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PubMedDate not supplied

Cadherins and integrins in renal cell carcinoma: an immunohistochemical study.

AIMS AND BACKGROUND: The aim of this study was to determine the expression of cadherins and integrins in renal cell carcinoma (RCC) and their relationship with tumor morphology and TNM status. METHODS: Cadherin and integrin expression was investigated using an indirect immunoperoxidase technique, applying antibodies to E-, N-, P- and VE-cadherin and to alpha1, alpha2, alpha3, alpha4, alpha5, alpha6, and alpha(v) integrin subunits. Correlation of semiquantitatively scored adhesion molecule levels with histopathological parameters (cytology, growth pattern, nuclear grade) and TNM status was performed for 24 RCCs (17 clear cell, 3 granular, 3 spindle cell and 1 chromophobe cell type according to the WHO classification). RESULTS: E-cadherin and N-cadherin were present in most cases (88% and 67%, respectively) and were usually coexpressed. T3 RCCs displayed higher E-cadherin and N-cadherin levels than T1/T2 tumors regardless of tumor grade, suggesting that impairment of their function might exist without actual loss from tumor cells. P-cadherin was found focally in two RCCs only, while VE-cadherin was present on stromal vessel endothelium in five tumors, showing no differences with regard to cell type, growth pattern, tumor grade or TNM status. All integrins were present in the studied RCCs (ranging from 12% for alpha5 to 79% for alpha3), including those that are normally absent from adult kidney tissue (alpha4 and alpha5). Tumors of higher grade showed increased alpha(v) and decreased alpha6 levels, while RCCs with metastases less often showed diffuse alpha3 presence and never expressed alpha5 integrin. CONCLUSIONS: Our results suggest that the level of expression of N-cadherin and some integrins (most notably alpha3, alpha6 and alpha5) is associated with the capacity of RCC for local and distant spread, regardless of tumor grade.

Antigens, CD↗

PubMed2002

The involvement of beta1 integrin in the modulation by collagen of chondrocyte-response to transforming growth factor-beta1.

The physiologic response of chondrocytes to maintenance of the matrix and response to injury likely involves signaling from multiple sources including soluble cytokines, mechanical stimulation, and signaling from the extracellular matrix. The signaling from the extracellular matrix may serve to effect cell differentiation and to modulate the response to cytokines. We have previously reported that type II collagen modulates the response of bovine articular chondrocytes to TGF-beta1. The molecular nature of the signaling mechanism has not been elucidated but presumably involves a similar mechanism by which the cell attaches to the surrounding matrix. An alginate bead culture system is utilized to which exogenous type II collagen is added. The inclusion of type II collagen results in an alteration of integrin expression with a down regulation of alpha2. The response of the chondrocyte to TGF-beta1 can be modulated by the inclusion of exogenous type II collagen. The modulation of DNA and proteoglycan synthesis was blocked by the treatment of anti-beta1 integrin antibody (4B4) or by cyclic RGD containing peptides. These events occur at concentrations that block cell adhesion to type II collagen. Linear RGD containing peptides and anti-anchorin antibodies had no effect on the modulation by type II collagen. These results suggest that type II collagen binding by chondrocytes at least in part occurs through the beta1 integrin. This binding results in modulation of the cell response to TGF-beta1. This modulation may serve to provide physiologic specificity to the cytokine-signaling cascade. An understanding of the regulatory milieu of the chondrocyte may permit the stimulation of an intrinsic repair of articular cartilage in the future. A near term application of this understanding can be made to tissue engineering attempts at articular cartilage repair.

Alginates↗

PubMed2000

Expression of the alpha2beta1 and alpha3beta1 integrins at the surface of mesothelial cells: a potential attachment site of endometrial cells.

OBJECTIVE: To localize alpha2beta1 and alpha3beta1 integrins in the cell membrane of peritoneal mesothelium in vivo and in vitro. DESIGN: Descriptive study using confocal and two-photon laser-scanning microscopy. SETTING: University-based laboratory. PATIENT(S): Women without endometriosis undergoing surgery for benign conditions. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Peritoneal biopsies (n = 9) and mesothelial monolayer cultures (n = 4) were incubated with antibodies to the alpha2 and alpha3 subunits and to the intact alpha2beta1 and alpha3beta1 integrins. Specimens were examined with laser-scanning microscopy. RESULT(S): The alpha2 and alpha3 subunits and the intact alpha2beta1 and alpha3beta1 integrins were identified at the base of the mesothelial cells (i.e., toward the basement membrane). There was also expression of the alpha2 and alpha3 subunits and the intact alpha2beta1 and alpha3beta1 integrins at the cell surface (i.e., toward the peritoneal cavity). CONCLUSION(S): The resolution of the confocal and two-photon laser-scanning microscope enabled localization of integrins in mesothelial cells. The presence of alpha2beta1 (collagen-laminin receptor) and alpha3beta1 integrins (collagen-laminin-fibronectin receptor) at the base of mesothelial cells suggests a role for these molecules in adhesion to the basement membrane. The presence of these molecules at the cell surface suggests a potential locus for cell adhesion in such processes as endometriosis and cancer metastasis.

