Gene Summary

Gene:MCAM; melanoma cell adhesion molecule
Aliases: CD146, MUC18, HEMCAM, METCAM, MelCAM
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cell surface glycoprotein MUC18
Source:NCBIAccessed: 31 August, 2019


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

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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.

  • Young Adult
  • Polymerase Chain Reaction
  • Breast Cancer
  • Disease Progression
  • TFAP2A
  • PAX5 Transcription Factor
  • Up-Regulation
  • Liver Cancer
  • Transcription
  • Cell Division
  • Down-Regulation
  • siRNA
  • Melanoma
  • DNA-Binding Proteins
  • Chromosome 11
  • Transcription Factors
  • CD Antigens
  • MCAM
  • Transfection
  • Neoplasm Metastasis
  • Prostate Cancer
  • Cell Proliferation
  • Antigens, Surface
  • Oligonucleotide Array Sequence Analysis
  • CD146 Antigen
  • Sequence Homology, Nucleic Acid
  • Cell Movement
  • Base Sequence
  • Cell Adhesion
  • Promoter Regions
  • DNA Methylation
  • Immunohistochemistry
  • Gene Expression Profiling
  • Apoptosis
  • Biomarkers, Tumor
  • Membrane Glycoproteins
  • Phenotype
  • Cancer Gene Expression Regulation
  • CpG Islands
  • Messenger RNA
  • Western Blotting
Tag cloud generated 31 August, 2019 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)

Chang L, Scott MA, Meyers CA, James AW
Pericytes in Sarcomas and Other Mesenchymal Tumors.
Adv Exp Med Biol. 2019; 1147:109-124 [PubMed] Related Publications
Tumors of mesenchymal origin are a diverse group, with >130 distinct entities currently recognized by the World Health Organization. A subset of mesenchymal tumors grow or invade in a perivascular fashion, and their potential relationship to pericytes is a matter of ongoing interest. In fact, multiple intersections exist between pericytes and tumors of mesenchymal origin. First, pericytes are the likely cell of origin for a group of mesenchymal tumors with a common perivascular growth pattern. These primarily benign tumors grow in a perivascular fashion and diffusely express canonical pericyte markers such as CD146, smooth muscle actin (SMA), platelet-derived growth factor receptor beta (PDGFR-β), and RGS5. These benign tumors include glomus tumor, myopericytoma, angioleiomyoma, and myofibroma. Second and as suggested by animal models, pericytes may give rise to malignant sarcomas. This is not a suggestion that all sarcomas within a certain subtype arise from pericytes, but that genetic modifications within a pericyte cell type may give rise to sarcomas. Third, mesenchymal tumors that are likely not a pericyte derivative co-opt pericyte markers in certain contexts. These include the PEComa family of tumors and liposarcoma. Fourth and finally, as "guardians" that enwrap the microvasculature, nonneoplastic pericytes may be important in sarcoma disease progression.

Dudzik P, Trojan SE, Ostrowska B, et al.
The Epigenetic Modifier 5-Aza-2-deoxycytidine Triggers the Expression of
Anticancer Res. 2019; 39(5):2395-2403 [PubMed] Related Publications
BACKGROUND/AIM: During cancer progression cells undergo epithelial-to-mesenchymal transition (EMT). Although EMT is a complex process, recently, it has been reported that CD146 overexpression in prostate cancer cells is sufficient to induce mesenchymal phenotype. The following study aimed to investigate whether the expression of CD146 is altered by an epigenetic modifier in prostate cancer cells, in vitro.
MATERIALS AND METHODS: Three human prostate cancer cell lines were treated with 5-aza-2-deoxycytidine; the expression of CD146 and EMT-related factors was analyzed by RT-PCR and western Blot. The methylation status of the CD146 promoter area was assessed using bisulfite sequencing.
RESULTS: Our data showed that, the expression of CD146 was evidently increased in all three studied cell lines in response to a demethylating agent, both at the mRNA and protein level, suggesting epigenetic regulation of the analyzed gene. However, there was no methylation in the studied CpG island in CD146 gene promoter. Moreover, the demethylating agent induced the expression of EMT-related transcription factors (SNAI1, SNAI2, TWIST1 and ZEB1), the pattern of which differed among the cell lines, as well as alterations in cell morphology; altogether accounting for the mesenchymal phenotype.
CONCLUSION: The demethylating agent 5-aza-2-deoxycytidine triggers the expression of CD146 in prostate cancer cells independently on the methylation status of the analyzed CpG island fragment in CD146 gene promoter. Moreover, demethylation treatment induces a mesenchymal profile in prostate cancer cells.

