TY - JOUR
T1 - Modulation of activated leukocyte cell adhesion molecule-mediated invasion triggers an innate immune gene response in melanoma
AU - van Kilsdonk, Jeroen W J
AU - Takahashi, Nozomi
AU - Weidle, Ulrich
AU - Burtscher, Helmut
AU - Jarry, Jonathan
AU - Daha, Mohamed R
AU - Swart, Guido W M
AU - van Kempen, Léon C L T
PY - 2012
Y1 - 2012
N2 - Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a progression marker of a variety of cancers, including melanoma, and is a marker for mesenchymal stem cells. ALCAM expression triggers matrix metalloproteinase activity and correlates with the transition between superficial melanoma growth and deep dermal invasion in vivo. We previously showed that manipulating ALCAM functionality could both decrease and increase melanoma invasion, depending on the manner by which ALCAM function was altered. How ALCAM exerts these opposing invasive phenotypes remained elusive. In the present study, we analyzed differences in melanoma cell gene expression in two- and three-dimensional cultures as function of ALCAM-mediated adhesion. We identified a cluster of genes highly responsive to ALCAM functionality and relevant for melanoma invasion. This cluster is characterized by known invasion-related genes similar to L1 neuronal cell adhesion molecule and showed a remarkable induction of several innate immune genes. Unexpectedly, we identified major variations in the expression of genes related to an immunological response when modulating ALCAM function, including complement factors C1r and C1s. The expression and function of these proteinases were confirmed in protein assays and in vivo. Together, our results demonstrate a link between ALCAM functionality and the immune transcriptome, and support the assumption that ALCAM-ALCAM interactions could function as a cell signaling complex to promote melanoma tumor invasion.
AB - Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a progression marker of a variety of cancers, including melanoma, and is a marker for mesenchymal stem cells. ALCAM expression triggers matrix metalloproteinase activity and correlates with the transition between superficial melanoma growth and deep dermal invasion in vivo. We previously showed that manipulating ALCAM functionality could both decrease and increase melanoma invasion, depending on the manner by which ALCAM function was altered. How ALCAM exerts these opposing invasive phenotypes remained elusive. In the present study, we analyzed differences in melanoma cell gene expression in two- and three-dimensional cultures as function of ALCAM-mediated adhesion. We identified a cluster of genes highly responsive to ALCAM functionality and relevant for melanoma invasion. This cluster is characterized by known invasion-related genes similar to L1 neuronal cell adhesion molecule and showed a remarkable induction of several innate immune genes. Unexpectedly, we identified major variations in the expression of genes related to an immunological response when modulating ALCAM function, including complement factors C1r and C1s. The expression and function of these proteinases were confirmed in protein assays and in vivo. Together, our results demonstrate a link between ALCAM functionality and the immune transcriptome, and support the assumption that ALCAM-ALCAM interactions could function as a cell signaling complex to promote melanoma tumor invasion.
KW - Activated-Leukocyte Cell Adhesion Molecule/genetics
KW - Cell Adhesion
KW - Cell Count
KW - Complement C1r/metabolism
KW - Complement C1s/metabolism
KW - Gene Expression Profiling
KW - Humans
KW - Immunity, Innate/genetics
KW - Melanoma/genetics
KW - Microarray Analysis
KW - Neoplasm Invasiveness/genetics
KW - Neoplasm Metastasis/genetics
KW - Phenotype
KW - RNA, Messenger/metabolism
KW - Skin Neoplasms/genetics
KW - Tumor Cells, Cultured
KW - Up-Regulation
U2 - 10.1038/jid.2011.487
DO - 10.1038/jid.2011.487
M3 - Article
C2 - 22318386
SN - 0022-202X
VL - 132
SP - 1462
EP - 1470
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -