From Normalcy to Neoplasia. The Role of Epithelial-Stromal Interactions in Regulating Mammary Growth and Differentiation PDF Download
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Languages : en
Pages : 115
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We identified molecules that are involved in the cross talk between the epithelial and mesenchymal components of the developing and involuting mammary gland. The EFGR protein was shown to mediate normal ductal morphogenesis by acting from the stromal cells on the development of the mammary epithelial ducts. Additional evidence was provided concerning the function of the Caspase 1 gene product during lobular-alveolar development and involution of the mammary gland after weaning. An interesting observation from this work was mammary epithelial cells that will succumb to apoptosis enter the cell cycle first. This observation implies that at least a subset of the redundant epithelial cells undergo activation before cell death. In preliminary work mammary glands from the MMP14 null mouse were shown to have less adipose tissue but ductal penetration of the fat pad and initial duct formation occurred by post-natal day 13. Further experimentation is required to determine if the reduction in adipose tissue is related - to the wasting phenotype of these animals, or is induced by the MMP14 null epithelial cells. The practical outcome of these studies is a better understanding of mammary gland development before, during and after pregnancy, and during the process of involution.
Author:
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ISBN:
Category :
Languages : en
Pages : 115
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Book Description
We identified molecules that are involved in the cross talk between the epithelial and mesenchymal components of the developing and involuting mammary gland. The EFGR protein was shown to mediate normal ductal morphogenesis by acting from the stromal cells on the development of the mammary epithelial ducts. Additional evidence was provided concerning the function of the Caspase 1 gene product during lobular-alveolar development and involution of the mammary gland after weaning. An interesting observation from this work was mammary epithelial cells that will succumb to apoptosis enter the cell cycle first. This observation implies that at least a subset of the redundant epithelial cells undergo activation before cell death. In preliminary work mammary glands from the MMP14 null mouse were shown to have less adipose tissue but ductal penetration of the fat pad and initial duct formation occurred by post-natal day 13. Further experimentation is required to determine if the reduction in adipose tissue is related - to the wasting phenotype of these animals, or is induced by the MMP14 null epithelial cells. The practical outcome of these studies is a better understanding of mammary gland development before, during and after pregnancy, and during the process of involution.
Author: Shiqing Wang
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Category : Estrogen
Languages : en
Pages : 268
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Author: Malgorzata Gajewska
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Category : Electronic books
Languages : en
Pages : 0
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Mammary gland is an organ, which undergoes the majority of its development in the postnatal life of mammals. The complex structure of the mammary gland comprises epithelial and myoepithelial cells forming the parenchymal tissue and adipocytes, fibroblasts, vascular endothelial cells, and infiltrating immune cell composing the stromal compartment. During puberty and in adulthood, circulating hormones released from the pituitary and ovaries regulate the rate of development and functional differentiation of the mammary epithelium. In addition, growing body of evidence shows that interactions between the stromal and parenchymal compartments of the mammary gland play a crucial role in mammogenesis. This regulation takes place on a paracrine level, by locally synthesized growth factors, adipokines, and cytokines, as well as via direct cell-cell interactions. This chapter summarizes the current knowledge about the complex nature of interactions between the mammary epithelium and stroma during mammary gland development in different mammalian species.
Author: Young Chul Kim
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Category :
Languages : en
Pages : 154
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Category :
Languages : en
Pages : 7
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A novel system for studying growth of normal human mammary epithelium in vivo as grafts in athymic nude mice has been developed. The key feature of this mode is the reconstitution of the epithelial-stromal interactions that occur in the normal human breast. This model has been used to demonstrate the ability of carcinoma associated fibroblasts to cause abnormal growth of normal human mammary epithelium. The renal grafting technique has also been used to study tumor growth and tumor inhibition.
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Languages : en
Pages : 0
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The purpose of this grant was to study mammary oncogenesis in transgenic mice that expressed a virus-derived growth factor, Shope growth factor (SGF), which resembles epidermal growth factor (EGF). Shope growth factor (SGF). Lines of SGF transgenic mice expressed this cytokine using inducible (metallothionein, MT) and constitutive (RSV-LTR) promoters. We have found that expression of SGF in transgenic mice under the control of the RSV-LTR as a promoter led to profound changes in mammary gland histology, resulting in a pathologic and molecular phenotype that shows changes characteristic of%late pregnancy or lactation. These changes include mammary gland differentiation: acinar proliferation, distention of glands and ducts by proteinaceous material consistent in appearance with lactation products (i.e., milk production), and comparable changes in mammary ducts. Corresponding alterations have been seen in patterns of gene expression in these mammary glands: expression of lactation-associated genes such as whey acidic protein, t3-casein, and WDNMI, was increased in SGF-transgenic mice. Transgenic mice expressing SCF under the control of metallothionein promoter (MT-SGF) generally showed similar findings when MT promoter activity was induced by feeding with Zn2+. These findings have profound implications for understanding mammary oncogenesis and, in particular, its inhibition. 1% qiRi%rT Th%M%
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Languages : en
Pages : 0
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A novel system for studying growth of normal human mammary epithelium in vivo as grafts in athymic nude mice has been developed. The key feature of this model is the reconstitution of the epithelial-stromal interactions required for normal growth and differentiation of the human mammary epithelium, which produces ducts that are comparable to the normal human mammary gland. Human breast epithelial organoids were combined with mammary fibroblasts from mouse or human origin in collagen gels, which were subsequently transplanted under the renal capsule of female nude mice hosts. The resulting grafts showed an increase in the ductal density than observed previously. These ducts expressed appropriate markers for luminal and myoepithelial cells and steroid receptors. This model allows for a variety of epithelial and stromal cells to be used in combination, which would aid in understanding key factors that regulate normal human mammary gland development. The manuscript detailing this data has been accepted for publication in the December 2002 issue of Endocrinology. The experiments currently in progress utilize both normal and tumor epithelium and carcinoma associated fibroblasts (CAF) in this model to assess the effect of CAF on the development of normal human mammary epithelium. CAF from a variety of tumors including ErbB2 positive tumors will be used.
