Role of CEACAM1 and CEACAM20 in an In Vitro Model of Prostate Morphogenesis

Zhang, Hui; Eisenried, Andreas; Zimmermann, Wolfgang; Shively, John E.

doi:10.1371/journal.pone.0053359

Cited by 15 publications

(13 citation statements)

References 39 publications

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“…With evidence pointing toward the importance of cell and tissue structure, an increasing number of in vitro systems incorporating physiologically relevant lumen structures to more accurately model vessels (12–18) and ductal structures (11, 34–36) have emerged. Some models use prepatterned lumens to allow user control and access to the lumens, while others rely on self‐organization of cells into luminal networks as a result of specific culture conditions (7, 17, 34–36). For example, endothelial cells can form vascular networks when cocultured with fibroblasts within 3D hydrogels (17).…”

Section: Resultsmentioning

confidence: 99%

The importance of being a lumen

et al. 2014

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Advances in tissue engineering and microtechnology have enabled researchers to more easily generate in vitro tissue models that mimic the tissue geometry and spatial organization found in vivo (e.g., vessel or mammary duct models with tubular structures). However, the widespread adoption of these models for biological studies has been slow, in part due to the lack of direct comparisons between existing 2-dimensional and 3-dimensional cell culture models and new organotypic models that better replicate tissue structure. Using previously developed vessel and mammary duct models with 3-dimensional lumen structures, we have begun to explore this question. In a direct comparison between these next generation organotypic models and more traditional methods, we observed differences in the levels of several secreted growth factors and cytokines. In addition, endothelial vessel geometry profoundly affects the phenotypic behavior of carcinoma cells, suggesting that more traditional in vitro assays may not capture in vivo events. Here, we seek to review and add to the increasing evidence supporting the hypothesis that using cell culture models with more relevant tissue structure influences cell fate and behavior, potentially increasing the relevance of biological findings.-Bischel, L. L., Sung, K. E., Jiménez-Torres, J. A., Mader, B., Keely, P. J., Beebe, D. J. The importance of being a lumen. FASEB J. 28, 4583-4590 (2014). www.fasebj.org Key Words: tissue engineering ⅐ cell culture ⅐ tissue geometry ⅐ microtechnology ⅐ microfluidics Current research tools for the study of cell-or tissue-level biological processes can be classified along a continuum of increasingly more complex models, ranging from 2-dimensional (2D) cell culture to in vivo animal models (Fig. 1). In vivo models involve the use of whole organisms, usually mice, which inherently account for many important complexities in the body (1-3). However, it is difficult to investigate the role of the many microenvironmental factors individually using in vivo models, due to challenges associated with isolating specific interactions. In addition, in vivo models tend to be time consuming and costly, limiting their use in routine assays. Moreover, the use of animal models comes with ethical issues, and, in many cases, animal biology is significantly different from humans. At the other end of the spectrum, in vitro 2D cell culture is commonly used to study specific cell behavior and interactions. While these assays have provided much scientific knowledge and insight, they typically lack numerous factors associated with complex microenvironments, including tissue structure, cell-cell interactions, or cell-extracellular matrix (ECM) interactions, raising questions regarding the relevance of 2D cell culture for modeling in vivo responses.To bridge this gap between in vivo and in vitro models and augment the tools available to biologists, there has been an increasing interest in the development of biomimetic tissue models with improved representation of in vivo condi...

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Section: Resultsmentioning

confidence: 99%

The importance of being a lumen

et al. 2014

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“…The primary human prostate cells formed organoids with a lumen and small tubular outgrowth, which was inhibited, when anti-CEACAM1 antibodies were added to the cultures or when CEACAM1 expression was reduced by about 50% with antisense oligonucleotides [47]. As these cells express both CEACAM1 isoforms, with either short or long cytoplasmic domain, it is unclear if one or both proteins are responsible for the phenotype.…”

Section: Signaling By Epithelial Ceacamsmentioning

confidence: 99%

Signaling by epithelial members of the CEACAM family – mucosal docking sites for pathogenic bacteria

2014

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Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) comprise a group of immunoglobulin-related vertebrate glycoproteins. Several family members, including CEACAM1, CEA, and CEACAM6, are found on epithelial tissues throughout the human body. As they modulate diverse cellular functions, their signaling capacity is in the focus of current research. In this review we will summarize the knowledge about common signaling processes initiated by epithelial CEACAMs and suggest a model of signal transduction by CEACAM family members lacking significant cytoplasmic domains. As pathogenic and non-pathogenic bacteria exploit these receptors during mucosal colonization, we try to highlight the connection between CEACAMs, microbes, and cellular responses. Special emphasis in this context is placed on the functional interplay between CEACAMs and integrins that influences matrix adhesion of epithelial cells. The cooperation between these two receptor families provides an intriguing example of the fine tuning of cellular responses and their manipulation by specialized microorganisms.

