Abstract:At the epithelial/mesenchymal interface of most tissues lies the basement membrane (BM). These thin sheets of highly specialized extracellular matrix vary in composition in a tissue-specific manner, and during development and repair. For about two decades it has been apparent that all BMs contain laminins, entactin-1/nidogen-1, Type IV collagen, and proteoglycans. However, within the past few years this complexity has increased as new components are described. The entactin/nidogen (E/N) family has expanded wit… Show more
“…They consist mostly of collagen type IV (COL4) admixed with laminins (LN), nidogens, and the heparan sulfate proteoglycan perlecan (PLN) and may contain small amounts of fibronectin (FN) (1,2). Although the BM structural role in defining tissue architecture and compartmentalization has long been recognized, its dynamic role in the modulation of cell behavior has only recently been documented (1).…”
Aberrant interaction of carcinoma cells with basement membranes (BM) is a fundamental pathophysiological process that initiates a series of events resulting in cancer cell invasion and metastasis. In this report, we describe the results of our investigations pertaining to the events triggered by the adhesion of normal (PNT1A) and highly metastatic (PC-3) prostate cells onto BM proteins. Unlike PNT1A, PC-3 cells adhered avidly to Matrigel BM matrix as well as to isolated collagen type IV, laminin, and heparan sulfate proteoglycan perlecan, main BM components. This aberrantly increased cancer cell adhesion resulted in sustained BRCA2 protein depletion and vigorous cell proliferation, a cascade triggered by  1 integrin-mediated phosphatidylinositol 3-kinase activation leading to BRCA2 degradation in the proteasome. This latter effect was orchestrated by phosphatidylinositol 3-kinase-dependent up-regulation of Skp2, a subunit of the Skp1-Cul1-F-box protein ubiquitin complex that directly associates with BRCA2 as demonstrated by coimmunoprecipitation assays, determines its ubiquitination, and ultimately targets it for proteasomal degradation. Inhibition of Skp2 expression by small interference RNA prevented BRCA2 depletion and inhibited the trophic effect upon cell proliferation. These results provide additional evidence on the role of BRCA2 as a modulator of cancer cell growth and elucidate the molecular mechanisms involved in its downregulation in cancer cells when interacting with BM, a crucial step in the biology of metastasis. Furthering the understanding of this molecular pathway may prove valuable in designing new therapeutic strategies aimed at modifying the natural history of prostate carcinoma.
Basement membranes (BM)2 are thin layers of specialized extracellular matrix (ECM) that surround and closely associate with epithelial and endothelial cells, muscle fibers, and nerves. They consist mostly of collagen type IV (COL4) admixed with laminins (LN), nidogens, and the heparan sulfate proteoglycan perlecan (PLN) and may contain small amounts of fibronectin (FN) (1, 2). Although the BM structural role in defining tissue architecture and compartmentalization has long been recognized, its dynamic role in the modulation of cell behavior has only recently been documented (1).Aberrant cancer cell interactions with BM proteins play a crucial role in the biology of metastasis (3). Cancer cells must be able to coordinately decrease cell-cell interactions and increase cell adhesion to an adjacent BM in order to become motile, which along with the capacity of degrading/remodeling a BM directly relates to their metastatic potential (4). This cell behavior is accompanied by changes in the expression and/or usage of various adhesion receptors, including integrins (5). Integrins are transmembrane adhesion receptors for ECM proteins that not only provide physical anchoring cell support but also play a pivotal role in triggering intracellular signaling in response to environmental changes through interactions with molecules ...
“…They consist mostly of collagen type IV (COL4) admixed with laminins (LN), nidogens, and the heparan sulfate proteoglycan perlecan (PLN) and may contain small amounts of fibronectin (FN) (1,2). Although the BM structural role in defining tissue architecture and compartmentalization has long been recognized, its dynamic role in the modulation of cell behavior has only recently been documented (1).…”
Aberrant interaction of carcinoma cells with basement membranes (BM) is a fundamental pathophysiological process that initiates a series of events resulting in cancer cell invasion and metastasis. In this report, we describe the results of our investigations pertaining to the events triggered by the adhesion of normal (PNT1A) and highly metastatic (PC-3) prostate cells onto BM proteins. Unlike PNT1A, PC-3 cells adhered avidly to Matrigel BM matrix as well as to isolated collagen type IV, laminin, and heparan sulfate proteoglycan perlecan, main BM components. This aberrantly increased cancer cell adhesion resulted in sustained BRCA2 protein depletion and vigorous cell proliferation, a cascade triggered by  1 integrin-mediated phosphatidylinositol 3-kinase activation leading to BRCA2 degradation in the proteasome. This latter effect was orchestrated by phosphatidylinositol 3-kinase-dependent up-regulation of Skp2, a subunit of the Skp1-Cul1-F-box protein ubiquitin complex that directly associates with BRCA2 as demonstrated by coimmunoprecipitation assays, determines its ubiquitination, and ultimately targets it for proteasomal degradation. Inhibition of Skp2 expression by small interference RNA prevented BRCA2 depletion and inhibited the trophic effect upon cell proliferation. These results provide additional evidence on the role of BRCA2 as a modulator of cancer cell growth and elucidate the molecular mechanisms involved in its downregulation in cancer cells when interacting with BM, a crucial step in the biology of metastasis. Furthering the understanding of this molecular pathway may prove valuable in designing new therapeutic strategies aimed at modifying the natural history of prostate carcinoma.
