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Review Article

Role of Integrins in Cancer: Survey of Expression Patterns

Molecular Medicine, Wadsworth Center, New York State Department of Health, Albany, New York 12201–0509

	Abstract

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Tumor cells are characterized by uncontrolled growth, invasion to surrounding tissues, and metastatic spread to distant sites. Mortality from cancer is often due to metastasis since surgical removal of tumors can enhance and prolong survival. The integrins constitute a family of transmembrane receptor proteins composed of heterodimeric complexes of noncovalently linked and ß chains. Integrins function in cell-to-cell and cell-to-extracellular matrix (ECM) adhesive interactions and transduce signals from the ECM to the cell interior and vice versa. Hence, the integrins mediate the ECM influence on cell growth and differentiation. Since these properties implicate integrin involvement in cell migration, invasion, intra- and extra-vasation, and platelet interaction, a role for integrins in tumor growth and metastasis is obvious. These findings are underpinned by observations that the integrins are linked to the actin cytoskeleton involving talin, vinculin, and -actinin as intermediaries. Such cytoskeletal changes can be manifested by rounded cell morphology, which is often coincident with tumor transformation via decreased or increased integrin expression patterns. For the various types of cancers, different changes in integrin expression are further associated with tumor growth and metastasis. Tumor progression leading to metastasis appears to involve equipping cancer cells with the appropriate adhesive (integrin) phenotype for interaction with the ECM. Therapies directed at influencing integrin cell expression and function are presently being explored for inhibition of tumor growth, metastasis, and angiogenesis. Such therapeutic strategies include anti-integrin monoclonal antibodies, peptidic inhibitors (cyclic and linear), calcium-binding protein antagonists, proline analogs, apoptosis promotors, and antisense oligonucleotides. Moreover, platelet aggregation induced by tumor cells, which facilitates metastatic spread, can be inhibited by the disintegrins, a family of viper venom–like peptides. Therefore, adhesion molecules from the integrin family and components of angiogenesis might be useful as tumor progression markers for prognostic and for diagnostic purposes. Development of integrin cell expression profiles for individual tumors may have further potential in identifying a cell surface signature for a specific tumor type and/or stage. Thus, recent advances in elucidating the structure, function, ECM binding, and signaling pathways of the integrins have led to new and exciting modalities for cancer therapeutics and diagnoses.

	Introduction

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
The integrin superfamily consists of a major class of transmembrane glycoproteins that mediate cell-matrix and cell-cell adhesion (1). Extracellular matrix (ECM) molecules serve as ligands for the integrins and are crucial for the orderly development of tissues during morphogenesis, maintenance of adult tissue, wound healing, and oncogenesis (2). Cell adhesion interactions with the ECM are mediated through the heterodimeric - and ß-chains of the integrins (3). Detailed studies of integrin expression in benign breast lesions (fibroadenoma or papilloma) and mammary adenocarcinomas show patterns of integrin type and distribution that are altered from normal breast tissue. Since altered expression of the various integrins occurs during tumor growth and progression, the integrins and their associated proteins could be potential targets for cancer diagnosis and therapy. Ironically, it is this altered integrin expression that may further contribute to the invasive and metatastic potential of tumor cells.

The objectives of this review are twofold: first, to organize, collate, and discuss recent advances concerning the role of integrins in cancer, and second, to survey integrin expression patterns during tumor transformation, growth and progression, invasion/metastases, angiogenesis, and apoptosis of various malignancies with special reference to breast cancer. Since this review was not intended to be encyclopedic, the reader is directed to the many reviews cited as the first several papers in the reference section. Comprehensive details on the structure, function, and physicochemical properties of integrins cannot be considered here. However, the variable names and classification schemes used in this rapidly advancing field justify a review that attempts to link structural descriptions with physiological data.

	Integrins and Their Ligands

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
The integrins are composed of a large family of heterodimeric integral cell surface receptors that mediate cell-to-extracellular matrix (ECM) and cell-to-cell interactions (1-3). Derangement of integrin expression may be responsible for a number of aberrant cellular activities during tumor onset, progression, and metastatic dissemination (4-6). ECM molecules play an important adjunct role in ontogenetic development, maintenance of adult cell physiology and tissue repair, hyperplastic growth, and tumor development (7-9). The integrins, composed of - and ß-chain heterocomplexes, serve as integral cell membrane receptors that form focal adhesion contacts with various ECM-ligands (i.e., fibronectin, laminin, vitronectin, the collagens, thrombospondin, entactin, fibrinogen, intercellular adhesion molecule (ICAM), and the vascular cell adhesion molecule (VCAM) (2, 8) (Tables I and II). Recent investigations have further linked integrin interactions with cytoplasmic cytoskeletal filament-associated proteins such as actin, vinculin, talin, -actinin, paxillin, and divalent cation-dependent proteins such as calreticulin (2, 4). (Table I and Fig. 1).

