Επίπεδα ινονεκτίνης σε φλεγμονώδη και κακοήθη γυναικολογικά νοσήματα

Abstract

Introduction Fibronectin is a large multidomain glycoprotein found in connective tissue, on cell surfaces, and in plasma and other body fluids. It interacts with a variety of macromolecules including components of the cytoskeleton and the extracellular matrix, circulating components of the blood clotting, fibrinolytic, acute phase and complement systems, and with cell-surface receptors on a variety of cells including fibroblasts, neurons, phagocytes and bacteria. Fibronectin also interacts with itself, forming fibrillar entities whose structure is poorly understood. In addition, it reportedly binds several small molecules such as gangliosides, sugars, and Ca ions. These diverse recognition functions are located on distinct fragments or domains, many of which have been expressed in recombinant form or isolated from proteolytic digests with retention of specific binding properties. Tom Saba et al suggested that the cryoprecipitate fraction of human plasma was able to restore the levels of "Opsonic a2-Surface Binding Glycoprotein" i.e., fibronectin, in the circulation of septic surgical and trauma patients. Although fibronectin ultimately proved ineffective as a clinical product, it became adept at purifying gram quantities of this interesting protein at a time when the number of papers being published each year was rising exponentially. Fibronectin Modules The amino acid sequence of Fn reveals three types of internally homologous repeats or modules separated by (usually) short connecting sequences. There are 12 type I, 2 type II and 15 type III modules, also referred to as Fn1, Fn2 and Fn3. Each module constitutes an independently folded unit, often referred to as a domain but not to be confused with "functional domains" that frequently contain more than one module. Modules homologous to those in fibronectin are also found in other proteins, especially the type III which is one of the most ubiquitous of all modules, being found in ~2% of animal proteins (as low as xenopus) and occasionally in a plant. Amino acid sequences of fibronectin modules are highly conserved, differing from their counterparts in other species by only a few percent; by contrast the similarity between different modules of the same type within a given protein is much less. Fibronectin modules, like most, fold independently and thus can exist in isolation from their neighbors. This was demonstrated in a few cases with proteolytic fragments that were small enough to contain only a single module and which, upon exposure to heat or chemical denaturants, underwent reversible unfolding. Such unfolding can be monitored by changes in the intensity and/or wavelength distribution of fluorescence as buried tryptophan side chains are exposed to the aqueous environment. Circular dichroism and scanning calorimetry provide additional information. The three dimensional structures of several examples of each type of fibronectin module have been determined. As expected from the well-known relationship between amino acid sequence and 3D structure, modules of the same type 79 Summary have similar folds. All three types of module are composed almost exclusively of antiparallel sheets and turns with little or no helix. Alternate Splicing of Fibronectin There are five sites of alternate splicing of fibronectin mRNA. The first two result in the insertion of extra type III domains, EDA and EDB after modules III-11 and III-7 respectively . These modules are virtually absent from adult tissue but are differentially expressed during embryonic development and again in malignant or injured tissue and during angiogenesis. The inclusion of EDA renders fibronectin a better substrate for cell spreading and migration and has been used as a marker for certain types of cancer. EDA-containing fibronectin is upregulated as part of the response to wound healing and both forms are increased in human plasma following trauma. This module is reported to serve as a ligand for integrins α9β1 and α4β1. No specific receptors or other ligands have been identified for EDB although it also is reported to support cell adhesion. EDB is also of interest as a marker for angiogenesis and as a potential target for tumor therapy. The third site of splicing is in the V (variable) region, which can be included either in its entirety or only partially depending on the tissue. In plasma fibronectin the V region is fully incorporated into one chain but entirely absent from the other, as shown in the scheme. Since the V region has at least two different integrin binding sites, its presence or absence will affect the adhesion of some types of cells. A fourth site of splicing occurs primarily in cartilage where the dominant form of fibronectin lacks not only the entire V region but modules III-15 and I-10 as well. Functional Domains of Fibronectin Digestion of fibronectin with any of a variety of proteases generates a collection of fragments that are sometimes referred to as functional domains because they retain the ability to interact with other macromolecules. When thermolysin is used, one obtains an N-terminal 29 kDa Fib-1/Hep-1 fragment (I1-5) that binds to fibrin, heparin and some bacteria, and is important for fibronectin matrix assembly....

Στη μελέτη αυτή έγινε προσπάθεια να μελετηθούν τα επίπεδα της φιμπρονεκτίνης του πλάσματος σε περιπτώσεις γυναικολογικών καρκίνων, καθώς και να επιβεβαιωθούν οι υπάρχουσες απόψεις σχετικά με τα αυξημένα επίπεδα της ουσίας σε γυναικολογικές φλεγμονές. Τα συμπεράσματα που προέκυψαν είναι τα ακόλουθα: 1) Επιβεβαιώνεται η αύξηση των επιπέδων της FBN πλάσματος σε κακοήθη νοσήματα ιδιαίτερα σε καρκίνο του τραχήλου και του μαστού 2) Καταγράφεται σημαντική διαφορά των επιπέδων σε καρκίνο του μαστού σε σχέση με τα άλλα κακοήθη νοσήματα 3) Επιβεβαιώνεται η ανίχνευση αυξημένων επιπέδων φιμπρονεκτίνης πλάσματος σε φλεγμονώδη γυναικολογικά νοσήματα 4) Φαίνεται ότι τα επίπεδα FBN πλάσματος μπορεί να αποτελέσουν αξιόπιστο προγνωστικό δείκτη, ωστόσο απαιτείται περαιτέρω επιστημονική έρευνα. Περιορισμένη φαίνεται να είναι η αξία της μέτρησης σε καρκίνο των ωοθηκών και του ενδομητρίου.