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Integrins in Cancer Cell Invasion

Pekka Koistinen and Jyrki Heino
A12398

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Integrins

Integrins are a family of transmembrane glycoprotein receptors that mediate cell-matrix and cell-cell interactions.1,2 Integrins consist of an α and αβ subunits. To date 24 distinct integrin heterodimers have been described, consisting of 18 α and 8 β subunits. The extracellular environment is known to have a pivotal role in cellular behavior. As receptors, integrins mediate anchorage and migration of cells via recognition of variable extracellular matrix molecules. Moreover, intracellular signals generated by integrins often influence gene expression, affecting the regulation of cell survival, differentiation and proliferation. Apart from their role in physiological events, integrins are also involved in many pathological conditions such as inflammation and tumor progression.

Integrins as Extracellular Matrix Receptors

There are 12 integrin heterodimers containing β1 subunits, which are receptors for various extracellular matrix (ECM) molecules such as collagens, laminins, fibronectin and tenascin. Integrins α1β1 and α2β1 are known to be primarily collagen receptors. The α1β1 integrin seems to bind principally to type IV collagen, but it can also recognize types I-VI and type XIII collagen,3,4,5while integrin α2β1 is a receptor for types I-VIII collagens.4,68 Furthermore, both α1β1 and α2β1 can bind to laminins 1, 2 and 4, and α2β1 will bind to tenascin as well.914 Integrin α3β1 can interact with some collagen subtypes, but it may not be primarily a collagen receptor.15 Instead, laminins 1 and 5 seem to be the main ligands for α3β1.16 Similarly, laminins are the ligands for integrins α6β1 and α7β1. The α6 subunit can also form a heterodimer with β4. This combination (α6β4) serves as a laminin receptor in hemidesmosomes, special adhesion sites linking epithelial cells to basement membranes. Recently, two novel collagen-binding integrin subunits, α10 and α11, have been discovered. Each of these forms heterodimers with β1 integrin. Integrin α10β1 was originally purified due to its binding to type II collagen,17 and integrin α11β1 has been shown to bind to at least type I collagen.18,19

Table 1

Table 1

 Integrin receptors for extracellular matrix

Table 1

Integrin receptors for extracellular matrix
Ligandsβ1 integrinsaV integrinsOthers
Collagensα1β1, α2β1, αβ1, α10β1, α11b1  
Lamininsα1β1, α2β1, α3 β1, α6β1, α7β1 α6β4
Fibronectinα4β1, α5β1, α8β1αVβ1, αVβ3, αVβ6, αVβ8α4β7, aIIbβ3
Vitronectin αVβ1, αVβ3, αVβ5, αVβ8 αIIbβ3
Fibrinogen  αIIbβ3
Tenascinα2β1,α8β1, α9β1  

Three different β1 integrins are known to mediate cell-fibronectin interactions. Although integrins α4β1 and α5β1 are both fibronectin receptors, their binding occurs through discrete interactions: α5β1 binds to an RGD motif, whereas α4β1 recognizes another short binding sequence, LDV. Moreover, integrin α8β1 is also capable of binding fibronectin in RGD-dependent manner.20

Another large subfamily of integrins is composed of heterodimers sharing the αV subunit. Integrins αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8 have been found to bind to fibronectin through the RGD motif, and most of them function as vitronectin receptors as well. Integrin αVβ5 is a preferential vitronectin receptor, while αVβ6 has a higher affinity for fibronectin. In addition to the αV integrins, the integrin αIIbβ3 can bind to the RGD motif in both vitronectin and fibronectin, although its main function is to mediate platelet binding to fibrinogen.

Integrin Structure

Each integrin subunit possesses a large extracellular domain and a transmembrane stretch. Additionally, each has a C-terminal, intracellular domain which is variable length but is usually 40-50 amino acids long. The shortest of these is in the α1 subunit, while the β4 subunit has an exceptionally long cytoplasmic tail composed of 1018 amino acids.

Integrin α subunits vary in size from 150 to 200 kDa. All α subunits contain seven N-terminal repeats of about 60 amino acids which form an extracellular structure known as the b-propeller. Together with the β subunit, this structure forms the ligand binding site. In most cases the b-propeller contains divalent cation binding sequences in repeats 4-6. Integrin α subunits may be composed of a heavy and a light chain which are bridged by a disulfide bond. The collagen binding subunits (α1, α2, α10, and α11) as well as certain cell-cell adhesion integrins (aD, aE, aL, aM, and aX subunits) have an extra “inserted” domain (I domain) about 200 amino acids in length. This feature, located between the second and third cation-binding domains on top of the b-propeller structure,21 participates in ligand binding. X-ray crystallography has revealed that the I domain has both a Rosmann fold22 and a Mg2+ coordination site. The presence of Mg2+ has been shown to be necessary for ligand binding.23,24

Integrin β subunits are highly homologous to each other. Most are 90–110 kDa in size, with the exception of β4 which is considerably larger (210 kDa). Several conserved, cysteine-rich repeats are present in the C-terminus of each β subunit.1,2529 A highly conserved, 200-amino acid region of the β subunit, the bI-like domain, contains a sequence of 12 amino acids that binds divalent cations. This structure, which is important for the function of the β subunit, has been reported to possess ligand-binding capability.3033 However, the bI-like domain may not have autonomous folding or function which is characteristic for α-subunit I domains; the presence of a neighboring b-propeller may be required to stabilize the active conformation.34

Integrins in Human Cancer

Since the first observations describing transformation-related changes in the integrin expression pattern,35 several in vitro and in vivo studies have demonstrated the association between the regulation of integrin expression and cancer. Changes in the integrin pattern during malignant transformation are highly dependent on the type of the cancer. An altered integrin pattern allows the cancer cells to recognize variable matrices, but it may also lead to altered signalling and changes in gene expression.

