Integrin Signaling: Cytoskeletal Complexes,MAP Kinase Activation,and Regulation of Gene Expression

Members of the integrin family of adhesion receptors mediate interactions of cells with the extracellular matrix. Besides their role in tissue morphogenesis by anchorage of cells to basement membranes and migration along extracellular matrix proteins, integrins are thought to play a key role in mediating the control of gene expression by the extracellular matrix. Studies over the past 10 years have shown that integrin-mediated cell adhesion can trigger signal transduction cascades involving translocation of proteins and protein tyrosine phosphorylation events. In this review, we discuss approaches used in our lab to study early events in integrin signalling as well as further downstream changes.     

Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion

The invasion of neoplastic cells into healthy brain tissue is a pathologic hallmark of gliomas and contributes to the failure of current therapeutic modalities (surgery, radiation and chemotherapy). Transformed glial cells share the common attributes of the invasion process, including cell adhesion to extracellular matrix (ECM) components, cell locomotion, and the ability to remodel extracellular space. However, glioma cells have the ability to invade as single cells through the unique environment of the normal central nervous system (CNS). The brain parenchyma has a unique composition, mainly hyaluronan and is devoid of rigid protein barriers composed of collagen, fibronectin and laminin. The integrins and the hyaluronan receptor CD44 are specific adhesion receptors active in glioma-ECM adhesion. These adhesion molecules play a major role in glioma cell-matrix interactions because the neoplastic cells use these receptors to adhere to and migrate along the components of the brain ECM. They also interact with the proteases secreted during glioma progression that degrade ECM allowing tumor cells to spread and diffusely infiltrate the brain parenchyma. The plasminogen activators (PAs), matrix metalloproteinases (MMPs) and lysosomal cysteine peptidases called cathepsins are also induced during the invasive process. Understanding the mechanisms of tumor cell invasion is critical as it plays a central role in glioma progression and failure of current treatment due to tumor recurrence from micro-disseminated disease. This review will focus on the impact of microregional heterogeneity of the ECM on glioma invasion in the normal adult brain and its modifications in tumoral brain.     

Inhibition of in vitro tumor cell invasion by Arg-Gly-Asp-containing synthetic peptides [published erratum appears in J Cell Biol 1989 Jun;108(6):following 2546]

The interaction of cells with extracellular matrix components such as fibronectin, vitronectin, and type I collagen has been shown to be mediated through a family of cell-surface receptors that specifically recognize an arginine-glycine-aspartic acid (RGD) amino acid sequence within each protein. Synthetic peptides containing the RGD sequence can inhibit these receptor-ligand interactions. Here, we use novel RGD-containing synthetic peptides with different inhibition properties to investigate the role of the various RGD receptors in tumor cell invasion. The RGD-containing peptides used include peptides that inhibit the attachment of cells to fibronectin and vitronectin, a peptide that inhibits attachment to fibronectin but not to vitronectin, a cyclic peptide with the opposite specificity, and a peptide, GRGDTP, that inhibits attachment to type I collagen in addition to inhibiting attachment to fibronectin and vitronectin. The penetration of two human melanoma cell lines and a glioblastoma cell line through the human amniotic basement membrane and its underlying stroma was inhibited by all of the RGD-containing peptides except for the one that inhibits only the vitronectin attachment. Various control peptides lacking RGD showed essentially no inhibition. This inhibitory effect on cell invasion was dose-dependent and nontoxic. A hexapeptide, GRGDTP, that inhibits the attachment of cells to type I collagen in addition to inhibiting fibronectin- and vitronectin-mediated attachment was more inhibitory than those RGD peptides that inhibit only fibronectin and vitronectin attachment. Analysis of the location of these cells that were prevented from invading indicated that they attached to the amniotic basement membrane but did not proceed further into the tissue. These results suggest that interactions between RGD-containing extracellular matrix adhesion proteins and cells are necessary for cell invasion through tissues and that fibronectin and type I collagen are important for this process.     

