Gene Summary

Gene:MCAM; melanoma cell adhesion molecule
Aliases: CD146, MUC18
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cell surface glycoprotein MUC18
Source:NCBIAccessed: 09 March, 2017


What does this gene/protein do?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Western Blotting
  • DNA Methylation
  • Cancer Gene Expression Regulation
  • Young Adult
  • Disease Progression
  • PAX5 Transcription Factor
  • CpG Islands
  • Liver Cancer
  • Messenger RNA
  • Up-Regulation
  • Neoplasm Invasiveness
  • siRNA
  • Cell Proliferation
  • Transcription
  • Cell Movement
  • Chromosome 11
  • Sequence Homology, Nucleic Acid
  • Biomarkers, Tumor
  • CD Antigens
  • Base Sequence
  • Gene Expression Profiling
  • Molecular Sequence Data
  • Transfection
  • Prostate Cancer
  • Neoplasm Metastasis
  • Breast Cancer
  • Transcription Factors
  • TFAP2A
  • DNA-Binding Proteins
  • Membrane Glycoproteins
  • Apoptosis
  • MCAM
  • Cell Division
  • Melanoma
  • Antigens, CD146
  • Promoter Regions
  • Oligonucleotide Array Sequence Analysis
  • Polymerase Chain Reaction
  • Antigens, Surface
  • Immunohistochemistry
  • Cell Adhesion
Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MCAM (cancer-related)

Mohammadi M, Nejatollahi F, Ghasemi Y, Faraji SN
Anti-Metastatic and Anti-Invasion Effects of a Specific Anti-MUC18 scFv Antibody on Breast Cancer Cells.
Appl Biochem Biotechnol. 2017; 181(1):379-390 [PubMed] Related Publications
Breast cancer is the most common malignancy in women. Altered expression of MUC18, a cell surface receptor, and its interaction with Wnt-5a as its ligand, affects the motility and invasiveness of breast cancer cells. In this study, we explored the Wnt-5a binding site and designed an antigenic epitope on the MUC18 receptor using in silico methods. A specific single-chain variable fragment (scFv) was isolated against the epitope by several panning processes. The binding ability of the scFv to the related epitope was evaluated in ELISA and flow cytometry. The inhibitory effects of the selected scFv on MUC18 positive cell line, MDA-MB231, was assessed by migration and invasion assays. The results demonstrated isolation of specific scFv with frequency of 40 % which showed significant binding with the epitope in both ELISA and fluorescence-activated cell sorting (FACS) analyses. The antibody inhibited the migration (76 %) and invasion (67 %) of MUC18 positive cell line. The results suggest the specific anti-MUC18 scFv as an effective antibody for breast cancer immunotherapy.

Sun H, England CG, Hernandez R, et al.
ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer.
Eur J Nucl Med Mol Imaging. 2016; 43(12):2169-2179 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
PURPOSE: Overexpression of CD146 in solid tumors has been linked to disease progression, invasion, and metastasis. We describe the generation of a (64)Cu-labeled CD146-specific antibody and its use for quantitative immunoPET imaging of CD146 expression in six lung cancer models.
METHODS: The anti-CD146 antibody (YY146) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with (64)Cu. CD146 expression was evaluated in six human lung cancer cell lines (A549, NCI-H358, NCI-H522, HCC4006, H23, and NCI-H460) by flow cytometry and quantitative western blot studies. The biodistribution and tumor uptake of (64)Cu-NOTA-YY146 was assessed by sequential PET imaging in athymic nude mice bearing subcutaneous lung cancer xenografts. The correlation between CD146 expression and tumor uptake of (64)Cu-NOTA-YY146 was evaluated by graphical software while ex vivo biodistribution and immunohistochemistry studies were performed to validate the accuracy of PET data and spatial expression of CD146.
RESULTS: Flow cytometry and western blot studies showed similar findings with H460 and H23 cells showing high levels of expression of CD146. Small differences in CD146 expression levels were found among A549, H4006, H522, and H358 cells. Tumor uptake of (64)Cu-NOTA-YY146 was highest in CD146-expressing H460 and H23 tumors, peaking at 20.1 ± 2.86 and 11.6 ± 2.34 %ID/g at 48 h after injection (n = 4). Tumor uptake was lowest in the H522 model (4.1 ± 0.98 %ID/g at 48 h after injection; n = 4), while H4006, A549 and H358 exhibited similar uptake of (64)Cu-NOTA-YY146. A positive correlation was found between tumor uptake of (64)Cu-NOTA-YY146 (%ID/g) and relative CD146 expression (r (2) = 0.98, p < 0.01). Ex vivo biodistribution confirmed the accuracy of the PET data.
CONCLUSION: The strong correlation between tumor uptake of (64)Cu-NOTA-YY146 and CD146 expression demonstrates the potential use of this radiotracer for imaging tumors that elicit varying levels of CD146. In the future, this tool may promote enhanced monitoring of therapeutic response and improved patient stratification.

Prosen L, Hudoklin S, Cemazar M, et al.
Magnetic field contributes to the cellular uptake for effective therapy with magnetofection using plasmid DNA encoding against Mcam in B16F10 melanoma in vivo.
Nanomedicine (Lond). 2016; 11(6):627-41 [PubMed] Related Publications
AIM: We explored the distribution and cellular uptake of intratumorally injected SPIONs-PAA-PEI-pDNA (magnetofection complexes), and antitumor effectiveness of magnetofection with plasmid DNA encoding short hairpin RNA (shRNA) against Mcam (pDNA(anti-MCAM)).
MATERIALS & METHODS: Analyses were made based on the histology, ultrastructure and quantitative measurements of magnetofection complexes, and quantification of the antitumor effectiveness in B16F10 melanoma in vivo.
RESULTS: Injected magnetofection complexes were distributed around the injection site. Exposure of tumors to external magnetic field contributed to the uptake of magnetofection complexes from extracellular matrix into melanoma cells. Three consecutive magnetofections of tumors with pDNA(anti-MCAM) resulted in significant reduction of tumor volume.
CONCLUSION: Magnetofection is effective for gene delivery to melanoma tumors, but requires a magnetic field for cellular uptake and antitumor effect.