Altered Integrin Expression in Three Common Types of Human Cancer

Melanoma

The action of integrins has been widely studied in malignant melanoma. In particular, integrin αVβ3 has been identified as a tumor progression marker. The increase in its expression correlates with the conversion of melanoma growth from radial to vertical.36 However, there are metastatic melanoma cells that express little or no αVβ3 integrin on their surface,37,38 suggesting that no single adhesion receptor is irreplaceable in melanoma progression. The binding of αVβ3 integrin is known to be RGD-dependent. Nevertheless, there may be an additional ligand binding site in αVβ3, which activates a cellular signalling cascade independently from RGD binding.39 Moreover, other molecules are also involved in αVβ3-related melanoma cell invasion. The function of a cell adhesion receptor, E-cadherin, is apparently related to melanoma cell growth control. Restored expression of E-cadherin was found to inhibit melanoma cell invasion by decreasing the expression of β3 integrin and MelCAM/MUC18, both receptors typical for invasive melanoma cells. In addition, expression of E-cadherin induced apoptosis in these cells.40

Integrins α2β1 and α3 β1, but not α6 integrins, have been found to play a role in melanoma cell migration on type IV collagen and laminin. In several studies, the expression of α2β1 and α3 β1 was increased in metastatic cells when compared to cells in the primary tumor.4146

Roles for integrins as prognostic markers in primary and metastatic human melanomas have been suggested. The expression of β1 integrin in primary melanomas has been proposed to augur the emergence of regional lymph node metastases.47 In contrast, the expression of β1 integrins in metastasis of melanoma has been shown to predict a loner disease-free period.48 Expression of integrin β3 has been reported to correlate positively to lung metastases. Furthermore, β3-positive melanomas are associated with poorer survival rates.49 Although these results are partly conflicting, they may be explained by differences in integrin function in primary sites as compared to metastatic sites.

It has also been proposed that laminin receptors, especially integrin α6β1 are involved in metastatic processes, possibly during extravasation. Multiple binding epitopes on α6β1 may contribute to the migratory and adhesive properties mediated by this integrin.45,50 Intravenously injected anti-α6 integrin antibody inhibited the formation of lung metastases of a highly invasive mouse melanoma cell line.51 Recently, in addition to receptor-ECM interactions, reciprocal association of different cell surface proteins has been suggested to play an important role in cancer cells. In particular, it has been found that α3 β1 and α6β1 integrins can interact with CD36, a protein located in membrane rafts which participates in integrin-related signal transduction. This interaction has been found to facilitate haptotactic cell migration.52 In contrast to α6 integrins, the expression of laminin receptor α7β1 seems to inhibit malignant features such as cell growth and metastasis in mouse melanoma cell lines.53

Fibronectin-binding integrin α5β1 has been described as having a stimulatory effect on the growth of quiescent human melanoma cells. This effect may be mediated in an RGD-dependent manner.54 Another fibronectin receptor, integrin α4β1, has been found to facilitate melanoma cell migration.55 Moreover, there is evidence that to achieve a proper α4β1-mediated binding to fibronectin, melanoma cells need direct contact with a cell surface chondroitin sulfate glycosaminoglycan.56 This interaction may modulate tumor invasion capacity via activation of a Rho-family GTPase, Cdc42, a Cdc42-associated protein, Ack-1, and the adapter protein p130cas followed by appropriate cytoskeletal reorganization.57 However, the mouse homologue to human melanoma proteoglycan (NG2) has been reported to have a negative effect on α4β1-mediated binding of mouse melanoma cells. Nevertheless, the expression of NG2 increased the lung metastasis formation in an experimental model.58 Like Cdc42, another GTPase, RhoC, has been proposed to enhance invasion of human and mouse melanoma, probably by modulating cytoskeletal assembly. In the same study, the expression of fibronectin and thymosin b4, a regulator of actin polymerization, was increased in both human and mouse melanoma cells with high metastatic capacity.59 These findings stress the role of intra- and extracellular regulators of cytoskeletal organization in melanoma cell invasion. Fibronectin-binding integrins may act as important mediators in this process. Furthermore, αIIbβ3 which is typically found in platelets, may also occur on metastatic murine melanoma cells as well as on human melanoma cells and may contribute to invasion.60,61

Breast Cancer

Changes in the expression pattern of integrins in breast cancer, the most common cancer among females, have been reported in several studies. Immunohistochemical analyses of poorly differentiated breast adenocarcinomas have shown marked decreases of integrin α2β1. Expression of α5β1 and αVβ3 integrins has also been reduced, although to a lesser degree.62 In situ hybridization of poorly differentiated breast adenocarcinoma has shown a reduction in the mRNA levels of α2, α5, and β1 integrins as compared to differentiated mammary epithelium.63 These studies emphasize the importance of α2β1 integrin in normal mammary epithelium. Further, by reexpressing integrin α2β1, the ability of poorly differentiated breast cancer cells to differentiate into gland-like structures has been restored, and the in vivo tumorigenicity has been clearly reduced.64 Some of the phenotypic changes introduced by reexpression of α2β1 integrin can be attributed to concomitantly increased expression of α6β4 integrin.65 Thus, it is possible that during malignant transformation, changes in the expression of a key integrin lead to altered expression of other integrins.