Adult↗

PubMed1997

The integrin alpha1 A-domain is a ligand binding site for collagens and laminin.

The integrin alpha1beta1 is a cell surface receptor for collagens and laminin. The alpha1 subunit contains an A-domain, and the A-domains of other integrins are known to mediate ligand binding. To determine the role of the alpha1 A-domain in ligand binding and the extent to which it reproduced the ligand binding activity and specificity of the parent molecule, we produced recombinant alpha1 A-domain and tested its ability to bind collagens and laminin. In solid phase assays, the A-domain from alpha1 was found to bind to collagen I, collagen IV, and laminin in a largely cation-dependent manner. The alpha2 A-domain, from the alpha2beta1 integrin, also bound to these ligands, but the binding hierarchy differed from that seen for alpha1. This is the first demonstration of laminin binding by A-domains. Specificity of A-domain-ligand binding was further investigated using the triple-helical proteolytic fragment of collagen IV, CB3, and its subfragments, F1 and F4. alpha1 A-domain bound to all three fragments, while the alpha2 A-domain bound CB3 less well and exhibited little binding to F1 and no binding to F4. These differences mirror previous reports of distinct integrin binding sites in collagen IV and for the first time identify a limited proteolytic fragment of a ligand that contains integrin A-domain binding activity. To gain insight into the contribution that the A-domain makes to ligand binding within the whole integrin heterodimer, we measured binding constants for A-domain-collagen interactions using surface plasmon resonance biosensor technology. The values obtained were similar to those reported for intact integrin binding, suggesting that the A-domain is the major collagen binding site in the alpha1beta1 and alpha2beta1 integrins.

Animals↗

PubMed2004

Loss of basement membrane, receptor and cytoskeletal lattices in a laminin-deficient muscular dystrophy.

Basement membrane laminins bearing the alpha2-subunit interact with alpha-dystroglycan and beta1-integrins, cell-surface receptors that are found within the rectilinear costameric lattices of skeletal muscle sarcolemma. Mutations of the alpha2 subunit are a major cause of congenital muscular dystrophy. To determine whether the costameres are altered as a result of laminin alpha2-mutations, the skeletal muscle surface of a dystrophic mouse (dy(2J)/dy(2J)) lacking the alpha2-LN domain was examined by confocal and widefield deconvolution immunomicroscopy. Although the dy(2J) dystrophic fibers possessed a normal-appearing distribution of alpha2-laminins and alpha-dystroglycan within a rectilinear costameric lattice at 6.5 weeks of age, by 11 weeks the surface architecture of these components were found to be disorganized, with frequent effacement of the circumferential and longitudinal lattice striations. The defect in the lattice organization was also noted to be a characteristic of type IV collagen, nidogen, perlecan, beta1(D)-integrin, dystrophin and vinculin. The development of this pattern change occurring only after birth suggests that although alpha2-laminins are not essential for the initial assembly of the costameric framework, they play a role in maintaining the stability and organization of the framework.

Aging↗

PubMed1998

Antagonistic regulation of cell migration by epidermal growth factor and glucocorticoid in human gastric carcinoma cells.

Epidermal growth factor (EGF) induced the disruption and scattering of colonies of TMK-1, a cell line derived from a human gastric carcinoma. A stimulatory action of EGF on cell migration was also observed as determined by a wound assay. However, these actions of EGF were inhibited if the cells were pretreated with dexamethasone, a synthetic glucocorticoid. Dexamethasone increased cell adhesion to collagen type IV and laminin, but not to poly-L-lysine and fibronectin. In contrast, EGF did not affect cell adhesion to these extracellular matrices whether dexamethasone was present or not. Dexamethasone enhanced the protein levels of both alpha1 and beta1 integrin subunits, and that of the alpha1 beta1 heterodimer. Further, flow cytometric analysis revealed that dexamethasone increased the expression of beta1 and alpha1 integrin subunits at the cell surface, whereas EGF increased expression of beta1 and alpha2 subunits at the cell surface. Antibodies against alpha1 and beta1 integrin subunits inhibited the increased cell adhesion seen in the presence of dexamethasone. An immunofluorescence study indicated that dexamethasone increased the formation of focal adhesions along the entire edges of cell colonies. In contrast, EGF led to the formation of focal adhesions preferentially at the cell front, and this EGF-induced preferential formation was not observed if the cells were pretreated with dexamethasone. These results suggest that glucocorticoid increased cell adhesion to the extracellular matrix via alpha1 beta1 integrin, and thereby antagonized EGF-induced cell migration.

