Review article
Activated leukocyte cell adhesion molecule: a new paradox in cancer

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The activated leukocyte cell adhesion molecule [ALCAM/CD166/melanoma metastasis clone D (MEMD)] is an immunoglobulin superfamily cell adhesion molecule. It is expressed developmentally in cells of all 3 embryonic lineages. The ALCAM expression is limited to subsets of cells in most adult tissues. ALCAM is localized at intercellular junctions in epithelium presumably as part of the adhesive complex that maintains tissue architecture. Over the past decade, alterations in expression of ALCAM have been reported in several human tumors (melanoma, prostate cancer, breast cancer, colorectal carcinoma, bladder cancer, and esophageal squamous cell carcinoma). This review summarizes the current knowledge of the role of ALCAM in malignancies.

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Transcriptional regulation and function

The gene encoding ALCAM is located on the long arm of human chromosome 3 (3q13.1-q13.2).14 It is organized into 16 exons that span nearly 150 kb of DNA.21 Work in our laboratory has started to provide the first insight into the transcriptional regulation of the ALCAM gene.22 The promoter is TATA-less and enriched with multiple GC-boxes in the proximal region. It contains multiple positive and negative regulatory regions, some with tissue-specific activity, which is consistent with the diametric

Melanoma

The initial studies that identified a role for ALCAM in malignancies were performed in melanoma cells and tumors; indeed, more studies have been performed on this tumor type than others (see review by Swart et al37). Studies of melanoma cell lines12 showed that expression of MEMD (ALCAM) correlated with cell–cell adhesion and therefore aggregation of tumor cells. These studies showed that homophylic ALCAM–ALCAM adhesion is essential in tumor (melanoma) cell clustering. Expression of MEMD

Prostate carcinoma

Several prostate cancer cell lines express ALCAM.42 The protein is located at cell–cell contacts (by immunocytochemistry) in DU-145 and LNCaP cells, in the cytoplasm in ALVA-31, PC-3, and PPC-1, and in multiple cellular compartments in JCA-1 and TSU-pr1 cell lines.42 Ectopic expression of α-catenin recruited ALCAM and E-cadherin to sites of cell–cell contact in ALVA-31, PC-3, and PPC-1 cell lines, which suggests a regulatory role for the catenin family in subcellular ALCAM localization.42

ALCAM

Breast cancer

ALCAM has been identified in the following breast cancer cell lines by Western blot analysis: MCF10A, MCF10AT, DCIS.com, MCF10CA Cl-A, MCF10CA Cl-D, and MDA-MB-23146 (King, unpublished results). Cell lines MCF-7 and MDA-MB-435 have weak or no detectable ALCAM protein expression (King, unpublished results) in agreement with earlier findings by Degen et al12 of weak ALCAM mRNA levels in MCF-7 cells.

Our studies offered the first analysis of ALCAM mRNA expression in breast cancer. In a study of 120

Colorectal carcinoma

Weichert et al54 evaluated the expression of ALCAM in colorectal cancer. Using immunohistochemical staining with a semiquantitative scoring system, cytoplasmic and membranous immunoreactivity were analyzed. Of the 111 colorectal carcinomas studied, 58.6% had strong cytoplasmic staining and 30.6% had strong membranous staining (compared with normal epithelium). No correlation was identified with patient age, tumor grade, stage, or nodal status. Membranous ALCAM expression correlated

Bladder cancer

Degen et al12 found strong expression of MEMD/ALCAM in the T24 bladder carcinoma cell line by Northern blot analysis for mRNA. Tomita et al55 studied the expression of ALCAM in the bladder using immunohistochemistry. Only the umbrella cells in normal bladder epithelium had positive membranous staining for ALCAM. Of 52 bladder carcinomas, 19 (36.5%) were positive for ALCAM, and those areas also showed aberrant expression of α-catenin and/or E-cadherin. ALCAM was expressed in 51.4% of high-stage

Esophageal squamous cell carcinoma

Verma et al56 reported expression of MEMD (ALCAM) in human esophageal squamous cell carcinoma. Using immunohistochemistry and semiquantitative reverse-transcription polymerase chain reaction, the investigators found that MEMD was overexpressed at both protein and mRNA levels. By immunohistochemistry, increased ALCAM expression was observed in 65% of esophageal squamous cell carcinomas and in 68% of dysplasias (compared with normal esophagus). ALCAM mRNA levels were increased in esophageal

Summary

ALCAM is a cell adhesion molecule expressed by epithelial cells in several organs. It is concentrated at sites of cell–cell contact and is associated intimately with adhesive structures that maintain the structural integrity of the epithelium in various organs. Cis-acting elements and transcription factors that regulate transcription of the ALCAM gene remain virtually unknown; however, emerging data implicate members of the rel family in ALCAM gene transactivation and AP-1 related factors in

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    Supported by grants from the American Heart Association (0655377B; to J.A.K.) and National Institutes of Health (HL077769; to S.F.O.-A.).

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