Disease relevance of ALCAM

• We have studied MEMD/ALCAM cell-cell interactions between human melanoma cells [1].
• Surprisingly, truncation of ALCAM severely impaired MMP-2 activation in a nude mouse xenograft model, in which we previously observed diminished primary tumor growth and enhanced melanoma metastasis [2].
• CONCLUSION: ALCAM expression is commonly disturbed in prostate cancer, which might indicate a role of ALCAM in the progression of this disease [3].
• MEMD/ALCAM: a potential marker for tumor invasion and nodal metastasis in esophageal squamous cell carcinoma [4].
• OBJECTIVE: To evaluate ALCAM protein expression in breast cancer by immunohistochemistry and to correlate expression levels with clinicopathological data [5].
• Decreased/lost ALCAM membrane expression is a marker of poorer outcome in epithelial ovarian cancer patients and might help to identify patients who could benefit from more frequent follow-up or alternative therapeutic modalities [6].

High impact information on ALCAM

• Cloning, mapping, and characterization of activated leukocyte-cell adhesion molecule (ALCAM), a CD6 ligand [7].
• This antigen, which we named ALCAM (activated leukocyte-cell adhesion molecule) because of its expression on activated leukocytes, appears to be the human homologue of the chicken neural adhesion molecule BEN/SC-1/DM-GRASP [7].
• We now demonstrate that besides their role in establishing initial contacts, CD6-ALCAM interactions are also required during the proliferative phase of the T-cell response; the presence of CD6-blocking antibodies or recombinant ALCAM-Fc proteins results in a strong and sustained inhibition of T-cell proliferation [8].
• Here, we show that CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are actively recruited to the antigen-induced dendritic cell (DC)-T-cell contact zone [8].
• Altogether, these results indicate that the HCA/ALCAM surface molecule is involved in homophilic or heterophilic (with CD6) adhesive interactions between early hematopoietic progenitors and associated stromal cells in primary blood-forming organs [9].

Chemical compound and disease context of ALCAM

• This report is the first evaluation of ALCAM/CD166 in an estrogen-dependent (MCF-7) and a metastatic (MDA-MB-231) breast cancer cell line and a reference breast cell line (HBL-100) [10].
• BACKGROUND: Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a 105-kDa transmembrane glycoprotein linked with cell migration and development and with cancer progression (malignant melanoma, prostate cancer and, very recently, breast cancer) [10].

Biological context of ALCAM

• Cell adhesion assays showed that CD6-ALCAM interactions mediate thymocyte-thymic epithelium cell binding [11].
• Herein we describe the preparation of domain-specific murine CD6 Rg fusion proteins and show that the membrane-proximal SRCR (scavenger receptor cysteine-rich) domain of CD6 contains the ALCAM binding site [11].
• These findings indicate that the CD6-ALCAM interaction results in activation of the three MAPK cascades, likely influencing the dynamic balance that determines whether resting or activated lymphocytes survive or undergo apoptosis [12].
• Receptor-ligand binding assays, antibody blocking experiments, and examination of the tissue distribution of these two cell surface proteins suggest that CD6-ALCAM interactions play an important role in mediating the binding of thymocytes to thymic epithelial cells and of T cells to activated leukocytes [13].
• Recently, homophilic (ALCAM-ALCAM) adhesion was shown to play important roles in tight cell-to-cell interaction and regulation of stem cell differentiation [14].

Anatomical context of ALCAM

• Moreover, the CD6-ALCAM interaction has been shown to be critical for proper immunological synapse maturation and T cell proliferative responses [12].
• CONCLUSION: ALCAM expression on PB and SF monocytes/macrophages is enhanced by M-CSF [15].
• ALCAM is also expressed by activated leukocytes and neurons and may be involved in interactions between T cells and activated leukocytes and between cells of the immune and nervous systems, respectively [11].
• ALCAM was expressed on monocyte-lineage cells in situ in inflamed synovium from patients with RA (9 of 9), but not in uninflamed synovium from patients with joint trauma (0 of 3) [15].
• Exposure of synovial fibroblasts to other cytokines or to the superantigen staphylococcal enterotoxin A also regulated binding of CD6 fusion protein and anti-ALCAM mAb in a discordant manner [16].

