Fibronectin as target for tumor therapy

Abstract

During cancer progression, the extracellular matrix (ECM) of the tissue in which the tumor grows is extensively remodeled, both by degradation of preexisting ECM molecules and by the neosynthesis of ECM components, which in many cases are not present in the ECM of normal tissues. Fibronectin (FN), a class of highmolecular-weight adhesive glycoproteins, plays a prominent role in mediating ECM function, because of its high abundance and its interaction with cellular components. Furthermore, the generation of tumor-associated FN isoforms allows the development of specific ligands (e.g., antibodies), which can be used for the selective delivery of therapeutic agents to the tumor environment. In view of these considerations, it is not surprising that FN is being used as a target for biomolecular intervention, both for the development of inhibitory molecules that block the interaction of FN with integrins and other receptors on the cell surface, and for the development of ligand-based targeted imaging and therapeutic strategies. In this review, we briefly present the essential properties of FN, and we then focus on the therapeutic strategies that are currently in preclinical or clinical development and feature FN as a target, or that are based on FN fragments so as to promote tumor-growth inhibition. ' 2005 Wiley-Liss, Inc.Key words: fibronectin; ECM; angiogenesis; EDB; vascular tumor targeting Tumor-associated extracellular matrix components Neoplastic cells are obviously the most important component of solid tumors, and it is not surprising that most efforts in cancer research focus on the characterization of the properties of tumor cells and of their molecules. However, the role of the tumor stroma (and in particular of its extracellular matrix (ECM) components) is becoming increasingly recognized as an important determinant for the growth and progression of solid tumors.1,2 The extensive remodeling of the normal ECM in tumors proceeds through 2 main processes: (i) degradation of preexisting ECM molecules by a number of hydrolytic enzymes (e.g., proteases) that are produced, activated and/or induced by neoplastic cells, and (ii) neosynthesis of ECM components, which in many cases, are not present (or present at low concentration) in the normal tissues. This tumor ECM may generate a more suitable and possibly more permissive and/or instructive environment for tumor growth and progression. Furthermore, tumor-associated ECM components, which may be produced by tumor cells, stromal cells and/or endothelial cells, often represent ideal targets for biomolecular intervention, as will be illustrated in this review. ECM tumor antigens are in general more abundant and possibly more stable than tumor-associated antigens of the tumor cell surface, thus facilitating tumor imaging and targeted therapeutic applications.Among the most abundant ECM components (such as collagens, tenascins, proteoglycans, glycosaminoglycans and laminin), 1 fibronectins (FNs) play a special role both in terms of their functional properties and becau...

Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation

“…FN usually exists as a dimer composed of two nearly identical ϳ250-kDa subunits linked covalently near their C termini by a pair of disulfide bonds (1,2). Each monomer is an extended and flexible molecule that is folded in a series of repeating protein domains known as type I, II, and III repeats.…”

Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models

“…Fibronectins are high-molecular-weight-adhesive glycoproteins abundantly expressed in vivo in the extracellular matrix and in body fluid (Kaspar et al, 2006). These play an important role in a number of biological phenomena such as maintenance of normal cell morphology, cell migration, haemostasis and thrombosis, wound healing, and oncogenic transformation .…”

“…Alternative splicing in the primary transcript results in multiple FN transcripts of the single copy gene. Three FN isoforms are expressed in tumour tissue and transformed cells, these include IIICS, extra domain A and ED-B Kaspar et al, 2006). Extra domain-B domain is a complete type III repeat composed of a sequence of 91 amino acids, coded by a single exon and is the most conserved region of FN.…”

“…It is usually absent in both plasma and tissue FN of adults, except in regenerating tissues, such as some vessels in the endometrium. However, it is overexpressed during active tissue remodelling, for example, angiogenesis in tumours, wound healing and embryogenesis Kaspar et al, 2006). It has been shown to accumulate specifically around neovasculature in studies of many different tumour types, making it a good marker for angiogenesis (Carnemolla et al, 1989;Kaczmarek et al, 1994;Neri et al, 1997;Kosmehl et al, 1999;Tarli et al, 1999;Viti et al, 1999;Demartis et al, 2001;Castellani et al, 2002;Birchler et al, 2003;Ebbinghaus et al, 2004).…”

“…Biodistribution experiments and RIT studies with the L19-SIP antibody have been carried out in tumour-bearing mice and rats, and have demonstrated selective localisation in different tumour models, for example, human melanomas, mouse embryonal teratocarcinomas, human head and neck squamous cell carcinomas, and rat gliomas Berndorff et al, 2005;Spaeth et al, 2006;Tijink et al, 2006). Finally, the therapeutic potential of 131 I-L19-SIP is currently being investigated in clinical trials in Italy and Switzerland (Kaspar et al, 2006).…”