Cova E, Pandolfi L, Colombo M, et al.
Pemetrexed-loaded nanoparticles targeted to malignant pleural mesothelioma cells: an in vitro study.
Int J Nanomedicine. 2019; 14:773-785 [PubMed] Free Access to Full Article Related Publications
Purpose: Malignant pleural mesothelioma (MPM) is an aggressive tumor characterized by poor prognosis. Its incidence is steadily increasing due to widespread asbestos exposure. There is still no effective therapy for MPM. Pemetrexed (Pe) is one of the few chemotherapeutic agents approved for advanced-stage disease, although the objective response to the drug is limited. The use of gold nanoparticles (GNPs) as a drug delivery system promises several advantages, including specific targeting of malignant cells, with increased intracellular drug accumulation and reduced systemic toxicity, and, in the case of MPM, direct treatment administration into the pleural space. This study aims at exploring CD146 as a potential MPM cell-specific target for engineered Pe-loaded GNPs and to assess their effectiveness in inhibiting MPM cell line growth.
Methods: MPM cell lines and primary cultures obtained by pleural effusions from MPM patients were assayed for CD146 expression by flow cytometry. Internalization by MPM cell lines of fluorescent dye-marked GNPs decorated with a monoclonal anti CD146 coated GNPs (GNP-HC) was proven by confocal microscopy. The effects of anti CD146 coated GNPs loaded with Pe (GNP-HCPe) on MPM cell lines were evaluated by cell cycle (flow cytometry), viability (MTT test), clonogenic capacity (soft agar assay), ROS production (electric paramagnetic resonance), motility (wound healing assay), and apoptosis (flow cytometry).
Results: GNP-HC were selectively uptaken by MPM cells within 1 hour. MPM cell lines were blocked in the S cell cycle phase in the presence of GNP-HCPe. Both cell viability and motility were significantly affected by nanoparticle treatment compared to Pe. Apoptotic rate and ROS production were significantly higher in the presence of nanoparticles. Clonogenic capacity was completely inhibited following nanoparticle internalization.
Conclusion: GNP-HCPe treatment displays in vitro antineoplastic action and is more effective than Pe alone in inhibiting MPM cell line malignant phenotype. The innovative use of specifically targeted GNPs opens the perspective of local intrapleural administration to avoid normal cell toxicity and enhance chemotherapy efficacy.

Zhang F, Wang J, Wang X, et al.
CD146-mediated acquisition of stemness phenotype enhances tumour invasion and metastasis after EGFR-TKI resistance in lung cancer.
Clin Respir J. 2019; 13(1):23-33 [PubMed] Related Publications
INTRODUCTION: Tumours are more likely to metastasize after the development of resistance to EGFR-TKIs. CD146 is a multifunctional molecule and is implicated in tumour invasion and metastasis; however, its role in lung cancer has not been clearly established.
OBJECTIVE: Here, we aimed to explore the relationship between CD146 pathway and stem cell phenotype after EGFR-TKI resistance in lung cancer.
METHODS: EGFR-TKI-resistant cell lines were established by exposing parental cells to erlotinib/gefitinib. The CD146 level was measured by a western blot, RT-PCR and immunocytochemistry fluorescent. Cell migration was examined by the transwell assay and the scratch assay. Stemness phenotype genes were evaluated by RT-PCR and stem cell phenotype was observed by the microsphere formation assay.
RESULTS: CD146 and stemness phenotype genes increased while β-catenin decreased in acquired EGFR-TKI-resistant cell lines. CD146's over-expression induced the up-regulation of stemness-related genes and was inversely correlated with the β-catenin expression, which further increased the migration capability of resistant cancer cells. CD146's knockdown suppressed cell migration and stemness phenotype.
CONCLUSIONS: CD146 molecule contributes to the stemness phenotype and migration in EGFR-TKI-resistant cells. CD146 might be a potential therapeutic target for EGFR-TKI-resistant lung cancer or metastasis prevention.

Hughes A, Dhoot GK
Dysregulated cancer cell transdifferentiation into erythrocytes is an additional metabolic stress in hepatocellular carcinoma.
Tumour Biol. 2018; 40(11):1010428318811467 [PubMed] Related Publications
A number of human and canine hepatocellular carcinoma tissues showed clear signs of hypoxia indicated by HIF1α-activation and the presence of large clusters of cells resembling erythrocytes at different stages of nuclear elimination without any defined endothelial cell lining or blood vessel walls. Differentiated erythrocytic identity of such cells in hepatocellular carcinoma tissues was apparent from their non-nucleated and evolving basophilic to eosinophilic staining characteristics. In addition to the fully differentiated non-nucleated mesenchymal cell clusters, the onset of erythroblastic transdifferentiation was apparent from the activation of Glycophorin A, a marker of erythrocytic progenitors, in some epithelial cancer cells. Activation of canonical Wnt signalling in such tumours was apparent from the expression of Wnt2 ligand and active β-catenin translocation into the nucleus indicating Wnt signalling to be one of the key signalling pathways participating in such cell transdifferentiation. Sonic hedgehog and bone morphogenetic protein signalling along with Sulf1/Sulf2 activation was also observed in such hepatocellular carcinoma tissue samples. The presence of stem cell markers and the cell signalling pathways associated with erythropoiesis, and the detection of messenger RNAs for both α and β haemoglobins, support the assumption that hepatocellular carcinoma cells have the potential to undergo cell fate change despite this process being dysregulated as indicated by the lack of simultaneous generation of endothelial cell lining. Lack of blood vessel walls or endothelial cell lining around erythrocytic clusters was confirmed by non-detection of multiple blood vessel markers such as vWF, CD146 and smooth muscle α-actin that were clearly apparent in normal and unaffected adjacent regions of hepatocellular carcinoma livers. In addition to the activation of Glycophorin A, transdifferentiation of some hepatocellular carcinoma hepatocytes into other cell fates was further confirmed by the activation of some stem cell markers, for example, NANOG and OCT4 transcription factors, not only by reverse transcription polymerase chain reaction but also by their restricted expression in such cells at protein level.

