MCAM

Official Full Name

melanoma cell adhesion molecule

Organism

Homo sapiens

GeneID

4162

Background

Involved in glomerular filtration and vascular wound healing. Acts upstream of or within angiogenesis. Located in external side of plasma membrane. Biomarker of chronic obstructive pulmonary disease and uveal melanoma. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

CD146; MUC18; HEMCAM; METCAM; MelCAM;

Protein Sequence

MGLPRLVCAFLLAACCCCPRVAGVPGEAEQPAPELVEVEVGSTALLKCGLSQSQGNLSHVDWFSVHKEKRTLIFRVRQGQGQSEPGEYEQRLSLQDRGATLALTQVTPQDERIFLCQGKRPRSQEYRIQLRVYKAPEEPNIQVNPLGIPVNSKEPEEVATCVGRNGYPIPQVIWYKNGRPLKEEKNRVHIQSSQTVESSGLYTLQSILKAQLVKEDKDAQFYCELNYRLPSGNHMKESREVTVPVFYPTEKVWLEVEPVGMLKEGDRVEIRCLADGNPPPHFSISKQNPSTREAEEETTNDNGVLVLEPARKEHSGRYECQGLDLDTMISLLSEPQELLVNYVSDVRVSPAAPERQEGSSLTLTCEAESSQDLEFQWLREETGQVLERGPVLQLHDLKREAGGGYRCVASVPSIPGLNRTQLVNVAIFGPPWMAFKERKVWVKENMVLNLSCEASGHPRPTISWNVNGTASEQDQDPQRVLSTLNVLVTPELLETGVECTASNDLGKNTSILFLELVNLTTLTPDSNTTTGLSTSTASPHTRANSTSTERKLPEPESRGVVIVAVIVCILVLAVLGAVLYFLYKKGKLPCRRSGKQEITLPPSRKSELVVEVKSDKLPEEMGLLQGSSGDKRAPGDQGEKYIDLRH

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Detailed Information

The MCAM (Melanoma Cell Adhesion Molecule, also known as CD146) gene is located on chromosome 11q23.3 and encodes a single-pass transmembrane adhesion protein belonging to the immunoglobulin superfamily. Its protein structure consists of five extracellular Ig-like domains, a transmembrane segment, and a short cytoplasmic tail. MCAM mediates signal transduction by binding to ligands such as Wnt5a and Laminin-411, which activate non-receptor tyrosine kinases like FYNK and focal adhesion kinase PTK2/FAK1, triggering calcium signaling and downstream pathways.

CD146 is expressed in various cell types:

Endothelial cells: Localized at cell junctions, they maintain vascular endothelial monolayer integrity and cooperate with VE-cadherin to regulate vascular permeability.
Tumor cells: Serves as a marker of invasiveness, mediating tumor-vascular interactions and promoting hematogenous metastasis. In osteosarcoma, CD146 mRNA levels are 3.1 times higher than in normal osteoblasts, and its overexpression enhances cell migration via the RAP1/MAPK signaling pathway.
Immune cells: Specifically expressed in macrophage subpopulations, regulating their recruitment to sites of tissue injury or tumors.

In terms of transcriptional regulation, CD146 promoter activity is significantly upregulated by hypoxia-inducible factor HIF-1α and the inflammatory cytokine TNF-α, while epigenetic modifications, such as histone H3K27 deacetylation, suppress its expression.

Biological Functions and Disease Mechanisms

CD146's primary role is to integrate environmental signals and reshape cellular behavior and tissue homeostasis:

A "molecular engine" of tumor metastasis: In osteosarcoma, CD146 drives malignancy through dual mechanisms:

Activation of the FAK/PI3K pathway to promote cytoskeletal remodeling and transendothelial migration;
Induction of epithelial-mesenchymal transition (EMT), with upregulation of SNAIL and Vimentin.

A hub for immune microenvironment regulation: A study by the Key Laboratory of Tumor Immunity and Prevention in Yunnan, published in Nature Communications, revealed that MCAM deletion in mammary epithelial cells activates macrophages through the Wnt5a/Ryk axis, forming a positive feedback loop:

Low CD146 expression → Wnt5a release → Ryk receptor phosphorylation in macrophages → IL-6/TGF-β secretion → epithelial cell proliferation → breast tumor initiation.
This mechanism explains the abnormal ductal branching observed in MCAM-deficient mice.

An amplifier of chronic inflammation: In COPD patients, CD146 is persistently overexpressed as a marker of endothelial injury. Flow cytometry indicates that during acute exacerbations, peripheral blood CD146 levels are 1.8 times higher than in stable phases. This is linked to NF-κB activation induced by TNF-α. High CD146 expression promotes neutrophil adhesion to pulmonary microvascular endothelium, exacerbating airway obstruction.

Figure 1. Schematic representation of CD146 cellular localization and regulation. (Joshkon A, et al., 2020)

Clinical Applications and Targeting Strategies

CD146 holds dual clinical value as both a diagnostic marker and therapeutic target:

Prognostic models and precision therapy: A four-gene risk model based on osteosarcoma microarray data (CD146, ENPEP, LRRC1, CPE) accurately predicts metastasis and survival. CD146 carries the highest weight (HR = 1.323); patients with high CD146 expression have a 3-year survival rate of only 41%, compared to 82% in the low-expression group. The model also predicts drug sensitivity: CD146-high tumors are resistant to cytarabine (3.2-fold increase in IC50) but more sensitive to anthracyclines.

A novel target for immunotherapy: The anti-CD146 monoclonal antibody ABX-MA1 shows triple efficacy in breast cancer models:

Blocks Wnt5a/Ryk signaling, polarizing macrophages toward the antitumor M1 phenotype;
Inhibits angiogenesis (60% reduction in microvessel density);
Enhances PD-1 antibody efficacy, increasing complete tumor regression from 20% to 55%.

Intervention in inflammatory diseases: The CD146-neutralizing antibody TF-016 reduces acute exacerbation frequency in COPD. Phase II clinical trials showed a 43% reduction in exacerbation events within 6 months and a 12.5% improvement in FEV1% predicted. The mechanism involves blocking neutrophil-endothelial adhesion.

Challenges and innovative directions: One challenge in targeting CD146 is tissue specificity. New peptide-antibody conjugates, such as CD146-PDPN bispecific antibodies, enable selective targeting of tumor vasculature and reduce side effects like skin hyperpigmentation. Additionally, patient stratification based on CD146 promoter methylation status (low methylation correlates with high expression) is advancing the development of personalized therapies.

References:

Joshkon A, Heim X, Dubrou C, et al. Role of CD146 (MCAM) in Physiological and Pathological Angiogenesis-Contribution of New Antibodies for Therapy. Biomedicines. 2020 Dec 19;8(12):633.
Abou Asa S. Immunohistochemical Expression of MCAM/CD146 in Canine Melanoma. J Comp Pathol. 2017 Jul;157(1):27-33.

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