Integrins are a widely distributed super family that plays a major role in cell adhesion to the extra cellular matrix (ECM) and cell-cell adhesion (Hynes, 1992). The integrin receptor family was recognized over 20 years ago (Hynes, 1987) and it is now the best understood cell adhesion receptors. Integrins anchor cells to the ECM but recently they have been found to have an important role in intracellular signalling and gene expression which leads to cell migration (Hirsch et al., 1996; Paulhe et al., 2001), proliferation (Hollenbeck et al., 2004; Miyata et al., 2000), differentiation and survival.
Integrins are transmembrane glycoproteins composed of heterodimers consisting of an α and β glycoprotein subunit that are non-covalently bound (Hynes, 2002) (Hynes, 1992). So far 24 human integrin heterodimers have been identified consisting of known 19α and 8β subunits (Humphries, 2000; Hynes, 1992). These can be further divided into subfamilies depending on subunit identity and ligands they bind. The two subunits consist of short cytoplasmic tail, single transmembrane domain and a multi-domain extra cellular portion. The role of integrin cytoplasmic domain in modulating integrin functions and signalling events are well established (Fornaro and Languino, 1997; Zheng et al., 1997).
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Normally integrins are expressed on cell surface in an inactive conformation. Integrins can be activated by binding to certain ligands or by inside-out signalling where the integrin is activated elsewhere in the cell and this triggers intracellular signalling resulting in protein interacting with cytoplasmic tail of integrin (Han et al., 2006). Outside-in signalling occurs when ligands bind to integrin extra cellular domain (Guo and Giancotti, 2004). The sequence arginine-glycine-aspartic acid (RGD) was identified as a general integrin-binding motif (Ruoslahti, 1986) but individual integrins are also specific for particular protein ligands. Integrins are found in many species, ranging from sponges to mammals (Brower et al., 1997). ECM molecules act ligands for integrins and play a crucial role in organ development, abnormal tissue growth and tumour progression(Tsuji, 2004) (Guo et al., 2005).
It is common for cancer cells to have a change in the number and identity of integrin receptors (Mizejewski, 1999) which results in an alteration of the ability of the malignant cells to interact with the ECM and promoting migration as well as facilitating survival outside tumour normal environment. Alterations of integrin expression levels in cancer cells correlate with changes in invasiveness tumour progression and metastatic potential.
In prostate cancer there is abnormal expression and functions of integrins and their ECM ligands (Boudreau and Bissell, 1998) (Fornaro et al., 2001). There is a down regulation of integrin expression as prostate cancer progresses to an advanced stage (Fornaro et al., 2001). Most α and β subunits are shown to be down regulated in prostate cancer.
Among α subunits, it is shown that α3, α4, α5, α7 and αv are down regulated, αIIb is up regulated and α2 and α6 are abnormally expressed. Integrin α7 forms a heterodimer with integrin β1 in the plasma membrane and is responsible for communication between the ECM and muscle cells (Echtermeyer et al., 1996). The expression of α7 has been shown to be altered in prostate cancer (LaTulippe et al., 2002; Luo et al., 2002; Yu et al., 2004). Prostate cancer cells have decreased expression of integrin α7 showing that α7 inhibits cell motility and reduces metastases. The function of integrin α7 in prostate gland appears to be related to the adhesion of the basement membrane and prevention of the random migration of these cells to other organs. α7 integrin also plays a role in limiting cell proliferation as the expression of integrin α7 induces the expression of proteins that inhibit cell cycle progression and cell growth. Integrin α7 appears to be a tumour suppressor that operates by suppressing tumour growth and retarding migration (Ren et al., 2007).
Among β subunits, it is shown that β1, β3 and β6 are up regulated in human prostate cancer. The β4 integrin facilitates key functions of carcinoma cells including the ability to migrate, invade, and evade apoptosis (Folgiero et al., 2007). The β1 integrins mediate interactions between cells and ECM (Perlino et al., 2000). β1C and β4 are down regulated in prostate cancer cells. There are five β1 variant subunits: β1A, β1B, β1C, β1C-2 and β1D. These are generated by alternative splicing. β1A and β1C are two variants that have been shown to be expressed in prostatic epithelial cells. β1C inhibits proliferation and β1A promotes proliferation (Perlino et al., 2000). β1C is expressed at mRNA levels in normal prostatic epithelial cells but is down regulated in cancerous prostatic epithelial cells(Fornaro et al., 1995; Meredith et al., 1995; Perlino et al., 2000). β1A found to be up regulated in human prostate cancer cells (Knox et al., 1994; Murant et al., 1997). The discovery that β1A is up regulated in prostate cancer cells and that it is necessary for cells to grow in an anchorage-independent manner show that the β1A may have an important role to play during prostate cancer progression and it will help in formulation of new therapeutic strategies (Goel et al., 2005)
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Expression of αIIb and β3 mRNA is present in a wide range of tumour cell lines (Chang et al., 1991). Functional αIIbβ3 are found on the surface of tumour cell lines which are localized to a region that interacts with the ECM (Chen et al., 1992; Chen et al., 1997; Honn et al., 1992; Trikha et al., 1996). αIIbβ3 is expressed in active form on tumour cells and adhesion is regulated by translocation of active integrin from intracellular pool to cell surface(Timar et al., 1998; Trikha et al., 1997). Tumour cells expressing αIIb showed an increase survival and growth in vivo (Trikha et al., 2002)and an increased metastatic potential (Chang et al., 1992). Abnormal truncated forms of subunits are found in prostate cancer cells and are secreted into the ECM. This is associated with alteration in affinity of integrins for its ligands, (O'Toole et al., 1994), changes in cell adhesion or alterations in signalling pathways. Truncated β3 integrin lacking cytoplasmic and transmembrane domain is found in prostate cancer cells. This inhibits adhesions to β3 ligands vitronectin and fibrinonectin. Regulation of normal and truncated β3 integrins provide a mechanism for control of cell migration and hence metastatic ability.