Kass L, Erler JT, Dembo M, Weaver VM.. Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int J Biochem Cell Biol 39: 1987-1994

Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States
The International Journal of Biochemistry & Cell Biology (Impact Factor: 4.05). 02/2007; 39(11):1987-94. DOI: 10.1016/j.biocel.2007.06.025
Source: PubMed


Stromal-epithelial interactions regulate mammary gland development and are critical for the maintenance of tissue homeostasis. The extracellular matrix, which is a proteinaceous component of the stroma, regulates mammary epithelial growth, survival, migration and differentiation through a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal responses to regulate processes including branching morphogenesis and alveolar differentiation. Malignant transformation of the breast is also associated with significant matrix remodeling and a progressive stiffening of the stroma that can enhance mammary epithelial cell growth, perturb breast tissue organization, and promote cell invasion and survival. In this review, we discuss the role of stromal-epithelial interactions in normal and malignant mammary epithelial cell behavior. We specifically focus on how dynamic modulation of the biochemical and biophysical properties of the extracellular matrix elicit a dialogue with the mammary epithelium through transmembrane integrin receptors to influence tissue morphogenesis, homeostasis and malignant transformation.

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Available from: Micah Dembo, Jan 21, 2014
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    • "It is well-appreciated that alterations in the extracellular matrix (ECM) contribute to important biological events which include wound healing, inflammation, tumor progression and metastasis [41], [42], [43]. The current investigation began with our initial observation that the provisional integrins, α4β1/αvβ3 induced migration requires a specific isoform of Rac, Rac2 in macrophages and endothelial cells and that this pathway regulated the postnatal angiogenic response in vivo [1], [2]. "
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    ABSTRACT: Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the α4β1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "The adhesion of tumor cells to the extracellular matrix (ECM) is a critical step in the process of cancer metastasis (Evans 1991; Weinberg 2007). Components of the tumor microenvironment modulate tumor cell behavior such as adhesion and invasion, often inducing cells to metastasize more readily (for recent reviews , see Kenny and Bissell 2003; Kopfstein and Christofori 2006; Funasaka and Raz 2007; Kass et al. 2007; Li et al. 2007; Bidard et al. 2008; Le Bitoux and Stamenkovic 2008; Kim et al. 2011). Fatty acids are present in the body in significant amounts, originating both from dietary sources and from release by phospholipases from cell membranes (Perez-Chacon et al. 2009). "
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    ABSTRACT: Arachidonic acid stimulates cell adhesion by activating α2β1 integrins in a process that depends on protein kinases, including p38 mitogen activated protein kinase. Here, we describe the interaction of cytoskeletal components with key signaling molecules that contribute to the spreading of, and morphological changes in, arachidonic acid-treated MDA-MB-435 human breast carcinoma cells. Arachidonic acid-treated cells showed increased attachment and spreading on collagen type IV, as measured by electric cell-substrate impedance sensing. Fatty acid-treated cells displayed short cortical actin filaments associated with an increased number of β1 integrin-containing pseudopodia, whereas untreated cells displayed elongated stress fibers and fewer clusters of β1 integrins. Confocal microscopy of arachidonic acid-treated cells showed that vinculin and phospho-p38 both appeared enriched in pseudopodia and at the tips of actin filaments, and fluorescence ratio imaging indicated the increase was specific for the phospho-(active) form of p38. Immunoprecipitates of phospho-p38 from extracts of arachidonic acid-treated cells contained vinculin, and GST-vinculin fusion proteins carrying the central region of vinculin bound phospho-p38, whereas fusion proteins expressing the terminal portions of vinculin did not. These data suggest that phospho-p38 associates with particular domains on critical focal adhesion proteins that are involved in tumor cell adhesion and spreading, and that this association can be regulated by factors in the tumor microenvironment.
    Full-text · Article · Dec 2013 · Biochemistry and Cell Biology
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    • "We compared the RNA levels of HOTAIR between the rBM 3-D ± Col-1 cultures using qRT-PCR (primer sequences listed Additional file 1: Table S1) [17]. We supplemented rBM 3-D culture with 2 mg/ml of Col-1 because this concentration of Col-1 in rBM 3-D culture yields a rigidity that is comparable to that observed in the stiff tumor microenvironment of patients with breast cancer [5,18,19]. Addition of Col-1 (Sigma, St. Louis MO) into rBM 3-D culture induced a 7.1- and 3.8-fold increase in the HOTAIR RNA levels in A549 and mK-ras-LE cells, respectively (Figure 1A & B). On the other hand Col-1 did not significantly alter the expression of three other lincRNA genes, namely H19, XIST, or MALAT1 in A549 cells (Figure 1C). "
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    ABSTRACT: Background The tumor microenvironment is a crucial determinant in tumor progression. Interstitial extracellular matrix (ECM), such as type I collagen (Col-1), is aberrantly enriched in the tumor microenvironment and promotes tumor progression. Long intergenic non-coding RNAs (lincRNA) are a new family of regulatory RNAs that modulate fundamental cellular processes via diverse mechanisms. Findings We investigated whether the expression of lincRNAs was regulated by the tumor promoting Col-1. In a three-dimensional organotypic culture model using the reconstituted basement membrane ECM Matrigel (rBM 3-D), supplementation of Col-1 disrupted acini, a differentiation feature of well-differentiated lung adenocarcinoma cells, and concurrently induced the expression of a tumor-promoting lincRNA, HOX transcript antisense RNA (HOTAIR). Induction of HOTAIR by Col-1 was diminished by a neutralizing antibody against the Col-1 receptor α2β1 integrin. Col-1 activates the expression of a reporter gene controlled by the human HOTAIR promoter. Moreover the expression of HOTAIR and Col-1 was concurrently up-regulated in human non-small cell lung cancer. Conclusions Our findings indicate that tumor-promoting Col-1 up-regulates the expression of HOTAIR in NSCLC cells. These initial results warrant further investigation of HOTAIR and other lincRNA genes in lung tumorigenesis.
    Full-text · Article · May 2013 · Journal of Hematology & Oncology
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