View larger version (45K): [in this window] [in a new window]   Figure 1.   A diagramatic representation of a universal integrin receptor heterocomplex is depicted. The - and ß-chains are displayed as noncovalently linked parallel subunits with insertions through the cell membrane. The long extracellular domains of both chains are contrasted with their short intracytoplasmic subunit chains. The binding pocket (BP) is depicted as the stippled portion of the opposing sides of both the - and ß-chains. The various extracellular matrix protein ligands are contained within the rectangular box at the top of the diagram. An RGD-containing peptide (adhesion inhibitor) is interposed between the ligand and the integrin binding site. Nonactivated integrins are thought to contain divalent cation salt bridges; the cations are then extruded upon binding of the integrin to the ECM-ligand. Linkage of signal transduction pathways via the ß- and/or -chains are pictured in schematic fashion at the bottom of the diagram. Symbols: NH2, amino terminal end of the peptide; COOH, carboxy terminal end of the peptide. , binding pocket (interface) composed of ß- and -chain lengths; I-, domain of the -chain that binds collagen; S-S, disulfide bridges; Ca++, divalent cations such as calcium, magnesium, manganese; , glycosylation sites, •, phosphorylation site.

It has been proposed that the N-terminal half of the integrin -chain is folded into a ß-sheet propeller motif that contains seven weak amino acid (FG-GAP) sequence repeats (11). The ß-sheets (secondary structure) are thought to be arranged in a toroidal geometric configuration around a central axis with Mg⁺⁺ ions bound to the upper faces of the propeller (blades) and Ca⁺⁺ ions bound to the lower faces. Subsequent studies have led to the proposal that ligand binding occurs on the upper surfaces of the propeller blades within the FG-GAP repeats as previously demonstrated by cross-linking to ligands and site-directed mutagenesis experiments (12, 13).

In contrast to their extracellular domains, the intracellular domains of both the - and ß-subunits are relatively short-chain segments (except ß4) following their transmembrane insertion. The short ß-cytoplasmic tails contain regions capable of binding to cytoskeletal-associated proteins that link the integrins to the actin cytoskeletal system (Table I and Fig. 1). In comparison to the ß-chains, little is known concerning -chain binding to cytoplasmic-associated proteins other than a calreticulin association that regulates calcium transmembrane channel influx (14). These cytoplasmic peptide tails could serve as prime targets for the development of therapeutic strategies aimed at uncoupling or disrupting signal transduction from the cell membrane to the nucleus and vice versa (15, 16).

Ligand binding of integrins is thought to be controlled by a mechanism requiring either a) receptor clustering alone; b) ligand occupancy plus receptor clustering; or c) clustering, ligand occupancy, and tyrosine kinase activation (17). The process of binding ligands to the integrins involves outside-in signaling initiated by receptor clustering accompanied by conformational changes in the /ß chains culminating in an affinity modulation for the ligand (18). In the course of this process, adhesion plaques form at the cytoplasmic face of the cell membrane that serve as focal points for recruitment of proteins (talin, veniculin, paxillin, etc.) to provide cascade interfaces for actin, G-proteins, tyrosine kinases, and transcription factors (see below and Fig. 1).

	The Integrin-ECM Relationship

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Studies of ECM interaction with cells via their integrin receptors have shown that the integrins function as bidirectional transducers of extra- and intracellular signals (19, 20). The regulation of cell proliferation, differentiation, survival, and immediate gene expression is influenced by integrin mediation of cell interaction with the ECM. The disruption of epithelial and endothelial cell interactions with the ECM induces programmed cell death, whereas fibroblast integrin adhesion can affect cell cycle activities by influencing cyclin-A and D expressions (21, 22). In addition to signal transduction to the actin cytoskeleton, the cytoplasmic domains of the integrins interact in cascade fashion with protein kinases, calcium-binding proteins, focal adhesion kinases, Na⁺/H⁺ antiporters, tyrosine and MAP kinases, and transcription nuclear factors such as NFB and API (23, 24). Recent reports that some of the signaling activated by integrins and growth factor receptors shares similar pathways suggest the possibility of cross-talk between ECM-induced and growth factor–induced (hormones, cytokines, etc.) signal transduction (15, 25). It has been observed that many members of the integrin subfamilies bind to more than one ECM ligand and demonstrate specificity in a cell-dependent fashion (26, see also Table II). The reason for the redundancy in ligand specificity is unclear; however, cell cooperative interactions and transmission of different information from the environment remain viable rationales. Correspondingly, the inhibitory effect on cell adhesion by individual anti-integrin antibodies is rarely reported as 100% (27). This again is likely due to the presence of multiple integrins on the cell that recognize the same ligands, thus bestowing overlapping specificities. Such backup systems are common in nature to provide failsafe systems for cell growth, homeostasis, and development.

	The Biodistribution of Integrins

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
The phylogenetic expression of cellular integrins and their tissue distribution appear to be universal from fungi to mammals (Table I). In fact, the sequences and genes of the Drosophila integrins are about as closely related to chordates as those comprising the most divergent vertebrate subunits (1, 8). The cell and tissue distribution of the integrins is indeed widespread. Integrins have been found on virtually every cell and tissue studied (28). During development, integrins are ubiquitously expressed. They are involved in regulating morphogenetic cell movements and migration; they are especially numerous during gastrulation, neurulation, and histogenesis (2). Integrin expression levels tend to decrease gradually during differentiation as adult structures emerge. The integrins further serve as receptors in inflammation, wound healing, and thrombotic events such as platelet aggregation (4, 6). In this regard, integrin antibodies and RGD peptides have been used to prevent or treat thrombus formation and related hemostatic events (29, 30). Finally, integrins are able to mediate adhesive events during various cancer stages such as malignant transformation, tumor growth and progression, invasion and metastasis, and apoptosis, as discussed below.