Kikalishvili N, Beriashvili R, Muzashvili T, Burkadze G
Georgian Med News. 2018; (282):156-161 [PubMed] Related Publications
The aim of the study was to explore and identify the relationship between endometrial proliferative/stem cell index and phenotypic characteristics under proliferative processes of endometrium using statistical correlation analysis. The study represents a retrospective research. The coded and depersonalized material data from Acad. N. Kipshidze Central University Clinic was used in the study. 5 study groups (83 cases) were selected from routine histopathology tissue specimens of uterus. Hematoxilyn-eosin technology and immunohistochemistry with markers ki67, CD146, PTEN was performed. The proliferative/stem cell index (PR/ST index) was calculated by the ratio of Ki67-positive cell percentage value divided by CD146-positive cell percentage value. PTEN expression score was evaluated by next scheme - PTEN positive cell numbers <10% - conditional negative, PTEN positive cell numbers 10-50 % - heterogenic, PTEN positive cell numbers >50% - conditional positive. The study showed that, PR/ST index in 1st study group Endometrial Hyperplasia ranges within the interval 15-23, PTEN is diffusely positive with focal heterogeneity 11.1%. 2nd study group Endometrial Dysplasia, the PR/ST index ranges within the interval 16.5-23.3. PTEN heterogeneity is 18.3%, negativity - 6.3%. 3rd study group Endometrioid Carcinoma Grade 1, the PR/ST index ranges between 21.7 and 25.5. PTEN is heterogenic in 35.7% of cases, negative in 14.3% of cases. 4th study group Endometrioid Carcinoma Grade 2, the PR/ST index ranges within the interval 23.2-27.8. PTEN is heterogenic in 43.5% of cases, negative in 30.4% of cases. 5th study group Endometrioid Carcinoma Grade 3, the PR/ST index ranges within the interval 25.8-29.4. PTEN is heterogenic in 33.3% of cases, negative in 41.7% of cases. It was found that, in endometrial hyperplasia and dysplasia cases the PR/ST index do not correlate with phenotypic characteristics, while in the cases of endometrial carcinoma different degrees of malignancy the PR/ST Index and phenotypic characteristics intensely and directly correlates. The high attention should be given to the fact that heterogeneity peak of PTEN expression takes place in the cases of endometrial carcinoma G2, but the negativity of PTEN protein is increasing in parallel with the malignancy increasing process and reaches peak performance in cases of endometrial carcinoma G3.

Errede M, Mangieri D, Longo G, et al.
Tunneling nanotubes evoke pericyte/endothelial communication during normal and tumoral angiogenesis.
Fluids Barriers CNS. 2018; 15(1):28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nanotubular structures, denoted tunneling nanotubes (TNTs) have been described in recent times as involved in cell-to-cell communication between distant cells. Nevertheless, TNT-like, long filopodial processes had already been described in the last century as connecting facing, growing microvessels during the process of cerebral cortex vascularization and collateralization. Here we have investigated the possible presence and the cellular origin of TNTs during normal brain vascularization and also in highly vascularized brain tumors.
METHODS: We searched for TNTs by high-resolution immunofluorescence confocal microscopy, applied to the analysis of 20-µm, thick sections from lightly fixed, unembedded samples of both developing cerebral cortex and human glioblastoma (GB), immunolabeled for endothelial, pericyte, and astrocyte markers, and vessel basal lamina molecules.
RESULTS: The results revealed the existence of pericyte-derived TNTs, labeled by proteoglycan NG2/CSPG4 and CD146. In agreement with the described heterogeneity of these nanostructures, ultra-long (> 300 µm) and very thin (< 0.8 µm) TNTs were observed to bridge the gap between the wall of distant vessels, or were detected as short (< 300 µm) bridging cables connecting a vessel sprout with its facing vessel or two apposed vessel sprouts. The pericyte origin of TNTs ex vivo in fetal cortex and GB was confirmed by in vitro analysis of brain pericytes, which were able to form and remained connected by typical TNT structures.
CONCLUSIONS: None of the multiple roles described for TNTs can be excluded from a possible involvement during the processes of both normal and pathological vessel growth. A possible function, suggested by the pioneering studies made during cerebral cortex vascularization, is in cell searching and cell-to-cell recognition during the processes of vessel collateralization and vascular network formation. According to our results, it is definitely the pericyte-derived TNTs that seem to actively explore the surrounding microenvironment, searching for (site-to-site recognition), and connecting with (pericyte-to-pericyte and/or pericyte-to-endothelial cell communication), the targeted vessels. This idea implies that TNTs may have a primary role in the very early phases of both physiological and tumor angiogenesis in the brain.

METCAM/MUC18 Decreases the Malignant Propensity of Human Ovarian Carcinoma Cells.
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
METCAM/MUC18 is an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family. It can carry out common functions of CAMs which is to perform intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, to interact with various signaling pathways and to regulate general behaviors of cells. We and other two groups previously suggested that METCAM/MUC18 probably be utilized as a biomarker for predicting the malignant tendency of clinical ovarian carcinomas, since METAM/MUC18 expression appears to associate with the carcinoma at advanced stages. It has been further postulated to promote the malignant tendency of the carcinoma. However, our recent research results appear to support the conclusion that the above positive correlation is fortuitous; actually METCAM/MUC18 acts as a tumor and metastasis suppressor for the ovarian carcinoma cells. We also suggest possible mechanisms in the METCAM/MUC18-mediated early tumor development and metastasis of ovarian carcinoma. Moreover, we propose to employ recombinant METCAM/MUC18 proteins and other derived products as therapeutic agents to treat the ovarian cancer patients by decreasing the malignant potential of ovarian carcinoma.

Glaser K, Dickie P, Dickie BH
Proliferative Cells From Kaposiform Lymphangiomatosis Lesions Resemble Mesenchyme Stem Cell-like Pericytes Defective in Vessel Formation.
J Pediatr Hematol Oncol. 2018; 40(8):e495-e504 [PubMed] Related Publications
Kaposiform lymphangiomatosis (KLA) is a vascular anomaly featuring lymphatic expansion. It has no known cause, no effective treatment, and is associated with high morbidity. Proliferative cells from 3 KLA patient lesions were characterized relative to adiopose-derived mesenchyme stem cells (ADSCs) and cells derived from a patient with the related disease kaposiform hemangioendothelioma (KHE). KLA cells variably expressed markers of mesenchyme stem cells (CD73, CD90, CD105, CD146) and lacked endothelial cell markers (CD31, CD34) as determined by flow cytometry. They expressed markers of vascular pericytes (neural/glial antigen 2, alpha-smooth muscle actin, platelet-derived growth factor-beta receptor, and CXCL12) as determined by quantitative reverse transcription polymerase chain reaction. Lesion cells transcribed vascular markers VEGFC and VEGFD, as well as VCAM-1, the latter of which was confirmed by flow cytometry, consistent with angiogenic MSC-like pericytes. Furthermore, conditioned medium from each was shown to promote the proliferation of growth factor-starved lymphatic endothelial cells. Unlike kaposiform hemangioendothelioma-derived MSC-like pericytes and ADSCs, KLA isolates were defective in support of vascular network formation in co-cultures with either vascular or lymphatic endothelial cells. Genetic analysis by whole exome sequencing revealed novel variant alleles in 2 populations of KLA cells (BAD, TSC1) that may bear on aberrant pericyte growth and function.

