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Maspin Suppresses Breast Cancer Cell Invasiveness by Modulating Integrin Expression and Function

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Introduction

Although the novel tumor suppressor gene maspin (mammary serine protease inhibitor) was originally isolated from normal mammary epithelium by subtractive hybridization and differential display almost seven years ago,12it is still unclear how it functions molecularly and biologically to regulate tumor cell motility, invasion and metastasis.13 The maspin protein has an Mr of 42,000 and contains sequence homology with members of the serine protease inhibitor superfamily (serpins), including plasminogen activator inhibitor-1, -2 (PAI-1 and PAI-2) and a1-antitrypsin, as well as sequence homology with noninhibitor serpins, such as ovalbumin.3 This apparent dual nature of maspin is consistent with the observations that while recombinant maspin can act at the cell membrane to inhibit cell migration and invasion and requires an intact reactive site loop, it can also function as a substrate rather than an inhibitor for a number of different serine proteases (e.g., tissue- and urokinase-type plasminogen activators; tPA and uPA).38 When acting as a serine protease inhibitor in vitro, maspin binds specifically to purified single chain tPA (sctPA) activated to cleave plasminogen to plasmin and results in biphasic effects on sctPA. This suggests a complex interaction between maspin and sctPA which could contribute to the regulation of plasminogen activation by sctPA when bound to the epithelial cell surface.9 Recently, recombinant maspin was shown to inhibit plasminogen activation to plasmin associated with uPA activity (but not tPA activity) at the cell surface of the prostate carcinoma cell line DU-145. This correlated quantitatively with maspin's inhibition of cell motility in vitro.10 There has also been a recent report that maspin is regulated by p53 in breast and prostate cancer cells lines.11,12 This suggests that maspin and p53 cooperate in the negative regulation of tumor cell invasion and metastasis. Taken together, these observations indicate that maspin may play a significant role in regulating processes that are associated with the progression and metastatic cascade of certain cancers (e.g., breast and prostate cancer), and could thereby present an unique and specific target for the diagnosis and therapeutic intervention of these cancers.

Tumor Cell Invasion and Metastasis

Tumor cell metastasis is a complex process which involves tumor cells moving from their primary site of growth and proliferation to distant sites in the body. The foci formed at these sites may act to harbor tumor cells that can remain dormant for extended periods of time (as in certain uveal metastatic melanoma),13 or function as sites of renewed tumor cell growth, proliferation and metastasis. As a result of the inherent complexity of this cascade, it has been helpful to describe and examine this process in terms of a continuum where discrete, specific steps may be identified, modeled and studied.14,15 In order to disseminate throughout the body, tumor cells must leave the primary area of growth and get in (intravasate) and out (extravasate) of the blood and lymphatic systems, their primary routes for dispersal. During this process, tumor cells must interact with a changing environment, avoid host defenses, and recognize and lodge at sites that can facilitate and support their renewed growth and proliferation. A key component of the metastatic cascade concerns how tumor cells leave the primary tumor and invade the vasculature. In this regard, tumor cell invasion has been defined as a series of steps which describe: a) how tumor cells attach to and interact with their extracellular environment (both cell-cell and cell-extracellular matrix); b) what proteases are involved in the proteolytic digestion of the extracellular matrix and how these proteases are regulated; and c) how tumor cells move through the digested barrier.1417

Integrins and Their Role in Tumor Cell Invasion

A primary focus of studies concerned with cancer progression and metastasis is the examination of how cells interact with their different, and at times rapidly changing, environment. In this regard, the family of transmembrane glycoproteins called integrins play a key role(s) in the invasive and metastatic processes. Integrins are heterodimeric glycoproteins composed of non-covalently linked α and β subunits which contain a short transmembrane segment, carboxy-terminal cytoplasmic domains of variable size, and large, extracellular ligand-binding sites composed of the N-terminal domains of the α and β subunits. In general, ligand specificity of the integrin is determined by the α subunit, and ligand-specific signals are conveyed to the cell via the cytoplasmic tail of some α subunits. In contrast, ligand-independent clustering of integrins to focal adhesion sites, where they become organized at the ends of actin filaments and associate with the proteins vinculin, talin, and α-actinin, occurs through the cytoplasmic tail of some b subunits. While just over 20 integrins have been identified so far, the theoretical number of possible integrins (including spliced variants) is greater than 100. Integrins historically fall into three groups based on similar chain structures and/or ability to recognize similar protein or adhesion motifs. These groups include the β1-containing integrins, β2-containing integrins and β3-(αv)-containing integrins. While some α subunits associate with only one of the different β subunits, other α subunits associate with more than one β subunit. The most promiscuous subunit, αv, has been found associated with at least five different β subunits in various different cell lines (for review see Refs. 18, 19).