	Integrin Signal Transduction

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Signal transduction in the course of integrin functioning is known to be bidirectional; that is, two-way signaling occurs from outside-to-inside and from inside-to-outside (22, 31, 32). The integrins must be activated to undergo adhesion and binding to the ECM. Activation of integrins (33) occurs by local stimuli such as soluble mediators (hormones, cytokines, growth factors, etc.) or by solid interfaces (ECM or other cells). Thus, cell activation may involve adhesion by clusters of various stimulated integrins culminating in signals triggered by local events in the cellular environment (i.e., thrombogenic agonists, antigen stimulation/processing, and T-cell activation (26). Equally important, integrins must then be inactivated to avoid cell adhesion and ECM binding at inopportune times and locations. Inappropriate adhesion can culminate in unwanted thrombosis and inflammation whereas adhered cells need to detach to undergo mitosis or migration (34, 35). It is obvious why cells require finely tuned attachment-detachment signals mediated by integrin interaction during rapid periods of flux such as embryogenesis and histogenesis (2). One may deduce that normal adult cells have homeostatic control of such signaling events whereas malignant cells may have lost these regulatory mechanisms of growth/no growth maintenance. Most probably, chemical factors that promote reversible forms of integrin inactivation, within controllable limits, will provide a potential source of antiproliferative agents for cancer therapy. Fetal proteins, such as -fetoprotein, that are associated with morphogenetic movements and migration could be a valuable source of such agents (36).

	Cell Attachment and Spreading

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Most cells (except blood cells) require attachment and subsequent spreading on the ECM substrate for proper growth, function, and survival (27). In tissue formation, cells are attached to each other and to the meshwork of the ECM, mediated by the family of integrins. Normal epithelial cells often undergo inappropriate apoptosis when deprived of the ECM (28). Cell growth and survival on subtratum (matrix) attachment has been termed anchorage dependence (35, 37). In cell culture, this linkage occurs at specialized membrane structures referred to as focal adhesions consisting of clusters of integrins that are firmly bound to the ECM interface (31, 37). More loosely bound focal contacts, characteristic of epithelial tissues, probably allow for some flexibility and cell movement. These integrin clusters serve as attachment points for intracellular actin stress fibers on the cytoplasmic surface of the plasma cell membrane, thus influencing cell shape. It is also at the focal point (see above) that integrins can trigger signaling pathways that cross-talk with growth factors, cytokines, and kinase pathways (38), the latter of which include the focal adhesion kinase (FAK) (39, 40). Such cascade interactions are reportedly linked to G-proteins and the tyrosine kinases of the src family. It has also been reported that tissue-derived cells that spread and then flatten appear to thrive, whereas cells that retain a rounded form fail to thrive (41). Depending on the integrin heterodimer involved, differing antiapoptotic effects of cell spreading have been delineated and described (35, 39, 41). These investigations revealed that following the ECM determination of cell morphology, cell shape, was a major factor in determining subsequent cell growth and survival. It becomes evident that therapeutic intervention at the integrin–ECM interface might provide a means of altering the cell signals responsible for the balance between cell death and cell survival.

	Cation-Dependent Processes

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Calcium influx and mobilization appear to be constituent parts of the intracellular signaling pathways associated with integrin ligation and occupation (7, 23). The position of the ECM-ligand binding site on the integrins has been deduced from chemical cross-linking data and has been localized to the four divalent cation-binding repeat regions of the integrin subunits (7). These Ca⁺⁺ binding regions on the -chain combine with amino acids 100–200 on the ß-chain to contribute to the interface of the ligand binding pocket (BP) (see Fig. 1). The binding of the integrins to their ligands (ECMs) is thus a cation-dependent process, which generally occurs with low binding affinities (10^–6 M). The presence of the divalent cations maintains the integrity and form of the BP, but the cations are extruded in the course of ligand binding and occupancy. Integrins recognize specific amino acid sequences in their ligands, such as RGD and related sequences (Table II) found in fibronectin, fibrinogen, thrombospondin, vitronectin, laminin, and the various collagen types (9, 42, 43). Other amino acid sequences such as DGEA, EILDV, GPRP, and REDV also serve as recognition sites for these and other ECMs, including ICAM and C3B (32). Calcium, and to a lesser extent magnesium (Mg⁺⁺), provide the cation requirements for ligand binding of the ECMs to integrins (13, 43, 44). Thus, Ca⁺⁺ and Mg⁺⁺ are potential physiological regulators of integrin-mediated cell adhesion via ECM-ligation. The two cations can exert different and/or opposite effects on the binding function of the various integrins, inhibiting binding in one instance and enhancing it in another. It is of special interest that manganese (Mn⁺⁺) at low concentrations also fulfills the divalent requirement for cell spreading on fibronectin (42).