Alterations in integrin receptor expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes

The abilities of malignant tumor cells to bind and migrate through basement membranes are important steps in invasion and metastasis. Malignant tumor cells would therefore be expected to express receptors on their surfaces for basement membrane and stromal components, such as collagens, laminin, and fibronectin, although the pattern of expression of these receptors on the malignant cells may be different from that on their normal progenitors. We report here that chemically transformed tumorigenic human cells express an altered pattern of integrin receptors on their cell surfaces as compared with their untransformed nontumorigenic counterparts. Specifically, N-methyl-N'-nitro-N-nitrosoguanidine transformation of HOS cells into highly tumorigenic cells results in a significant specific increase in the expression of (in descending order of level of cell surface expression) the integrins alpha 6/beta 1, alpha 2/beta 1, and alpha 1/beta 1, which are receptors for laminin, collagens, and collagen type IV and laminin, respectively. The level of expression of two fibronectin receptor integrins, alpha 5/beta 1 and alpha 3/beta 1, are, however, unaltered, whereas the level of expression of vitronectin receptor integrin, alpha v/beta 3, is drastically reduced on the transformed cells. Consistent with the increased expression of laminin and collagen receptors and the decreased expression of vitronectin receptors on the transformed cells, these cells attached three- to fivefold more strongly to laminin and collagen but attached very poorly to vitronectin. The MNNG-HOS cells were also found to have a greater potential for invasion through reconstituted basement membrane, matrigel, the major components of which are laminin and type IV collagen. The invasion of both the HOS and MNNG-HOS cells was inhibited 45-50% by a polyclonal anti-fibronectin receptor antibody. However, although the invasion of HOS cells could be inhibited up to 75% by an anti-alpha 6 monoclonal antibody, a similar concentration of this antibody had no effect on the alpha 6-overproducing MNNG-HOS cells. A fivefold higher concentration of this antibody did result in partial inhibition of MNNG-HOS invasion. These data indicate a critical role for the alpha 6/beta 1 laminin receptor in the invasion of these cells through basement membranes and demonstrate that chemical transformation of nontumorigenic human cells to highly tumorigenic cells is associated with an altered pattern of integrin expression which may play a direct role in the increased capacity of these cells to bind and invade through basement membranes.     

Syndecan-1 and -4 differentially regulate oncogenic K-ras dependent cell invasion into collagen through α2β1 integrin and MT1-MMP

Syndecans function as co-receptors for integrins on different matrixes. Recently, syndecan-1 has been shown to be important for α2β1 integrin-mediated adhesion to collagen in tumor cells by regulating cell adhesion and migration on two-dimensional collagen. However, the function of syndecans in supporting α2β1 integrin interactions with three-dimensional (3D) collagen is less well studied. Using loss-of-function and overexpression experiments we show that in 3D collagen syndecan-4 supports α2β1-mediated collagen matrix contraction. Cell invasion through type I collagen containing 3D extracellular matrix (ECM) is driven by α2β1 integrin and membrane type-1 matrix metalloproteinase (MT1-MMP). Here we show that mutational activation of K-ras correlates with increased expression of α2β1 integrin, MT1-MMP, syndecan-1, and syndecan-4. While K-ras-induced α2β1 integrin and MT1-MMP are positive regulators of invasion, silencing and overexpression of syndecans demonstrate that these proteins inhibit cell invasion into collagen. Taken together, these data demonstrate the existence of a complex interplay between integrin α2β1, MT1-MMP, and syndecans in the invasion of K-ras mutant cells in 3D collagen that may represent a mechanism by which tumor cells become more invasive and metastatic.     

alpha-v-beta 3整合素与恶性肿瘤侵袭转移关系的研究进展

整合素家族是细胞粘附分子的重要种类之一,主要作用是介导细胞与细胞之间、细胞与细胞外基质之间的粘附效应。医学 研究证实整合素家族与肿瘤的侵袭及远处转移等生物学行为密切相关。整合素alpha-v-beta-3是整合素家族中的一种重要分子,肿瘤血管内 皮细胞中alpha-v-beta-3的表达水平对肿瘤侵袭转移及血管生成有着重要作用,调节琢v茁3的表达水平可明显影响肿瘤的侵袭转移及肿瘤组 织中新生血管的形成。深入研究整合素alpha-vbeta-3的分子调节机制可以为肿瘤治疗提供新的治疗靶点。     

Role of integrins in cancer: survey of expression patterns

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 alpha and beta 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 alpha-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.     