Links between the integrins and other important factors contributing to the progression of breast tumors have also been traced. It has been postulated that hepatocyte growth factor/scatter factor (HGF/SF) is able to increase the adhesion of breast cancer cells to laminins 1 and 5, fibronectin, and vitronectin through a PI3 kinase-related mechanism. Several integrins, such as β1, β3, β4 and β5 may be affected by HGF-mediated regulation of integrin avidity.66 The interactions between bone matrix proteins and invading breast cancer cells are pivotal because bone is a typical site of breast cancer metastasis. Integrins αVβ3 and αVβ5 are involved in bone sialoprotein-induced cancer cell adhesion, proliferation and migration. However, the function of these integrins differs so that αVβ3, whose expression is suggested to be in relation to metastatic potential, participates in cell migration, whereas αVβ5 is likely to facilitate cell adhesion and proliferation.67,68 In highly invasive mammary epithelial cells, the process of osteopontin-induced migration, which is dependent mainly on αVβ3 integrin, involves the activation of the HGF receptor (Met).69 Likewise, insulin-like growth factor I (IGF-I) stimulates an increase in the activity of integrin αVβ5 and MMP-9, thereby increasing cell migration through vitronectin-coated filters. Additionally, IGF-I is reportedly able to stimulate cell migration on type IV collagen and vitronectin-coated membranes. These effects are presumably mediated by αVβ5 and α2β1 integrins.70,71

TGF-β has also been reported to participate in the migration of mammary epithelial cells. TGF-β-related responses have been linked to the PI3-kinase/Akt-signaling route, and they have been proposed to result in the delocalization of E-cadherin and β1 integrin from cell junctions.72 Additionally, interaction between E-cadherin and αV integrins has been postulated. The introduction of dominant-negative E-cadherin into cells has led to increased migration on vitronectin as a result of increased activity of the αVβ1 and αVβ5 integrins.73 Furthermore, epidermal growth factor and its receptor (EGFR), as well as the breast cancer-related protein ERBB-2, have been reported to mediate up-regulation of β1 integrin function and breast cancer progression. Activation of PI3-kinase plays a role in the signalling of both of these receptors.74 It has also been suggested that the overexpression of breast cancer-related protein ERBB-2 may induce fibronectin-dependent invasion with concomitant down-regulation of α4 integrin cell surface expression.75

Integrin α3 β1 is involved in breast cancer cell migration and invasion by regulating the production of MMP-2. It may also participate in the rearrangement of cytoskeleton. Both phenomena are PI3-kinase dependent.76 Cdc42 and Rac1 may be the signaling factors between integrins and PI3-kinase.77 Moreover, the expression of α3β1 integrin is reported to be related to the metastatic capacity of breast cancer cells by increasing the activity of MMP-9.78 The expression of a variety of MMPs may be modulated by integrin-associated cell-cell contacts and cell-matrix contacts. Coculturing of invasive breast carcinoma cells with bone marrow fibroblasts has been shown to increase the production of MMP-1 and MMP-2 in culture supernatant. Elevated levels of MMPs have contributed to cell migration through fibroblast monolayers, and migration has been inhibited by antibodies against variable integrins.79

Lung, liver and brains are typical loci for breast cancer metastasis. Increased expression or, in contrast, loss of multiple integrins has been found to assist the formation of invasive phenotypes. In addition to changes in the integrin expression pattern, general features of malignant cells are changes in cell polarization, adherens junctions and cytoskeletal organization.80 In an experimental model, the migratory potential of breast cancer cells has been improved by coexpression of the intermediate filaments keratin and vimentin. This may be due to the decrease in α2 and α3 integrins and the increase in α6 integrin expression.81

Immunostaining of breast cancer tissue sections has indicated that the loss of α1β1, α2β1, α3 β1, α6β1, αVβ1 and αVβ5 integrins is associated with the formation of axillary metastases.82 Somewhat controversially, it has been reported that increased levels of α2, α4, α6, and αV integrins may increase the malignant capacity of the breast cancer cells. The expression of these integrins is inhibited by the tumor suppressor gene maspin which, in contrast, induces the expression of α5 integrin.83,84 The expression of α6β4 integrin may also inhibit malignant properties of breast cancer cells by inducing apoptosis via activation of p53. However, the expression of this integrin may facilitate carcinoma progression if p53 is in a mutated, inactive form.85,86 It has also been suggested that integrin α6β4-mediated invasion occurs through PI3-kinase signalling.87

In human breast cancer, integrin αVβ3 has been found in both active and inactive forms. It has been proposed that the active form promotes metastatic capability via interaction with platelets.88 In one experimental mouse model, the metastatic capacity of human breast cancer cells has been reduced by using the snake venom disintegrin, contortrostatin, which can bind to αVβ3 integrin.89 Another vitronectin receptor, αVβ5, has also been found to have a role in the invasion process. Some results indicate that αVβ5-dependent breast cancer cell migration may be partly regulated by urokinase. Urokinase receptor (uPAR) can interact with αVβ5 and αVβ1 integrins, and αVβ5-mediated cytoskeletal rearrangement and activation of protein kinase C occurs in response to urokinase. uPAR-triggered, integrin-dependent cell migration probably occurs via activation of Ras, MEK, ERK and myosin light chain kinase.90,91 The pineal gland hormone, melatonin, may have an inhibitory effect on invasion via induction of β1 integrin and E-cadherin expression.92

Table 2

Table 2

 Changes in the integrin expression pattern of histological (more...)

