ALCAM (Activated Leukocyte Cell Adhesion Molecule)

2017-06-01   Esra Yavuz , Merve Oyken , Ayse Elif Erson Bensan 

Esra Yavuz: Department of Biological Sciences, Middle East Technical University, Ankara, Turkey, yavuzesra3@gmail.com; oyken.merve@metu.edu.tr; erson@metu.edu.tr

Identity

HGNC
LOCATION
3q13.11
IMAGE
Atlas Image
LEGEND
Local order of ALCAM is shown together with leading and subsequent genes on chromosome 3. The direction of arrows indicates transcriptional direction on the chromosome and arrow sizes approximate gene sizes.
LOCUSID
ALIAS
CD166,MEMD
FUSION GENES

Abstract

ALCAM (Activated Leukocyte Cell Adhesion Molecule), also known as CD166 (cluster of differentiation 166), is a member of a subfamily of immunoglobulin receptors with five immunoglobulin-like domains (VVC2C2C2) in the extracellular domain.

DNA/RNA

Atlas Image
Exons are shown as boxes, introns are shown as lines.

Description

ALCAM gene is 210,200 bp long and resides on the positive strand on DNA. The gene has a total of 16 exons.

Transcription

ALCAM gene codes for 9 transcripts, 4 of them are protein coding (4701, 4189, 2496, 1818 bp) and 5 of them are non-protein coding transcripts (2845, 1770, 1242, 783, 564 bp).

Pseudogene

No reported pseudogenes for ALCAM.

Proteins

Note

ALCAM is a glycoprotein of the immunoglobulin superfamily and has an estimated molecular weight of 100-105 kDa.
Atlas Image
Domains are shown as bars.

Expression

ALCAM is expressed in almost every tissue. Higher expression is observed in parathyroid gland. Tissues with medium ALCAM expression are cerebral cortex, cerebellum, thyroid gland, tonsil, nasopharynx, bronchus, lung, liver, gallbladder, pancreas, salivary gland, stomach, urinary bladder, kidney, epididymis, prostate, seminal vesicle, breast, cervix, uterine, endometrium and fallopian tube. Tissues with low expression are hippocampus, caudate, adrenal gland, appendix, lymph node, oral mucosa, rectum, duodenum, small intestine, colon, ovary, placenta, soft tissue and skin. Spleen, bone marrow, heart muscle, smooth muscle, skeletal muscle, esophagus, testis, vagina and adipose tissue have no ALCAM expression (The Human Protein Atlas, http://www.proteinatlas.org/).

Localisation

ALCAM protein is localized to the cell membrane (Bowen et al., 1995).

Function

ALCAM is a type-I transmembrane protein, which belongs to the immunoglobulin superfamily (Bowen et al., 1995). It constitutes 5 immunoglobulin-like domains and a short COOH-terminal cytoplasmic tail (Weidle et al., 2010). ALCAM was first shown as a ligand of CD6 on activated leukocytes (Whitney et al., 1995). Then, it was found on hematopoietic stem cells and myeloid progenitors (Swart, 2002). ALCAM-CD6 interaction mediates T-cell activation or proliferation. In addition, ALCAM-ALCAM homophilic interaction contributes to cellular changes, such as angiogenesis, immune response and cell migration during the neuronal development (van Kempen et al., 2001). The expression of ALCAM was found during organ development in the central and peripheral nervous system, sensory organs, hematopoiesis, endothelial and epithelial lineage (Swart, 2002). Furthermore, a short ALCAM transcript leads to a soluble isoform of ALCAM (sALCAM). This isoform has only one immunoglobulin-like domain (D1), which is important for ligand binding (Ikeda and Quertermous, 2004). The roles of sALCAM were considered to block hemophilic binding of ALCAM and endogenous ALCAM function (Swart, 2002). Moreover, sALCAM was also shown to inhibit tumor progression in melanoma cells (van Kilsdonk et al., 2008).

Mutations

Note

There are only a few reported mutations in ALCAM. One of the known cases is the deletion of ALCAM at 3q13.1 in a keratocystic odontogenic tumor. This mutation is thought to contribute to a matrix metalloproteinase-mediated proteolytic cascade, leading to tumor growth (Heikinheimo et al., 2007). In addition, it was reported that deletion of ALCAM might be related to craniofacial abnormalities (Simovich et al., 2008).

