Abstract
BackgroundThe initial step of metastasis in carcinomas, often referred to as the epithelial-mesenchymal transition (EMT), occurs via the loss of adherens junctions (e.g. cadherins) by the tumor embolus. This leads to a subsequent loss of cell polarity and cellular differentiation and organization, enabling cells of the embolus to become motile and invasive. However highly malignant inflammatory breast cancer (IBC) over-expresses E-cadherin. The human xenograft model of IBC (MARY-X), like IBC, displays the signature phenotype of an exaggerated degree of lymphovascular invasion (LVI) in situ by tumor emboli. An intact E-cadherin/α, β-catenin axis mediates the tight, compact clump of cells found both in vitro and in vivo as spheroids and tumor emboli, respectively.MethodsUsing electron microscopy and focused ion beam milling to acquire in situ sections, we performed ultrastructural analysis of both an IBC and non-IBC, E-cadherin positive cell line to determine if retention of this adhesion molecule contributed to cellular organization.ResultsHere we report through ultrastructural analysis that IBC exhibits a high degree of cellular organization with polar elements such as apical/lateral positioning of E-cadherin, apical surface microvilli, and tortuous lumen-like (canalis) structures. In contrast, agarose-induced spheroids of MCF-7, a weakly invasive E-cadherin positive breast carcinoma cell line, do not exhibit ultrastructural polar features.ConclusionsThis study has determined that the highly metastatic IBC with an exaggerated malignant phenotype challenges conventional wisdom in that instead of displaying a loss of cellular organization, IBC acquires a highly structured architecture.These findings suggest that the metastatic efficiency might be linked to the formation and maintenance of these architectural features. The comparative architectural features of both the spheroid and embolus of MARY-X provide an in vitro model with tractable in vivo applications.
Highlights
The initial step of metastasis in carcinomas, often referred to as the epithelialmesenchymal transition (EMT), occurs via the loss of adherens junctions by the tumor embolus
The human xenograft model of inflammatory breast cancer (IBC) (MARY-X), like IBC, displays the signature phenotype of an exaggerated degree of lymphovascular invasion (LVI) in situ by tumor emboli and over-expresses E-cadherin. This over-expression of Ecadherin by MARY-X is maintained throughout the metastatic progression (Figure 1)
Transmission electron microscopic (TEM) analysis was performed to investigate the paradox of E-cadherin overexpression in the MARY-X spheroid and whether it extended beyond the molecular function and contributed to cellular organization
Summary
The initial step of metastasis in carcinomas, often referred to as the epithelialmesenchymal transition (EMT), occurs via the loss of adherens junctions (e.g. cadherins) by the tumor embolus This leads to a subsequent loss of cell polarity and cellular differentiation and organization, enabling cells of the embolus to become motile and invasive. In normal epithelial tissue polarity results in an asymmetric distribution of protein receptors/ transporters, signaling complexes, ion channels and lipids between two surfaces, the apical and basolateral [1]. It is the maintenance of the architectural integrity and function of the two surfaces which traditionally distinguish normal from aberrant cells
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