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“…The evidence for regulation of DNMT1 by miR-342 is further supported by studies on prostate cells, where both ID4 and DNMT1 show interactions in both cell lines and prostate cancer tissue (47) where up-or down-regulation of CEACAM1 is also observed (51). Taken together, the fine-tuning of the lumen formation program involves two negative acting signals.…”

Section: Discussionmentioning

confidence: 73%

miRNA-342 Regulates CEACAM1-induced Lumen Formation in a Three-dimensional Model of Mammary Gland Morphogenesis

Weng

Shively

2016

Journal of Biological Chemistry

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Lumen formation of breast epithelium is rapidly lost during tumorigenesis along with expression of cell adhesion molecule CEACAM1. CEACAM1 induces lumena in a three-dimensional culture of MCF7/CEACAM1 cells that otherwise fail to form lumena. We hypothesized miRNAs may be involved because >400 genes were up-or down-regulated in MCF7/CEACAM1 cells and miRNAs may modify global expression patterns. Comparative analysis of miRNA expression in MCF7 versus MCF7/ CEACAM1 cells revealed two miRNAs significantly down-regulated (hsa-miR-30a-3p by 6.73-fold and hsa-miR-342-5p by 5.68-fold). Location of miR-342 within an intron of the EVL gene, hypermethylated and involved in tumorigenesis, suggested that miR-342 overexpression may block lumen formation. In fact, overexpression of miR-342 in MCF7/CEACAM1 cells significantly blocked lumen formation (p < 0.001). ID4, a dominant-negative inhibitor of basic helix-loop-helix transcription factors, up-regulated in MCF7/CEACAM1 cells, down-regulated in breast cancer, and containing a miR-342 binding site, was tested as a potential target of miR-342. The ratio of ID4 to miR-342 increased from 1:2 in MCF7 cells to 30:1 in MCF7/ CEACAM1 cells and a miR-342 inhibitor was able to induce 3-UTR ID4 reporter activity in MCF7 cells. Because 5-methylcytosine methyltransferase DNMT1 is also a potential target of miR-342, we inhibited miR-342 in MCF7 cells and found DNMT1 was up-regulated with no change in EVL expression, suggesting that miR-342 regulates DNMT1 expression but DNMT1 does not affect the EVL expression in these cells. We conclude that the regulation of lumen formation by miR-342 involves at least two of its known targets, namely ID4 and DNMT1.Lumen formation of mammary epithelial cells in a threedimensional culture is an in vitro assay that phenocopies mammary epithelial gland formation (1-3). The loss of lumen formation as exhibited by most, if not all, breast cancer cells in the three-dimensional culture assay phenocopies the premalignant stage of breast cancer know as ductal carcinoma in situ. One approach to identify genes that may govern the change from normal to (pre)malignancy is to transfect breast cancer cells with genes down-regulated in breast cancer and assay their regain of function in the lumen formation assay. A second approach is to block suspect gene expression in breast cancer cells for regain of function, or block gene expression in normal breast epithelial cells for loss of function. One gene that stands out in these assays is the cell-cell adhesion molecule CEACAM1 that is highly expressed in normal breast with a luminal expression pattern (4, 5), and is consistently down-regulated in premalignant and invasive breast cancer (4, 5).Previously, we have shown that transfection of CEACAM1 into MCF7 breast cancer cells resulted in lumen formation when the cells were cultured three-dimensionally (6), whereas anti-CEACAM1 antibodies blocked lumen formation of the normal breast epithelial cell line MCF10F that express CEACAM1 (5). Although CEACAM1 is expressed as mu...

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Role of CEACAM1 and CEACAM20 in an In Vitro Model of Prostate Morphogenesis

Cited by 15 publications

References 39 publications

The importance of being a lumen

The importance of being a lumen

Signaling by epithelial members of the CEACAM family – mucosal docking sites for pathogenic bacteria

miRNA-342 Regulates CEACAM1-induced Lumen Formation in a Three-dimensional Model of Mammary Gland Morphogenesis

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