Usubutun A, Selcuk I, Boyraz G, Tuncer ZS
An incidentally diagnosed epithelioid trophoblastic tumor in hysterectomy.
Pathologica. 2015 Sep-Dec; 107(3-4):201-4 [PubMed] Related Publications
Epithelioid trophoblastic tumor is a rare non-molar gestational trophoblastic disease. A 40-year-old multiparous woman was incidentally diagnosed with epithelioid trophoblastic tumor after hysterectomy. Hysterectomy specimen revealed multiple small, tan to yellow nodules measuring 0.3-0.8 cm just below the endometrium. In the microscopic examination uniform neoplastic cells with varying cellularity were accompanied by necrotic zones and eosinophilic hyaline material. Immunohistochemically neoplastic cells were diffusely stained with CK 7, inhibin-alpha, p63, hPL, and CD146. There was no staining with beta-HCG, SMA, PLAP, or h-caldesmon. Ki-67 proliferative index was approximately 10% and cyclin E was stained in approximately 10% of the neoplastic cells. Although immunohistochemical studies are helpful in classifying gestational trophoblastic lesions, borderline values can cause diagnostic confusion between neoplastic and reactive lesions, particularly in inadequate endometrial biopsies.

Jiang G, Zhang L, Zhu Q, et al.
CD146 promotes metastasis and predicts poor prognosis of hepatocellular carcinoma.
J Exp Clin Cancer Res. 2016; 35:38 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Recurrence and metastasis after curative resection remain critical obstacles in HCC treatment. CD146 predicted poor prognosis of a variety of cancers including melanoma, breast tumors, prostate cancer, and gastric cancer. However, the role of CD146 in HCC has not yet been systematically explored.
METHODS: To investigate the role of CD146 in HCC, we evaluated its expression in HCC tissues and HCC cell lines using real-time PCR and western blotting (WB). Second, we established HCC cell lines that stably overexpressed and interfered CD146 and explored the function of CD146 in HCC in vitro and in vivo. Third, we conducted microarray analysis to investigate the potential mechanism by identifying differentially expressed genes. Last, follow ups were conducted to help uncover the connection of CD146 expression and the prognosis of HCC patients.
RESULTS: We found that CD146 was overexpressed in HCC tissues and that high CD146 expression predicted poor overall survival time and shorter recurrence period in HCC patients. In vitro and in vivo experiments indicated that CD146 promoted migration and invasion of HCC cell lines. Further study indicated that CD146 promoted epithelial mesenchymal transition (EMT), IL-8 upregulation, and STAT1 downregulation. CD146 was upregulated in HCC tissues and cell lines.
CONCLUSIONS: CD146 promoted metastasis of HCC cells and predicted poor prognosis of HCC patients. CD146 induced EMT, and IL-8 upregulation and STAT1 downregulation may be the potential underlying mechanism. The exact mechanism still needs further investigation.

Wragg JW, Finnity JP, Anderson JA, et al.
MCAM and LAMA4 Are Highly Enriched in Tumor Blood Vessels of Renal Cell Carcinoma and Predict Patient Outcome.
Cancer Res. 2016; 76(8):2314-26 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. We identified a panel of genes consistently upregulated by tumor blood vessels, of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. Cancer Res; 76(8); 2314-26. ©2016 AACR.

Wu GJ, Zeng GF
METCAM/MUC18 is a novel tumor and metastasis suppressor for the human ovarian cancer SKOV3 cells.
BMC Cancer. 2016; 16:136 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: Increased expression of METCAM/MUC18, a trans-membrane cell adhesion molecule in the Ig-like gene superfamily, has been associated with the malignant progression of epithelial ovarian carcinomas. To investigate if this is a fortuitous correlation or if METCAM/MUC18 actually plays a role in the progression of the cancer, we tested effects of enforced expression of METCAM/MUC18 on in vitro behaviors, in vivo tumorigenesis, and in vivo malignant progression of human ovarian cancer SK-OV-3 cells, which minimally expressed this protein.
METHODS: For in vitro and in vivo tests, we transfected human METCAM/MUC18 cDNA gene into SK-OV-3 cells in a mammalian expression vector pcDNA3.1+ and obtained G418-resistant (G418(R)) clones, which expressed various levels of human METCAM/MUC18. To mimic physiological situations, we used pooled METCAM/MUC18-expressing and control (vector) clones for testing effects of human METCAM/MUC18 over-expression on in vitro motility and invasiveness, and on in vivo tumor formation and metastasis in female athymic nude mice. Effects of METCAM/MUC18 on the expression of various downstream key factors related to tumorigenesis were also evaluated by Western blot analyses.
RESULTS: The over-expression of METCAM/MUC18 inhibited in vitro motility and invasiveness of SK-OV-3 cells. SK-OV-3 cells of the control (vector) clone (3D), which did not express human METCAM/MUC18, supported the formation of a solid tumor after SC injection of the cells at dorsal or ventral sites and also formation of solid tumor and ascites after IP injection in the intraperitoneal cavity of nude mice. In contrast, SK-OV-3 cells from the METCAM/MUC18-expressing clone (2D), which expressed a high level of METCAM/MUC18, did not support the formation of a solid tumor at SC sites, or formation of ascites in the intraperitoneal cavity of nude mice. Expression levels of downstream key factors, which may affect tumor proliferation and angiogenesis, were reduced in tumors induced by the METCAM/MUC18-expressing clone (2D).
CONCLUSIONS: We conclude that increased human METCAM/MUC18 expression in ovarian cancer SK-OV-3 cells suppressed tumorigenesis and ascites formation in nude mice, suggesting that human METCAM/MUC18 plays a suppressor role in the progression of ovarian cancer, perhaps by reducing proliferation and angiogenesis.