Associations of ALCAM with chemical compounds

• Immunohistochemical study showed that ALCAM was expressed on endometrial luminal and glandular epithelial cells but not on the endometrial stromal cells in either the proliferative or secretory phase [14].
• PKC inhibition by chelerythrine chloride and myristoylated PKC pseudosubstrate, as well as PKC downregulation by PMA strongly reduce cytoskeleton-dependent ALCAM-mediated adhesion [17].
• Since serine and threonine residues are dispensable for ALCAM-mediated adhesion and ALCAM is not phosphorylated, we can rule out that ALCAM itself is a direct PKC substrate [17].
• Previously, six ALCAM residues were identified by alanine scanning mutagenesis to contribute to the interaction with CD6 [18].
• RESULTS: High levels of ALCAM significantly correlated with small tumor diameter (p=0.009), low tumor grade (p=0.001), and the presence of progesterone (p=0.009) and estrogen (p=0.006) receptors [19].

Physical interactions of ALCAM

• In this study, we report that the amino-terminal Ig-like domain of human ALCAM specifically binds to the third membrane-proximal scavenger receptor cysteine-rich (SRCR) domain of human CD6 [13].
• This resulted not only in the correct assembly of E-cadherin/alpha-catenin complexes at the cell membrane but also in localization of ALCAM to cell-cell contacts, indicating that indeed alpha-catenin affects ALCAM localization [20].

Regulatory relationships of ALCAM

• The reverse transition from mesenchymal invasive to a resident epithelial-like phenotype implicates a role for Tiam1/Rac signaling in the control of cell-cell contacts through a novel ALCAM-mediated mechanism [21].
• Knowledge that CD166 was expressed in normal human salivary epithelium led to these studies of CD166 and CD6 in diseased mouse salivary glands, that resemble pathology seen in the human disease, Sjögren's syndrome [22].

Other interactions of ALCAM

• Cytokine-regulated expression of activated leukocyte cell adhesion molecule (CD166) on monocyte-lineage cells and in rheumatoid arthritis synovium [15].
• RESULTS: The monocyte differentiation factors interleukin-3, macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor augmented ALCAM expression on PB monocytes [15].
• Partial sequences for the ligands of these molecules, known as CD72 and CD166 (or ALCAM), respectively, are provided for Bos taurus in this communication [23].
• In contrast, in cell lines that lack alpha-catenin expression (ALVA-31, PC-3, and PPC-1), E-cadherin-mediated adhesion is disturbed and ALCAM staining is cytoplasmic [20].
• A role of alpha-catenin in the recruitment of E-cadherin and ALCAM to cell-cell contacts was established by transfection of an alpha-N-catenin construct into cell lines ALVA-31 and PC-3 [20].

Analytical, diagnostic and therapeutic context of ALCAM

• This effect was also observed upon CD6 ligation with a chimerical ALCAM protein (ALCAM-Fc) [12].
• On the other hand, nested RT-PCR analysis demonstrated that ALCAM mRNA was expressed in human blastocysts but not in the embryos in the 8-cell or morula stages, which were obtained from patients undergoing in vitro fertilization treatment [14].
• Flow cytometry confirmed cell surface expression of ALCAM on endometrial epithelial cells [14].
• Northern blot analysis of isolated endometrial epithelial cells and stromal cells showed that ALCAM mRNA was expressed in endometrial epithelial cells [14].
• Anti-mCD6 mAb enhanced allogeneic mixed leukocyte reactions (MLR), indicating that CD6-ALCAM interactions may regulate the proliferative capacity of T cells [24].

References