Classically, integrins are cell adhesion molecules involved in both cell-extracellular matrix and cell-cell adhesion interactions. However, subsequent studies have shown that integrins also play a significant role in signal transduction events, gene expression, cell proliferation, regulation of cell apoptosis (and anoikis), invasion and metastasis, embryogenesis, tumor progression, inflammation and immunity, hemostasis, angiogenesis, and in mediating the entry of certain infectious agents into cells.18,19 While cells can vary in their ability to respond to different environmental cues as a result of the particular integrin(s) expressed on their surface, they may also respond differently to specific ligands at different times and under different conditions through activation and deactivation of their integrins. This change in activation state involves conformational changes in the integrins' extracellular domain and can result from alterations in the degree of phosphorylation of the β subunit,20 as well as interaction between integrins and lipid-derived mediators.21

Another parameter contributing to the modulation and function of integrins is their association and interaction with other integrins, as well as other membrane proteins.2231 Cells can express a number of different integrins on their surface while at the same time experience a complex extracellular environment which contains many different integrin ligands. While each ligand has the potential to interact with a different integrin, there are individual ligands that can interact with a number of different individual integrins, and individual integrins that can interact with a number of different ligands. In order for cells to respond in a coordinated manner to this complex (and potentially changing) environment, recent studies suggest that there is a unidirectional cascade between transducer integrins, which can modulate the function of other integrins, and integrins (i.e., target integrins) which are subsequently modulated by these transducer integrins.28 This coordination and modulation of an intgerin's function by another integrin is called integrin crosstalk,2831 and appears to occur by way of the integrins' β-subunit cytoplasmic tails.30

An important example of how membrane associated proteins other than integrins modulate integrin function has been observed using the human embryonic kidney 293 cell model where the cells were transfected with cDNA for the urokinase-type plasminogen activator receptor (uPAR).23 uPAR is the major cellular binding site for urokinase-type plasminogen activator (uPA) which operates as a fibrin-independent, largely receptor-bound plasminogen activator,32,33 and the stability of uPA bound to uPAR is directly coupled to the activity of uPA.32 Plasminogen activator inhibitor-1 (PAI-1) can bind active uPA to form a complex which can bind the α2-macroglobulin/liproprotein-receptor related protein (LRP) and result in the clearance of uPA/PAI-1 and uPAR from the cell surface. This suggests that PAI-1 regulates both fibrinolysis and the cell-surface expression of uPAR. When the human embryonic kidney 293 cells were transfected with uPAR, the resulting glycosylphosphatidylinositol (GPI)-linked cell surface uPAR was found to interact with the active form of β1-containing integrins and caveolin to form a stable integrin-uPAR-caveolin complex. Although this complex was found to suppress normal β1-integrin binding to fibronectin, uPAR itself can function as an adhesion receptor for vitronectin and contains distinct sites for binding both vitronectin and urokinase. As a result, transfection of uPAR into these cells resulted in a marked increase in their ability to adhere to vitronectin, and an inhibition of their normal β1-dependent adhesion to fibronectin.23 This observation, however, contrasts with other reports that indicate that uPAR promotes normal functions in β1- and β2-containing integrins.33 A possible explanation for this paradox may be found in recent reports that indicate that integrin clusters contain only a few uPAR molecules that are bound to the integrins in a ligand-like fashion.23,33The uPAR functions by enriching the clusters with signaling molecules while at the same time preventing a few uPAR-bound integrins from binding their natural ligands. This results in a sacrifice of some ligand-binding capacity for an enrichment of integrin clusters with signaling molecules.23,33