Table 2

Changes in the integrin expression pattern of histological sections in three types of cancer. As a result of cancer progression the expression of integrins is either increased () or decreased (↓)
CancerIntegrinsType of cancerReference
Melanomaβ3primary and metastatic human melanomasAlbelda et al, 1990192
 α2, α3, α4, b, α6β1↓primary and metastatic human melanomasMoretti et al, 1993193
 α4, α5β, αVβ3, α6↓, b4↓primary and metastatic human melanomasDanen et al, 1994194
 αVβ3, αVβ5↓primary and metastaticDanen et al, 199537
 α3 β1primary and metastatic human melanomasNatali et al, 199342
 β1primary human melanomasHieken et al, 199647
 β1↓metastasis of human melanomasVihinen et al, 200048
 β3primary human melanomasHieken et al, 199949
Breast cancerα2β1↓breast adenocarcinomasZutter et al, 199062
 α1β1↓, α2β1↓, α3β1↓, α6β1↓, αVβ1↓, αVβ5↓sections from primary human breast cancersGui et al, 199582
Prostate cancerβ4↓sections from human prostatic intraepithelial neoplasiaDavis et al, 2001102
 α6β4↓human prostatic intraepithelial neoplasiaNagle et al, 1995105
 α2β1, a6lymph node metastases of human prostate cancerBonkhoff et al, 199393
 α5, β1rat prostatic adenocarcinomaMacCalman et al, 1994112

Prostate Carcinoma

Only limited observations targeted to integrin expression patterns in prostate cancer have been made. In one report, all primary and metastatic carcinomas expressed α2β1 and α6 integrins. The expression level of α2β1 was down-regulated in grade I and II tumors. In grade III tumors the expression was heterogenous, but α2β1 expression was again up-regulated in lymph node metastases.93 Some integrins that have been implicated in melanoma, and breast cancer progression may also be responsible for the development of prostate carcinoma. An example of this is the vitronectin receptor αVβ3, which has been found to increase metastatic capability. This may be partly due to its interaction with fibronectin and vitronectin bound on the surfaces of endothelial cells.94,95 Such binding may help cancer cells to extravasate. In prostate cancer cells, as well as in other types of cancer cells studied, the ligand binding of αVβ3 integrin can lead to phosphophorylation of focal adhesion kinase (FAK) and trigger the PI3-kinase/Akt pathway. However, this activation seems to be ligand specific.96,97 Mutation in a tumor suppressor gene PTEN, a negative regulator of Akt, and activation of integrin-linked kinase (ILK) may also play a role in malignant transformation.98,99 Akt may also inhibit the expression of p27(Kip1), an inhibitor of certain cyclin/cyclin-dependent kinase complexes and cell cycle progression.100

Partially conflicting reports exist about the role of laminin receptor integrins in the progression of prostate cancer. It has been proposed that the increased expression of α6 integrin may contribute to the invasive capacity of prostate cancer cells.95,101 On the other hand, the loss of β4 integrin, the counterpart of the α6 subunit, has been reported to occur in prostate cancer progression concomitantly with the loss of its ligand, laminin-5.102 Furthermore, malignant prostate cancer cells may lose their ability to polarize and regulate a normal acinar morphogenesis because of decreases or changes in the distribution of α6β1 integrin.103,104 The reduction of integrin α6β4 as a tumor progression-promoting factor may be explained by the fact that α6β4 participates in the formation of hemidesmosomes, which are pivotal for the attachment of differentiated epithelial cells to the basal lamina.105,106 The decrease in α6β4 integrin expression may occur due to androgen regulation in androgen-sensitive cancer cells. In contrast, androgen-independent prostate cancer cells may maintain their expression of α6β4, which supports their high invasion capacity, whereas α6β1 and α3 β1 expression may be related to less invasive phenotypes.107,108 The differences in the functions of α6β1 and α6β4 integrins may be partly explained by their distinct signal transduction pathways.109

Table 3

Table 3

 Integrins that either contribute () or decrease (↓) (more...)