T lymphocytes bind to ICAM-1 through LFA-1 complexes. Mn⁺⁺ can alter the conformation of the LFA-1 to favor ligand binding (44) whereas Ca⁺⁺ ions serve to maintain LFA-1 in an inactive state. Calcium is also required for the establishment of multilayered basement membranes that contain laminin and entactin (45, 46). Both Mg⁺⁺ and Ca⁺⁺ form salt bridges that stabilize the -ß-integrin binding complex. These structures influence both the ECM binding activity and proteolytic susceptibility of the integrin complex (23, 43, 44). Although these cation binding regions of the integrin are very similar to the Ca⁺⁺ binding loop in the EF band motif of calmodulin, these sequences more closely resemble the bacterial galactose-binding protein in lacking one of the conserved coordinating side chains (42,47). Since a glutamate (Glu) is missing in the Ca⁺⁺ binding loop of the eukaryotic homologs, integrin binding to the ECM might alter the receptor conformation to accommodate the missing Glu. In the presence of high Mn⁺⁺ or Mg⁺⁺, this conformation could be supplied by the RGD sequence, which resembles the lysine-isoleucine-glycine (KIG) of the galactose binding protein.

	Calcium-Related Proteins; Calreticulin

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Calcium ions constitute a second messenger system that encompasses one or more of the following processes: a) regulation of metabolic pathways; b) synthesis and release of hormones and neurotransmitters; c) muscle and nonmuscle cell motility; d) lipid and carbohydrate metabolism; e) programmed cell death; and f) mitosis (23). A stringent requirement for cytosolic Ca⁺⁺ at submicromolar levels is maintained by Ca⁺⁺ buffering proteins in an intracellular system of storage and transport pathways. Such buffering proteins may include calmodulin, calsequestrin, calponin, calbindin, and calreticulin (48). Although the major Ca⁺⁺ binding/storage protein in the sarcoplasmic reticulum (ER) is calsequestrin, the major nonmuscle ER Ca⁺⁺ binding protein is calreticulin (CRT), which is especially abundant in smooth muscle and liver (45, 48, 49). The CRT molecule provides both high affinity/low capacity and low affinity/high capacity Ca⁺⁺-binding sites and, thus, is well suited for Ca⁺⁺ sequestration and deposition within the cell (49).

There is recent evidence that CRT, a 46-kDa polypeptide, is a highly conserved, ubiquitously expressed Ca⁺⁺ binding protein of the cytosol, which may serve multiple functions (50, 51). It constitutes a portion of the systemic lupus antigen nucleoprotein complex that acts as a human auto-antigen (52). Additional isoforms exist at various cell locations including the cell surface membrane, the nucleus, and the ER. An additional form circulates as a plasma anticoagulant protein (53, 54). Although most CRT isoforms contain a terminal KDEL for ER retention, CRT appears capable of shuttling between the cytosol, the ER, and the nucleus (55-57). One form of CRT is found complexed with the cytoplasmic domains of all integrin -subunits bound through the integrin sequence motif KXGFFKR (58, 59). A similar amino acid sequence (KXFFKVR, where X is G, A, or V) is also present in the DNA-binding domain (zinc fingers) of all known members of the steroid receptor superfamily (60-62). Amino acids in this region of the nuclear receptors make direct contact with nucleotides of the hormone response element since the receptors themselves are transcription factors. CRT has been demonstrated to inhibit the transcriptional activities of the retinoic acid (63), androgen (61), vitamin D₃ (64), and glucocorticoid receptors in vitro and in vivo (62) and the peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in vitro (65). Thus, CRT can act as a modulator of the regulation of steroid-inducible gene transcription and expression. It would follow logically that CRT may then serve as a signal transduction modifier between the cell membrane, the cytoplasm, and the nucleus by virtue of its binding to the -integrin subunit (66). Interruption or uncoupling of this transduction signal could influence cell growth (mitosis) and differentiation, and possibly, tumor transformation and progression.

Previous reports have indicated further that CRT is an essential modulator of both integrin-mediated calcium adhesive functions and integrin-initiated signaling (65, 66). Signals can be transduced to transcription factors by two main groups of receptors: 1) integral plasma membrane receptors; and 2) the intracellular nuclear steroid/thyroid hormone receptor superfamily. Although the classical activation pathway of the nuclear receptors is via direct transmembrane diffusion of the hormone into the cytoplasm, an alternate pathway of nuclear receptor activation has been identified and described (67). This alternate pathway involves a nonligand activation of the steroid receptors by signals transduced by growth factor receptors on the cell surface (67, 68). A level of further control can be interspersed in this pathway by direct protein-to-protein interactions of the receptors with other cytoplasmic transcription factors such as AP-1 (fos/jun) and NfB (69, 70). Thus, CRT bound to the -subunit of the integrins has been proposed to serve as a second messenger in the alternate pathway based on the above postulates. If that is the case, CRT and proteins of its associated pathways might be used as potential targets for cancer therapy/treatment.

