Cells adhere to the extracellular matrix throughout most of their lifetime. This close, intimate contact with the matrix exerts an extraordinary control on the behavior of cells, determining whether they move or stay put, proliferate or remain quiescent, and even live or die. Attachment to the matrix not only enables cells to respond to soluble growth factors and cytokines but also determines the nature of the response. The integrins are a large family of receptors that attach cells to the matrix, organize their cytoskeleton, and cooperate with receptor protein tyrosine kinases to regulate cell fate. Research on integrin signaling is beginning to explain the complex and specific effects that the extracellular matrix exerts on cells.
"Besides controlling GF bioavailability, the ECM also modulates GF signaling through the interplay between GFs, ECM proteins, cell-adhesion receptors, and GF receptors (Giancotti and Tarone, 2003; Hynes, 2009; Kim et al., 2011). For example, the binding of VEGF 165 to fibronectin forms molecular complexes that induce the formation of clusters between VEGF receptor and integrins (Wijelath et al., 2006; Martino et al., 2011, 2013). "
[Show abstract][Hide abstract] ABSTRACT: Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis onVEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.
Frontiers in Bioengineering and Biotechnology 04/2015; 3(45). DOI:10.3389/fbioe.2015.00045
"Adhesion by integrin-mediated junctions allows tissues to withstand mechanical load and is essential for tissue integrity. Integrinbased signalling regulates cell migration, division, and differentiation (Bokel and Brown, 2002; Giancotti and Tarone, 2003; Meighan and Schwarzbauer, 2008). Thus, integrins are the major family of cell surface receptors that mediate cell attachment to the extracellular matrix and can mediate cell– cell interactions (Hynes, 1992; Hynes 1999; Li and Sakaguchi, 2002). "
[Show abstract][Hide abstract] ABSTRACT: How the neural retina is held in its place in the human physiological living body) Bratislava 2014 Original self-publishing first edition of the monograph, entitled " Gergely's retinal linkage (How the neural retina is held in its place in the human physiological living body) " by Gergely K (contact: email@example.com); affiliation: Faculty of Medicine in Bratislava, Comenius University in Bratislava, Slovak Republic; This work may not be translated or copied in whole or in part without the written permission of the publisher Květoslava Gergelyova, MD; Prague, Czech Republic (contact: firstname.lastname@example.org), except for brief excerpts in connection with scientific articles or scholarly analysis [regular citation: Gergely K. Gergely's retinal linkage (How the neural retina is held in its place in the human physiological living body). Publisher Gergelyova, 2014]. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.
"Such cancer cell/ECM interactions are facilitated by the integrin family of cell adhesion molecules including tyrosine-phosphorylated substrates (the tyrosine kinase Src and focal adhesion kinase) . Integrins are trans-membranous α/β heterodimeric receptors that mediate cell-cell interactions and cell attachment to extracellular matrix (ECM) , and they serve as receptors for some ECM proteins (e.g., Fibronectin, Vitronectin, Laminin and Collagen) . Altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. "
[Show abstract][Hide abstract] ABSTRACT: Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D-mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new therapeutic targets for managing pancreatic cancer.
PLoS ONE 08/2014; 9(8):e105245. DOI:10.1371/journal.pone.0105245 · 3.23 Impact Factor
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