Table 3

Integrins that either contribute () or decrease (↓) malignant properties in cell lines of three types of cancer
CancerIntegrinsCell typesReference
Melanoma αVβ3WM1552C and WM1341D melanoma cellsHsu et al,199836
 αVβ3, αVβ5↓, α7β1↓K1735 murine melanoma cellsLi et al, 1998195; Ziober et al, 199953
 α2β1MV3 and BLM human melanoma cellsKlein et al, 199141
 α2β1four human melanoma cell linesEtoh et al, 199344
 α2β1, α6β1six human melanoma cell linesDanen et al, 199345
 α3 β1Me665/2 human melanoma cellsMelchiori et al, 199546
 α6β16/129 melanoma cellsRuiz et al, 199351
 α5β1human melanoma cell linesMortarini et al, 199254
 α4β1A375-SM human melanoma cellsMould et al, 199455
 αIIbβ3WM-983B human melanoma cellsTrikha et al, 199761
Breast cancerα6β↓mm5MT murine breast carcinoma cellsSun et al, 199865
 αVβ3, αVβ5, α3β1, αβ4↓MDA-MB-231 human breast carcinoma cellsJones et al, 199785; Sung et al 199867; Sugiura et al, 199976; Morini et al, 200078
 αVβ3MDA-MB-435 human breast carcinoma cells and metastatic human breast carcinoma cellsTuck et al, 200069; Felding-Haberman et al, 200188
 αVβ5, a2β1MCF-7 human breast cancer cellsDoerr et al, 199670; Carriero et al, 199990; Mira et al, 199971
 αVβ5, αVβ1ZR75-1 human breast cancer cellsvon Schlippe et al, 200073
Prostate cancerαVβ3, α3β1, a5β1, α6, αIIbβ3DU145 prostate cancer cellsRabinovitz et al, 1995101; Trikha et al. 1996123; Romanov et al, 199994
 α3β1↓, α6β4, α2β1, α3β1PC-3 human prostate cancer cellsDedhar et al, 1993107; Kostenuik et al, 1997119; Festuccia et al, 2000108
 α4β1↓four different human prostate cancer cell linesRokhling et al, 1995110

Taken together, laminin-receptor integrins may maintain differentiated phenotypes when they are localized in a polarized manner. Alternatively, if the tumor cell has been able to break the polarized alignment of the laminin receptors, these integrins may promote the malignant phenotype. Androgens may be involved in this regulation of integrin distribution.

Several fibronectin-binding integrins have been proposed as having distinct roles in the progression of prostate cancer. When comparing the integrin expression patterns between tumorigenic and nontumorigenic cell lines, α4 integrin was found to be expressed only on nontumorigenic cells. However, RGD-binding integrins α5β1 and α3 β1 were present in tumor cells.110,111 Likewise, in rat prostate adenocarcinoma cell lines mRNA levels of α5 and β1 integrin subunits were increased as compared to normal cells of the rat prostate gland, accompanied by the loss of E-cadherin.112 Moreover, plasma fibronectin was necessary to stimulate invasion of human and rat prostate carcinoma cells through in vitro basement membrane analog.113

Much attention has been drawn to the role of β1 integrin splice variants in prostate carcinoma. It has been postulated that the β1 integrin splice variant, β1C, inhibits proliferation of prostate cells by regulating cell cycle inhibitor, p27(Kip1). As seen at both at mRNA and protein level, β1C is down-regulated in prostate cancer cells. Interestingly, the total β1 integrin is similarly down-regulated at the mRNA level, but at the protein level there is no difference in total β1 expression between malignant and nonmalignant prostate cells.114117 The activation of another cell cycle inhibitor, cyclin-depended kinase inhibitor, p21WAF1, by interferon-α (IFN-α) leads to a phenotype in which the expression of α3 integrin is increased. This may be characteristic for the nontumorigenic state.118

Bone is the main target of metastatic prostate cancer cells. Bone cells may produce proteins that facilitate the migratory and invasive potentials of prostate cancer cells. One of these mediators might be TGF- β1, which is secreted by osteoblasts. TGF- β1 increases the cell adhesion to type I collagen and invasion through reconstituted basement membranes. In this process, increases in α2β1 and α3β1 expression levels have been reported.119,120 Similarly, in studies on the adhesion of prostate epithelial cells or human prostate carcinoma cells to type I collagen or to the stroma of human bone marrow, it has been evident that the interactions are predominantly mediated by α2β1 integrin.119,121,122

Integrin αIIbβ3 has also been suggested as having a role in the metastasis of prostate cancer. Cell surface expression of αIIbβ3 integrin is reported to be regulated by protein kinase C.123,124

Integrins and Invasion

As the main link between a cell and the ECM, integrins have an essential role in the invasion process. The cellular integrin expression pattern is highly variable between cancer types, in individual tumors, and even in separate tumor cells inside a single tumor. Thus, it is difficult to estimate the involvement of an individual adhesion receptor. The data that have accumulated with respect to integrin expression in various types of human cancer allow some conclusions to be drawn. Some integrins, especially αVβ3, seem to promote tumor progression and metastasis. The fact that some aggressive cells are negative for this integrin indicates that none of the adhesion receptors are irreplaceable.37 It is also obvious that some integrins have distinct functions depending on cell type. For example, α2β1 integrin may participate in the maintenance of differentiated cell phenotype in breast epithelial cells, and therefore it is often down-regulated in breast cancer.63 However, in melanoma,41 prostate93 and gastric carcinoma,125 α2β1 expression is associated to tumor progression and invasion. In addition, many experimental models support the idea that α2β1 integrin is essential for cancer cell migration, invasion and metastasis formation.126128

It is also important to remember that down-regulation of an integrin subunit in cancer cells does not necessarily mean that the receptor is unimportant for malignant phenotype or that it has a tumor suppressor function. Maximum cell migration speed is dependent on optimal ligand concentration, integrin expression, and ligand-integrin affinity.129 Therefore, a decrease in integrin expression may actually promote cell migration. The role of the integrins is not limited to their function as a mechanical bond in cell-matrix contact sites, but, after binding extracellular ligands, integrins are also capable of sending signals into the cell. The cancer-related genomic instability leads to variable changes in the expression of cellular signalling molecules and most probably affect also integrin-linked pathways. Thus, the function of an integrin may change during tumor progression. The integrin may be down-regulated during transformation because it supports a normal phenotype or inhibits cell growth. However, it may also play an essential role in invasive cancer.