Invasive depth of extravillous trophoblast correlates with cellular phenotype: a comparison of intra- and extrauterine implantation sites

During intrauterine human placentation, extravillous trophoblast invades uterine tissues starting with proliferating stem cells at the basement membrane of anchoring villi. Transition to the postproliferative invasive phenotype takes place several cell layers distant. Here we show that in intrauterine pregnancies invasive trophoblast comprises three cellular phenotypes: a. Small spindle-shaped trophoblast cells are found along the whole invasive pathway throughout pregnancy. They are embedded in little heterogeneous extracellular matrix but expose only fibronectin receptors (integrins alpha5beta1, alphavbeta3/5), resulting in a partial integrin-matrix mismatch. b. Large polygonal trophoblast cells are rare in early pregnancy but increase in number towards term. They secrete ample heterogeneous extracellular matrix and expose integrins specifically matching the opposing matrix molecules (integrins alpha6beta4, alpha5beta1). c. Multinucleated giant cells in all stages of pregnancy form a kind of peripheral shell of trophoblast.In contrast to intrauterine pregnancies, in viable tubal pregnancies, Mib-1 expression indicating proliferation, extends deeply into the invasive pathway. Trophoblast cells of the invasive pathway mostly belong to the small spindle-shaped phenotype and secrete little extracellular matrix, mainly fibronectins. At the transition to the second cellular layer of cell columns expression of integrin alpha6beta4 switches to expression of alpha5beta1 and alphavbeta3/5. Viable tubal pregnancies are characterised by a broad overlap of proliferative with invasive phenotype as well as a general integrin-matrix mismatch. The differences in proliferation patterns, cellular phenotype and matrix-integrin co-localisation may well explain the increase of invasiveness of normal extravillous trophoblast from term intrauterine via early intrauterine to viable tubal pregnancies.     

Tissue architecture: the ultimate regulator of epithelial function?

The architecture of a tissue is defined by the nature and the integrity of its cellular and extracellular compartments, and is based on proper adhesive cell-cell and cell-extracellular matrix interactions. Cadherins and integrins are major adhesion-mediators that assemble epithelial cells together laterally and attach them basally to a subepithelial basement membrane, respectively. Because cell adhesion complexes are linked to the cytoskeleton and to the cellular signalling pathways, they represent checkpoints for regulation of cell shape and gene expression and thus are instructive for cell behaviour and function. This organization allows a reciprocal flow of mechanical and biochemical information between the cell and its microenvironment, and necessitates that cells actively maintain a state of homeostasis within a given tissue context. The loss of the ability of tumour cells to establish correct adhesive interactions with their microenvironment results in disruption of tissue architecture with often fatal consequences for the host organism. This review discusses the role of cell adhesion in the maintenance of tissue structure and analyses how tissue structure regulates epithelial function.     

Tumor-stroma interactions: their role in the control of tumor cell invasion

The development and progression of tumors result from the concerted activity not only of tumor cells with neighboring cells e.g., fibroblasts and inflammatory cells. Host-tumor interactions are considered critical in tumor invasion and metastasis. In vitro studies as well as established in vivo models have analysed the reciprocal effects of tumor-host interactions for the tumor invasion process. These studies have shown that modifications in the extracellular matrix composition surrounding the tumors as well as alterations in the expression of tumor cell receptors or in the expression of growth factors/cytokines and proteases, are critical regulators of a developing tumor. We shortly review the most important and well characterized mechanisms involved in the progression of tumor cells through tissues, especially those participating in cellular communication, cell adhesion, and proteolysis.     

Integrins contribute to the establishment and maintenance of cell polarity in the follicular epithelium of the Drosophila ovary

The generation of epithelial cell polarity is a key process during development. Although the induction and orientation of cell polarity by cell-cell and cell-extracellular matrix (ECM) interactions is well established, the molecular mechanisms by which signals from the ECM control cell polarity in developing epithelial tissues remain poorly understood. Here, we have used the follicular epithelium of the Drosophila ovary to investigate the role that integrins, the main cell-ECM receptors, play in the establishment of apicobasal polarity. Mature follicle cells have an apical side facing the germ line and a basal side in contact with a basement membrane. Our results show that integrins - presumably via interactions with the basement membrane - play a reinforcing role in follicle cell polarization, as they are required to establish and/or maintain follicle cell membrane asymmetry only when contact with the germ line is prevented. We suggest that the primary cue for polarization of the follicular epithelium is contact with the germline cells. In addition, while interfering with apical and lateral polarization cues leads to apoptosis, we show here that inhibition of contact with the basement membrane mediated by integrins does not affect cell survival. Finally, we provide evidence to suggest that integrins are required to orientate epithelial polarity in vivo.     