Classically, the ability of cells to recognize, attach and adhere to specific extracellular components is a primary function of integrins; however, they have also been shown to play a significant role in transducing signals to the cell that contribute to regulating the response and interactions of the cells to their extracellular environment. Work by Werb and colleagues34 demonstrated that perturbation or ligation of the α5β1 integrin (classical fibronectin receptor) with fibronectin fragments could transduce extracellular signals in rabbit synovial fibroblasts which resulted in a change in the expression and extracellular levels of collagenase and stromelysin. Furthermore, subsequent work demonstrated that ligation of the αvβ3 integrin (classical vitronectin receptor) on a moderately invasive human melanoma cell line (A375M) with vitronectin (either bound or soluble), or an activating antibody to the αv subunit, increased the expression and extracellular levels of the matrix-metalloproteinase-2 (MMP-2) concomitant with an increase in the cells' ability to invade in vitro.35 In contrast, however, it was found that a highly aggressive human melanoma cell line (C8161), which expressed little-to-no αvβ3 integrin on the cell surface, did not respond in the same way to either vitronectin or the activating anti-αv antibody. These cells became more invasive in vitro when treated with either fibronectin, an anti-α5β1 perturbing antibody, or an anti-α5 integrin subunit antibody. These changes were accompanied by increases in the expression and extracellular levels of MMP-2.36 Together, these results suggested that integrin interactions could result in the generation of signals which contribute to changes in cellular behavior and pathological phenotype.

rMaspin Suppresses Breast Cancer Cell Invasiveness In Vitro22

Although the role of maspin as an inhibitory or non-inhibitory serpin remains unclear, we examined how maspin might function in modulating tumor cell aggressiveness by treating the human breast cancer cell line MDA-MB-435 with recombinant maspin (rMaspin), then measuring potential changes in their invasive ability in vitro using the Membrane Invasion Culture System (MICS) model.3537 Treatment of these cells with rMaspin (20 μg/ml for 24 hours) resulted in a 43% decrease in their ability to invade through a fibronectin/gelatin defined matrix barrier in the MICS assay. Based on previous observations that maspin acts at the cell surface, we evaluated the integrin profiles of MDA-MB-435 cells before and after treatment with rMaspin. Using fluorescence activated cell (FAC) analyses, we determined the percent mean fluorescence of 5,000 cells labeled with the appropriate primary anti-integrin subunit antibody and FITC-conjugated secondary antibody, and corrected for autofluorescence and nonspecific binding by the secondary antibody. We compared the resulting percent mean fluorescence of the treated and untreated cells and found that there was a significant increase in expression of the α3- and α5-containing integrins (21% and 49%, respectively), a modest increase in the α4-containing integrin (7%), and decreases in the α2-, α6-, αv- and β1-containing integrins (11%, 15%, 23% and 21%, respectively) in response to treatment with rMaspin. Northern blot analysis corroborated the FAC analysis for the α5-integrin subunit and demonstrated a 30% increase in the α5-integrin subunit mRNA in the rMaspin-treated cells, although no change was seen in the mRNA for the α3 subunit. Furthermore, immunofluorescence microscopy demonstrated an increase in distribution of the α5β1 integrin (classical fibronectin receptor) on the rMaspin treated cells, and a change in cell morphology to a more epithelial-like phenotype compared to the more fibroblastic phenotype displayed by the control cells.22

To determine whether the rMaspin-induced change in integrin profile was biologically significant, cellular adhesion and in vitro invasion assays were performed on the control compared to the rMaspin treated cells. Cells treated with rMaspin were 27% more adhesive to fibronectin than the untreated control cells, but showed little-to-no change in adhesion to laminin, vitronectin, collagen IV or collagen I. Furthermore, pretreating the rMaspin-treated cells with a function blocking antibody to the α5β1 integrin prior to plating in the adhesion assay prevented the induced increase in adhesion. Cells treated with rMaspin were also 43% less invasive (in vitro) through a fibronectin/gelatin matrix compared to the untreated control cells. Cells pretreated with a function blocking antibody to the α5β1 integrin for 15 minutes before the assay resulted in a recovery of the cells' invasive potential to within 9% of the control cells' invasiveness. As a control for the specificity of the α5β1/rMaspin interaction, the invasion assay was repeated using a laminin/gelatin matrix barrier with and without a blocking antibody to the α6-integrin subunit. Cells treated with rMaspin were 27% less invasive through the laminin/gelatin matrix than the untreated control cells, and addition of a blocking anti-α6 antibody did not change this result.