Cadherins↗

PubMed1999

Site-specific experimental metastasis patterns of two human breast cancer cell lines in nude rats.

Animal models for breast cancer metastasis are valuable tools for studying mechanisms of metastasis and for preclinical testing of anti-metastatic therapy regimens. Using MA-11 and MT-1, two oestrogen and progesterone receptor-negative human breast cancer cell lines, we developed new models in nude rats with patterns of experimental metastasis resembling those frequently observed in humans. MA-11 cells showed a clear preference for growth in the CNS. Fourteen of 15 animals injected with MA-11 cells into the left ventricle of the heart developed hind-leg paralysis, and tumours were observed in the spinal cord. MT-1 cells consistently exhibited bone/bone marrow metastases after intracardial injection, in addition to tumours in the brain and spinal cord. When injected into the cisterna magna, both cell lines gave rise to leptomeningeal neoplastic disease. Injection of MA-11 cells into the tibial bone marrow resulted in tumours in only 2 of 13 rats, whereas all animals injected with MT-1 cells developed tumours. Only 2 of 6 rats injected i.v. with MA-11 cells developed lung colonies compared with all 9 animals injected with MT-1 cells. Cell-surface expression of the following was examined: EGP2; MUC1; EGFr; E- and N-cadherin; the alpha2, alpha3, alpha5, beta1 and beta4 integrins; c-erb-B2; and N-CAM. c-erb-B2 was expressed in a higher percentage of the bone-metastasizing MT-1 cells than the MA-11 cells, whereas E-cadherin was expressed in MA-11 but not MT-1 cells. In animals injected with MA-11 and MT-1 cells in the left cardiac ventricle, treatment with cisplatin and doxorubicin did not improve survival. In summary, these clinically relevant animal models may be used for studies related to site-specific growth and metastasis and for assessing effects of experimental therapy against human breast cancer.

Animals↗

PubMed2005

Matrix metalloproteinase activity synergizes with alpha2beta1 integrins to enhance collagen remodeling.

Cell-matrix interactions transmit a wealth of information about the extracellular environment. In return, a variety of responses from the cell are initiated by changes in the matrix. One such response involves the positive regulation of matrix metalloproteinases (MMPs) by alpha2beta1 integrin attaching to a specific extracellular matrix component, collagen. This study explores the relationship between mechanical and biochemical functions of alpha2beta1 integrins as it pertains to regulating matrix remodeling. To understand this relationship, the individual influences of MMP activity and alpha2beta1 integrin function on collagen gel contraction were studied. We have observed little evidence of mutual participation in matrix remodeling by the alpha2beta1 integrin and MMP activity in cell models where alpha2 is minimally expressed. In cells expressing high levels of alpha2, we see an increase in gel contraction that is enhanced by MMP activity. Measuring tension as it builds within the gel reveals that alpha2beta1 integrin presence correlates with force output but is insensitive to MMP activity. These data strongly suggest that alpha2beta1 regulates collagen gel remodeling through multiple simultaneous mechanisms including force generation and modulation of MMP activity.

Bone Remodeling↗

PubMed2002

Proximal tubular epithelial cell integrins respond to high glucose by altered cell-matrix interactions and differentially regulate matrixin expression.

Thickening of the tubular basement membrane (TBM) occurs in diabetic nephropathy, but the effects of high glucose on the functional aspects of proximal tubular epithelial cells are not clearly understood. In the present study, we examined the effects of elevated glucose concentrations on (a) integrin expression by human proximal tubular epithelial cells (HK-2) and integrin-mediated interactions with type IV collagen (colIV) and laminin, major components of TBM; (b) the expression of matrixins/matrix metalloproteinases (MMPs), which is regulated by integrins; and (c) the expression of tissue inhibitors of metalloproteinases (TIMPs). HK-2 cells cultured in 25 mM glucose underwent a reduction of the expression of alpha3, beta1, alpha(v)beta3, and alpha5 integrin subunits, with a concomitant increase of the alpha2 subunit, compared with cells grown in 5 mM glucose. Adhesion experiments demonstrated that high glucose led to increased cell adhesion on either colIV or laminin. Experiments of competition of adhesion using anti-integrin antibodies indicated that HK-2 cells in 5 mM glucose used mainly alpha(v)beta3 and alpha5beta1 integrins to adhere to colIV, whereas in 25 mM glucose they additionally used alpha2beta1. In the case of laminin, a beta1-mediated adhesion was observed when HK-2 cells were in 5 mM glucose, whereas in 25 mM glucose, alpha2beta1 and alpha(v)beta3 were also involved. Elevated glucose concentrations resulted in decreased expression of MMP-9 and MMP-2, whereas an increase in TIMP-1 and a decrease in TIMP-2 expression were observed. We also examined which integrins mediated the expression and secretion of matrixins MMP-2 and MMP-9. Ligation of alpha3beta1 with mAbs resulted in induction of MMP-2 expression and secretion, whereas antibody ligation of alpha(v)beta3 led to down-regulation of MMP-9. The above data implicate integrins of proximal tubular epithelial cells in the regulation of MMPs and in the development of TBM thickening in diabetic nephropathy.