CD44/chondroitin sulfate proteoglycan and alpha 2 beta 1 integrin mediate human melanoma cell migration on type IV collagen and invasion of basement membranes.

Tumor cell invasion of basement membranes (BM) represents one of the critical steps in the metastatic process. Tumor cell recognition of individual BM matrix components may involve individual cell adhesion receptors, such as integrins or cell surface proteoglycans, or may involve a coordinate action of both types of receptors. In this study, we have focused on the identification of a cell surface CD44/chondroitin sulfate proteoglycan (CSPG) and alpha 2 beta 1 integrin on human melanoma cells that are both directly involved in the in vitro invasion of reconstituted BM via a type IV collagen-dependent mechanism. Interfering with cell surface expression of human melanoma CSPG with either p-nitro-phenyl-beta-D-xylopyranoside treatment or anti-CD44 monoclonal antibody (mAb) preincubation (mAb) preincubation inhibits melanoma cell invasion through reconstituted BM. These treatments also strongly inhibit melanoma cell migration on type IV collagen, however, they are ineffective at inhibiting cell adhesion to type IV collagen. Purified melanoma cell surface CD44/CSPG, or purified chondroitin sulfate, bind to type IV collagen affinity columns, consistent with a role for CD44/CSPG-type IV collagen interactions in mediating tumor cell invasion. In contrast, melanoma cell migration on laminin (LM) does not involve CD44/CSPG, nor does CD44/CSPG bind to LM, suggesting that CD44/CSPG-type IV collagen interactions are specific in nature. Additionally, anti-alpha 2 and anti-beta 1 integrin mAbs are capable of blocking melanoma cell invasion of reconstituted BM. Both of these anti-integrin mAbs inhibit melanoma cell adhesion and migration on type IV collagen, whereas only anti-beta 1 mAb inhibits cell adhesion to LM. Collectively, these results indicate that melanoma cell adhesion to type IV collagen is an important consideration in invasion of reconstituted BM in vitro, and suggest that CD44/CSPG and alpha 2 beta 1 integrin may collaborate to promote human melanoma cell adhesion, migration, and invasion in vivo.     

Release of cell fragments by invading melanoma cells

Tumor cell invasion requires coordinated cell adhesion to an extracellular matrix (ECM) substrate at the leading edge and concomitant detachment at the cell rear. Known detachment mechanisms include the slow sliding of focal contacts, the detachment of adhesion receptors by affinity and avidity regulation, as well as the shedding of adhesion receptors, most notably integrins. In highly invasive melanoma cells migrating within 3D collagen matrices, beta1 integrins and CD44 are released upon retraction of the trailing edge, together with ripping-off complete cell fragments to become deposited along the migration trail of remodeled matrix. Cell fragments reach a size up to 12 microm in diameter, contain cytoplasm and occasionally polymerized actin enclosed by intact cell membrane including surface beta1 integrins, but do not include nuclear material. The release of cell fragments was migration dependent, as impairment of motility by a blocking anti-beta1 integrin antibody also blocked cell particle release. Invasion-associated deposition of cell fragments combines the secretory-type release of vesicles with a physical mechanism of rear retraction and migration efficiency. The deposition of cell fragments may further represent a disregulated detachment strategy with implications for neoplastic cell behavior, such as the paracrine effects on neighbor cells or a negative impact on immune effector cells.     