	Disintegrins and Tumor-Induced Platelet Aggregation

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Recently, a wide array of true viper and pit viper venoms has been demonstrated to contain peptides, termed disintegrins, that block integrin function and are potent inhibitors of platelet aggregation (71, 72). Such polypeptides are readily distinguished from the cobra-like venoms, which act as neurotoxins. Most disintegrins contain the RGD cell attachment recognition sequence, are rich in cysteine, and function to block platelet aggregation. Inhibition results from blocking the binding of the GPIIa/IIIb platelet-integrin complex to ECM proteins such as fibrinogen and von Willebrand's factor (73-75). Since most disintegrins possess an RGD sequence, they are capable of further inhibiting the adhesive functions of other RGD-dependent integrins such as _vß₃ and _vß₅ (vitronectin receptors) and ₅ß₁, a fibronectin receptor (76, 77). However, by comparison with the integrins, other amino acid adhesion sequences, such as Lys-Gly-Asp, may be operational in the disintegrins. The disintegrins may represent models for designing novel and potent compounds with therapeutic value in the inhibition of platelet aggregation and the blockage of the tumor-induced platelet aggregation stage of metastasis (see below), due to their broad spectrum of reactivity with many integrins.

Tumor cell–induced platelet aggregation (TCIPA), as a required component of metastasis, was first described by Gasic in the early 1970s (78). Tumor cells in the vasculature are frequently observed in complexes with platelets and this association, together with the hypercoagulable state of malignant disease, appears to be essential for successful metastasis (79, 80). The ability of tumor cells to induce platelet aggregation is widespread among cancers including breast carcinoma, colon adenocarcinoma, lung carcinoma, melanomas, and others (81, 82). Platelet participation in the metastatic process is thought to result from a) direct binding of platelets to tumor cells, and b) the release of soluble inducer agents from the tumor cells. These agents would include the classical platelet aggregation activators such as ADP, cathepsin B, thrombin-like proteinases, collagen, and tissue factor-generated thrombin (83). Thus, platelets may act to facilitate all the intermediate steps of transvascular metastasis including tumor cell retention and arrest, subendothelial interaction, and extravasation from the microvasculature. Blockage at these steps might retard or reduce tumor cell metastasis.

The disintegrins, purified components from viper snake venoms, contain the RGD and related adhesion sequences and bind with high affinity to the surface of platelets, affecting aggregation inhibition. Recently, two disintegrin antiplatelet peptides, naturally occurring trigramin and rhodostomin, were shown to be 6,000–18,000 times more potent than synthetic RGD-peptides in the inhibition of TCIPA (79, 82). However, the two disintegrins employ different adhesion inhibition pathways to achieve the TCIPA blockade. Trigramin is a specific antagonist of platelet-to-platelet membrane GPIIb/3a integrin interaction with breast cancer cells, whereas rhodostomin inhibits platelet aggregation by antagonism of the GPIIb/3a-fibrinogen interaction with colon adenocarcinoma cells (79). With breast, prostate, and colon cancer cells, TCIPA, induced by tissue factor activation of thrombin, could be inhibited by both trigramin and rhodostomin (79, 80, 82). Thus, the disintegrins represent a class of chemicals whose therapeutic potential for metastasis has not yet been fully realized.

	Tumor Transformation

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Malignant transformation is characterized by disruption of cytoskeletal organization, decreased adhesion, and altered adhesion-dependent responses. Studies of integrin expression in transformed cells suggest that various integrin subunits may contribute either positively or negatively to the transformed cell phenotype (84). Changes in the expression of fibronectin- binding integrins have been observed in some types of transformed fibroblasts, whereas other changes in integrin expression have been observed among a myriad of malignant cells (85). In general, a transformed cell phenotype may contain several alterations in cell adhesion receptors (86, 87) (Table III). For example, high levels of ₅ß₁-integrin seem to correlate with low levels of transformation for certain tumors. However, increased expression of _vß₃ appear to be positively correlated with increased malignancy in melanomas (88). A consistent finding is the lack of spatial organization of integrin expression in epithelial tumors. In carcinomas, the spatial arrangement of integrins becomes quite disordered, with a diffuse and less abundant cellular distribution. These changes in integrin cell-surface distribution can affect ligand binding affinity, and correlate with a concomitant disorganization of the structure of the basement membrane itself. Reduced levels of ₅, ₃, and ₂ integrin expression have been reported in carcinomas, whereas increased levels of ₆ß₄ appear in head, neck, and skin tumors.

	Integrin Expression During Primary Tumor Growth and Progression

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

Although the expression of integrin receptors is altered in malignant compared to normal cells, most tumors maintain normal expression of at least some of their integrins. The changes in integrin expression and the cell surface distribution are specific to the tumor cell type (Tables III and IV). In one group, carcinomas of breast, prostate, and colon exhibit a loss of ₃ß₁, ₂ß₁, ₅ß₁, and ₆ß₄ integrin expression; however, the highly malignant sarcomas (osteosarcoma, rhabdomyosarcoma) overexpress the ₂ß₁ collagen receptor believed to play a role in metastasis (98, 99). In a third group, the melanomas demonstrate overexpression of the ₂ß₃ integrins, which are known to promote cell proliferation while inhibiting apoptosis (93).