Epigenetics

ALCAM promoter contains several cis-acting elements including RELA (p65 NF-kB) binding motif. This motif has several CpG residues and it is highly methylated in breast cancer cells, resulting with loss of ALCAM expression (King et al., 2010). Hypermethylation of ALCAM promoter was also observed in preeclampsia placentas (Yeung et al., 2016).

Implicated in

Entity name
Acute Myeloid Leukemia (AML)
Note
CD166/ALCAM protein levels were reported to be significantly upregulated in AML cell lines and AML blasts of some patients (Strassberger et.al., 2014).
Entity name
Brain Tumors
Note
ALCAM was reported to be enriched in brain tumor cells to promote invasion (Kijima et.al., 2012). It was suggested that ALCAM/ALCAM interaction may play an important role in early stages of metastasis seeding in the brain (Soto et.al., 2014).
Entity name
Breast Cancer
Note
Loss of ALCAM expression was found to increase the invasiveness of breast cancer cells and reduced levels of ALCAM was associated with poor prognosis. ALCAM overexpression caused cell growth reduction and a decrease in adhesion to matrix and migration. Low levels of ALCAM in breast cancer cells have been linked to bone matrix adhesion, which leads to bone metastasis (Davies S. and Jiang W.G., 2010). It was suggested that high ALCAM levels were seen in normal and cancerous breast epithelial cells and loss of ALCAM expression is associated with tumor progression, accelerated cell proliferation and decrease in survival (Brandt et.al., 2014). Furthermore, low expression of ALCAM contributes to a more aggressive phenotype among African-American women (Tan et.al., 2014). Interestingly, elevated serum levels of ALCAM was found to be correlated with aggressive tumor behavior in breast cancer patients indicating that serum ALCAM may be used as a biomarker (Witzel et.al., 2012).
Entity name
Chordoma
Note
ALCAM is a positive biomarker for chordoma and might play an important role for chordoma relapse (Chen et.al., 2015).
Entity name
Cholangiocarcinoma
Note
ALCAM protein is expressed on the membranes of invasive Cholangiocarcinoma cells so that might be used as a biomarker for diagnosis, prognosis and therapy (Adisakwattana et.al., 2015).
Entity name
Endometrial Cancer
Note
ALCAM is an early stage endometrioid endometrial cancer biomarker and important in regulation of cell migration, invasion and metastasis of endometrial cancer (Devis et.al., 2016).
Entity name
Gall Bladder Cancer
Note
SNPs within ALCAM (ALCAM rs1157G>A) gene, may play a role in GBC susceptibility (Yadav et.al., 2015).
Entity name
Gastric Cancer
Note
Elevated levels of miR-9 may lead to ALCAM mRNA level reduction in SGC-7901 human gastric cancer cells (Ye et.al., 2004).
Entity name
Colorectal Cancer
Note
PROM1 (CD133) and ALCAM co-localization is seen during early stages of colon tumorigenesis, indicating well differentiation (Margaritescu et.al., 2014). ALCAM expression was detected in colon CSCs in humans and also in premalignant adenomatous polyps (Leavell et.al., 2012). Difference in cellular location of ALCAM cause differences in prognostic value and cytoplasmic expression is associated with worse prognosis outcome and CD166 expression of it, is an indicator of advanced T category and N-positive status in colorectal cancer (Ni et.al., 2013).
Entity name
Liver Cancer
Note
ALCAM and CD44 promote tumorigenesis of liver cells and might be important for therapy strategies (Ma et.al., 2014). It was also shown that the ALCAM/AKT axis regulates tumorigenesis by post-translational modifications and cytosolic accumulation of FOXO proteins in hepatoma cells (Yu et.al., 2014).
Entity name
Lung Cancer
Note
ALCAM was reported to be overexpressed in small cell lung cancers (Teicher A.B., 2014). Overexpression of ALCAM leads to malignancy in non-small cell lung carcinomas (NSCLC) (Ishiguro et.al., 2013). ALCAM expression levels were associated with smaller tumors with no lymph node metastasis in primary NSCLC lesions (Tachezy et.al., 2014).
Entity name
Melanoma
Note