Martinez LM, Labovsky V, Calcagno Mde L, et al.
Comparative prognostic relevance of breast intra-tumoral microvessel density evaluated by CD105 and CD146: A pilot study of 42 cases.
Pathol Res Pract. 2016; 212(4):350-5 [PubMed] Related Publications
UNLABELLED: Angiogenesis is a key process for metastatic progression. While it has been established that the evaluation of breast tumoral microvessel density by CD105 marker is a potential prognostic parameter, its evaluation by CD146 marker has been poorly studied.
AIM: The purpose of this study was to compare the prognostic value of intra-tumoral microvessel density assayed by CD105 and CD146 in early breast cancer patients.
METHODS: 42 women with breast infiltrative ductal carcinoma (I and II-stages) were retrospectively reviewed. Intra-tumoral microvessel density was immunohistochemically examined using antibodies anti-CD105 and CD146 in paraffin-embedded tissues, and their association with classical prognostic-markers, metastatic recurrence, metastasis-free survival and overall survival was analyzed.
RESULTS: High microvessel density assessed by CD146 was significantly associated with a higher risk of developing metastasis (p=0.0310) and a shorter metastasis-free survival (p=0.0197). In contrast, when we used the CD105-antibody, we did not find any significant association. Finally, CD146 showed to be an independent predictive indicator for metastasis-free survival (p=0.0055).
CONCLUSION: Our data suggest that the intra-tumoral microvessel density evaluated by CD146 may be a more suitable predictor of metastatic development than that evaluated by CD105 in early breast cancer.

Kushitani K, Amatya VJ, Mawas AS, et al.
Use of Anti-Noxa Antibody for Differential Diagnosis between Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia.
Pathobiology. 2016; 83(1):33-40 [PubMed] Related Publications
OBJECTIVES: The histological differential diagnosis between epithelioid mesothelioma (EM) and reactive mesothelial hyperplasia (RMH) is not always straightforward. The aim of the present study was to search for new immunohistochemical markers to distinguish EM from RMH.
METHODS: We evaluated and compared the expression of apoptosis-related genes in EM and RMH by real-time RT-PCR array analysis followed by clustering of significant gene expression. Immunohistochemical staining and statistical analysis of Noxa expression in 81 cases of EM and 55 cases of RMH were performed and compared with the utility of other previously reported antibodies such as Desmin, EMA, GLUT-1, IMP-3 and CD146.
RESULTS: Noxa mRNA expression levels were found to be increased in EM when compared to RMH by RT-PCR array analysis. In the immunohistochemical analysis, Noxa showed sensitivity of 69.0%, specificity of 93.6% and positive predictive value of 93.0% as a positive marker of EM in distinguishing it from RMH, and these values were almost similar to IMP-3.
CONCLUSION: Noxa is a marker with relatively high specificity, and can be used to distinguish EM from RMH. It would be a valuable addition to the current antibody panel used for the differential diagnosis of EM and RMH.

Kawai T, Tominaga S, Hiroi S, et al.
Peritoneal malignant mesothelioma (PMM), and primary peritoneal serous carcinoma (PPSC) and reactive mesothelial hyperplasia (RMH) of the peritoneum. Immunohistochemical and fluorescence in situ hybridisation (FISH) analyses.
J Clin Pathol. 2016; 69(8):706-12 [PubMed] Related Publications
AIMS: Peritoneal malignant mesothelioma (PMM) is an uncommon tumour, accounting for only 7-9% of all mesotheliomas in Japan. Differential diagnosis between PMM and primary peritoneal serous carcinoma (PPSC), a high-grade serous carcinoma, may be difficult, and separating reactive mesothelial hyperplasia (RMH) from PMM can be even more challenging.
METHODS: To help differentiate PMM from PPSC and RMH, we used immunohistochemistry to examine mesothelial-associated markers (calretinin, AE1/AE3, CK5/6, CAM5.2, D2-40, WT-1, HBME1, thrombomodulin), adenocarcinoma-associated markers (CEA, BerEP4, MOC31, ER (estrogen receptor), PgR, TTF-1, Claudin-4, Pax8), and malignant-related and benign-related markers (epithelial membrane antigen (EMA), desmin, GLUT-1, CD146 and IMP3), and FISH to examine for homozygous deletion of 9p21. We used formalin-fixed, paraffin-embedded blocks from 22 PMMs (M:F=18:4; subtypes: 16 epithelioid, 6 biphasic), 11 PPSCs and 23 RMHs.
RESULTS: Seventeen of the mesotheliomas (four PMM from women) were classified as diffuse, while five were localised. Calretinin was 91% positive in PMM, but negative in PPSC (specificity, 100%). BerEP4, Claudin-4 and PAX8 were all 100% positive in PPSC (specificities, 100%, 95% and 95%, respectively, for excluding PMM). For distinguishing PMM and RMH, sensitivity for EMA in mesothelioma was 68%, while for IMP3 and GLUT-1 it was 64% and 50%, respectively, all with high specificities. FISH analysis revealed homozygous deletion of the 9p21 locus in 11/13 PMMs, but in 0/11 RMHs.
CONCLUSIONS: Calretinin and BerEP4 may be the best positive markers for differentiating PMM from PPSC. EMA, in combination with IMP3 and desmin, is useful, and homozygous deletion of 9p21 may be helpful, for differentiating PMM from RMH.

Schneck H, Gierke B, Uppenkamp F, et al.
EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer.
PLoS One. 2015; 10(12):e0144535 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Circulating tumor cells (CTCs) are the potential precursors of metastatic disease. Most assays established for the enumeration of CTCs so far-including the gold standard CellSearch-rely on the expression of the cell surface marker epithelial cell adhesion molecule (EpCAM). But, these approaches may not detect CTCs that express no/low levels of EpCAM, e.g. by undergoing epithelial-to-mesenchymal transition (EMT). Here we present an enrichment strategy combining different antibodies specific for surface proteins and extracellular matrix (ECM) components to capture an EpCAMlow/neg cell line and EpCAMneg CTCs from blood samples of breast cancer patients depleted for EpCAM-positive cells. The expression of respective proteins (Trop2, CD49f, c-Met, CK8, CD44, ADAM8, CD146, TEM8, CD47) was verified by immunofluorescence on EpCAMpos (e.g. MCF7, SKBR3) and EpCAMlow/neg (MDA-MB-231) breast cancer cell lines. To test antibodies and ECM proteins (e.g. hyaluronic acid (HA), collagen I, laminin) for capturing EpCAMneg cells, the capture molecules were first spotted in a single- and multi-array format onto aldehyde-coated glass slides. Tumor cell adhesion of EpCAMpos/neg cell lines was then determined and visualized by Coomassie/MitoTracker staining. In consequence, marginal binding of EpCAMlow/neg MDA-MB-231 cells to EpCAM-antibodies could be observed. However, efficient adhesion/capturing of EpCAMlow/neg cells could be achieved via HA and immobilized antibodies against CD49f and Trop2. Optimal capture conditions were then applied to immunomagnetic beads to detect EpCAMneg CTCs from clinical samples. Captured CTCs were verified/quantified by immunofluorescence staining for anti-pan-Cytokeratin (CK)-FITC/anti-CD45 AF647/DAPI. In total, in 20 out of 29 EpCAM-depleted fractions (69%) from 25 metastatic breast cancer patients additional EpCAMneg CTCs could be identified [range of 1-24 CTCs per sample] applying Trop2, CD49f, c-Met, CK8 and/or HA magnetic enrichment. EpCAMneg dual-positive (CKpos/CD45pos) cells could be traced in 28 out of 29 samples [range 1-480]. By single-cell array-based comparative genomic hybridization we were able to demonstrate the malignant nature of one EpCAMneg subpopulation. In conclusion, we established a novel enhanced CTC enrichment strategy to capture EpCAMneg CTCs from clinical blood samples by targeting various cell surface antigens with antibody mixtures and ECM components.

