Attenuation of melanoma invasion by a secreted variant of activated leukocyte cell adhesion molecule

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 NH(2)-terminal fragment, sALCAM, to test the hypothesis that ALCAM coordinates tissue growth and cell migration. Ove...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2008-05, Vol.68 (10), p.3671-3679
Hauptverfasser: van Kilsdonk, Jeroen W J, Wilting, Roel H, Bergers, Mieke, van Muijen, Goos N P, Schalkwijk, Joost, van Kempen, Léon C L T, Swart, Guido W M
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container_issue 10
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container_title Cancer research (Chicago, Ill.)
container_volume 68
creator van Kilsdonk, Jeroen W J
Wilting, Roel H
Bergers, Mieke
van Muijen, Goos N P
Schalkwijk, Joost
van Kempen, Léon C L T
Swart, Guido W M
description 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 NH(2)-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 NH(2)-terminally truncated, transmembrane variant (DeltaN-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 DeltaN-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.
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subjects Activated-Leukocyte Cell Adhesion Molecule - chemistry
Animals
Basement Membrane - metabolism
Cell Adhesion
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Leukocytes - cytology
Melanoma - pathology
Melanoma - therapy
Mice
Mice, Nude
Neoplasm Invasiveness
Neoplasm Metastasis
Neural Cell Adhesion Molecule L1 - metabolism
Protein Structure, Tertiary
title Attenuation of melanoma invasion by a secreted variant of activated leukocyte cell adhesion molecule
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