Aida S, Aida J, Naoi M, et al.
Measurement of telomere length in cells from pleural effusion: Asbestos exposure causes telomere shortening in pleural mesothelial cells.
Pathol Int. 2018; 68(9):503-508 [PubMed] Related Publications
We estimated the telomere lengths of neoplastic and non-neoplastic mesothelial cells and examined their correlation with asbestos exposure and the expression of markers of mesothelial malignancy. Cell blocks of pleural effusion obtained from 35 cases of non-neoplastic disease (NN), 12 cases of malignant mesothelioma (MM) and 12 cases of carcinomatous effusion due to lung adenocarcinoma (LA) were examined. Fifteen of the 35 NN cases had pleural plaques (NNpp+) suggestive of asbestos exposure, and the other 20 cases had no pleural plaques (NNpp-). Telomere length was measured using the tissue quantitative fluorescence in situ hybridization method, and expressed as normalized telomere-to-centromere ratio. NN cases had significantly longer telomeres than MM (P < 0.001) and LA (P < 0.001) cases. Telomeres in NNpp+ cases were slightly shorter than those of NNpp- cases (P = 0.047). MM and LA showed almost the same telomere length. NN cases with shorter telomeres tended to show aberrant expression of epithelial membrane antigen (EMA), CD146, glucose transporter 1 (GLUT1) and IGF-II messenger RNA-binding protein 3 (IMP3). These results suggest that telomere shortening and subsequent genetic instability play an important role in the development of MM. Measurement of telomere length of cells in pleural effusion might be helpful for earlier detection of MM.

Almeida PN, Barboza DDN, Luna EB, et al.
Increased extracellular matrix deposition during chondrogenic differentiation of dental pulp stem cells from individuals with neurofibromatosis type 1: an in vitro 2D and 3D study.
Orphanet J Rare Dis. 2018; 13(1):98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Neurofibromatosis 1 (NF1) presents a wide range of clinical manifestations, including bone alterations. Studies that seek to understand cellular and molecular mechanisms underlying NF1 orthopedic problems are of great importance to better understand the pathogenesis and the development of new therapies. Dental pulp stem cells (DPSCs) are being used as an in vitro model for several diseases and appear as a suitable model for NF1. The aim of this study was to evaluate in vitro chondrogenic differentiation of DPSCs from individuals with NF1 using two-dimensional (2D) and three-dimensional (3D) cultures.
RESULTS: To fulfill the criteria of the International Society for Cellular Therapy, DPSCs were characterized by surface antigen expression and by their multipotentiality, being induced to differentiate towards adipogenic, osteogenic, and chondrogenic lineages in 2D cultures. Both DPSCs from individuals with NF1 (NF1 DPSCs) and control cultures were positive for CD90, CD105, CD146 and negative for CD13, CD14, CD45 and CD271, and successfully differentiated after the protocols. Chondrogenic differentiation was evaluated in 2D and in 3D (pellet) cultures, which were further evaluated by optical microscopy and transmission electron microscopy (TEM). 2D cultures showed greater extracellular matrix deposition in NF1 DPSCs comparing with controls during chondrogenic differentiation. In semithin sections, control pellets hadhomogenous-sized intra and extracelullar matrix vesicles, whereas NF1 cultures had matrix vesicles of different sizes. TEM analysis showed higher amount of collagen fibers in NF1 cultures compared with control cultures.
CONCLUSION: NF1 DPSCs presented increased extracellular matrix deposition during chondrogenic differentiation, which could be related to skeletal changes in individuals with NF1.

Ma Y, Zhang H, Xiong C, et al.
CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition.
Cancer Lett. 2018; 430:201-214 [PubMed] Related Publications
Cadherin switch is an initiating factor of epithelial-mesenchymal transition (EMT) and is intimately correlated with cancer metastatic potential; however, its underlying mechanisms remain unclear. Here, using a transforming growth factor-β (TGF-β)-induced EMT model, we provide explicit evidence that CD146, with elevated expression and activity in a variety of cancers, is a key factor involved in the cadherin switch. We show that CD146 can be induced by TGF-β signaling. Moreover, CD146 expression is positively correlated with the activation levels of STAT3/Twist and ERK pathways. Transcriptional response of the CD146/STAT3/Twist cascade inhibits E-cadherin expression, whereas the CD146/ERK cascade enhances N-cadherin expression. CD146 overexpression also significantly promotes EMT in both mouse embryonic fibroblasts (MEFs) and ovarian cancer cells. Clinically, ovarian cancer patients with detectable CD146 expression had a significantly lower survival rate than that of patients without CD146 expression. Furthermore, CD146-deficient MEFs exhibited decreased motility as a result of reversion in this cadherin switch, strongly suggesting that targeting CD146 is a potential strategy for cancer treatment. Therefore, CD146-mediated regulation of the E-cadherin-to-N-cadherin switch provides an insight into the general mechanisms of EMT as well as cancer metastasis.