High levels of ALCAM expression in primary tumors indicate poor prognosis and invasive phenotype (Donizy et.al., 2015).
Entity name
Mesothelioma
Note
ALCAM, was detected as one of the most highly upregulated genes in all 20 cell lines of Mesothelioma which may indicate that ALCAM overexpression is associated with tumor progression and ALCAM may be a target for treatment (Ishiguro et.al., 2012).
Entity name
Note
It was reported that ALCAM is associated with cell migration and invasion in myeloma cell lines (NCI-H929, JJN3, KMS-11, MM1S, OPM2, RPMI-8226, U266, and U266-LR7 (Paiva et.al., 2015).
Entity name
Nasopharyngeal Carcinoma
Note
ALCAM is a positive marker of Cancer Stem Cells and expressed in nasopharyngeal carcinoma cells (Chen et.al., 2015).
Entity name
Ovarian Cancer
Note
ALCAM levels are associated with progression-free survival in ovarian cancer cells as a MIR378A target (Chan et.al., 2014). EGFR was found to control the release of ALCAM from ovarian cancer cells via a metalloproteinase associated mechanism (Lozneanu et.al., 2015). Serum sALCAM levels were found to be significantly higher in epithelial ovarian cancer (EOC) compared to controls and elevated serum levels of sALCAM were associated with MUC16 (CA125) level and more aggressive (type II) tumors (Carbotti et.al., 2013). It was shown that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells and may be internalized after soluble ligand engagement (Nuti et.al., 2013).
Entity name
Pancreatic Cancer
Note
ALCAM is expressed in most of the pancreatic cancer lesions, but there is not any association between clinical and pathological data (Tachezy et.al., 2012). ALCAM expressing (CD166+) pancreatic cancer cells are reported to be strongly tumorigenic, but interestingly, CD166- pancreatic cancer cells show stronger invasive and migratory activities. (Fujiwara et. al., 2014). ALCAM levels are upregulated in Pancreatic Stellate Cells of pancreatic cancer tissues, which may indicate a role for ALCAM to regulate pancreatic cancer cell-pancreatic stellate cell interaction (Zhang et.al., 2016).
Entity name
Rectal Cancer
Note
It was found that ALCAM expression is upregulated after radiochemotherapy compared to pre-treatment stage in rectal cancer patients, indicating that radiochemotherapy upregulates stem cell markers in patients with rectal cancer (Deng et.al., 2014).  
Entity name
Salivary Gland Tumor
Note
ALCAM is overexpressed in both benign and malignant salivary gland tumors. ALCAM expression is associated with more aggressive behavior in malignant tumors (Andisheh-Tadbir et.al., 2015).
Entity name
Thyroid Carcinoma
Note
Elevated levels of ALCAM are associated with aggressive tumors and lymph node metastasis of thyroid carcinoma Chaker et.al., 2013).
Entity name
Other diseases
Note
Higher ALCAM expression reported in other cases are listed below:
  • Dental follicles in children (Kang et al., 2016)
  • The urine of Type I diabetes patients (Suh et al., 2015)
  • Scrub typhus patients (Otterdal et al., 2014)
  • Salivary gland epithelial cells of Sjögrens syndrome patients (Le Dantec et al., 2013)
  • Subcutaneous abdominal adipose tissue of male obese patients (Gonzalez-Muniesa et al., 2013)
  • Human immunodeficiency virus (HIV)-infected patients with diapedesis compared to HIV seronegative (Williams et al., 2014) ALCAM has been implicated in various pathologies other than cancer. For example, multiple sclerosis is speculated to be associated with genetic variations of ALCAM. (Wagner et al., 2013, Wagner et al., 2014).
    Elevated ALCAM expression could increase the recruitment of leukocytes into the microvasculature, leading to atherosclerosis (Zimmerman et al., 2006). Another study reported that ALCAM could promote heart injury (Lolyeva et.al., 2013).
    Higher ALCAM concentrations in plasma of people with acute ischemic stroke have lower survival rate (Smedbakken et al., 2011).
    Single nucleotide polymorphisms (SNPs) in ALCAM were associated with active adult-onset nonallergic asthma, Crohns disease, rheumatoid arthritis and type I diabetes (Siroux et al., 2014, Eleftherohorinou et al.,, 2009).
  • Bibliography