Dynamic alterations in integrin α4 expression by hypoxia are involved in trophoblast invasion during early implantation

Implantation of the blastocyst into the maternal endometrium is mediated by a population of well-differentiated primary cells of the placenta known as trophoblasts, which grow in an invasive and destructive fashion similar to tumor cells. Interactions between the endometrium and trophoblasts are regulated by a coordinated interplay of extracellular matrix (ECM) proteins secreted by the invading extravillous trophoblasts. Integrins act as adhesion receptors and mediate both cell-ECM and cell-cell interactions. However, the correlation between integrin expression and trophoblast invasion under hypoxia is unclear. Here, we analyzed the expression of integrins in HTR-8/SVneo trophoblast cells exposed to hypoxic conditions in order to demonstrate an association between invasion activity and integrin expression in trophoblasts. Trophoblasts were examined by microarray analysis, RT-PCR, western blotting, and zymography after 1% hypoxic treatment, and cell invasion was estimated. The dynamic expression of integrins and human matrix metalloproteinases (MMPs) was observed under hypoxic conditions. The invasiveness of trophoblasts cultured under 1% hypoxic conditions was significantly greater than that of trophoblasts cultured under normoxic conditions through alterations in MMP-2 and -9 (P < 0.05). Notably, integrin α4 expression during early hypoxia was negatively regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) expression in trophoblasts. The downregulation of integrin α4 expression by siRNA treatment controlled trophoblast invasion activity (P < 0.05). Taken together, we suggest that dynamic changes in integrins, including those in integrin α4 expression by hypoxia, play a regulatory role in trophoblast invasion. These findings expand our understanding of the potential roles of integrin α4 in implantation.     

Altered expression of integrins and basement membrane proteins in malignant and pre-malignant lesions of oral mucosa

Integrins are transmembrane receptors that regulate cell-cell and cell-extracellular matrix (ECM) contact. In epithelial tissues, they interact with ECM components of the basement membrane (BM) to maintain the homeostasis and the architecture of the tissue. This interaction controls several cell functions such as adhesion, migration, proliferation, differentiation, and therefore has a key role in cancer development and metastasis. We studied the expression of integrins and ECM components of the BM by immunohistochemistry in frozen specimens of malignant squamous cell carcinoma (SCC), pre-malignant lesions of the oral mucosa (leucoplakia) and oral lichen planus. In invasive SCC, we observed altered polarity and distribution of alpha2beta1, alpha6beta4 and alpha3beta1 integrins, whereas in the in situ carcinoma alpha6beta4 and alpha3beta1 patterns only were altered. Immunostaining for ECM components such as Laminin-1 (Ln-1), Ln-5, and Collagen IV (Coll IV) was discontinuous and interrupted in invasive SCC, whereas it was normal in the in situ carcinoma. In both pre-malignant lesions and lichen planus specimens, integrins were expressed in a polarized manner in the presence of a normal BM, whereas were abnormally distributed in those tissues with altered staining patterns of the ECM components. In conclusion, we suggest that abnormal re-distribution of alpha3beta1 and alpha6beta4 integrins and expression of ECM components such as Ln-5 could play an important role in SCC invasion and metastasis.     

Expression of integrin beta 6 enhances invasive behavior in oral squamous cell carcinoma.

Oral squamous cell carcinoma (SCC) is characterized by invasive growth and the propensity for distant metastasis. The expression of specific adhesion receptors promotes defined interactions with the specific components found within the extracellular matrix (ECM). We previously showed that the alpha v beta 6 fibronectin receptor is highly expressed in oral SCC. Here we forced expression of the beta 6 subunit into poorly invasive SCC9 cells to establish the SCC9 beta 6 cell line and compared these two cell lines in several independent assays. Whereas adhesion to fibronectin was unaffected by the expression of beta 6, migration on fibronectin and invasion through a reconstituted basement membrane (RBM) were both increased. Function-blocking antibodies to alpha v beta 6 (10D5) reduced both migration on fibronectin and invasion through an RBM, whereas anti-alpha 5 antibodies were effective only in suppressing migration on fibronectin, not invasion. Expression of beta 6 also promoted tumor growth and invasion in vivo and modulated fibronectin matrix deposition. When grown as a co-culture with SCC9 cells, peritumor fibroblasts (PTF) organized a dense fibronectin matrix. However, fibronectin matrix assembly was decreased in co-cultures of SCC9 beta 6 cells and PTF and this decrease was reversed by the addition of function-blocking anti-alpha v beta 6 antibodies. The expression of beta 6 also resulted in increased levels of matrix metalloproteinase 3. Addition of the general MMP inhibitor GM6001 to SCC9 beta 6/PTF co-cultures dramatically increased fibronectin matrix assembly in a similar fashion as incubation with anti-alpha v beta 6 antibodies. These results demonstrate that expression of beta 6 (1) increases oral SCC cell motility and growth in vitro and in vivo; (2) negatively affects fibronectin matrix assembly; and (3) stimulates the expression and activation of MMP3. We suggest that the integrin alpha v beta 6 is a key component of oral SCC invasion and metastasis through modulation of MMP-3 activity.     