Integrins and MMPs

Integrins are needed in cell movement, but they might also have other roles in cancer invasion. Importantly, they induce the expression of different ECM degrading proteases, especially members of the MMP family. The interplay between integrins and the matrix metalloproteinases may be one of the key phenomena in the invasion process.

a Vb3-Activated MMP Expression

Interaction of αVβ3 with fibronectin and vitronectin induces the expression of MMP-2.130132 In melanoma cells, the modulation of proMMP-2 to its invasion-contributing active form is regulated by membrane type-1 metalloproteinase (MT1-MMP), whose activation may be inhibited by tissue inhibitor of metalloproteinases-2 (TIMP-2).133

In our own experiments with human osteosarcoma cells, we have used an intracellular, single-chain anti-αV-integrin antibody to prevent the transport of maturing αV integrin from the endoplasmic reticulum to the cell surface.134 In antibody-transfected clones, the cell surface expression of αV was reduced by approximately 70-100%. When cells were plated on fibronectin or vitronectin matrices, we could see a marked reduction in the RNA levels of MMP-2. Furthermore, cell spreading and adhesion decreased significantly in comparison with control cells.

Collagen Receptor-Activated MMP Expression

We have hypothesized135 that the invasion of some cells through fibrillar collagen can be a stepwise process in which α2β1 integrin binds to type I collagen in three-dimensional matrices. The binding up-regulates expression of MMP-1,136,137 which is able to degrade fibrillar collagens. Collagen degradation by MMP-1 is followed by denaturation, uncovering RGD sequences. The RGD motif acts as a ligand for αVβ3 integrin, which in turn may induce the production of MMP-2. Finally, this enzyme completes the degradation of collagen.

Fibronectin Receptor-Activated MMP Expression

Fibronectin receptors α4β1 and α5β1 have been found to have different influences on the expression of three MMPs in rabbit synoviocytes. As already described above, these integrins bind to separate regions of the fibronectin molecule. Thus, different splice variants of fibronectin may have distinct effects on cellular gene expression. Integrin α5β1 increases the expression of MMP-1, MMP-3 and MMP-9,138 whereas the production of these MMPs is reduced after fibronectin binding via α4β1 integrin.139 However, in human intestinal mesenchymal cells, the binding of activating, monoclonal anti-α4 antibody leads to up-regulation of MMP-2-activating membrane type-1-matrix metalloproteinase (MT1-MMP) and thus increases the activated form of MMP-2.140

Cellular Signals Between Integrins and MMP Genes

Formation of focal adhesion sites and clustering of integrins are needed for ligand binding and signal transduction to the cell nucleus.141143 Signalling cascades may be activated when the cytoplasmic tails of integrin subunits bind to specific proteins inside the cell. The activation of focal adhesion kinase (FAK) within focal adhesion sites requires both ligand binding to integrins and intact cytoskeleton. FAK has binding capacity to β1, β2 and β3 subunits,144 as well as to cytoskeletal proteins such as paxillin, talin and potentially, vinculin.145147 Interestingly, paxillin has been reported to bind also α4 integrin cytoplasmic tail.148 Moreover, integrin-ligand binding results in FAK autophosphorylation. Phosphorylated tyrosine 397 acts in turn as a binding site for kinases like Csk, Fyn, and Src.149 These events may lead to induction of MAPK/ERK/JNK pathway and among other things, MMP production. In many cases cytokines participate in MMP induction in an activating or synergistic manner.

Integrin-Related Signals and the Expression of Gelatinases (MMP-2 and MMP-9)

When ovarian carcinoma cells are cultured inside a three-dimensional collagen gel, MMP-2 is activated. The activation has also been seen when human breast cancer cells have been cultured in collagen gels. Furthermore, the induction of pro-MMP-2 and TIMP-2 have taken place after treatment of cells with soluble anti- β1-integrin antibody. When cells have come into contact with beads coated with an integrin aggregation-promoting, anti-β1 antibody, the pro-MMP-2 activator, MT-1-MMP, has been accumulated, suggesting that integrin aggregation may have a part in metalloproteinase activation processes. The activation of MMP-2 by β1 integrins has been suggested as being dependent on tyrosine kinases.150,151

Treatment of human glioblastoma cell lines with anti-α3β1-integrin antibody has been suggested to reduce the cell surface expression of α3 β1 and to increase both MMP-2 activity and the cells' ability to invade the synthetic basement membrane, Matrigel.152 Similar results have been obtained with rhabdomyosarcoma cells, although the cell surface expression of α3 β1 after antibody treatment was not studied.153 Other studies have given more evidence about the connection between α3β1 integrin and MMP-2. It has been suggested that α3β1 integrin and tetraspanin protein complexes regulate the production of MMP-2 and cell invasion via PI3K-dependent signalling routes. Moreover, actin cytoskeleton rearrangement may also take place in the invasion process. At least talin and MARCKS but not vinculin are reported to codistribute with tetraspanins.154,155 In addition to PI3K, PI4K is also thought to be activated by certain integrin α3β1/tetraspannin complexes. This signalling route may have an effect on cell motility.156,157 Tetraspanins are known to be of the family of transmembrane proteins, which form membrane complexes with at least integrins α3β1 and α6β1; several of them have been suggested as tumor-specific antigens.155,158160 Besides tetraspanins, integrin α3β1 has been described as forming a complex with the EMMPRIN/basigin/OX47/M6, a transmembrane protein, which contains two immunoglubulin domains.161 So far it is not known whether this protein complex has an effect on integrin signalling.

