Influence of Stress on Extracellular Matrix and Integrin Biology
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Oncogene (2011) 30, 2697–2706 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc REVIEW Influence of stress on extracellular matrix and integrin biology C Jean1,2,3, P Gravelle1,2,3, J-J Fournie1,2,3 and G Laurent1,2,3,4 1INSERM UMR1037-Cancer Research Center of Toulouse, Toulouse, France; 2Universite´ de Toulouse, Toulouse, France; 3CNRS ERL, Toulouse, France and 4Service d’He´matologie, CHU Purpan, Toulouse, France Dynamic interactions between cells and extracellular Keywords: stress; ECM; integrin biology; remodeling; matrix (ECM) through integrins influence most cellular cellular response functions. Normal cells, but even more, tumor cells are subjected to different forms of stress, including ischemia, radical oxygen species production, starvation, mechanical stress or genotoxic insults due to anti-cancer drugs or Introduction irradiation. In these situations, an adaptative cellular response occurs, integrating a complex network of Tissues are made of cells and a protein support, termed intracellular signaling modules, which, depending on stress extracellular matrix (ECM). ECM contains a variable intensity, may result to either damage repair followed by proportion of a large variety of matrix and non-matrix complete restitution of cellular functions, or programmed proteins. The latter consists of growth factors, inflamma- cell death. Because of its implication in oncogenesis and tory molecules, or immune soluble mediators. These anti-cancer therapy, cellular stress response has been proteins can be retained by ECM, thus acting as a thoroughly investigated. However, most of these studies reservoir for these important regulators. In this review, the have been performed in the context of isolated cells term of ECM is restricted to intrinsic matrix proteins such without taking into consideration that most cells are part as collagens (27 members), glycoproteins (fibronectin, of the tissue within which they interact with ECM through laminin, vitronectin, tenascin, thrombospondin, SPARC integrin. Few studies have described the influence of stress for secreted protein acidic and rich in cysteine), proteogly- on cell-to-ECM interaction. However, one can speculate cans (aggrecan, decorin, perlecan, syndecan and versican) that, in these conditions, cells could functionally interact and elastin. ECM composition notably influences its with protein microenvironment either to create positive mechanical properties such as compliance, which, at least interactions to survive (for example by facilitating in part, regulates integrin biology. For example, collagen, protective pathways) or negative interaction to die (for especially when polymerized, increases the stiffness of the example by facilitating detachment). In this review, matrix support, compared with fibronectin. we summarize the knowledge relative to the influence of ECM composition is regulated through synthesis and different stress modalities on ECM remodeling, integrin degradation. It is generally believed that, in tumors, the expression and/or function modifications, and possible main cellular source of ECM is resident fibroblasts, even if functional consequences, independently from the cellular virtually all types of cells may synthesize ECM proteins. model as these findings came from a large variety of Degradation is under control of many proteases among cells (mesenchymal, endothelial, muscular, epithelial and which metalloproteases (MMPs) have one of the most glandular) and fields of application (cancer, vascular important role. MMP family consists in 23 members of biology and tissue engineering). Most studies support the Zn-dependent endopeptidases with variable spectrum of general notion that non-lethal stress favors ECM stiffness, specificity, collagen and fibronectin being the main integrin activation and enhanced survival. This field opens substrates. Synthesis and degradation often appear as large perspectives not only in tumor biology but also in two coordinated processes for ECM remodeling, resulting anti-cancer therapy by targeting one or several steps of in precise mechanical properties (from stiff to soft) the integrin-mediated signaling pathway, including inte- depending on the tissue function and organization. grin ligation, or activation of integrin-linked enzymes or Cells interact physically and functionally with ECM integrin adaptors. through transmembrane proteins termed integrins, Oncogene (2011) 30, 2697–2706; doi:10.1038/onc.2011.27; which connect ECM to cell cytoskeleton (for review, published online 21 February 2011 see Desgrosellier and Cheresh, 2010). Integrin proteins are heterodimers composed of an a-chain (18 types) and a b-chain (8 types) for a total of 24 