In general, the loss or gain of expression of particular integrins appears to be indirectly implicated in malignant transformation and directly involved with tumor progression and metastasis. Therefore, the concept of therapeutic targeting of integrins specific to certain tumors via antibodies, peptide antagonists, and/or disintegrins may provide viable options for nontoxic therapeutic treatment modalities (see below, angiogenesis). Such therapeutic modalities might also bypass the development of drug resistance, which has emerged as a confounding factor in cancer chemotherapy.

	Tumor Cell Invasion and Metastasis

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Metastasis is a process in which cancer cells detach from the primary tumor site, enter the circulation, and extravasate at distant sites. Tumor cell entrance into the vascular system involves the loss of cell adhesion and the release of proteolytic enzymes to digest a tunnel through a number of tissue membrane barriers. The metastatic process involves making and breaking contacts with different ECM components at these sites, and may require changes in the integrins expressed by the tumor cells (Table III). Invasive tumor cells express genetic alterations that permit development of cell surface integrin-controlled signal transduction pathways that respond to paracrine and autocrine stimulation in an abnormal manner. Moreover, the most frequent cause of death in breast cancer patients can be attributed to metastasis of tumor cells and their growth at distal regions rather than the in situ effects of the malignancy at the primary site (38).

It is clear that tumor cells can migrate effectively on ECM (i.e., fibronectin) substrates, and that multiple integrins functioning in concert contribute to this process (100, 101). Clearly, cell adhesion via receptor clustering is required so that cells can pull themselves along a migration path. Integrin clustering greatly influences ECM binding affinity. Chemical agents that modulate cell adhesion could alter cell migration, and thereby, cell invasiveness. Thus, the overall process of invasion involves the adhesion of tumor cells to basement membrane matrices, partial proteolytic digestion of basement membrane layers, followed by cell penetration (migration) through the disrupted membranes. Interestingly, _vß₃ integrin colocalizes with the ECM metalloproteinase-MMP2 on the surface of invasive melanoma cells thereby facilitating tumor cell invasion by degradation of the ECM (102).

Currently, anti-integrin antibodies, disintegrins, and synthetic peptides have been reported to be effective antimetastatic agents. The antibodies and peptides function by preventing clustering of the receptors, occupying the receptors at the sites to which ligands attach, and inducing conformational subunit chain alterations (see Integrins and Their Ligands). Such agents have a potential for clinical treatment (20). In addition, blocking of receptors by monoclonal antibodies or synthetic peptides may also influence wound healing, wound contraction, and angiogenesis (30, 103). The RGD-directed integrins, for example _vß₃, have been demonstrated to be essential components of newly developing capillaries, both in granulation tissue (inflammation) and the developing stroma of tumors. Blocking angiogenesis is thus a prime objective for the interference and regression of tumor growth.

Blocking the binding of tumor cells to platelets is also regarded as a potential method to inhibit metastasis (as described in Disintegrins and Tumor-Induced Platelet Aggregation). Tumor cell attachment to platelets is an early stage in increased expressions of vascular invasion and transudation (6, 32). Among the integrins, ₄ß₁ initiates the growth and spread of melanoma cells (27, 32). ₅ß₁ and _vß₃ are expressed in advanced melanoma and metastases suggesting that integrins may have prognostic value (Table III). In human melanoma patients, the expression of increased ₄ß₁ together with decreased ₆ß₁ significantly correlate with the occurrence of metastases (26, 93). Thus, the correlation of the expression and derepression of integrins coupled with the use of anti-integrin antibodies (i.e., anti-₆ß₁ integrins for melanoma), disintegrins, and peptides such as RGD and YIGSR suggest that treatment regimes for specific cancers may be feasible.

	Tumor Angiogenesis

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
Angiogenesis, defined as the initiation and control of capillary growth, provides an exciting potential for future targets of anticancer therapy. During tumor growth, new blood vessels are recruited first at the outer tissue rim and later within the interstitial mass of the growing tumor. The increased mass of the developing tumor requires continual neovascularization since cell proliferation requires continuous supplies of both oxygen and nutrients. The limitations of oxygen and nutrient diffusion require that tumor cells induce new capillary ingrowth to form solid masses exceeding 1.0 mm³ in size (103). Anti-angiogenesis agents seem to be capable of suppressing tumor growth specifically without causing systemic toxicity. These agents also decrease the likelihood of developing drug resistance in the tumor. Toxic side effects should be minimal in nontumor tissues since normal capillary endothelial cells grow very slowly (express low levels of integrins) whereas tumor vessels multiply at rapid rates and display increased expression of integrins (30).

The control of capillary cell growth, vascular differentiation, or involution can be affected in vitro by varying the ECM coating densities for vascular endothelial cells in culture (32). Also, altering the ability of the substratum to support cell tension appears to play a role. Data suggest that ECM molecules may control capillary morphogenesis by binding specific endothelial cell surface integrins and resisting mechanical loads applied to these ECM-receptors (103). In this context, cell shape is a major factor of mechanical loading since extended cells proliferate more rapidly as ECM coating densities are increased (32). Further, ECM molecules (i.e., fibronectin) regulate capillary cell growth by altering the setpoint of the cell surface integrin Na⁺/H + antiporter systems (100, 101). Activation of antiporter exchange in control of intracellular pH is a property shared by many integrin family members, including ₅, _v,ß₁,ß₂, and ß₃ subunits (24).

