced a fibroblast-like morphology, simultaneously with a reduced expression of syndecans-1 and 2. TGF-beta 2 enhanced the focal contacts and showed a marked up-regulation of syndecan-4 and down-regulation of syndecan-1. Interestingly, TGF-beta 2 delayed the nuclear transport of syndecan-1 concomitantly with an antiproliferative effect.


CONCLUSIONS
Growth factor signalling seems to be delicately controlled by an autoregulatory loop involving the syndecan expression levels and amounts of soluble HS chains shed into the medium.
Dobra
Katalin
K
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, F46, Huddinge University Hospital, S-14186 Huddinge, Sweden. katalin.dobra@impi.ki.se
Nurminen
Mervi
M
Hjerpe
Anders
A
D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology*; D010997:Pleural Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011509:Proteoglycans / Q000096:biosynthesis* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053668:Syndecan-1; D053669:Syndecan-2; D053671:Syndecan-4; D053667:Syndecans
D006133:Growth Substances; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508241:SDC1 protein, human; C508245:SDC2 protein, human; C508304:SDC4 protein, human; D053668:Syndecan-1; D053671:Syndecan-4; D053667:Syndecans; D053669:Syndecan-2