combinations. Although a-chain is involved in ligand specificity, Correspondence: Dr C Jean, CPTP, INSERM UMR1037, Pavillon b-chain binds to cytoskeleton and transduces the signal Lefebvre Bat. B, Place du Dr. Baylac, CHU PURPAN, BP 3028, from ECM to the cell (see below). Integrins can also be Toulouse 31024, France. E-mail: [email protected] classified according to ligand specificity region. Thus, Received 16 December 2010; revised and accepted 16 January 2011; GFOGER, an amino peptide sequence contained in published online 21 February 2011 most collagen fraction, reacts with a2b1 integrin. RGD, Influence of stress on ECM and integrin biology C Jean et al 2698 a consensus sequence present in fibronectin and invasiveness. The decrease in integrin function results vitronectin, binds to avb3 and a5b1. Laminin receptors in reduced adhesion and ultimately to cell detachment. and leukocytes-specific receptors bind to a6b1 and a4b1, In non-transformed cells, cell detachment results, respectively, the latter being widely expressed in hemato- in turn, in a type of programmed-cell death termed poietic cells. anoı¨kis. This has been described in normal epithelial Upon binding, integrins gather together in mem- and endothelial cells, whereas tumor cells are most brane-specific region and recruits through their intra- often resistant to anoı¨kis (for review, see Frisch and cellular domains several coupling proteins, which form Ruoslahti, 1997). Anoı¨kis may also be facilitated by the focal adhesion complex. Among these proteins, focal the loss of cell-to-cell contacts following dissociation adhesion kinase (FAK), a non-receptor tyrosine kinase, of the cadherin-catenin complexes (Fouquet et al., 2004; has a central role in transducing integrin-mediated Hofmann et al., 2007; Lugo-Martinez et al., 2009). signal through focal adhesion contact (for review, see This observation strengthens the notion that anoı¨kis Berrier and Yamada, 2007). FAK and Src, another non- activation is a more general process for preventing receptor tyrosine kinase, control the recruitment inappropriate cell detachment, and, for this reason, of adaptor proteins that behave as molecular hubs for considered as a tumor suppressor mechanism. However, transducing integrin signals. Among them, the most some cells are resistant to anoı¨kis, and thus may detach important are p130Cas (BCAR1) and NEDD9 (neural while remaining alive. Resistance to anoı¨kis can be precursor cell expressed, developmentally downregu- related to intrinsic cellular defects or external signals. lated 9). Through these proteins, integrin engagement Among the former, FAK overexpression or constitutive results in the activation of a vast spectrum of signaling activation, and ERK deregulation, may indeed con- pathways involving protein tyrosine kinase, small tribute to protection against anoı¨kis (Frisch et al., 1996; GTPase of the Rho family, as well as the activation of Howe et al., 2002). Alternatively, external signals may JNK, ERK and PI3K/Akt modules (for review, see Guo also regulate anoı¨kis. For example, it has been shown and Giancotti, 2004). Strong evidences support the that some specific laminin domains, laminin-proteogly- notion that not only FAK, but also integrin adap- can complexes or collagen IV are highly efficient to tors, have a role in cell transformation, tumor progres- block anoı¨kis (Weber et al., 2008; Salo et al., 2009; sion and chemoresistance (Cabodi et al., 2010). Munoz et al. 2010). Resistance to anoı¨kis is a pre- ECM-cell interaction acts in two ways. From ECM to requisite for epithelial-mesenchymal transition, and the cell, in so far as it has been shown that integrin- acquisition of invasion capacity. mediated signal is strongly influenced by spatial Normal cells, but even more, tumor cells are subjected organization (2D versus 3D) and mechanical properties to different forms of stress, including radical oxygen (stiff versus soft) of ECM support. In this context, species production, ischemia, starvation, mechanical integrins act as sensors of mechanical constraints stress, genotoxic insults or irradiation. It has recently generated by the microenvironment and which convey emerged that cellular stress may affect ECM remodeling these informations to the cell. This ‘outside-in’ signaling and integrin biology, and subsequently may deregulate may influence through FAK and other key regulators, virtually all the processes described above. The influence important cellular functions such as proliferation, of the redox balance on ECM-cell interaction has been survival or motility. From the cell to ECM, in so far recently reviewed (Chiarugi, 2008). We review below the as it has been also shown that forces exerted on influence of other forms of stress on ECM composition, the cytoskeleton regulate, in turn, integrin-binding integrin