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Languages : en
Pages : 0
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Extracellular matrix (ECM) proteins are critical for the differentiation of normal mammary epithelial cells, but pronounced changes in the ECM occur during breast cancer. We have determined that estrogen receptor-positive breast cancer cells (MCF-7 and T47D) cultured on laminin have reduced, or lack, estrogen responsiveness. Estrogen-induced proliferation, following anti-estrogen treatment, did not occur on laminin (T4?D) or was significantly reduced (MCF-7), but did occur on collagen I or fibronectin. Laminin inhibited basal proliferation of MCF-7, T4?D and the ER- negative MDA MB23 1 cells, but did not inhibit IGF-I or EGF induced proliferation, indicating that tumor cells on laminin do not become refractory to mitogens.
Author: Alvin Tu Lo
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Category :
Languages : en
Pages : 111
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It is now known, the microenvironment including the stroma play an important role in both organ specificity and mammary cancer. In characterizing the interactions between stroma and epithelium, it is useful to develop an ex vivo model to more freely dissect out the intricate network of signals that are necessary to allow functional differentiation in vivo. With this in mind, my first aim was to develop such models to study the mammary gland outside the animal in designer microenvironments. It has been known for some time that once cells are removed from their native tissue environment and placed into traditional two-dimensional (2D) cultures, cells lose functional performance and relevant morphology (M.J. Bissell 1981). In 1977, Emerman and Pitelka using a technique developed by Michalopoulas and Pitot placed mammary cells on top of collagen-1 gels and allowed it to float (Michalopoulos & Pitot 1975; Emerman & Pitelka 1977). In the presence of lactogenic hormones, mammary cells were able to produce milk proteins. These studies were reproduced and colleagues showed that in the floating collagen gel the important component produced by the cells was laminin-111 (Danielson et al. 1984; Parry et al. 1987). Following these studies, the Bissell laboratory discovered in 1989 that a gel mimicking the properties of the basement membrane, a specialized form of extracellular matrix in glandular tissues, allows mammary cells to produce milk and secrete it vectorially (Barcellos-Hoff et al. 1989; Streuli et al. 1991; Streuli et al. 1995). In this dissertation, I utilized an organoid technique developed in the Bissell laboratory to recapitulate both form and function of mammary gland from small pieces of mammary tissue. By using these culture models, we were able to systematically define the biochemical and environmental signaling cues that are important in mammary gland form and function. As such, we have composed and detailed a number of matrices to reproduce the developmental processes ex vivo similar to what is observed in vivo in the developing mammary gland (Lo et al. 2012). These methodologies illustrate a way to investigate elaborately the epithelium outside the complex microenvironment of the tissue, and provide a system for investigating not only normal developmental processes but also diseases such as cancer. We then applied the use of these three-dimensional (3D) culture models to investigate the developmental processes of mammary gland branching. Invasion is a key step of branching morphogenesis, the process by which simple epithelial structures form elaborate branched networks (Williams & Daniel 1983; Montesano et al. 1991; Hirai et al. 1998; Simian et al. 2001; Fata et al. 2007). This process requires invasion through a type-I collagen rich stroma in vivo. Matrix metalloproteinases were shown to be expressed both in the epithelium and stroma of the invading terminal end buds, suggesting that these enzymes enable epithelial invasion into the mammary fat pad (Talhouk et al. 1991; Simian et al. 2001; Wiseman et al. 2003; Mori et al. 2009; Mori et al. 2013). To dissect whether matrix metalloproteinase 14 (MMP14) is a key signaling molecule in branching morphogenesis, we utilized 3D culture models comprised of primary mammary organoids and mammary epithelial cell (MEC) line for our study. Motivated by data from a genetic MMP14 mutant mouse, we were able to use our 3D models to uncover reciprocal pathways required for mammary branching morphogenesis (Yana et al. 2007). We found that MMP14 is required for invasion of MECs through stroma and these interactions drive MEC invasion through a collagen-1 microenvironment. Additionally, we identified signals downstream of MMP14 and uncovered the interaction between MMP14 and integrin-[beta]1 (ITGB1) that is essential for MEC invasion to occur. Given the high expression levels of MMP14 in breast cancer, we proposed that the mechanisms we uncovered for branching of normal mammary epithelium are also relevant to the invasion of breast cancer cells through the stroma that surrounds the mammary carcinoma (Mori et al. 2013). From using 3D models to study development and the interactions of MMP14 in branching morphogenesis, it became apparent that we could further utilize this assay as a system to elucidate the means by which cells become cancerous. Utilizing an elaborate genetic backcross study, we sought to analyze the genetic contributions involved in mammary cancer susceptibility in response to a stimulus such as low dose radiation. Using our 3D culture model and a genome-wide single nucleotide polymorphisms (SNPs) analysis, we revealed how treatment with ionizing radiation led to interactions with the genetic loci and identified TGF-1 as a factor regulating cancer susceptibility. Our ex vivo models allowed us to assess the particular signaling components that provide resistance to cancer risk thus opening possible new avenues to identify individual risk for environmental exposure and cancer (Zhang P*, Lo A* et al. 2015).
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ISBN: 9780670064663
Category :
Languages : en
Pages : 50
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Raised to be a thief, blind orphan Peter Nimble, age ten, steals from a mysterious stranger three pairs of magical eyes, that lead him to a hidden island where he must decide to become a hero or resume his life of crime.
