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Attenuation of Melanoma Invasion by a Secreted Variant of Activated Leukocyte Cell Adhesion Molecule

¹ Department of Biomolecular Chemistry 271, Institute for Molecules and Materials and Nijmegen Centre for Molecular Life Sciences, Faculty of Science, Radboud University Nijmegen; and Departments of ² Dermatology and ³ Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands

Requests for reprints: Guido W.M. Swart, Department of Biomolecular Chemistry 271, Institute for Molecules and Materials and Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, the Netherlands. Phone: 31-24-3614266; Fax: 31-24-2540525; E-mail: G.Swart{at}ncmls.ru.nl.

Key Words: cell adhesion • proteolysis • tumor microenvironment • invasive growth • immunoglobulin superfamily

Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a marker of various cancers and mesenchymal stem cells, is involved in melanoma metastasis. We have exploited a secreted NH₂-terminal fragment, sALCAM, to test the hypothesis that ALCAM coordinates tissue growth and cell migration. Overexpression of sALCAM in metastatic melanoma cells disturbed clustering of endogenous ALCAM and inhibited activation of matrix metalloproteinase-2 (MMP-2). Exposure of HT1080 fibrosarcoma cells to sALCAM similarly inhibited MMP-2, suggesting a broader effect on ALCAM-positive tumor cells. In contrast to the previously reported, promotive effects of an NH₂-terminally truncated, transmembrane variant (N-ALCAM), sALCAM impaired the migratory capacity of transfected cells in vitro, reduced basement membrane penetration in reconstituted human skin equivalents, and diminished metastatic capacity in nude mice. Remarkably, L1 neuronal cell adhesion molecule (L1CAM/CD171), another progression marker of several cancers including melanoma, was suppressed upon sALCAM overexpression but was up-regulated by N-ALCAM. The partially overlapping and opposite effects induced by alternative strategies targeting ALCAM functions collectively attribute an integrative role to ALCAM in orchestrating cell adhesion, growth, invasion, and proteolysis in the tumor tissue microenvironment and disclose a therapeutic potential for sALCAM. [Cancer Res 2008;68(10):3671–9]