    Pubmed IDLast YearTitleAuthors
    221662642012CD166/activated leukocyte cell adhesion molecule is expressed on glioblastoma progenitor cells and involved in the regulation of tumor cell invasion.Kijima N et al
    259870482015ALCAM is a Novel Cytoplasmic Membrane Protein in TNF-α Stimulated Invasive Cholangiocarcinoma Cells.Adisakwattana P et al
    254725862015Clinical implication of CD166 expression in salivary gland tumor.Andisheh-Tadbir A et al
    77600071995Cloning, mapping, and characterization of activated leukocyte-cell adhesion molecule (ALCAM), a CD6 ligand.Bowen MA et al
    252703392014Loss of ALCAM expression is linked to adverse phenotype and poor prognosis in breast cancer: a TMA-based immunohistochemical study on 2,197 breast cancer patients.Burandt E et al
    231694482013Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors.Carbotti G et al
    233193402013Secretome proteins as candidate biomarkers for aggressive thyroid carcinomas.Chaker S et al
    246807692014MiR-378 as a biomarker for response to anti-angiogenic treatment in ovarian cancer.Chan JK et al
    257389232015Differential proteomic profiling of primary and recurrent chordomas.Chen S et al
    263528782015Analysis of the differential secretome of nasopharyngeal carcinoma cell lines CNE-2R and CNE-2.Chen ZT et al
    272525382016Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier.Curis C et al
    205304232010ALCAM, activated leukocyte cell adhesion molecule, influences the aggressive nature of breast cancer cells, a potential connection to bone metastasis.Davies S et al
    243270172014ALDH1 is an independent prognostic factor for patients with stages II-III rectal cancer after receiving radiochemotherapy.Deng Y et al
    278733062017Activated leukocyte cell adhesion molecule (ALCAM) is a marker of recurrence and promotes cell migration, invasion, and metastasis in early-stage endometrioid endometrial cancer.Devis L et al
    261345002015Prognostic significance of ALCAM (CD166/MEMD) expression in cutaneous melanoma patients.Donizy P et al
    199566482009Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases.Eleftherohorinou H et al
    252219992014CD166/ALCAM expression is characteristic of tumorigenicity and invasive and migratory activities of pancreatic cancer cells.Fujiwara K et al
    239751652013Differential proinflammatory and oxidative stress response and vulnerability to metabolic syndrome in habitual high-fat young male consumers putatively predisposed by their genetic background.González-Muniesa P et al
    175253552007Genetic changes in sporadic keratocystic odontogenic tumors (odontogenic keratocysts).Heikinheimo K et al
    154964152004Molecular isolation and characterization of a soluble isoform of activated leukocyte cell adhesion molecule that modulates endothelial cell function.Ikeda K et al
    231697712013Novel role for ALCAM in lymphatic network formation and function.Iolyeva M et al
    5491641978[Therapeutic results of diatherm coagluation in dysplasia, moderate intraepitelial neoplasia and carcinoma in situ].Salas O et al
    227227892012Activated leukocyte cell-adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma.Ishiguro F et al
    276562182016Comparison of Stemness and Gene Expression between Gingiva and Dental Follicles in Children.Kang CM et al
    209295682010Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer.King JA et al
    235760602013Rationale for treating primary Sjögren's syndrome patients with an anti-CD6 monoclonal antibody (Itolizumab).Le Dantec C et al
    225625382012Associations between markers of colorectal cancer stem cells and adenomas among ethnic groups.Leavell BJ et al
    263396052015Lesser-Known Molecules in Ovarian Carcinogenesis.Lozneanu L et al
    249496082014CD133/CD166/Ki-67 triple immunofluorescence assessment for putative cancer stem cells in colon carcinoma.Mărgaritescu C et al
    250940492014Cluster of differentiation 166 (CD166) regulates cluster of differentiation (CD44) via NF-κB in liver cancer cell line Bel-7402.Ma L et al
    239406742013Prognostic value of CD166 expression in cancers of the digestive system: a systematic review and meta-analysis.Ni C et al
    240444342013Selective arylsulfonamide inhibitors of ADAM-17: hit optimization and activity in ovarian cancer cell models.Nuti E et al
    230357532013HMMC-1, a human monoclonal antibody to fucosylated core 1 O-glycan, suppresses growth of uterine endometrial cancer cells.Oikawa F et al
    249958492014Increased endothelial and macrophage markers are associated with disease severity and mortality in scrub typhus.Otterdal K et al
    185360492008Delineation of the proximal 3q microdeletion syndrome.Simovich MJ et al
    243117772014Genetic heterogeneity of asthma phenotypes identified by a clustering approach.Siroux V et al
    217576612011Activated leukocyte cell adhesion molecule and prognosis in acute ischemic stroke.Smedbakken L et al
    252558612014Enhanced down-regulation of ALCAM/CD166 in African-American Breast Cancer.Tan F et al
    243116392014Functional role of endothelial adhesion molecules in the early stages of brain metastasis.Soto MS et al
    244870952014A comprehensive surface proteome analysis of myeloid leukemia cell lines for therapeutic antibody development.Strassberger V et al
    261436442015Quantitative Differences in the Urinary Proteome of Siblings Discordant for Type 1 Diabetes Include Lysosomal Enzymes.Suh MJ et al
    121134722002Activated leukocyte cell adhesion molecule (CD166/ALCAM): developmental and mechanistic aspects of cell clustering and cell migration.Swart GW et al
    227456982012ALCAM (CD166) expression and serum levels in pancreatic cancer.Tachezy M et al
    240910172014Targets in small cell lung cancer.Teicher BA et al
    252167422014ALCAM and CD6--multiple sclerosis risk factors.Wagner M et al
    235074762013ALCAM--novel multiple sclerosis locus interfering with HLA-DRB1*1501.Wagner M et al
    209527582010ALCAM/CD166: cancer-related issues.Weidle UH et al
    75430971995The membrane-proximal scavenger receptor cysteine-rich domain of CD6 contains the activated leukocyte cell adhesion molecule binding site.Whitney GS et al
    254209152015JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals.Williams DW et al
    263184302016Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility, prognosis, and survival.Yadav A et al
    253950972015Overexpression of activated leukocute cell adhesion molecule in gastric cancer is associated with advanced stages and poor prognosis and miR-9 deregulation.Ye M et al
    269685482016DNA methylation profiles in preeclampsia and healthy control placentas.Yeung KR et al
    248911172014CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT.Yu W et al
    275734192016Activated leukocyte cell adhesion molecule regulates the interaction between pancreatic cancer cells and stellate cells.Zhang WW et al
    163528062006Long-term engagement of CD6 and ALCAM is essential for T-cell proliferation induced by dendritic cells.Zimmerman AW et al
    113065702001Molecular basis for the homophilic activated leukocyte cell adhesion molecule (ALCAM)-ALCAM interaction.van Kempen LC et al
    184832492008Attenuation of melanoma invasion by a secreted variant of activated leukocyte cell adhesion molecule.van Kilsdonk JW et al