Previous studies have shown that angiogenesis inhibitors, including collagen cross-linking/deposition blockers, proline analogs, retinoids, disintegrins, and steroid/heparin combinations show promise in vivo as antiangiogenic cancer therapies (103). Furthermore, inhibition of basement membrane biosyntheses was shown to prevent tumor angiogenesis. Finally, the role of integrins in tumor angiogenesis can be aptly demonstrated by _vß₃ in melanomas; differential integrin expression was found on newly formed vessels but not on pre-existing vessels (32).

Vascular cell integrins _vß₃ and _vß₅ have now been implicated in neovascularization and tumor-induced angiogenesis. In particular, _vß₃ contributes to the survival, proliferation, and metastasis of melanomas and ovarian tumors (104, 105). Since angiogenesis is a critical process for the growth and metastasis of most solid tumors, it should be feasible to devise therapeutic modalities to disrupt and uncouple signal transduction specifically and selectively in vascular tumor cells undergoing angiogenesis within tumors. Antagonists to the vascular cell integrins (monoclonal antibodies, peptides inhibitors, antisense ß₃ and ß₅ oligonucleotides) cause regression of pre-established human tumor xenografts in animals and may ultimately prove effective in human patients (106, 107). Thus, the inhibition of angiogenesis by attacking the tumor's blood supply and preventing new vessel outgrowth is one of the most promising areas of anticancer drug development that is now approaching clinical trials (108-110).

	Apoptosis in Tumor Cells

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
The term anoikis was coined to denote the specific apoptosis that occurs in cells that undergo matrix detachment (110). This anchorage-dependent programmed cell death was observed in epithelial and endothelial cells that were physically dissociated from their extracellular matrices. It was further shown that integrin-signaling via protein kinase pathways controlled both the positive and negative aspects of anoikis and that the process was reversible in vitro by rapidly replating the dissociated cells (111). Anoikis can be distinguished from necrosis by cell/nuclear morphology, internucleosomal DNA cleavage, nuclear lamina cleavage, and loss of Bcl-2. Anoikis occurs both in vitro and in vivo, preventing cells from colonizing promiscuously when detached (112). It is an important process in embryonic cells undergoing cavitation (113) and in cancer cells of low tumorigenic potential (114). Only specific - and ß- integrins appear capable of suppressing anoikis in a single cell type, demonstrating that the various integrins differ in their ability to downregulate cell death (115). It is for this reason that tumor cells might often express aberrant, substitute, or altered integrin patterns to evade and escape cell death of the anoikis type.

As discussed in the Tumor Angiogenesis section, antagonists to the integrin _vß₃ disrupt neovascularization in melanomas; this occurs by promotion of the unscheduled apoptosis of newly sprouted blood vessels (116). In human cells undergoing angiogenesis, tumor regression can be promoted by intravascular injection of cyclic peptides or monoclonal antibodies directed against the integrin receptors. Interruption of ligand binding of _v ß₃ in melanoma cells induces apoptosis in the proliferative angiogenic vascular cells, leaving pre-existing quiescent blood vessels unaffected (117). Finally, ₅ß₁ integrin was shown to prevent apoptosis of cells attached to fibronectin by activating the Bcl-2 pathway that protects against apoptosis (118).

Recent reports have further shown that components of the ECM can function as cell survival factors through the suppression of apoptosis (119). For example, ECM proteins such as fibronectin suppress apoptosis in normal human melanocytes through integrin-dependent, anchorage-dependent regulation (120). Apoptosis could be reversed in these cells by anti-₅ß₁ monoclonal antibodies and/or RGD peptides; furthermore, apoptosis was only detectable in ₅ß₁-positive human tumor cell lines (121). Such studies have suggested that fibronectin induced programmed cell death via its interaction with ₅ß₁ integrin. However, in rectal carcinomas, the laminin-binding ₆ß₄ integrins contribute to the function of epithelial cells and their oncogene-transformed derivatives (122). These studies demonstrated that activation of the ₆ß₄ integrin induced both the p21 cyclin-dependent kinases and apoptosis in its signal transduction pathway (123). Furthermore, the rectal carcinoma cells that lacked expression of the ₆ß₄ but included ₆ß₁ integrins bound laminin less avidly. In studies of canine kidney tumor cells, collagen-sepharose affinity chromatography and immunoblotting demonstrated both the presence and collagen- binding (Mg⁺⁺-dependent) activity of the ₂ß₁ integrins. Loss of this integrin class resulted in increased apoptosis, cyst formation, and other morphogenetic changes (124).