Cell Line↗

PubMed1998

A human vascular endothelial cell model to study angiogenesis and tumorigenesis.

Endothelial cell biology has recently been the subject of considerable interest in thrombosis and cancer research. However, the successful establishment of immortalized human endothelial cells which retain differentiated cell characteristics has been rare. We have successfully established immortalized human umbilical vein endothelial cells (HUVECs) by human papilloma virus (HPV)-16 E6-E7. HPV-16 E6, E7 and E6-E7 were successfully introduced into HUVEC cells. Both E6 and E7 cultures had an extended lifespan but eventually underwent senescence. E6-E7 cultures 4-5-2G, however, acquired an indefinite lifespan in culture but did not undergo malignant conversion. Telomerase activity was not detected in either E6 or E7 cultures; however, telomerase was detected in E6-E7 4-5-2G cells. The cells exhibited a 'cobblestone' morphology and developed a capillary-like tube structure upon reaching confluence. The 4-5-2G line expressed Factor VIII related antigen and took up DiI-Ac-LDL as markers of endothelial origin. The line expressed integrin subunits (alpha(v)beta3, alph(v)beta5, beta1, alpha2, alpha3, beta4 and alpha6) consistent with an endothelial origin. The higher passage of 4-5-2G line showed a similar intensity of integrin immunostaining to that of primary HUVECS. Subsequent infection of these immortal cells with the Kirsten murine sarcoma virus which contains an activated K-ras oncogene induced morphological transformation that led to the acquisition of invasion capability and neoplastic properties. Telomerase was also detected in the tumorigenic v-Ki-ras transformed cell line. These cell lines should be useful for studies of the molecular mechanisms underlying normal and neoplastic endothelial cell proliferation and migration, and might also provide an in vitro model for development of pharmacologic and gene therapy for cardiovascular thrombosis and cancer.

Cell Line, Transformed↗

PubMed2003

Behavior of SaOS-2 cells cultured on different titanium surfaces.

Surface properties may affect the clinical outcome of titanium dental implants. The aim of the present study was to investigate the effects of 3 different titanium surfaces-smooth (S), sandblasted (SB), and titanium plasma-sprayed (TPS)-on proliferation, differentiation, and apoptosis of human osteoblast-like cells, SaOS-2. Cell proliferation was significantly (p < 0.05) higher on the S surface, and synthesis of extracellular matrix proteins was more abundant on TPS and SB than on S surfaces. Analysis of integrin receptors showed a higher expression of alpha2, alpha5, alphaVbeta3, and ss1 on TPS as compared with SB and S surfaces. An increase in alkaline phosphatase activity was detected only on SB and TPS surfaces. Analysis of cell apoptosis did not demonstrate any significant difference among the 3 different surfaces. The results indicate that titanium surface topography affects proliferation and differentiation of osteoblast-like SaOS-2 cells, suggesting that surface properties might be important for bone response around dental implants in vivo.

Alkaline Phosphatase↗

PubMed2003

Identification of sites in the cysteine-rich domain of the class P-III snake venom metalloproteinases responsible for inhibition of platelet function.

Atrolysin A and jararhagin are class P-III snake venom metalloproteinases (SVMPs) with three distinct domains: a metalloproteinase, a disintegrin-like and a cysteine-rich. The metalloproteinase and the disintegrin-like domains of atrolysin A and jararhagin contain peptide sequences that interact with alpha2beta1 integrin and inhibit the platelet responses to collagen. Recently, the recombinant cysteine-rich domain of atrolysin A was shown to have similar effects, but the sequence(s) responsible for this is unknown. In this report, we demonstrate two complete peptide sequences from the homologous cysteine-rich domains of atrolysin A and jararhagin that inhibit both platelet aggregation by collagen and adhesion of alpha2-expressing K562 cells to this protein. In addition, the peptide effects on platelets do not seem to involve an inhibition of GPVI. These results identify, for the first time, sites in the cysteine-rich domain of SVMPs that inhibit cell responses to collagen and reveal the complexity of the potential biological effects of these enzymes with multifunctional domains.