Dufies M, Nollet M, Ambrosetti D, et al.
Soluble CD146 is a predictive marker of pejorative evolution and of sunitinib efficacy in clear cell renal cell carcinoma.
Theranostics. 2018; 8(9):2447-2458 [PubMed] Free Access to Full Article Related Publications
The objective of the study was to use CD146 mRNA to predict the evolution of patients with non-metastatic clear cell renal cell carcinoma (M0 ccRCC) towards metastatic disease, and to use soluble CD146 (sCD146) to anticipate relapses on reference treatments by sunitinib or bevacizumab in patients with metastatic ccRCC (M1).

Kikalishvili N, Beriashvili R, Muzashvili T, Burkadze G
Georgian Med News. 2018; (276):117-123 [PubMed] Related Publications
Endometrial neoplasia is the most common malignant tumor of female genital system in developed countries. The incidence of endometrial cancer has increased in the last years and despite advances in diagnosis and treatment, the death rates have steadily been increasing over the past 20 years. Therefore aspects of endometrial cancer development, pathogenesis and effective treatment is especially urgent to this day, as much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Endometrial stem cells take the special place among somatic stem cells of female reproductive system-the detection of them and identification of their location in the complex cellular hierarchy still remains challenging. Further study of endometrial stem cells will clarify their role in gynecologic pathologies associated with hyper-proliferative states of endometrium. The aim of our study was to explore the specificities of endometrial proliferative/stem cell index distribution under endometrioid carcinoma of different grade of malignancy. The study represents a retrospective research. The coded and depersonalized material data from Acad. N. Kipshidze Central University Clinic was used in the study. 3 study groups - 1st study group "Endometrioid Carcinoma Grade 1" (14 cases), 2nd study group "Endometrioid Carcinoma Grade 2" (23 cases) and 3rd study group "Endometrioid Carcinoma Grade 3" were selected from routine histopathology tissue specimens of uterus. Hematoxilyn-eosin technology and immunohistochemistry with proliferation marker ki67 and stem cell marker CD146 was performed. The proliferative/stem cell index was calculated by the ratio of Ki67-positive cell percentage value divided by CD146-positive cell percentage value. The study showed that in the 1st study group labeled as "Endometrioid Carcinoma Grade 1", the proliferative/stem cell index ranges between 21.7 and 25.5. Its mean average value in the age distribution subgroups accounts for: 1.1) reproductive age - 22.4; 1.2) menopause - 23.5; 1.3) post-menopause - 24.8. Proliferative/stem cell index reaches its maximum in the samples retrieved from post-menopause age, and decreases significantly in reproductive age individuals. In the 2nd study group labeled as "Endometrioid Carcinoma Grade 2", the proliferative/stem cell index increases and ranges within the interval 23.2-27.8. Its mean average value in the age distribution subgroups accounts for: 2.1) reproductive age -23.7; 2.2) menopause - 24.2; 2.3) post-menopause - 25.8. In the 3rd study group labeled as "Endometrioid Carcinoma Grade 3", the proliferative/stem cell index markedly increases and ranges within the interval 25.8-29.4. Its mean average value in the age distribution subgroups accounts for: 3.1) reproductive age - 28.4; 3.2) menopause - 28.5; 3.3) post-menopause - 28.5. It was found that average value of proliferative/stem cell index in the 1st and 2nd study groups (EC Grade 1/2) keeps the same tendencies of increase in age subgroups as well as at endometrial hyperplasia conditions - in particular in both study groups increase in value of the proliferative/stem cell index in age subgroups makes about 1% (1st study group-0,97%, 2nd study group-0,96%). What about 3rd study group (EC Grade 3) average value of proliferative/stem cell index in age subgroups is almost the same. It was found that average value of proliferative/stem cell index in endometrioid carcinoma most markedly differs from the norm in post-menopause period. The study showed that average value of proliferative/stem cell index in endometrioid carcinoma cases (EC Grade 1/2) tends to increase with age like endometrial hyperplasia conditions, in contrast with the norm, where it is observed to progressively decrease with aging. The attention should be given to the fact that the mean average value of proliferative/stem cell index in endometrioid carcinoma Grade 3 is almost constant.

Tsao SC, Wang J, Wang Y, et al.
Characterising the phenotypic evolution of circulating tumour cells during treatment.
Nat Commun. 2018; 9(1):1482 [PubMed] Free Access to Full Article Related Publications
Real-time monitoring of cancer cells' phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as "cell signature"), without the need for isolating individual CTCs. We observe cell heterogeneity and phenotypic changes of melanoma cell lines during molecular targeted treatment. Furthermore, we follow the CTC signature changes of 10 stage-IV melanoma patients receiving immunological or molecular targeted therapies. Our technique maps the phenotypic evolution of patient CTCs sensitively and rapidly, and shows drug-resistant clones having different CTC signatures of potential clinical value. We believe our proposed method is of general interest in the CTC relevant research and translation fields.

Sadeghi RS, Kulej K, Kathayat RS, et al.
Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior.
Elife. 2018; 7 [PubMed] Free Access to Full Article Related Publications
Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remain unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity. We found phosphorylation increased APT1 depalmitoylating activity and reduced APT1 dimerization. We further determined APT1 phosphorylation increases melanoma invasion in vitro, and also correlated with increased tumor grade and metastasis. Our results further establish APT1 as an important regulator of melanoma invasion and metastatic behavior. Inhibition of APT1 may represent a novel way to treat Wnt5a driven cancers.