Bai Q, Liu L, Long Q, et al.
Decreased expression of mucin 18 is associated with unfavorable postoperative prognosis in patients with clear cell renal cell carcinoma.
Int J Clin Exp Pathol. 2015; 8(9):11005-14 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: MUC18 is correlated with tumor progression and metastasis in types of malignancy. But the role of MUC18 in clear cell renal cell carcinoma remains unclear. In this study, we aimed to investigate the expression of MUC18 and its correlation with clinical outcomes in clear cell renal cell carcinoma.
PATIENTS AND METHODS: Immunohistochemical staining was performed in samples from 288 patients with clear cell renal cell carcinoma. We used Kaplan-Meier method and Cox proportional hazard models to value the association between MUC18 expression and clinical outcome. Nomogram was constructed to predict overall survival at 5 and 8 years after nephrectomy.
RESULTS: MUC18 expression was significantly decreased in tumor compared to non-tumor tissue (P<0.001). Lower MUC18 expression in tumor predicted a shorter survival time (P=0.007). By multivariate cox analysis, MUC18 was defined as an independent prognostic factor (P=0.006). The nomogram performed better in predicting 5- and 8-year overall survival than the TNM stage alone in clear cell renal cell carcinoma.
CONCLUSION: MUC18 is an independent prognostic factor for clear cell renal cell carcinoma and could be incorporated with the other parameters to predict 5- and 8-year overall survival for clear cell renal cell carcinoma patients.

Yang Y, Hernandez R, Rao J, et al.
Targeting CD146 with a 64Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas.
Proc Natl Acad Sci U S A. 2015; 112(47):E6525-34 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Given the highly heterogeneous character of brain malignancies and the associated implication for its proper diagnosis and treatment, finding biomarkers that better characterize this disease from a molecular standpoint is imperative. In this study, we evaluated CD146 as a potential molecular target for diagnosis and targeted therapy of glioblastoma multiforme (GBM), the most common and lethal brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and radiolabeled for noninvasive positron-emission tomography (PET) imaging of orthotopic GBM models. (64)Cu-labeled YY146 preferentially accumulated in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of high-contrast PET images of small tumor nodules (∼ 2 mm). Additionally, we found that tumor uptake correlated with the levels of CD146 expression in a highly specific manner. We also explored the potential therapeutic effects of YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) properties of U87MG cells, demonstrating that YY146 can mitigate those aggressive phenotypes. Using YY146 as the primary antibody, we performed histological studies of World Health Organization (WHO) grades I through IV primary gliomas. The positive correlation found between CD146-positive staining and high tumor grade (χ(2) = 9.028; P = 0.029) concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and validated the clinical value of YY146. In addition, we demonstrate that YY146 can be used to detect CD146 in various cancer cell lines and human resected tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung), indicating a broad applicability of YY146 in solid tumors.

Wei Q, Tang YJ, Voisin V, et al.
Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma.
Oncotarget. 2015; 6(37):40283-94 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Tumor-propagating cells (TPCs) are believed to drive cancer initiation, progression and recurrence. These cells are characterized by enhanced tumorigenicity and self-renewal. The ability to identify such cells in primary human sarcomas relies on the dye exclusion ability of tumor side population (SP) cells. Here, we performed a high-throughput cell surface antigen screen and found that CD146 is enriched in the SP population. In vivo serial transplantation assays showed that CD146+ cells are highly tumorigenic, capable of self-renewal and thus enriches for the TPC population. In addition, depletion of SP cells from the CD146+ population show that CD146+ cells and SP cells are a distinct and overlapping TPC populations. Gene expression profiling of CD146+ and SP cells revealed multiple pathways commonly upregulated in both of these populations. Inhibition of one of these upregulated pathways, Notch signaling, significantly reduced tumor growth and self-renewal. Our data demonstrate that CD146 is an effective cell surface marker for enriching TPCs in primary human sarcomas. Targeting differentially activated pathways in TPCs may provide new therapeutic strategies for treating sarcoma.

Luo YH, Tseng PC, Lee YC, et al.
A prospective study of the use of circulating markers as predictors for epidermal growth factor receptor-tyrosine kinase inhibitor treatment in pulmonary adenocarcinoma.
Cancer Biomark. 2016; 16(1):19-29 [PubMed] Related Publications
BACKGROUND: The use of liquid tissue, such as circulating cells, to predict treatment response is attracting more attention.
OBJECTIVE: The aim of this study was to evaluate association between circulating markers and treatment response.
METHODS: One hundred and twelve advanced pulmonary adenocarcinoma patients who were going to receive epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were included. Tumor tissue and plasma specimens were collected before treatment and analyzed for EGFR mutation and plasma IL-6 and IL-8. Pre-treatment peripheral blood CD146+/CD3- cells (as circulating endothelial cells, CECs), CD34+/CD45- cells (as endothelial progenitor cells, EPCs), and CD133+ cells (as cancer stem cells, CSCs) were measured with flow cytometry.
RESULTS: The progression-free survival (PFS) was significantly longer in patients with low CEC, low EPC, and low CSC counts than in those with high cell counts (p < 0.001, 0.041, and 0.001, respectively). Multivariate analysis showed that mutant plasma EGFR (pEGFR) was a poor prognostic factor in EGFR-mutated patients (p = 0.048), and there was a tendency for EGFR mutation-negative patients with high IL-6 level to have worse overall survival (p = 0.051).
CONCLUSIONS: CECs, EPCs, CSCs, and mutant pEGFR are useful predictive biomarkers of EGFR-TKI treatment efficacy. IL-6 may predict prognosis in advanced lung cancer.

