Coordinated expression of the vitronectin receptor and the urokinase-type plasminogen activator receptor in metastatic melanoma cells.

Abstract

Integrin avj83 is a marker of progression in malignant melanoma. Previously we reported that human melanoma cells derived from regional lymph node metastases had increased a483-mediated adhesion to lymph node vitronectin. In the present study, the expression and function of tvf33 were further investigated with emphasis on the functional relationship between a433 and the urokinase-type plasminogen activator system of proteolysis. We found that metastasesderived melanoma MeWo LNI 61 (61) and MIM/8 LNI cells had a markedly increased expression of i,1 mRNA transcripts relative to the parent lines which was reflected in significantly elevated levels of the av83 heterodimers on the cell surface. These cells also expressed elevated levels of urokinase plasminogen activator receptor (uPAR) mRNA and had higher levels of surface bound urokinase plasminogen activator as detected by immunolabeling. To determine whether the expression of uPAR and a, were linked, a, synthesis in the metastatic melanoma cells was suppressed using ae antisense phosphorothioate oligonucleotides. This resulted in a marked decrease in detectable ci, mRNA and protein and a corresponding substratum-specific reduction in cell adhesion to vitronectin. When uPAR expression in these cells was subsequently analyzed, we found a reduction of -50% in uPAR mRNA levels: On the other hand, ligation of the a413 receptor on the melanoma cells by immobilized antibody resulted in a twofold increase in uPAR mRNA. The results suggest that the expression of uPAR in metastatic melanoma cells is linked to the expression and function of the vitronectin receptor. (J. Clin. Invest. 1995. 95:2096-2103 Key words: metastasis * melanoma * integrin * vitronectin receptor * urokinase plasminogen activator receptor.

Elevated urokinase-type plasminogen activator receptor expression in a colon cancer cell line is due to a constitutively activated extracellular signal-regulated kinase-1-dependent signaling cascade

“…Secondly, the binding site can internalize urokinase that is covalently linked to its physiological inhibitor PAI-1 . Thirdly, the receptor can interact with vitronectin thereby modulating cellular adhesion (Wei et al, 1994;Nip et al, 1995).…”

Expression of αv integrins and vitronectin receptor identity in breast cancer cells

“…In melanoma, for example, the expression of avP3 correlates with invasiveness (Gehlsen et al, 1992) and there is a correlation between avP3 and tumorigenic capacity (Marshall et al, 1991;Marshall and Hart, 1996). Recently, there has been evidence of a close functional inter-relationship between members of the av subfamily and the uPA/uPAR proteolytic system (Nip et al, 1995;Stefansson and Lawrence, 1996;Yebra et al, 1996). This is of particular interest in breast cancer in which uPA (Duffy et al, 1990) and uPAR expression have been shown to correlate with prognosis (Duggan et al, 1995).…”

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

“…A 1.3-kb BamH1 CathL cDNA fragment and a 1.5-kb EcoRI-18S cDNA fragment were obtained from the pCDNA3-CathL and pCDNA3.1-18S (a gift from Dr Shafaat Rabani, McGill University, Montreal, Quebec, Canada) plasmids, respectively. The DNA fragments were recovered from agarose gel, labelled with [a-32 P]dCTP using the ReadyTo-Go DNA Labelling Beads (GE Healthcare, Baie D'Urfe, Quebec, Canada), as per the manufacturer's instructions and used to hybridize the membranes as we described previously (Nip et al, 1995;Long et al, 1998).…”