Huang Q, Wang FB, Yuan CH, et al.
Gelatin Nanoparticle-Coated Silicon Beads for Density-Selective Capture and Release of Heterogeneous Circulating Tumor Cells with High Purity.
Theranostics. 2018; 8(6):1624-1635 [PubMed] Free Access to Full Article Related Publications

Haddada M, Draoui H, Deschamps L, et al.
Kallikrein-related peptidase 7 overexpression in melanoma cells modulates cell adhesion leading to a malignant phenotype.
Biol Chem. 2018; 399(9):1099-1105 [PubMed] Related Publications
We recently reported that human melanoma cells, but not benign melanocytes, aberrantly express kallikrein-related peptidase 7 (KLK7). Here, we show a KLK7 overexpression-mediated decrease of cell adhesion to extracellular matrix binding proteins, associated with downregulation of α5/β1/αv/β3 integrin expression. We also report an up-regulation of MCAM/CD146 and an increase in spheroid formation of these cells. Our results demonstrate that aberrant KLK7 expression leads to a switch to a more malignant phenotype suggesting a potential role of KLK7 in melanoma invasion. Thus, KLK7 may represent a biomarker for melanoma progression and may be a potential therapeutic target for melanoma.

Matak A, Lahiri P, Ford E, et al.
Stochastic phenotype switching leads to intratumor heterogeneity in human liver cancer.
Hepatology. 2018; 68(3):933-948 [PubMed] Free Access to Full Article Related Publications
Intratumor heterogeneity is increasingly recognized as a major factor impacting diagnosis and personalized treatment of cancer. We characterized stochastic phenotype switching as a mechanism contributing to intratumor heterogeneity and malignant potential of liver cancer. Clonal analysis of primary tumor cell cultures of a human sarcomatoid cholangiocarcinoma identified different types of self-propagating subclones characterized by stable (keratin-7-positive or keratin-7-negative) phenotypes and an unstable phenotype consisting of mixtures of keratin-7-positive and keratin-7-negative cells, which lack stem cell features but may reversibly switch their phenotypes. Transcriptome sequencing and immunohistochemical studies with the markers Zeb1 and CD146/MCAM demonstrated that switching between phenotypes is linked to changes in gene expression related but not identical to epithelial-mesenchymal transition. Stochastic phenotype switching occurred during mitosis and did not correlate with changes in DNA methylation. Xenotransplantation assays with different cellular subclones demonstrated increased tumorigenicity of cells showing phenotype switching, resulting in tumors morphologically resembling the invasive component of primary tumor and metastasis.
CONCLUSION: Our data demonstrate that stochastic phenotype switching contributes to intratumor heterogeneity and that cells with a switching phenotype have increased malignant potential. (Hepatology 2017).

Ouhtit A, Abdraboh ME, Hollenbach AD, et al.
CD146, a novel target of CD44-signaling, suppresses breast tumor cell invasion.
Cell Commun Signal. 2017; 15(1):45 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We have previously validated three novel CD44-downstream positively regulated transcriptional targets, including Cortactin, Survivin and TGF-β2, and further characterized the players underlying their separate signaling pathways. In the present study, we identified CD146 as a potential novel target, negatively regulated by CD44. While the exact function of CD146 in breast cancer (BC) is not completely understood, substantial evidence from our work and others support the hypothesis that CD146 is a suppressor of breast tumor progression.
METHODS: Therefore, using molecular and pharmacological approaches both in vitro and in breast tissues of human samples, the present study validated CD146 as a novel target of CD44-signaling suppressed during BC progression.
RESULTS: Our results revealed that CD44 activation could cause a substantial decrease of CD146 expression with an equally notable converse effect upon CD44-siRNA inhibition. More interestingly, activation of CD44 decreased cellular CD146 and increased soluble CD146 through CD44-dependent activation of MMP.
CONCLUSION: Here, we provide a possible mechanism by which CD146 suppresses BC progression as a target of CD44-downstream signaling, regulating neovascularization and cancer cell motility.

Tampakis A, Tampaki EC, Trafalis D, et al.
Nestin and CD146 expression in metaplastic breast cancer: stem-cell therapy in need? Lessons reported from a male patient.
Eur Rev Med Pharmacol Sci. 2017; 21(18):4137-4140 [PubMed] Related Publications
OBJECTIVE: Metaplastic breast carcinomas represent a rare subtype of breast cancer exhibiting aggressive clinical features. They appear as highly chemoresistant tumors, therefore showing poor outcome and high rates of local recurrence or distant metastasis.
CASE REPORT: A 37-year-old greek man was referred to our hospital for evaluation of a locally advanced, ulcerated, fixed, irregular and hard in consistency mass covering his left breast and chest wall. Further work out with CT and biopsy of the tumor revealed a triple negative metaplastic breast cancer classified as cT4cN3cM1. The patient received first line chemotherapy and afterward a palliative resection of the tumor. The histology revealed the presence of a combined triple negative adenocarcinoma with a predominant metaplastic squamous carcinoma and a spindle cell (sarcomatoid) carcinoma of the breast. In the tissue sample stem cell markers, nestin and CD146 (MCAM) were expressed, enhancing the theory that cancer cells of this tumor could possibly harbor stem cell properties. The patient received several chemotherapy regimens but died 6 months after the initiation of treatment.
CONCLUSIONS: Metaplastic breast cancer consists of cells with stem cell properties. New targeted therapies are warranted in the view of the tumor's high resistance to conventional chemotherapy. Targeting nestin and CD146 might be a promising therapy as they seem to be implicated in the EMT pathway.

