Attenuation of Melanoma Invasion by a Secreted Variant of Activated Leukocyte Cell Adhesion Molecule

Kilsdonk, Jeroen W.J. van; Wilting, Roel H.; Bergers, Mieke; Muijen, G.N.P. van; Schalkwijk, Joost; Kempen, Léon C van; Swart, Guido W.M.

doi:10.1158/0008-5472.can-07-5767

Cited by 59 publications

(64 citation statements)

References 49 publications

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“…These results are in line with the fact that ALCAM is a cell-to-cell adhesion receptor known to play a major role in mediating the interactions between endothelial and tumor or immune cells during transendothelial migration (39)(40)(41). Moreover, ALCAM was found to be involved in cell movement (42) and in the conversion of the prometastatic pro-MMP-2 to its active form in malignancy (43). On the other hand, modulations of integrin levels were associated with various metastatic phenotypes (35,(44)(45)(46).…”

Section: Discussionsupporting

confidence: 74%

miR-214 and miR-148b Targeting Inhibits Dissemination of Melanoma and Breast Cancer

et al. 2016

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miR-214 and miR-148b have been proposed to antagonize the effects of each other in enabling or blocking metastasis, respectively. In this study, we provide evidence deepening their role and interrelationship in the process of metastatic dissemination. Depleting miR-214 or elevating miR-148b blocked the dissemination of melanoma or breast cancer cells, an effect that could be accentuated by dual alteration. Mechanistic investigations indicated that dual alteration suppressed passage of malignant cells through the blood vessel endothelium by reducing expression of the cell adhesion molecules ITGA5 and ALCAM. Notably, transendothelial migration in vitro and extravasation in vivo impaired by singly alternating miR-214 or miR-148b could be overridden by overexpression of ITGA5 or ALCAM in the same tumor cells. In clinical specimens of primary breast cancer or metastatic melanoma, we found a positive correlation between miR-214 and ITGA5 or ALCAM along with an inverse correlation of miR-214 and miR-148b in the same specimens. Our findings define an antagonistic relationship of miR-214 and miR-148b in determining the dissemination of cancer cells via tumor-endothelial cell interactions, with possible implications for microRNA-mediated therapeutic interventions aimed at blocking cancer extravasation.

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Section: Discussionsupporting

confidence: 74%

miR-214 and miR-148b Targeting Inhibits Dissemination of Melanoma and Breast Cancer

et al. 2016

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“…Significantly, the fraction of ALCAM-positive lesions increases according to invasiveness (Clark level) and thickness (Breslow index) of the melanocytic tumor (8). It was shown that any interference with ALCAM function affects melanoma cell movement and invasion (9,10) and that ALCAM triggers MMP2 and MMP14 activity (11). However, it is still not known how ALCAM overexpression is induced in melanomas and how it coordinates metastasis formation.…”

Section: Introductionmentioning

confidence: 99%

miR-214 Coordinates Melanoma Progression by Upregulating ALCAM through TFAP2 and miR-148b Downmodulation

et al. 2013

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Malignant melanoma is one of the most aggressive human cancers, but the mechanisms governing its metastatic dissemination are not fully understood. Upregulation of miR-214 and ALCAM and the loss of TFAP2 expression have been implicated in this process, with TFAP2 a direct target of miR-214. Here, we link miR-214 and ALCAM as well as identify a core role for miR-214 in organizing melanoma metastasis. miR-214 upregulated ALCAM, acting transcriptionally through TFAP2 and also posttranscriptionally through miR-148b (itself controlled by TFAP2), both negative regulators of ALCAM. We also identified several miR-214-mediated prometastatic functions directly promoted by ALCAM. Silencing ALCAM in miR-214-overexpressing melanoma cells reduced cell migration and invasion without affecting growth or anoikis in vitro, and it also impaired extravasation and metastasis formation in vivo. Conversely, cell migration and extravasation was reduced in miR-214-overexpressing cells by upregulation of either miR-148b or TFAP2. These findings were consistent with patterns of expression of miR-214, ALCAM, and miR-148b in human melanoma specimens. Overall, our results define a pathway involving miR-214, miR-148b, TFAP2, and ALCAM that is critical for establishing distant metastases in melanoma. Cancer Res; 73(13); 4098-111. Ó2013 AACR.

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“…Thus, ALCAM expression has been implicated in apoptosis [5], angiogenesis [6], migration, and invasion [7] of various cell types. Concerning the role of ALCAM in human cancer, the results are partly controversial: In many tumors, ALCAM expression is associated with high invasive and metastatic potential and poor prognosis, i.e., in melanoma [8,9], colorectal cancer [10], oral cancer [11], pancreatic carcinoma [12], and esophageal carcinoma [13].…”

Section: Introductionmentioning

confidence: 99%

Biologic role of activated leukocyte cell adhesion molecule overexpression in breast cancer cell lines and clinical tumor tissue

Hein

Müller

Köhler

et al. 2010

Breast Cancer Res Treat

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The activated leukocyte cell adhesion molecule (ALCAM) is overexpressed in many mammary tumors, but controversial results about its role and prognostic impact in breast cancer have been reported. Therefore, we evaluated the biologic effects of ALCAM expression in two breast cancer cell lines and a larger cohort of mammary carcinomas. By stable transfections, MCF7 cells with ALCAM overexpression and MDA-MB231 cells with reduced ALCAM levels were generated and analyzed in functional assays and cDNA microarrays. In addition, an immunohistochemical study on 347 patients with breast cancer with long-term follow-up and analysis of disseminated tumor cells (DTCs) was performed. In both cell lines, high ALCAM expression was associated with reduced cell motility. In addition, ALCAM silencing in MDA-MB231 cells resulted in lower invasive potential, whereas high ALCAM expression was associated with increased apoptosis in both cell lines. Among genes which were differentially expressed in clones with altered ALCAM expression, there was an overlap of 15 genes between both cell lines, among them cathepsin D, keratin 7, gelsolin, and ets2 whose deregulation was validated by western blot analysis. In MDA-MB231 cells, we observed a correlation with VEGF expression which was validated by enzyme-linked immuno sorbent assay (ELISA). Our IHC results on primary breast carcinomas showed that ALCAM expression was associated with an estrogen receptor-positive phenotype. In addition, strong ALCAM immunostaining correlated with nodal involvement and the presence of tumor cells in bone marrow. By Kaplan-Meier analysis, strong ALCAM expression in ductal carcinomas correlated with shorter recurrence-free intervals (P=0.048) and overall survival (OAS, P=0.003). Our results indicate that the biologic role of ALCAM in breast cancer is complex, but overexpression might be relevant for outcome in ductal carcinomas.

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Attenuation of Melanoma Invasion by a Secreted Variant of Activated Leukocyte Cell Adhesion Molecule

Cited by 59 publications

References 49 publications

miR-214 and miR-148b Targeting Inhibits Dissemination of Melanoma and Breast Cancer

miR-214 and miR-148b Targeting Inhibits Dissemination of Melanoma and Breast Cancer

miR-214 Coordinates Melanoma Progression by Upregulating ALCAM through TFAP2 and miR-148b Downmodulation

Biologic role of activated leukocyte cell adhesion molecule overexpression in breast cancer cell lines and clinical tumor tissue

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