Bande MF, Santiago M, Muinelo-Romay L, et al.
Detection of circulating melanoma cells in choroidal melanocytic lesions.
BMC Res Notes. 2015; 8:452 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
PURPOSE: To detect and quantify circulating tumour cells (CTCs) in peripheral blood of patients with uveal melanoma primary non-metastatic tumours, and to analyze the possible relationship between CTCs and clinical risk factors.
METHODS: Prospective study with two clinical groups: 4 patients diagnosed with choroidal nevus and 8 patients with choroidal melanoma prior to treatment. A single sample of 7.5 mL of peripheral blood was taken and the CTCs were isolated using a CellSearch system that captures positive cells for the CD146 antigen (MUC18).
RESULTS: None of the patients with choroidal nevus showed CTCs in peripheral blood. More than one CTC/7.5 mL was detected in 50 % of patients with choroidal melanoma prior to treatment. The higher level of CTC cells in peripheral blood (3/7.5 mL) was detected in the patient with the larger choroidal melanoma which also presented extrascleral extension and epithelioid pathology.
CONCLUSION: Performing an analysis with the CellSearch system allows to quantify the choroidal melanoma CTCs in peripheral blood. This finding highlights the potential usefulness of this technique to achieve the correct stratification and monitoring of the treatment.

Zhou Y, Huang H, Yuan LJ, et al.
CD146 as an adverse prognostic factor in uterine sarcoma.
Eur J Med Res. 2015; 20:67 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: Uterine sarcoma is an aggressive malignancy with a poor prognosis. This study aimed to determine the expression of CD146, P53, and Ki-67 in uterine sarcoma and to evaluate their prognostic significance.
METHODS: We retrospectively analyzed the prognosis and clinicopathologic features of 68 patients with uterine sarcoma. Immunohistochemical analyses of CD146, P53, and Ki-67 were performed in tissue samples collected from these patients and their relationship with prognosis was investigated.
RESULTS: The 5-year overall survival (OS) rate was 46 %. Endometrial stromal sarcoma (ESS) patients had a better prognosis than leiomyosarcoma (LMS) patients, with a 2-year survival rate of 82 %. The membrane and cytoplasm of tumor cells exhibited CD146 overexpression in 8 (32 %) ESS cases, which was less than the 25 (69.4 %) cases observed in LMS and 2 (28.6 %) in MMMT. CD146 overexpression in the membrane and cytoplasm of tumor cells was closely related to lymph node metastasis (P = 0.021) and Ki-67 overexpression (P = 0.0053); there was no significant correlation with age, tumor size, International Federation of Obstetrics and Gynecology stage, or P53 overexpression in LMS.
CONCLUSIONS: CD146, P53, and Ki-67 are overexpressed in uterine sarcoma. CD146 expression correlates with lymph node metastasis and is associated with poor OS in LMS; it may be a potential prognostic marker for LMS.

Correa D, Somoza RA, Lin P, et al.
Mesenchymal stem cells regulate melanoma cancer cells extravasation to bone and liver at their perivascular niche.
Int J Cancer. 2016; 138(2):417-27 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Skeleton and liver are preferred organs for cancer dissemination in metastatic melanoma negatively impacting quality of life, therapeutic success and overall survival rates. At the target organ, the local microenvironment and cell-to-cell interactions between invading and resident stromal cells constitute critical components during the establishment and progression of metastasis. Mesenchymal stem cells (MSCs) possess, in addition to their cell progenitor function, a secretory capacity based on cooperativity with other cell types in injury sites including primary tumors (PT). However, their role at the target organ microenvironment during cancer dissemination is not known. We report that local MSCs, acting as pericytes, regulate the extravasation of melanoma cancer cells (MCC) specifically to murine bone marrow (BM) and liver. Intra-arterially injected wild-type MCC fail to invade those selective organs in a genetic model of perturbed pericyte coverage of the vasculature (PDGF-B(ret/ret)), similar to CD146-deficient MCC injected into wild type mice. Invading MCC interact with resident MSCs/pericytes at the perivascular space through co-expressed CD146 and Sdf-1/CXCL12-CXCR4 signaling. Implanted engineered bone structures with MSCs/pericytes deficient of either Sdf-1/CXCL12 or CD146 become resistant to invasion by circulating MCC. Collectively, the presence of MSCs/pericytes surrounding the target organ vasculature is required for efficient melanoma metastasis to BM and liver.

Jang MH, Kim HJ, Kim EJ, et al.
Expression of epithelial-mesenchymal transition-related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome.
Hum Pathol. 2015; 46(9):1267-74 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) is a heterogeneous group of disease with a well-known association with epithelial-mesenchymal transition (EMT) and breast cancer stem cell phenotype. Recent studies have shown that TNBC can be classified into 6 subtypes, including basal-like, mesenchymal-like, and mesenchymal stem-like subtypes. However, clinical significance of the EMT in TNBC remains unclear. We analyzed immunohistochemical expression of EMT-related markers, including EMT markers (expression of vimentin, smooth muscle actin, osteonectin, and N-cadherin; loss of E-cadherin), EMT inducers (ZEB1 and CD146), and breast cancer stem cell markers (CD44(+)/CD24(-) and aldehyde dehydrogenase 1) in 173 TNBCs and correlated their expression with clinicopathological features of the tumors, including clinical outcome. Expressions of vimentin, CD44(+)/CD24(-), and CD146 were more frequent in basal-like TNBCs than non-basal-like TNBCs. Whereas CD146 expression was closely associated with the expression of various EMT markers and CD44(+)/CD24(-) phenotype, ZEB1 expression correlated only with the expression of smooth muscle actin. Expressions of vimentin, smooth muscle actin, osteonectin, and ZEB1 and loss of E-cadherin were more frequently found in metaplastic carcinomas than in other histologic subtypes. In survival analyses, EMT markers were not associated with patients' clinical outcomes. However, ZEB1 expression was found to be an independent prognostic factor for poor disease-free survival. These findings indicate that expression of EMT-related markers in TNBCs can be a signature of a certain subgroup of TNBC, which is associated with metaplastic carcinoma, and ZEB1 expression can serve as a potential biomarker to define a subgroup of TNBC associated with poor clinical outcomes.