Sumardika IW, Youyi C, Kondo E, et al.
Oncol Res. 2018; 26(3):431-444 [PubMed] Related Publications
We previously identified novel S100A8/A9 receptors, extracellular matrix metalloproteinase inducer (EMMPRIN), melanoma cell adhesion molecule (MCAM), activated leukocyte cell adhesion molecule (ALCAM), and neuroplastin (NPTN) β, that are critically involved in S100A8/A9-mediated cancer metastasis and inflammation when expressed at high levels. However, little is known about the presence of any cancer-specific mechanism(s) that modifies these receptors, further inducing upregulation at protein levels without any transcriptional regulation. Expression levels of glycosyltransferase-encoding genes were examined by a PCR-based profiling array followed by confirmation with quantitative real-time PCR. Cell migration and invasion were assessed using a Boyden chamber. Western blotting was used to examine the protein level, and the RNA level was examined by Northern blotting. Immunohistochemistry was used to examine the expression pattern of β-1,3-galactosyl-

Jang MH, Kim HJ, Gwak JM, et al.
Prognostic value of microRNA-9 and microRNA-155 expression in triple-negative breast cancer.
Hum Pathol. 2017; 68:69-78 [PubMed] Related Publications
MicroRNAs (miRNAs) are involved in regulation of epithelial-mesenchymal transition (EMT) during breast cancer progression. The purpose of this study was to analyze the clinicopathologic significance of expression of EMT-related miRNAs, miR-9 and miR-155, in triple-negative breast cancers (TNBCs). We analyzed relative expression levels of miR-9 and miR-155 in 190 surgically resected TNBC specimens using quantitative real-time polymerase chain reaction. Then we analyzed the relationship between these miRNA expression levels and EMT marker expression (vimentin, smooth muscle actin [SMA], osteonectin, N-cadherin, E-cadherin, CD146, and ZEB1) assessed by immunohistochemistry. We also evaluated the prognostic significance of these miRNA expression levels. While miR-9 expression level showed a positive correlation with pT category, miR-155 expression level did not correlate with any clinicopathologic features of TNBCs. In relation to EMT phenotype, miR-9 expression was not associated with EMT marker expression except for SMA. However, miR-155 expression level correlated inversely with the expression of several EMT markers including SMA, osteonectin, and CD146. We observed that both miR-9 and miR-155 could be prognostic markers in TNBC in opposite ways; high level of miR-9 expression showed significant association with poor disease-free survival and distant metastasis-free survival (DMFS) in TNBC, while high level of miR-155 expression was associated with better DMFS. Our study suggests that expression levels of both miR-9 and miR-155 can serve as candidates for prognostic biomarkers in TNBCs.

Lia G, Brunello L, Bruno S, et al.
Extracellular vesicles as potential biomarkers of acute graft-vs-host disease.
Leukemia. 2018; 32(3):765-773 [PubMed] Related Publications
Acute graft-vs-host disease (GVHD) is a serious complication after allografting. We carried out an exploratory study to investigate a potential correlation of surface antigens on extracellular vesicles (EVs) and acute GVHD. EVs were extracted from serum samples from 41 multiple myeloma patients who underwent allografting. EVs were characterized by flow cytometry using a panel of 13 antibodies against specific membrane proteins that were reported to be predictive of acute GVHD. We observed a correlation between three potential biomarkers expressed on EV surface and acute GVHD onset by both logistic regression analysis and Cox proportional hazard model. In our study, CD146 (MCAM-1) was correlated with an increased risk-by almost 60%-of developing GVHD, whereas CD31 and CD140-α (PECAM-1 and PDGFR-α) with a decreased risk-by almost 40 and 60%, respectively. These biomarkers also showed a significant change in signal level from baseline to the onset of acute GVHD. Our novel study encourages future investigations into the potential correlation between EVs and acute GVHD. Larger prospective multicenter studies are currently in progress.

England CG, Jiang D, Hernandez R, et al.
ImmunoPET Imaging of CD146 in Murine Models of Intrapulmonary Metastasis of Non-Small Cell Lung Cancer.
Mol Pharm. 2017; 14(10):3239-3247 [PubMed] Free Access to Full Article Related Publications
CD146 has been identified as an excellent biomarker for lung cancer as its overexpression in solid tumors has been linked to disease progression, invasion, and metastasis. Previously, our group described a positive correlation between

García-Donas J, Leon LA, Esteban E, et al.
A Prospective Observational Study for Assessment and Outcome Association of Circulating Endothelial Cells in Clear Cell Renal Cell Carcinoma Patients Who Show Initial Benefit from First-line Treatment. The CIRCLES (CIRCuLating Endothelial cellS) Study (SOGUG-CEC-2011-01).
Eur Urol Focus. 2017; 3(4-5):430-436 [PubMed] Related Publications
BACKGROUND: Markers able to predict the response to antiangiogenics in metastatic clear cell renal cell carcinoma (ccRCC) are not available. The development of new treatment options like immunotherapy are reaching the clinic; therefore, predictors of benefit from these different available treatments are increasingly needed.
OBJECTIVE: In this study, we prospectively assessed the association of circulating endothelial cells (CECs) in peripheral blood with long-term benefit from first-line treatment in ccRCC.
DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study was designed involving 13 institutions of the Spanish Oncology Genitourinary Group. Adult patients diagnosed with advanced ccRCC who had achieved response or disease stabilization after 3 mo on first-line therapy were eligible.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: CECs were isolated from peripheral blood, captured with ferrofluids coated with monoclonal antibodies directed against the CD146 antigen, and assessed centrally with an automated standardized system. CECs were defined as 4',6-diamidino-2-phenylindole+, CD105+, and CD45-. Blood samples were systematically taken every 6 wk for 15 mo or until tumor progression, whichever occurred first. Clinical data were externally monitored at all centers.
RESULTS AND LIMITATIONS: From August 9, 2011, to January 17, 2013, 75 patients were enrolled in the study. Patients with baseline CECs above the median showed a significantly longer progression-free survival than those with low CECs (22.2 mo vs 12.2 mo) with a hazard ratio of 2.5 (95% confidence interval: 1.2-5.3, p=0.016). There was no difference between CEC levels at baseline and at tumor progression (medians of 50 CECs/4ml and 52 CECs/4ml, respectively).
CONCLUSIONS: Under antiangiogenic treatment, the detection of higher CEC levels is associated with clinical benefit in terms of progression-free survival in ccRCC.
PATIENT SUMMARY: Antiangiogenics are the cornerstone of treatment in kidney cancer. Since they target endothelial rather than tumor cells, we studied the correlation between levels of circulating endothelial cells in peripheral blood and long-term benefit in patients on antiangiogenic therapy. Higher levels were associated with long-term benefit, suggesting that this determination could help to separate best responders from those who could require a more intensive approach.