    Other Information

    Locus ID:

    NCBI: 214
    MIM: 601662
    HGNC: 400
    Ensembl: ENSG00000170017

    Variants:

    dbSNP: 214
    ClinVar: 214
    TCGA: ENSG00000170017
    COSMIC: ALCAM

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000170017ENST00000306107Q13740
    ENSG00000170017ENST00000465413H7C543
    ENSG00000170017ENST00000472644Q13740
    ENSG00000170017ENST00000486979F5GXJ9

    Expression (GTEx)

    0
    50
    100
    150
    200

    Pathways

    PathwaySourceExternal ID
    Cell adhesion molecules (CAMs)KEGGko04514
    Cell adhesion molecules (CAMs)KEGGhsa04514
    Developmental BiologyREACTOMER-HSA-1266738
    Axon guidanceREACTOMER-HSA-422475
    L1CAM interactionsREACTOMER-HSA-373760

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    181571322008Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system.125
    206066802010Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer.87
    199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
    208261542010Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract.78
    196264932009Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer.72
    239226982013Mechanisms of HIV entry into the CNS: increased sensitivity of HIV infected CD14+CD16+ monocytes to CCL2 and key roles of CCR2, JAM-A, and ALCAM in diapedesis.64
    247104102014miR-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting RhoGDI1 and ALCAM.60
    182798102008Activated leukocyte cell adhesion molecule: a new paradox in cancer.52
    211196042011MicroRNA-192 and -215 are upregulated in human gastric cancer in vivo and suppress ALCAM expression in vitro.45
    124812532003ALCAM/CD166 is up-regulated in low-grade prostate cancer and progressively lost in high-grade lesions.43

    Citation

    Esra Yavuz ; Merve Oyken ; Ayse Elif Erson Bensan

    ALCAM (Activated Leukocyte Cell Adhesion Molecule)

    Atlas Genet Cytogenet Oncol Haematol. 2017-06-01

    Online version: http://atlasgeneticsoncology.org/gene/616/alcam-(activated-leukocyte-cell-adhesion-molecule)