Friedlander LT, Hussani H, Cullinan MP, et al.
VEGF and VEGFR2 in dentigerous cysts associated with impacted third molars.
Pathology. 2015; 47(5):446-51 [PubMed] Related Publications
The aims of this study were to determine the presence and distribution of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR2) in dentigerous cysts compared with normal dental follicles as a control tissue and to evaluate endothelial cells and proliferating cells as indicators of angiogenic activity in these tissues.Twenty specimens histologically diagnosed as dentigerous cysts and 20 dental follicle specimens were included. Immunohistochemistry (IHC) using anti-VEGF and anti-VEGFR2 antibodies stained for the growth factor and its receptor, while anti-CD34 and anti-CD146 antibodies were used to identify endothelial cells. Anti-proliferating cell nuclear antigen (PCNA) antibody detected proliferating cells within the specimens. Slides were examined microscopically and results evaluated using kappa statistics, negative binomial regression and ordinal logistic regression.The mean age for patients with dentigerous cysts was 23 years and they were more common in males. Proteins for VEGF, VEGFR2, PCNA, CD34, and CD146 were expressed in all dentigerous cysts and dental follicles. VEGF and VEGFR2 were expressed on several cell types within the tissues, however there was a significantly greater percentage of positive staining in dentigerous cysts compared with dental follicles (odds ratio = 31.24, p < 0.001). CD34(+), CD146(+), and PCNA(+) cells were observed in both dentigerous cysts and dental follicles but for all markers there were significantly more positive cells in dentigerous cysts (p < 0.001); this was especially evident in cases associated with inflammation. PCNA was seen in most endothelial cells lining small thin walled blood vessels suggesting endothelial proliferation. There was a high level of intra- and inter-examiner agreement (kappa 0.77 and 0.75, respectively).VEGF and VEGFR2 and angiogenic activity are present in dental follicles and dentigerous cysts and may contribute to local bone resorption for tooth eruption or the development and progression of dentigerous cysts.

Shen J, Shrestha S, Yen YH, et al.
Pericyte antigens in angiomyolipoma and PEComa family tumors.
Med Oncol. 2015; 32(8):210 [PubMed] Related Publications
Perivascular epithelioid cell tumors (PEComas) are an uncommon family of soft tissue tumors with dual myoid-melanocytic differentiation. Although PEComa family tumors commonly demonstrate a perivascular growth pattern, pericyte antigen expression has not yet been examined among this unique tumor group. Previously, we demonstrated that a subset of perivascular soft tissue tumors exhibit a striking pericytic immunophenotype, with diffuse expression of αSMA, CD146, and PDGFRβ. Here, we describe the presence of pericyte antigens across a diverse group of PEComa family tumors (n = 19 specimens). Results showed that pericyte antigens differed extensively by histological appearance. Typical angiomyolipoma (AML) specimens showed variable expression of pericyte antigens among both perivascular and myoid-appearing cells. In contrast, AML specimens with a predominant spindled morphology showed diffuse expression of pericyte markers, including αSMA, CD146, and PDGFRβ. AML samples with predominant epithelioid morphology showed a marked reduction in or the absence of immunoreactivity for pericyte markers. Lymphangiomyoma samples showed more variable and partial pericyte marker expression. In summary, pericyte antigen expression is variable among PEComa family tumors and largely varies by tumor morphology. Pericytic marker expression in PEComa may represent a true pericytic cell of origin, or alternatively aberrant pericyte marker adoption. Markers of pericytic differentiation may be of future diagnostic utility for the evaluation of mesenchymal tumors, or identify actionable signaling pathways for future therapeutic intervention.

Najjar F, Al-Massarani G, Banat I, Alammar M
Circulating endothelial cells for evaluation of tumor response in non-small cell lung cancer patients receiving first-line chemotherapy.
Int J Biol Markers. 2015; 30(4):e374-81 [PubMed] Related Publications
BACKGROUND: Circulating endothelial cells (CECs) reflect the neovascularization in the tumor mass. We therefore investigated the potential role of CEC kinetics after first-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients.
METHODS: Peripheral blood samples were obtained from 45 healthy subjects and 51 naïve patients with advanced NSCLC. Quantification of CD146+ CECs was performed using immunomagnetic separation (IMS).
RESULTS: Pretreatment and posttreatment CEC levels in NSCLC patients were significantly higher than in healthy subjects (p<0.0001). An objective response was achieved after chemotherapy with partial response (PR) or stable disease (SD) in 26 patients, whereas the remaining 25 patients had progressive disease (PD). Baseline CEC levels were significantly higher in PR/SD patients than in PD patients (p = 0.039). After chemotherapy, CEC count significantly decreased in PR/SD patients (p = 0.014) and increased in patients with PD (p = 0.019). Moreover, there was a significant difference in the percentage change of CEC counts between the 2 groups (p = 0.0016). No significant difference in the median progression-free survival and overall survival (OS) was observed between patients with high baseline CEC counts and those with low baseline CEC levels. However, patients with high percentage change in CEC count had longer OS than those with low percentage change after chemotherapy (p = 0.05).
CONCLUSIONS: Changes in CEC counts after chemotherapy reflect tumor response in advanced NSCLC patients. Moreover, high percentage changes in CEC counts after chemotherapy may predict longer OS in advanced NSCLC. High baseline CEC levels might be an indicator of tumor response in advanced NSCLC patients after first-line chemotherapy.