Figure 1
Figure 1

Figure 1

 Integrin-related signalling leads to production of (more...)
An external file that holds a picture, illustration, etc., usually as some form of binary object. The name of referred object is ch157f1.jpg.

Figure 1

.

Integrin-related signalling leads to production of MMPs essential for cancer progression. (A) α2β1 integrin regulates MMP-1 and MMP-13 through distinct pathways. Ligand binding leads to activation of protein kinase Cz (PKCz) and tetraspanin, nuclear factor-κB (NFkB), which up-regulates MMP-1 expression. MMP-13 is up-regulated via Cdc42, a GTPase of the Rho family, and the a isoform of p38 (p38a). (B) Ligand binding by multiple integrins can trigger a signalling cascade through p130cas, a tyrosine-phosphorylated, SH3 domain-containing docking protein, which is located in focal adhesions. p130cas activates metalloproteinase-activating zinc finger protein, CIZ, which leads to activation of several MMPs. (C) Integrin α3β1 forms a cell surface complex with tetraspannin protein TMSF4. PI4-kinase is activated by an integrin-TMFS4 complex. PI4-kinase can then activate the PI3-kinase-dependent signalling route that results in the expression of MMP-2.136,154,156,157,178,183,186,187

In colon adenocarcinoma cells, another laminin binding receptor, α6β4 integrin, may also facilitate signals that leads to increased expression of MMP-2 and tumor invasion.162 In addition to regulation of MMP-2, it has been proposed that α3 β1 integrin participates in the regulation of MMP-9 expression. Anti-α3 or anti-β1, but not other anti-integrin antibodies, have been found to induce the expression of MMP-9 in human keratinocytes.163 The association between α3β1 integrin and MMP-9 expression has been established with immortalized mouse keratinocytes as well.164 Metastatic cells from mammary carcinomas showed increased expression of α3β1 integrin when compared to primary carcinomas. Function-blocking anti-α3 antibody could inhibit in vitro migration and invasion of these cells, and the antibody treatment could also reduce the activity of MMP-9.78

MMP-9 expression and invasion of ovarian cancer cells have been found to be induced by the peritoneal expression of fibronectin. These effects could be blocked by both an anti-α5 integrin antibody and RGD polypeptides.165 It has also been shown that in ovarian carcinoma, the cell-cell interaction between carcinoma cells and fibroblasts causes induction of pro-MMP-2 release from fibroblasts. Type I collagen and anti-β1 integrin antibody could then induce the activation of pro-MMP-2 produced by tumor-derived fibroblasts.166 Collagen receptor integrins (at least α2β1 but not α3β1) seem to have a role in the activation of MMP-2, which is reported to happen via MT1-MMP.167 Both MMP-9 activity and the retinoic acid-dependent invasion of squamous cell carcinoma lines have been down-regulated by applying anti-β1 integrin antibodies or mitogen-activated protein kinase inhibitors.168

The mechanisms underlying the integrin-associated induction of MMP-9 have been elucitated in a model where MMP-9 gene expression was studied during macrophage differentiation with human myeloid leukemia cells. In accordance with previous studies, monoclonal anti-fibronectin or anti-α5β1 integrin antibodies could inhibit fibronectin-induced cell adhesion and MMP-9 expression. The macrophage-differentiation and cell-adhesion promoting agent, phorbol 12-myristate 13-acetate (PMA), could induce MMP-9 expression but there was no induction in PKC-b deficient variants. The disruption of cytoskeletal integrity by the inhibitors of actin polymerization, cytochalasins B and D, inhibited the production of MMP-9.169 Similar findings have been made by studying human glioma cells.170 On the other hand, cytochalasin D treatment could markedly increase fibronectin-induced MMP-9 and MMP-2 expression in human T lymphocytes.132 These findings indicate the importance of the cytoskeletal arrangement in proteinase regulation in addition to protein kinases.