In some neuroblastomas, abrogation of cell adhesion through downregulation of integrin receptors plays a crucial role in the induction of apoptosis (124-126). In this regard, it was reported that cell growth and survival are mediated by ß₁ integrins in normal breast epithelium but not breast carcinomas (125). Using anti-ß₁ and anti-₂ antibodies, cellular binding to collagen type-I was clearly demonstrated in the normal epithelium, but was impaired or lost in breast carcinomas. Thus, the loss of proper integrin-mediated cell-ECM interaction may be crucial to breast tumor formation and cell survival. In subsequent studies employing colon cancer cells, certain patterns of integrin expression on normal and tumor cells regulated both cell proliferation and programmed cell death (124-127).

	Summary Update of Integrins in Breast Cancer

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
An important part of present day research is a focus on integrin expression patterns and their involvement in adhesion processes and signal transduction in human breast cancer. The ₂ß₁ (collagen/laminin receptor) is highly expressed on the epithelium of ductules of normal breast tissue and benign fibroadenomas (102, 126, 128-132). In contrast, markedly decreased ₂ß₁ expression together with loss of estrogen receptor expression were found on poorly differentiated breast adenocarcinoma cells. Similar but less extensive decreases were also observed with ₅ß₁ (fibronectin receptor) and _vß₃ (vitronectin receptor) integrin expression in these mammary tumors (127, 128). In comparison, highly differentiated breast adenocarcinoma cells exhibited intermediate expression levels of these integrins. Table IV further displays integrin expression patterns on various cell types in normal versus neoplastic breast tissue. Furthermore, significant downregulation of ₁, ₃, ₆, ß₁, and ß₄ subunits were observed in all neoplastic breast epithelia. These integrins have been shown to regulate anchorage-independent growth of mammary tumor cells in culture (133, 134).

A reduction in breast cancer cell contacts is also crucial for the initiation of metastatic growth, again implicating the ₂ß₁ integrin whose expression may be downregulated by oncogenes (135). The regulation of ₂ß₁ expression by oncogenes is associated with the disruption of tissue architecture that precedes invasive breast cancer. In comparison, increased or maintained expression of the ₆ß₄ integrin is predictive of a poor prognosis, especially in laminin-positive breast tumors (136, 137). In tissue-culture studies, substantial _vß₃ expression in breast tumors was positively correlated with the cell's ability to adhere and migrate, thus increasing its metastatic potential. Furthermore, the _vß₅ and _vß₁ integrins, which mediate adhesion to vitronectin, were observed to be widely distributed among a variety of breast cancer cell lines. The survival of metastatic human breast carcinoma was found to be promoted by the expression of ₆ß₁ integrin and its ligand, epiligrin, which also regulates metastatic potential (138). Finally, a reduction in the expression of breast tumor integrins has been correlated with positive lymph node status (139). These integrins include ₂ß₁, ₃ß₁, ₆ß₁, _vß₁, and _vß₅. When challenged for contact to their respective ligands, all the integrins showed significantly less adhesion potential. Such studies demonstrate a link between altered integrin expression and function in primary breast cancer cells predisposed to metastasize.

Recent studies have now shown that breast tumorigenesis depends not only on genetic constitution but also on cellular milieu factors such as cell-cell and cell-ECM contacts (140). Investigators have demonstrated that monoclonal antibodies to ß₁-integrins can block intracellular signaling, causing breast cancer cells to revert to nontumorigenic cells. The antibody-treated cells 1) stopped dividing; 2) formed cell-to-cell contacts; 3) produced an organized cytoskeleton; and 4) became polarized by secreting a basal-surface basement membrane and displaying apical surface integrin subtypes. These same cells could then be converted back to the malignant type by exposure to anti-ß₄ or anti-₆ monoclonal antibodies using a similar protocol. Thus, it is increasingly evident that breast cancer progression results not only from genetic clonal expansion (genetic constitution), but also from interactions between the cell and its microenvironment such as the ECM (141).

	Concluding Remarks

Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 
It now seems feasible that interference with integrin signaling could provide a basis for the development of treatments for cancer growth, progression, metastases, and angiogenesis. Anti-integrin antibodies and RGD and related peptides have shown promise in both tumor therapy and diagnosis. Interruption of the adhesive interaction of tumor cells may serve to arrest disease progression (142). The observations that different integrins present on various tumor types are differentially expressed during tumor transformation, progression, and metastasis, suggesting that integrins may also be prognostic markers. Agents that block or interfere with the initial attachment of integrins to ECM components, signal events leading to proliferation, protease induction, cell migration/invasion, or angiogenesis could thus constitute a formidable armamentarium of detection markers and nontoxic anticancer agents. Such antiadhesive agents may find application in the treatment of the four major classes of human diseases: neoplasia, inflammation, trauma, and infection.

	Footnotes

 
¹ To whom requests for reprints should be addressed at Division of Molecular Medicine, Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY 12201–0509.

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Top Abstract Introduction Integrins and Their Ligands The Integrin-ECM Relationship The Biodistribution of Integrins Integrin Signal Transduction Cell Attachment and Spreading Cation-Dependent Processes Calcium-Related Proteins;... Disintegrins and Tumor-Induced... Tumor Transformation Integrin Expression During... Tumor Cell Invasion and... Tumor Angiogenesis Apoptosis in Tumor Cells Summary Update of Integrins... Concluding Remarks References

 

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