While maspin occurs in normal breast tissue and normal breast cells in culture, it is not present in breast cancer tissue and breast cancer cells in culture. The results presented here suggest a biologically relevant explanation concerning the mechanism(s) by which addition of rMaspin inhibits the maspin-deficient human breast cancer cell line MDA-MB-435 from invading in vitro. Addition of rMaspin to these cells resulted in a decrease in their in vitro invasiveness coincident with an increase in their cell surface expression of the α5-containing integrin, and an increase in their adherence to fibronectin. These results were corroborated by Northern blot analysis, which showed an increase in mRNA for the α5-integrin subunit in rMaspin treated cells, and by the observations that addition of a blocking antibody to the α5β1 integrin 1) inhibited their increased adhesion to fibronectin, and 2) facilitated their ability to invade through the fibronectin/gelatin matrix in vitro at a rate equivalent to the untreated control cells. These observations also support previous observations that there is a competitive reversal of rMaspin action in breast cancer cells treated with an RGD peptide known to block integrin function.37 Together, these results indicate a functional change in the response of MDA-MB-435 cells to their environment which can be induced by rMaspin and involves both transcriptional and translational processes in the cells. A significant observation from these studies is that the fibroblastic-like, invasive and metastatic cells appear to assume a more benign, epithelial-like morphology in response to rMaspin.22 While E-cadherin expression did not appear to increase in response to rMaspin, this could indicate that the actual junctional adhesion complexes had not formed during the 24 hour period of these observations. Although rMaspin treatment also caused a decrease in the cell surface expression of the α2-, α6-, αv- and β1-containing integrins, a change was not seen in the cells' ability to adhere to any of the ligands normally associated with these integrins. Furthermore, the inability of a blocking antibody to the α6-subunit to restore the invasiveness of the rMaspin treated cells through the laminin/gelatin matrix barrier in the in vitro invasion assay suggests that there is a specific relationship between the α5-containing integrin and rMaspin which apparently does not exist with the other integrins.

In summation, these observations indicate that rMaspin reduces the invasive potential of MDA-MB-435 cells by altering their integrin profile which changes how they perceive and interact with their extracellular environment. rMaspin treated cells become more adherent to fibronectin-containing biological substrates and are subject to phenotypic changes that result in the conversion from an invasive, fibroblastic phenotype to an epithelial-like, less invasive phenotype.

Role of MMP-2 in the Suppression of Breast Cancer Cell Invasiveness In Vitro by Maspin

As described above, MDA-MB-435 cells treated with rMaspin were less invasive in vitro, more adherent to fibronectin, and expressed a significant increase in the α5-containing integrin on their cell surface. Given our previous work which demonstrated a change in the expression and extracellular levels of MMP-2 in response to perturbation and ligation of different integrins on human melanoma cells coincident with the cells' ability to invade in vitro,35,36 we examined whether treatment with rMaspin altered the expression and extracellular levels of MMP-2 in MDA-MB-435 cells. Cells plus or minus 20 μg/ml rMaspin were plated in serum-free medium on laminin, fibronectin, collagen IV, collagen I or Matrigel. After 24 hours, the media was removed from the cells, centrifuged to remove cells and cellular debris, and the supernatants analyzed by substrate incorporated sodium dodecylsulfate polyacrylamide gel electrophoresis (i.e., SDS-PAGE zymography). The resulting zymograms were digitized, and the images analyzed to determine pixel densities of the bands relative to the control samples normalized to a value of 1.00. As shown in Figure 1, there was a 47% decrease in MMP-2 (pro-enzyme) activity in the sample plated on fibronectin and treated with rMaspin, and relatively little change in any of the other samples. Northern blot analysis corroborated this result and revealed a 35% decrease in mRNA for MMP2 in the cells treated with rMaspin and plated on fibronectin. In order to determine if the α5β1 integrin is involved in modulating the expression of MMP-2, this experiment was repeated on fibronectin in the presence of either an RGD peptide known to block the function of α5β1 and other RGD-binding integrins, or an RGE peptide (non-blocking) control peptide. As shown in Figure 2, treatment with the RGD peptide abrogated the decrease in MMP-2 activity induced by rMaspin while the RGE peptide did not. This result suggests that rMaspin is modulating the expression of MMP-2 in MDA-MB-435 cells through an integrin signaling pathway, and in light of our previous observations, most probably via the α5β1 integrin.

Figure 1. rMaspin reduces the extracellular levels of pro-MMP-2 in MDA-MB-435 cells plated on fibronectin.

Figure 1

rMaspin reduces the extracellular levels of pro-MMP-2 in MDA-MB-435 cells plated on fibronectin. MDA-MB-435 cells were plated in serum-free medium onto laminin, fibronectin, collagen IV, collagen I or Matrigel matrices plus or minus 20 μg/ml of (more...)

Figure 2. An RGD peptide abrogates the decrease in MMP-2 activity induced by rMaspin in MDA-MB-435 cells cultured on fibronectin.

Figure 2

An RGD peptide abrogates the decrease in MMP-2 activity induced by rMaspin in MDA-MB-435 cells cultured on fibronectin. MDA-MB-435 cells were plated in serum-free medium on fibronectin, plus or minus rMaspin, plus or minus RGD or RGE peptides. After 24 (more...)