Zeng P, Li H, Lu PH, et al.
Prognostic value of CD146 in solid tumor: A Systematic Review and Meta-analysis.
Sci Rep. 2017; 7(1):4223 [PubMed] Free Access to Full Article Related Publications
CD146, also known as melanoma cell adhesion molecule, was initially identified as a marker of melanoma progression and metastasis. Recently many clinical studies investigated overexpression of CD146 predict poor prognosis of solid tumor, however, the results was inconclusive, partly due to small numbers of patients included. This present meta-analysis was therefore performed utilizing the results of all clinical studies concerned to determine the prognostic value of CD146 expression in solid tumors. Relevant articles were identified through searching the PubMed, Web of Science and Embase database. In this meta-analysis, 12 studies involving 2,694 participants were included, and we drew the conclusion that strong significant associations between CD146 expression and all endpoints: overall survival (OS) [hazard ratio (HR) = 2.496, 95% confidence interval (95% CI) 2.115-2.946], time to progression (TTP) (HR = 2.445, 95% CI 1.975-3.027). Furthermore, the subgroup analysis revealed that the associations between CD146 overexpression and the outcome endpoints (OS or TTP) were significant in Mongoloid patients and Caucasian patients, as well in patients with lung cancer and digestive system cancer. In conclusion, these results showed that high CD146 was associated with poor survival in human solid tumors. CD146 may be a valuable prognosis predictive biomarker; nevertheless, whether CD146 could be a potential therapeutic target in human solid tumors needs to be further studied.

Tripathi SC, Fahrmann JF, Celiktas M, et al.
MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway.
Cancer Res. 2017; 77(16):4414-4425 [PubMed] Free Access to Full Article Related Publications
Despite favorable responses to initial therapy, small-cell lung cancer (SCLC) relapse occurs within a year and exhibits resistance to multiple drugs. Because of limited accessibility of patient tissues for research purposes, SCLC patient-derived xenografts (PDX) have provided the best opportunity to address this limitation. Here, we sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines and in chemoresistant PDX compared with matched treatment-naïve tumors. MCAM depletion in chemoresistant cells reduced cell proliferation and reduced the IC

Delaunay T, Deschamps L, Haddada M, et al.
Aberrant expression of kallikrein-related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion.
Mol Oncol. 2017; 11(10):1330-1347 [PubMed] Free Access to Full Article Related Publications
Members of the tissue kallikrein-related peptidase (KLK) family not only regulate several important physiological functions, but aberrant expression has also been associated with various malignancies. Clinically, KLKs have been suggested as promising biomarkers for diagnosis and prognosis in many types of cancer. As of yet, expression of KLKs and their role in skin cancers are, however, poorly addressed. Malignant melanoma is an aggressive disease associated with poor prognosis. Hence, diagnostic biomarkers to monitor melanoma progression are needed. Herein, we demonstrate that although mRNA of several KLKs are aberrantly expressed in melanoma cell lines, only the KLK7 protein is highly secreted in vitro. In line with these findings, ectopic expression of KLK7 in human melanomas and its absence in benign nevi were demonstrated by immunohistochemistry in vivo. Interestingly, overexpression of KLK7 induced a significant reduction in melanoma cell proliferation and colony formation. Moreover, KLK7 overexpression triggered an increase in cell motility and invasion associated with decreased expression of E-cadherin and an upregulation of MCAM/CD146. Our results demonstrate, for the first time, that aberrant KLK7 expression leads to a switch from proliferative to invasive phenotype, suggesting a potential role of KLK7 in melanoma progression. Thus, we hypothesize that KLK7 may represent a potential biomarker for melanoma progression.

Feng G, Huang HB, Ye XB, et al.
CD146 Promoter Polymorphism (rs3923594) Is Associated with Recurrence of Clear Cell Renal Cell Carcinoma in Chinese Population.
Dis Markers. 2017; 2017:2543059 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: CD146 is a membrane signal receptor in tumor-induced angiogenesis. However, limited studies have focused on the CD146 promoter polymorphisms in clear cell renal cell carcinoma (ccRCC).
PURPOSE: The purpose of this study was to investigate the association between polymorphisms located in the promoter region of the CD146 gene and characteristics of ccRCC in Chinese population. The association between the CD146 promoter polymorphisms and CD146 expression was also investigated in ccRCC.
MATERIALS AND METHODS: A total of 600 samples including 300 ccRCC patients and 300 healthy controls were collected for analysis of the CD146 promoter polymorphisms by direct sequence. The CD146 expressions were measured by qRT-PCR.
RESULTS: We had not found any significant differences in genotypic and allelic frequencies of CD146 promoter polymorphisms between ccRCC patients and controls. The rs3923594 was associated with stage and metastasis (300 cases) and recurrence (263 cases) of ccRCC in Chinese population. A significant association was also observed between the rs3923594 and CD146 expression (227 cases) in ccRCC.
CONCLUSIONS: CD146 promoter polymorphisms were not associated with the risk of ccRCC in Chinese population. The rs3923594 was an independent predictor of recurrence in Chinese patients with localized ccRCC.

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