Basement membranes (BM)2 are thin layers of specialized extracellular matrix (ECM) that surround and closely associate with epithelial and endothelial cells, muscle fibers, and nerves. They consist mostly of collagen type IV (COL4) admixed with laminins (LN), nidogens, and the heparan sulfate proteoglycan perlecan (PLN) and may contain small amounts of fibronectin (FN) (1, 2). Although the BM structural role in defining tissue architecture and compartmentalization has long been recognized, its dynamic role in the modulation of cell behavior has only recently been documented (1).Aberrant cancer cell interactions with BM proteins play a crucial role in the biology of metastasis (3). Cancer cells must be able to coordinately decrease cell-cell interactions and increase cell adhesion to an adjacent BM in order to become motile, which along with the capacity of degrading/remodeling a BM directly relates to their metastatic potential (4). This cell behavior is accompanied by changes in the expression and/or usage of various adhesion receptors, including integrins (5). Integrins are transmembrane adhesion receptors for ECM proteins that not only provide physical anchoring cell support but also play a pivotal role in triggering intracellular signaling in response to environmental changes through interactions with molecules ...
“…The formation of basement membrane is indispensable for normal tissue development and function (Smyth et al, 1999;Miner and Yurchenco, 2004). BM regulates diferent biological activities, like development, proliferation, diferentiation, growth, migration of cells, cell polarity, adhesion, among others (Erickson and Couchman, 2000;Kruegel and Miosge, 2010). Histological analysis suggests that the migration and adhesion of cells might be interfered in Ric-8 À/À embryos and the morphogenesis impaired.…”
Section: Ric-8 2/2 Embryos Are Not Competent In Organogenesismentioning
The guanine nucleotide exchange factor RIC-8 is a conserved protein essential for the asymmetric division in the early embryogenesis in different organisms. The function of RIC-8 in mammalian development is not characterized so far. In this study we map the expression of RIC-8 during the early development of mouse. To elucidate the RIC-8 function we used Ric-8 2/2 mutant embryos. The Ric-8 2/2 embryos reach the gastrulation stage but do not develop further and die at E6.5-E8.5. We characterized the Ric-8 2/2 embryonic phenotype by morphological and marker gene analyses. The gastrulation is initiated in Ric-8 2/2 embryos but their growth is retarded, epiblast and mesoderm disorganized. Additionally, the basement membrane is defective, amnion folding and the formation of allantois are interfered, also the cavitation. Furthermore, the orientation of the Ric-8 2/2 embryo in the uterus was abnormal. Our study reveals that the activity of RIC-8 protein is irreplaceable for the correct gastrulation of mouse embryo. Developmental Dynamics 239:3404-3415,
“…Functionally, the ILM is more appropriately considered as an adhesive sheet that facilitates the connection of the vitreous body (VB) with the retina. Identical to other BMs, [1][2][3] the ILM consists of about ten high-molecular weight extracellular matrix (ECM) proteins that include members of the laminin family, nidogen1 and 2, collagen IV and three heparan sulphate proteoglycans, agrin, perlecan and collagen XVIII. 4,5 The ILM is invisible by conventional light microscopy but can be readily visualized by immunocytochemistry using antibodies to any of the BM components ( Figure 1a).…”
The inner limiting membrane (ILM) and the vitreous body (VB) are two major extracellular matrix (ECM) structures that are essential for early eye development. The ILM is considered to be the basement membrane of the retinal neuroepithelium, yet in situ hybridization and chick/quail transplant experiments in organcultured eyes showed that all components critical for ILM assembly, such as laminin or collagen IV, are not synthesized by the retina. Rather, ILM proteins, with the exception of agrin, originate from the lens or (and) ciliary body and are shed into the vitreous. The VB serves as a reservoir providing high concentrations of ILM proteins for the instant assembly of new ILM during rapid embryonic eye growth. The function of the retina in ILM assembly is to provide the cellular receptor proteins for the binding of the ILM proteins from the vitreous. The VB is a gelatinous ECM structure that fills the vitreous cavity of the eye. Its major structural proteins, collagen II and fibrillin, originate primarily from the ciliary body. Reverse transcription-PCR and western blotting show that the rate of synthesis of structural, monomeric ILM and VB proteins, such as laminin, collagen IV and II is very high during embryogenesis and very low in the adult. The downregulation of ILM and VB protein synthesis occurs during early postnatal life, and both ILM and VB are from then on maintained throughout life with minimum turnover. Our data explain why ILM and VB do not regenerate after vitrectomy and ILM peeling.
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