Maspin Re-expression Alters Cell Morphology, uPAR and α 5 β 1 Integrin Distribution on Human Breast Cancer Cells

As an extension of this work, MDA-MB-435 cells were transfected with maspin cDNA and their morphology, in vitro invasiveness and distribution of the α5β1 integrin and uPAR examined. Re-expression of maspin caused these cells to appear less fibroblastic and assume a more epithelial-like phenotype (Fig. 3A and B sham transfected controls compared to C and D maspin transfectants). In addition, the α5β1 integrin appeared widely distributed throughout the more extensive filopodial and lamillapodial network projections observed in the T6 transfectant (Fig. 3C) compared to the Nn-3 control neo/sham transfectants (Fig. 3A). While uPAR appeared clustered polarly in the perinuclear region of the Nn-3 cells (Fig. 3B), it displayed a uniform perinuclear distribution pattern in the T6 cells (Fig. 3D). Western blot analysis of whole cell lysates from maspin transfected T6 and Tn-15 cells cultured on either plastic or fibronectin confirmed that these cells expressed the maspin protein compared to the control Nn-12 sham transfected cells which did not express maspin when cultured on either surface (Fig. 4). As shown in Figure 5, T6 and Tn-15 cells were 46% and 41% less invasive in vitro (respectively) than the control neo/sham transfectants Nn-3 and Nn-12.

Figure 3. Immunocytochemical analysis of Nn-3 (neo/sham) and T6 (maspin) transfected MDA-MB-435 cells using anti-α5β1 and anti-urokinase plasminogen activator antibodies.

Figure 3

Immunocytochemical analysis of Nn-3 (neo/sham) and T6 (maspin) transfected MDA-MB-435 cells using anti-α5β1 and anti-urokinase plasminogen activator antibodies. Nn-3 (A, B) and T6 (C, D) transfected cells were cultured on glass coverslips (more...)

Figure 4. MDA-MB-435 cells transfected with maspin express the Mr 42,000 maspin protein.

Figure 4

MDA-MB-435 cells transfected with maspin express the Mr 42,000 maspin protein. The T6 and Tn-15 maspin transfectants and Nn-12 neo/sham transfected cells were plated on plastic or fibronectin for 1 hour. The cells were then scraped into RIPA buffer and (more...)

Figure 5. MDA-MB-435 cells transfected with maspin are less invasive in vitro through a fibronectin/gelatin matrix than neo/sham transfected cells or untreated control cells after 24 hours.

Figure 5

MDA-MB-435 cells transfected with maspin are less invasive in vitro through a fibronectin/gelatin matrix than neo/sham transfected cells or untreated control cells after 24 hours. MDA-MB-435 untreated control cells and Nn-3 and Nn-12 neo/sham transfected (more...)

Conclusion

It is clear from the information presented in this review that maspin, whether added exogenously as a recombinant molecule or transfected into a human breast cancer cell line, can regulate a cell's invasive and morphological properties, as well as the expression and extracellular levels of the invasion/metastasis associated matrix metalloproteinase MMP-2. Furthermore, this regulation appears to occur through a signaling pathway associated with the α5β1 integrin. In light of the recent report that recombinant maspin inhibited plasminogen activation to plasmin associated with uPA (but not tPA) activity at the cell surface of the prostate carcinoma cell line DU-145,10 and our observation that both uPAR and the α5β1 integrin displayed an altered distribution pattern on T6 maspin transfected cells, these data strongly suggest that maspin's regulation of the pathogenic phenotype extends past the control of just MMP-2 expression and extracellular levels, and involves the regulation of the plasminogen activator/plasmin system as well. This is highly significant since the plasminogen activator/plasmin system is not only important for intravascular thrombolysis, but has also been implicated in the processes of angiogenesis, tumor progression and inflammatory reactions important to host defense and wound repair.24 Collectively, these results identify unique and novel interactions that occur between maspin and breast cancer cells, and begin to reveal how these interactions function to regulate tumor cells aggressiveness. The next phase of this research will begin an examination of specific integrin and uPAR/PAR signaling pathways that might be involved in and/or facilitate the effects that maspin has on cells. As a result of this work, it is hoped that a better understanding of how maspin functions will lead to the identity of specific targets that will prove useful for the diagnosis and therapeutic intervention of breast and prostate (and possibly other) cancers.

Acknowledgements

This work was supported by the NIH/NCI grant CA75681 to MJCH.

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