Patenaude A, Woerher S, Umlandt P, et al.
A novel population of local pericyte precursor cells in tumor stroma that require Notch signaling for differentiation.
Microvasc Res. 2015; 101:38-47 [PubMed] Related Publications
Pericytes are perivascular support cells, the origin of which in tumor tissue is not clear. Recently, we identified a Tie1(+) precursor cell that differentiates into vascular smooth muscle, in a Notch-dependent manner. To understand the involvement of Notch in the ontogeny of tumor pericytes we used a novel flow immunophenotyping strategy to define CD146(+)/CD45(-)/CD31(-/lo) pericytes in the tumor stroma. This strategy combined with ex vivo co-culture experiments identified a novel pericyte progenitor cell population defined as Sca1(hi)/CD146(-)/CD45(-)/CD31(-). The differentiation of these progenitor cells was stimulated by co-culture with endothelial cells. Overexpression of the Notch ligand Jagged1 in endothelial cells further stimulated the differentiation of Sca1(hi)/CD146(-)/CD45(-)/CD31(-) cells into pericytes, while inhibition of Notch signaling with a γ-secretase inhibitor reduced this differentiation. However, Notch inhibition specifically in Tie1-expressing cells did not change the abundance of pericytes in tumors, suggesting that the pericyte precursor is distinct from the vascular smooth muscle cell precursor. Transplant experiments showed that the bone marrow contributes minimally to tumor pericytes. Immunophenotyping revealed that Sca1(hi)/CD146(-)/CD45(-)/CD31(-) cells have greater potential to differentiate into pericytes and have increased expression of classic mesenchymal stem cell markers (CD13, CD44, Nt5e and Thy-1) compared to Sca1(-/lo)/CD146(-)/CD45(-)/CD31(-) cells. Our results suggest that a local Sca1(hi)/CD146(-)/CD45(-)/CD31(-) pericyte progenitor resides in the tumor microenvironment and requires Notch signaling for differentiation into mature pericytes.

Shen J, Shrestha S, Yen YH, et al.
Pericyte Antigens in Perivascular Soft Tissue Tumors.
Int J Surg Pathol. 2015; 23(8):638-48 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
INTRODUCTION: Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear line of differentiation, although most are presumed to originate from pericytes or modified perivascular cells. Among these, glomus tumor, myopericytoma, and angioleiomyoma share a spectrum of histologic findings and a perivascular growth pattern. In contrast, solitary fibrous tumor (previously termed hemangiopericytoma) was once hypothesized to have pericytic differentiation.
METHODS: Here, we systematically examine pericyte immunohistochemical markers among glomus tumor (including malignant glomus tumor), myopericytoma, angioleiomyoma, and solitary fibrous tumor. Immunohistochemical staining and semiquantification was performed using well-defined pericyte antigens, including αSMA, CD146, and PDGFRβ.
RESULTS: Glomus tumor and myopericytoma demonstrate diffuse staining for all pericyte markers, including immunohistochemical reactivity for αSMA, CD146, and PDGFRβ. Malignant glomus tumors all showed some degree of pericyte marker immunoreactivity, although it was significantly reduced. Angioleiomyoma shared a similar αSMA + CD146 + PDGFRβ+ immunophenotype; however, this was predominantly seen in the areas of perivascular tumor growth. Solitary fibrous tumors showed patchy PDGFRβ immunoreactivity only.
DISCUSSION: In summary, pericyte marker expression is a ubiquitous finding in glomus tumor, myopericytoma, and angioleiomyoma. Malignant glomus tumor shows a comparative reduction in pericyte marker expression, which may represent partial loss of pericytic differentiation. Pericyte markers are essentially not seen in solitary fibrous tumor. The combination of αSMA, CD146, and PDGFRβ immunohistochemical stainings may be of utility for the evaluation of pericytic differentiation in soft tissue tumors.

Yuan DM, Zhang Q, Lv YL, et al.
Predictive and prognostic significance of circulating endothelial cells in advanced non-small cell lung cancer patients.
Tumour Biol. 2015; 36(11):9031-7 [PubMed] Related Publications
The aim of this study was to evaluate the predictive and prognostic values of circulating endothelial cells (CECs) in patients with advanced non-small cell lung cancer (NSCLC). A total of 102 newly diagnosed advanced NSCLC patients were enrolled in this study. The amount of CECs was enumerated by flow cytometry (CD45- CD31+ CD146+) at baseline. CEC counts of 56 patients were detected before and after two cycles of chemotherapy. We correlated the baseline and reduction of CECs after therapy with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The CEC level was significantly higher in advanced NSCLC patients, ranging from 57 to 1300 cells/10(5) cells (mean ± SD = 299 ± 221 cells/10(5) cells), than in patients with benign lesions (205 ± 97 cells/10(5) cells) and healthy volunteers (117 ± 33 cells/10(5) cells). When the cutoff value of CEC counts was 210 cells/10(5) cells, there was no significant association between CEC counts and OR/PFS/OS of the enrolled patients. However, patients with CEC response after chemotherapy have more chances to achieve OR (P < 0.001), and such patients showed longer PFS (P = 0.048) and OS (P = 0.018) than those without CEC response. In the multivariate analysis, the independent prognostic roles of brain metastasis (HR 6.165, P = 0.001), and CEC response (HR 0.442, P = 0.044) were found. The CEC counts could be considered as diagnostic biomarker for advanced NSCLC patients. And the reduction of CECs after treatment might be more ideal than the baseline CEC counts as a predictive or prognostic factor in patients treated with chemotherapy or anti-angiogenic therapy.

Roland CL, Ross MI, Hall CS, et al.
Detection of circulating melanoma cells in the blood of melanoma patients: a preliminary study.
Melanoma Res. 2015; 25(4):335-41 [PubMed] Related Publications
Significant prognostic heterogeneity exists within the substages of melanoma; therefore, novel prognostic biomarkers are needed to provide information on the risk of recurrence. Limited available data suggest prognostic significance for circulating melanoma cells (CMCs); there is a need for a sensitive, reproducible, and standardized identification technique. Using a semiautomated technology, we sought to determine whether CMCs could be identified reliably in stage I-IV melanoma patients and whether the presence of CMC correlated with known prognostic factors. CMCs were detected in the peripheral blood (7.5 ml) of patients with stage I-IV melanoma (n=89) using the CellSearch system. CD146 cells were immunomagnetically enriched; nucleated HMW-MAA/CD45/CD34 cells were considered CMCs. One or more CMCs was detected in 45% of all patients, varying with stage of disease (stages I/II, III, and IV: 35, 44, and 86%, respectively; P=0.03, for stage I/II vs. stage IV); 55% had one CMC, 32% had two CMCs, and 13% had three or more CMCs identified. The presence of CMCs in the blood was associated with histologic subtype, particularly in patients with stage I/II disease (superficial spreading 18% vs. acral lentiginous 75%). Using a semiautomated technique, CMCs can be identified in a significant number of melanoma patients. These data support further study with longer follow-up and longitudinal/serial time points to better determine the identification rates and prognostic significance of CMCs in stage I-IV melanoma patients.

