Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewE-cadherin's dark side: Possible role in tumor progression
Introduction
Cadherins are a family of cell surface glycoproteins that play a prominent role in cell–cell adhesion. Classical cadherins were the first members of the cadherin superfamily to be identified and are key structural components of the adherens junctions [1]. Cadherins mediate Ca2 + dependent, homophilic cell–cell adhesion via their extracellular domains [2]. In addition, they link the extracellular environment to the cytoskeleton and participate in cell signaling through the interaction of their conserved cytoplasmic domains with the catenins, in particular p120-, α- and β-catenins (reviewed in [3], [4]). E-cadherin, a type I classical cadherin, is a key component in the formation of cell–cell adherens-type junctions in epithelial tissues [3], [4].
Studies in a variety of cancers have documented E-cadherin's role as a tumor suppressor; the evidence for this is covered briefly here, as it has been extensively reviewed elsewhere [5], [6], [7], [8]. At the experimental level, suppression of E-cadherin function or expression leads to mesenchymal morphology and increased cell migration and invasion [9], [10] as well as metastasis [11], [12], [13]. Loss of E-cadherin facilitates the initial invasive behavior of certain epithelial-derived cancers [11], [14] which may allow basement membrane transgression and spread [10]. Conversely, re-introduction of E-cadherin in cell lines lacking expression leads to reversal of poorly differentiated carcinoma phenotypes (i.e. fibroblastic, highly invasive, poorly cell–cell adherent) back to a well-differentiated, minimally invasive epithelioid phenotype with well developed cell–cell junctions [15], [16], [17], [18]. Loss of E-cadherin leads to activation of known oncogenic signaling pathways, including mitogen activated kinase (MAPK), rat sarcoma viral oncogene (Ras) and ras-related C3 botulinum toxin substrate (Rac1) [19], [20], as well as loss of Hippo signaling [21].
At the physiological level, the tumor suppressor role of E-cadherin has been particularly studied in breast cancer (reviewed in [7], [22]), where loss of heterozygosity in chromosome region 16q22.1, the gene region encoding E-cadherin (CDH1), is frequent [22]. In fact, loss of E-cadherin is one of the main phenotypic traits of lobular carcinoma, a breast carcinoma subtype characterized by prominent single cell infiltration, which has been colorfully referred to in classic pathology teaching as “indian filing”. A tumor suppressor role for E-cadherin has also been established or suggested in a variety of additional epithelial malignancies, including hepatocellular carcinoma [23], squamous cell carcinomas of the skin, head and neck [24], [25], and esophagus [26], as well as melanoma [27]. Many of these cancers do not show a high frequency of somatic mutations in CDH1; however E-cadherin expression can also be downregulated by promoter hypermethylation [28]. Inherited germline mutations in CDH1 are also a feature of hereditary gastric cancer [29].
The experimental and physiological observations regarding the tumor suppressor role of E-cadherin are often interpreted in the context of the epithelial–mesenchymal transition (EMT). This developmentally-important process includes a spectrum of changes that lead to the transient downregulation of epithelial cell traits such as apical–basal polarization and organized cell–cell adhesion and the acquisition of a mesenchymal cellular phenotype that is less adherent and more migratory (the process of EMT has been reviewed in [30], [31]). Together, these changes facilitate tissue reorganization and morphogenesis during the development. It is increasingly apparent that facets of EMT underlie the progression of carcinomas (tumors of epithelial origin) toward increasingly malignant states (reviewed in [32], [33], [34], [35]). One component of the EMT process is the cadherin “switch” whereby the expression of epithelial cadherins (e.g. E-cadherin) is downregulated and conversely mesenchymal cadherins (N-cadherin) are expressed (reviewed in [6], [36], [37]). Such changes in cadherin expression have been reported for a variety of cancers [37], and, as described above, are experimentally linked to increased cell motility and the ability to invade and/or metastasize. It is in this context that E-cadherin's tumor suppressor role in cancer is most often viewed. In the most simplified model, E-cadherin's presence prevents cell motility, invasion, and metastasis.
Although E-cadherin's role as a tumor suppressor is established by agreed upon criteria with firm supporting experimental evidence, in recent years alternative roles for E-cadherin in tumor progression have become apparent. Particularly, in tumors from the ovary, a classical epithelial–mesenchymal transition does not occur, and to the contrary E-cadherin is consistently upregulated [38]. Similarly, although an EMT operates in breast carcinoma, evidence supports an important role for E-cadherin in tumor intravasation, which itself is a critical step required for metastasis ([39], reviewed by [40]). For example, most breast ductal carcinomas, both primary and metastatic, consistently express E-cadherin [41], and E-cadherin plays an important role in maintaining intravasated microemboli in inflammatory breast carcinoma models, as described below. E-cadherin may also be important in stem cell biology, increasingly recognized as an important facet of tumor progression [42]; for example, in some studies E-cadherin upregulation increases the clonogenic activity of human embryonic stem cells in the absence of an effect on cell motility [43].
These observations suggest that E-cadherin not only acts as a tumor suppressor, but may also have a promoting role in tumor progression. A variety of proteins function as tumor suppressors or promoters, depending on the specific context; TGF-β is one example [44]. While compelling, the positive functions of E-cadherin in tumor progression have not yet been explored in a systematic fashion. In the remainder of this review we consider E-cadherin's alternative, non-tumor suppressive roles, using specific tumor types as examples.
Section snippets
Support of intravasation and tumor cell survival in inflammatory breast carcinoma
Carcinoma of the breast is a tumor type in which the epithelial–mesenchymal transition with associated down regulation of E-cadherin has been studied extensively. Lobular carcinoma is a morphologic subtype, the hallmark of which is absence of E-cadherin expression [45], a diagnostically useful marker. However, the role of E-cadherin in breast cancer biology might be more complex, and a simple downregulation of E-cadherin may not accurately describe the whole process. In fact, invasive ductal
Positive role of E-cadherin in tumor progression: possible mechanisms
As the previous discussion emphasizes, tumor conditions exist in which E-cadherin is present, and its presence makes tumor progression worse. Much remains to be learned about this positive role for E-cadherin in tumor-progression, in particular with respect to tumor context and specific mechanisms. In some cases, like the formation of tumor emboli that is seen in inflammatory breast carcinoma, cadherin-based cell–cell contacts may promote tumor cell survival, growth and invasion. In other
Conclusion
Conventional interpretation of the key mediators of tumor promotion/progression has emphasized the presence of tumor suppressors and oncoproteins, roles that are discussed in sharply separated contexts. However, as we dissect the complex molecular mechanisms of cancer, it becomes evident that genes and proteins may have opposing roles depending on the specific context. E-cadherin has been well established as an important tumor suppressor in a variety of tumor types by a strong body of
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- 1
Contributed equally to the work.
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Present address: Department of Pathology, Division of Neuropathology, Johns Hopkins University, 720 Rutland Avenue, Baltimore MD, 21205, USA.