Cleavage of activated leukocyte cell adhesion molecule: a gateway to melanoma metastasis?

Guido WM Swart, Ph.D., LCLT van Kempen, Ph.D., MJF Kersten-Niessen

University of Nijmegen - NCMLS, 161 Biochemistry, P.O. Box 9101, NL-6500 HB Nijmegen, Netherlands

Melanoma growth proceeds from RGP, via VGP to metastasis. Intriguingly, de novo expression of ALCAM (activated leukocyte cell adhesion molecule) in VGP promotes clustering of tumor cells and raises the question why ALCAM is induced in cells that are about to leave the tumor. Interestingly, culturing metastatic cells under superconfluent conditions is accompanied by increased proteolysis, extracellular ALCAM cleavage and progressive loss of cell-cell clustering capacity. To mimic the effects of partial ALCAM cleavage we overexpressed NH2-terminally truncated ALCAM (ΔN-ALCAM) in metastatic cells expressing endogenous wild type ALCAM. The transmembrane ΔN-ALCAM (i) markedly inhibited cell clustering and increased migration in vitro, (ii) switched the phenotype in skin reconstructs from mainly epidermal, expansive growth of the primary tumor to steady migration of released cells into the dermis, and (iii) significantly reduced primary xenograft growth and accelerated formation of lung metastases in nude mice. Our data strongly suggest that the observed events of (1) ALCAM expression in VGP, (2) increased cell clustering, and (3) ALCAM cleavage are sequential steps in a cellular program that couples growth and migration and facilitates metastasis. We postulate that fully functional ALCAM in steps 1 and 2 prevents migration in favor of primary tumor growth thereby raising the migratory potential of tumor cells, so that triggering of proteolytic cascades, which causes loss of cell anchoring in step 3, induces rapid cell release into the surrounding host tissue. Remarkably, co-expression of wild-type ALCAM and ΔN-ALCAM bypasses further primary tumor growth and allows the straight passage of metastatic cells through step 3.

KEY WORDS: cell adhesion, proteolysis.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.

This presentation was a winner in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.