Tang X, Chen X, Xu Y, et al.
CD166 positively regulates MCAM via inhibition to ubiquitin E3 ligases Smurf1 and βTrCP through PI3K/AKT and c-Raf/MEK/ERK signaling in Bel-7402 hepatocellular carcinoma cells.
Cell Signal. 2015; 27(9):1694-702 [PubMed] Related Publications
Both Cluster of Differentiation 166 (CD166) and Melanoma Cell Adhesion Molecule (MCAM) play critical roles in maintaining transformative phenotype of Hepatocellular Carcinoma (HCC) cells. However, the relationship between these two membrane proteins remains unknown. Here, we found that CD166 has a positive impact on the expression of MCAM, while MCAM has no feedback on CD166. Tissue microarray analysis (TMA) also showed a positive correlation between CD166 and MCAM. Depletion of CD166-induced anti-carcinogenic phenotype could be reversed by overexpression of MCAM, suggesting MCAM is functional important in the CD166-induced liver tumorigenesis. Furthermore, we found CD166 regulates MCAM mainly through protecting MCAM from ubiquitin-mediated protein degradation. Mechanically, CD166 down-regulated two ubiquitin E3 ligases, βTrCP and Smurf1, which play critical roles in the destability of MCAM protein. In addition, overexpression of βTrCP and Smurf1-reduced transformative phenotype could be partially reversed by MCAM, providing evidence that MCAM is a target of βTrCP and Smurf1. Moreover, we identified c-Raf/MEK/ERK signaling acts as a downstream effecter of CD166/PI3K/AKT axis to stimulate ubiquitination and destability of βTrCP and Smurf1. Taken together, we establish a model that CD166 regulates MCAM through a signaling flow from activation of PI3K/AKT and c-Raf/MEK/ERK signaling to the inhibition of potential MCAM ubiquitin E3 ligases, βTrCP and Smurf1, blockage of this signaling cascade may be useful in the treatment of CD166 and MCAM-dependent HCC.

Wang WM, Zhao ZL, Zhang WF, et al.
Role of hypoxia-inducible factor-1α and CD146 in epidermal growth factor receptor-mediated angiogenesis in salivary gland adenoid cystic carcinoma.
Mol Med Rep. 2015; 12(3):3432-8 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Adenoid cystic carcinoma (AdCC) of the salivary gland in the head and neck is characterized by indolent yet persistent growth, multiple local recurrences and early hematogenous metastasis. Considering the possible association between the epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis in various types of cancer and the overexpression of EGFR in AdCC, it is reasonable to examine the correlation between angiogenesis and the EGFR signaling pathway in this carcinoma. In the present study, the expression of EGFR, CD31, CD146 and hypoxia‑inducible factor‑1α (HIF‑1α) were evaluated by immunohistochemical staining with tissue microarray containing normal salivary gland (NSG), pleomorphic adenoma (PMA) and AdCC tissues. Pearson's correlation coefficient was conducted to demonstrate the correlation between EGFR, CD31, CD146 and HIF‑1α. To determine their similarity and intimacy, hierarchical analysis was performed with Cluster 3.0 and then visualized using TreeView software. Immunohistochemical results of tissue microarrays were quantified, revealing that the expression of EGFR, CD146 and HIF‑1α increased in AdCC compared with in PMA and NSG tissues. The association between the expression of EGFR and CD31 was significant and positive. The expression of CD146 and HIF‑1α was positively correlated with EGFR and CD31, respectively. These findings suggest that the EGFR signaling pathway has a vital role in AdCC progression and may be associated with HIF‑1α‑mediated angiogenesis. These results may enhance our understanding of the mechanism underlying AdCC progression and provide potential clinical therapeutic strategies based on the inhibition of EGFR.

Liu XS, Genet MD, Haines JE, et al.
ZBTB7A Suppresses Melanoma Metastasis by Transcriptionally Repressing MCAM.
Mol Cancer Res. 2015; 13(8):1206-17 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
UNLABELLED: The excessive metastatic propensity of melanoma makes it the most deadly form of skin cancer, yet the underlying mechanism of metastasis remains elusive. Here, mining of cancer genome datasets discovered a frequent loss of chromosome 19p13.3 and associated downregulation of the zinc finger transcription factor ZBTB7A in metastatic melanoma. Functional assessment of ZBTB7A-regulated genes identified MCAM, which encodes an adhesion protein key to melanoma metastasis. Using an integrated approach, it is demonstrated that ZBTB7A directly binds to the promoter and transcriptionally represses the expression of MCAM, establishing ZBTB7A as a bona fide transcriptional repressor of MCAM. Consistently, downregulation of ZBTB7A results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis. An inverse correlation of ZBTB7A and MCAM expression in association with melanoma metastasis is further validated with data from analysis of human melanoma specimens.
IMPLICATIONS: Together, these results uncover a previously unrecognized role of ZBTB7A in negative regulation of melanoma metastasis and have important clinical implications.

Wang W, Runkle KB, Terkowski SM, et al.
Protein Depalmitoylation Is Induced by Wnt5a and Promotes Polarized Cell Behavior.
J Biol Chem. 2015; 290(25):15707-16 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Wnt5a signaling regulates polarized cell behavior, but the downstream signaling events that promote cell polarity are not well understood. Our results show that Wnt5a promotes depalmitoylation of the melanoma cell adhesion molecule (MCAM) at cysteine 590. Mutation of Cys-590 to glycine is sufficient to polarize MCAM localization, similar to what is observed with Wnt5a stimulation. Inhibition of the depalmitoylating enzyme APT1 blocks Wnt5a-induced depalmitoylation, asymmetric MCAM localization, and cell invasion. Directly altering expression of the basal protein palmitoylation machinery is sufficient to promote cell invasion. Additionally, cancer mutations in palmitoyltransferases decrease MCAM palmitoylation and have impaired ability to suppress cell invasion. Our results provide evidence that Wnt5a induces protein depalmitoylation, which promotes polarized protein localization and cell invasion.

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