Molecules mediating cell-ECM and cell-cell communication in human heart valves

The specific phenotype of different tissues depends on the interactions of cells with neighboring cells and the surrounding extracellular matrix, which is mediated by cell adhesion receptors including integrins, immunoglobulin family members, syndecans, and selectins. The aim of this study was to investigate the adhesion profile of native human valve interstitial cells (ICs) in situ and in vitro by analyzing these adhesion receptors. Flow cytometry and immunocytochemistry was used to quantify the expression of the specific receptors on ICs cultured from all human cardiac valves, and immunohistochemistry were used to profile their distribution pattern in valve tissue sections. The valve leaflets and cultured ICs from all valves expressed alpha1, alpha2, alpha3, alpha4, and alpha5 integrins to varying degrees and percentages with very little expression of alpha6 and alphaV. Valve leaflet ICs from all valves, expressed predominantly beta1 integrin but no beta3 or beta4 integrin. Syndecan-1 and Syndecan-4 were not detected. Intercellular adhesion molecule-1 was weakly detected, whereas vascular adhesion molecule-1 was barely detectable and E-selectin was not detected. This study has delineated the identity of some of the integrins synthesized and expressed by human valve ICs and the specificity of adhesion molecules with which the valve ICs interact with the extracellular matrix and mediate intercellular interactions. This pattern of expression of cell surface adhesion molecules may be considered as a basis for a fingerprint on which to base future cell alternatives and would provide useful information for valve tissue engineering.     

The interplay of cell-cell and cell-matrix interactions in the invasive properties of brain tumors

Impairment of tissue cohesion and the reorganization of the extracellular matrix are crucial events during the progression toward invasive cell phenotype. We studied the in vitro invasion patterns of nine brain tumor cell lines in three-dimensional collagen gels. Cell-cell and cell-matrix interactions were quantified and correlated with the expression level of specific molecules: N-cadherin, matrix metalloproteinases, and their inhibitor. Pattern evolution was studied as a function of time and collagen concentration. Cells with low metalloproteinase expression or high tissue cohesion showed limited invasive potential. Higher metalloproteinase expression and intermediate tissue cohesion resulted in configurations with hypercellular zones surrounding regions mostly devoid of cells and with digested collagen, akin to pseudopalisades in surgically removed malignant astrocytoma specimens. In physical terms, these configurations arise as the result of competition between cell-cell and cell-matrix interactions. Our findings suggest specific ways to characterize, control, or engineer cell migratory patterns and hint at the importance of the interplay between biophysical and biomolecular factors in the characterization of invasive cell behavior and, more generally, in epithelial-mesenchymal transitions.     

Syndecans in tumor cell adhesion and signaling

Anchorage of cells to "heparin" – binding domains that are prevalent in extracellular matrix (ECM) components is thought to occur primarily through the syndecans, a four-member family of transmembrane heparan sulfate proteoglycans that communicate environmental cues from the ECM to the cytoskeleton and the signaling apparatus of the cell. Known activities of the syndecans trace to their highly conserved cytoplasmic domains and to their heparan sulfate chains, which can serve to regulate the signaling of growth factors and morphogens. However, several emerging studies point to critical roles for the syndecans' extracellular protein domains in tumor cell behavior to include cell adhesion and invasion. Although the mechanisms of these activities remain largely unknown, one possibility involves "co-receptor" interactions with integrins that may regulate integrin function and the cell adhesion-signaling phenotype. Thus, alterations in syndecan expression, leading to either overexpression or loss of expression, both of which take place in tumor cells, may have dramatic effects on tumor cell invasion.