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      Epithelial-Stromal Interactions in Human Breast Cancer: Effects on Adhesion, Plasma Membrane Fluidity and Migration Speed and Directness

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          Abstract

          Interactions occurring between malignant cells and the stromal microenvironment heavily influence tumor progression. We investigated whether this cross-talk affects some molecular and functional aspects specifically correlated with the invasive phenotype of breast tumor cells (i.e. adhesion molecule expression, membrane fluidity, migration) by co-culturing mammary cancer cells exhibiting different degrees of metastatic potential (MDA-MB-231>MCF-7) with fibroblasts isolated from breast healthy skin (normal fibroblasts, NFs) or from breast tumor stroma (cancer-associated fibroblasts, CAFs) in 2D or 3D (nodules) cultures. Confocal immunofluorescence analysis of the epithelial adhesion molecule E-cadherin on frozen nodule sections demonstrated that NFs and CAFs, respectively, induced or inhibited its expression in MCF-7 cells. An increase in the mesenchymal adhesion protein N-cadherin was observed in CAFs, but not in NFs, as a result of the interaction with both kinds of cancer cells. CAFs, in turn, promoted N-cadherin up-regulation in MDA-MB-231 cells and its de novo expression in MCF-7 cells. Beyond promotion of “cadherin switching”, another sign of the CAF-triggered epithelial-mesenchymal transition (EMT) was the induction of vimentin expression in MCF-7 cells. Plasma membrane labeling of monolayer cultures with the fluorescent probe Laurdan showed an enhancement of the membrane fluidity in cancer cells co-cultured with NFs or CAFs. An increase in lipid packing density of fibroblast membranes was promoted by MCF-7 cells. Time-lapsed cell tracking analysis of mammary cancer cells co-cultured with NFs or CAFs revealed an enhancement of tumor cell migration velocity, even with a marked increase in the directness induced by CAFs.

          Our results demonstrate a reciprocal influence of mammary cancer and fibroblasts on various adhesiveness/invasiveness features. Notably, CAFs' ability to promote EMT, reduction of cell adhesion, increase in membrane fluidity, and migration velocity and directness in mammary cancer cells can be viewed as an overall progression- and invasion-promoting effect.

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          Most cited references 53

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          Feature point tracking and trajectory analysis for video imaging in cell biology.

          This paper presents a computationally efficient, two-dimensional, feature point tracking algorithm for the automated detection and quantitative analysis of particle trajectories as recorded by video imaging in cell biology. The tracking process requires no a priori mathematical modeling of the motion, it is self-initializing, it discriminates spurious detections, and it can handle temporary occlusion as well as particle appearance and disappearance from the image region. The efficiency of the algorithm is validated on synthetic video data where it is compared to existing methods and its accuracy and precision are assessed for a wide range of signal-to-noise ratios. The algorithm is well suited for video imaging in cell biology relying on low-intensity fluorescence microscopy. Its applicability is demonstrated in three case studies involving transport of low-density lipoproteins in endosomes, motion of fluorescently labeled Adenovirus-2 particles along microtubules, and tracking of quantum dots on the plasma membrane of live cells. The present automated tracking process enables the quantification of dispersive processes in cell biology using techniques such as moment scaling spectra.
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            Random versus directionally persistent cell migration.

            Directional migration is an important component of cell motility. Although the basic mechanisms of random cell movement are well characterized, no single model explains the complex regulation of directional migration. Multiple factors operate at each step of cell migration to stabilize lamellipodia and maintain directional migration. Factors such as the topography of the extracellular matrix, the cellular polarity machinery, receptor signalling, integrin trafficking, integrin co-receptors and actomyosin contraction converge on regulation of the Rho family of GTPases and the control of lamellipodial protrusions to promote directional migration.
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              Reconstruction of functionally normal and malignant human breast tissues in mice.

              The study of normal breast epithelial morphogenesis and carcinogenesis in vivo has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                10 December 2012
                : 7
                : 12
                Affiliations
                [1 ]Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore, Roma, Italia
                [2 ]Istituto di Fisica, Università Cattolica del Sacro Cuore, Roma, Italia
                [3 ]Istituto di Ricovero e Cura a Carattere Scientifico - Fondazione G.B. Bietti, Roma, Italia
                [4 ]Dipartimento per la Tutela della Salute della Donna e della Vita Nascente, del Bambino e dell'Adolescente - Unità Operativa di Chirurgia Senologica, Facoltà di Medicina e Chirurgia “A. Gemelli”, Università Cattolica del Sacro Cuore, Roma, Italia
                University of Edinburgh, United Kingdom
                Author notes

                Competing Interests: One of the authors Riccardo Masetti is the president of the Italian affiliate of the Susan G. Komen Breast Cancer Foundation. The other authors have declared that no competing interests exist.

                Conceived and designed the experiments: CA GM GS MDS. Performed the experiments: CA GM GL GP AC MP A. Maiorana A. Micera ADL OB. Analyzed the data: CA GM GP MP A. Maiorana. Contributed reagents/materials/analysis tools: MDS GS RM. Wrote the paper: CA GM GS MDS.

                Article
                PONE-D-12-22839
                10.1371/journal.pone.0050804
                3519494
                23251387

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 13
                Funding
                Funding was provided by the Susan G. Komen Italian Affiliate (Rome, Italy). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Molecular Cell Biology
                Cell Adhesion
                Gene Expression
                Medicine
                Obstetrics and Gynecology
                Breast Cancer
                Oncology
                Basic Cancer Research
                Metastasis
                Cancers and Neoplasms
                Breast Tumors
                Physics
                Biophysics
                Cell Motility

                Uncategorized

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