Increasing evidence indicates a correlation between the expressions of α5β1 integrin and MMP-9. PMA was found to increase mRNA and protein levels of both fibronectin and fibronectin-binding α5β1 integrin in human myeloid leukemia cells. Furthermore, anti-TNF-α antibody could inhibit the expression of α5 and β1 integrins, resulting in decresed cell adhesion, spreading, and MMP-9, but not MMP-2, expression.171 Fibronectin-dependent production of MMP-2 and MMP-9 has been reduced in human T lymphocyte culture by applying monoclonal anti-α4, -α5, and -αV antibodies.132 Both platelet-derived growth factor and basic fibroblast growth factor have synergistic roles in up-regulation of MMP-9. These functions occur in combination with either TNF-α or interleukin-α in rabbit and human dermal fibroblasts.172 One possible signalling cascade leading to MMP-9 expression may go through Raf-1 and mitogen-activated protein kinases.173 On the other hand, it has been suggested that in human T-cells, ligation with fibronectin induces both activating and inhibiting signals for MMP-2 and MMP-9 expression. The activation occurs through Src-type tyrosine kinase while inhibition takes place through a Ras/MAP kinase pathway.132

Nuclear binding sites of nuclear factor-κB (NF-κB), Sp-1, and activator protein-1 (AP-1) may be involved at least in TNF-α-related induction of MMP-9 expression.172,174 In human breast cancer cells, overexpression of bcl-2 was found to increase NF-κB-dependent transcriptional MMP-9 activity.175 In a murine model, spontaneous metastasis could be prevented by retroviral delivery of dominant-negative NF-κB, which also resulted in down-regulation in MMP-9 expression. Moreover, TIMP-1 and -2 were up-regulated.176 However, v-Src-mediated activation of the AP-1 binding site and of a GT box located downstream from the AP-1 site has been described as being involved in an inflammatory cytokine-independent pathway by which the expression of MMP-9 is activated.177 These kinds of signalling mechanisms may correspondingly be involved in MMP-9-dependent invasion of other types of cancer cells.

Integrin-activated signals and the expression of collagenases (MMP-1 and MMP-13)

Integrin α2β1 has been shown to up-regulate MMP-1 expression in osteosarcoma cells when the cells are in contact with type I collagen.136 In dermal fibroblasts, the α2β1-dependent up-regulation of MMP-1 inside a three-dimensional collagen gel has been reportedly mediated by increased activity of PKC-z and NF-κB, a transcription factor downstream of PKC-z.178 Additionally, α2β1-mediated induction of MMP-1 can be abrogated by using tyrosine kinase inhibitors.179,180 Integrin αV may also have a regulatory role in MMP-1 gene expression with the dermatan sulfate proteoglycan, decorin. When rabbit synovial fibroblasts were plated on matrices of either decorin and vitronectin or decorin and a 120-kDa fragment of fibronectin, the expression of MMP-1 was induced.181 Integrin α5β1-induced collagenase expression has been reported to be mediated via PEA3- and AP1-binding sites in a collagenase promoter.182

Recently, a novel metalloproteinase-activating zinc finger protein, CIZ, has been described. It can function together with p130cas, which is a tyrosine-phosphorylated, SH3 domain-containing docking protein located in focal adhesions. p130cas is activated as a result of integrin ligand binding, and it can further activate CIZ. CIZ is suggested to be a nucleocytoplasmic shuttling protein that can bind to certain consensus sequences in matrix metalloproteinase genes. CIZ overexpression has been found to up-regulate the transcription of MMP-1, MMP-3, and MMP-7.183 The activation of p130cas via tyrosine phosphorylation after integrin-mediated cell adhesion onto fibronectin, vitronectin, laminin and collagen is in close relation to FAK. Depolymerization of actin networks with cytochalasin D could hinder phosphorylation.184,185 So far it is not known how a specific integrin receptor can cause the up-regulation of a specific MMP by using this signaling route.

Beyond the modulation of MMP-1 and MT-1-MMP/MMP-2 expression, collagen-binding integrins play a role in the regulation of MMP-13 (collagenase-3). Culturing of human dermal fibroblasts inside a three-dimensional collagen lattice induced the expression and proteolytic activation of MMP-13. This induction could be inhibited by function-blocking anti-α2 integrin antibodies. Similarly, activating anti-β1 integrin antibody could enhance the MMP-13 induction. Thus, ligand binding by α2β1 integrin stimulated the production of MMP-13. Furthermore, it was found that activation of p38 is required for MMP-13 induction and that the induction was repressed by active ERK 1,2.186 Integrin α2β1 has been shown to activate the a isoform of p38 via Cdc42 in a process that requires the cytoplasmic domain of α2 subunit.187

Integrins as MMP Receptors

There is an increasing body of evidence that some integrins can modulate the action of MMPs by binding directly to them. This kind of interaction is understandable in terms of cell movement because it enables the cell to direct proteolytic activity in the desired manner at its migrating edge. After cleaveage of the ECM components, the migrating cell can use the same integrin for attachment. The first integrin-MMP interaction that was identified was between αVβ3 and MMP-2 on angiogenic blood vessels and melanoma cells.188 There is some evidence that vascular invasion is inhibited when the interaction of integrin αVβ3 and MMP-2 is abrogated.189 Additionally, αVβ3 integrin may have some modulatory properties on MMP-2 activity. It has been suggested that integrin αVβ3 could inhibit the cleavage of pro-MMP-2 to the active form by receptor clustering without any change in MT1-MMP expression.190 MT1-MMP and MMP inhibitor TIMP-2 have been localized with caveolin-1 in the same domain of cell membranes with MMP-2 and αVβ3 integrin by using immunofluorescence and confocal microscopy, although direct interaction with αVβ3 integrin has not been shown.191 The binding of MMPs to cell surface integrins may be a more general phenomenon. Thus, it is possible that pericellular proteolysis is both activated and targeted by integrins.

Acknowledgments

We wish to thank Dr. Wendy Connors for critical reading of the manuscript and Mr. Rolf Sara for computer graphics.

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