Amino Acid Sequence↗

PubMed2005

Monitoring the expression profiles of integrins and adhesion/growth-regulatory galectins in adamantinomatous craniopharyngiomas: their ability to regulate tumor adhesiveness to surrounding tissue and their contribution to prognosis.

OBJECTIVE: The purpose of this study was to identify biological markers that may be involved in the adhesiveness of craniopharyngiomas to optical chiasms and/or pituitary stalks. METHODS: We determined the complete pattern of integrin expression in three craniopharyngiomas by means of a complementary deoxyribonucleic acid microarray. We quantitatively determined the levels of immunohistochemical expression of the different integrins in a series of 37 cases and the pattern of immunohistochemical expression of 10 extracellular matrix components (acting as integrin ligands) in 7 optical chiasms and 11 pituitary stalks. We also quantitatively (computer-assisted microscopy) determined the levels of immunohistochemical expression of galectin-1, -3, -4, -7, and -8 in 50 adamantinomatous craniopharyngiomas. RESULTS: The present study shows that at both the ribonucleic acid and protein levels, adamantinomatous craniopharyngiomas express the alpha2, alpha6, alpha(v), beta1, beta5, and beta8 integrin subunits, whereas optical chiasms and pituitary stalks express vitronectin, thrombospondin, and various forms of collagens. CONCLUSION: Our data suggest that at least part of the adhesiveness of craniopharyngiomas to the surrounding tissue, such as optical chiasms and pituitary stalks, could be explained by the interactions between alpha(2beta1) integrin expressed by craniopharyngiomas and collagens on the one hand, and vitronectin expressed by the surrounding tissue on the other hand. In addition, a Cox regression analysis has revealed that the levels of galectin-4 contribute significant information toward the delay in recurrence independently of surgical status.

Carotid Artery, Internal↗

PubMedDate not supplied

Diffuse leiomyomatosis of the esophagus: disorder of cell-matrix interaction?

Diffuse leiomyomatosis (DL) is rare condition characterized by proliferation of smooth muscle in the upper gastrointestinal tract. Most cases are associated with X-linked Alport syndrome and have partial deletions in the genes encoding both the alpha5 and alpha6 chains of collagen type IV. We studied aspects of cell-matrix interaction of myocytes in an esophagogastrectomy specimen from a 12-year-old patient with DL. Myocytes had central areas of cytoplasmic rarefaction, which were actin positive and desmin poor, with the reverse pattern of staining at the cell periphery. Electron microscopy (EM) showed that the areas of rarefaction consisted of disorganized aggregates of filaments. The basement membranes ranged from thickened to thinned or absent. Immunohistochemical staining for the alpha1-alpha4 chains of collagen type IV, the alpha1, alpha2, beta2, and gamma1 chains of laminin, nidogen, type VI collagen, and fibronectin was normal. There was loss of the alpha5 and alpha6 chains of collagen type IV and the beta1 chain of laminin. Normal staining for alpha1, alpha2, alpha3, alpha4, alpha6, alpha8, and beta1 integrins was noted. Staining for alpha5 integrin varied from normal to reduced or negative in different cells. In DL, a primary abnormality of basement membrane may be associated with disorganization of the contractile apparatus and alterations of certain integrins. This may reflect a disturbance of cell-matrix interactions that play a role in cell differentiation and internal organization.

Barrett Esophagus↗

PubMed2005

Selective down-regulation of the alpha6-integrin subunit in melanocytes by UVB light.

In vivo, melanocytes bind to laminin (LM) molecules of the basement membrane (BM) via the integrins alpha3beta1 and alpha6beta1, and they adhere to neighbouring keratinocytes via E-cadherin. Only few studies have addressed the impact of ultraviolet (UV) light on the interaction of melanocytes with their microenvironment. In this report, we examined the influence of UVB irradiation on the expression of the most important melanocyte-adhesion molecules (E-, N-cadherin, alpha2-, alpha3-, alpha5-, alpha6-, alphaV-, beta1-, beta3-integrins and ICAM-1) in vitro by flow cytometry. We were able to demonstrate that the alpha6-integrin subunit is selectively and reversibly down-regulated by UVB in a dwzm 150ose-dependent manner. In comparison, keratinocytes lacked UVB-inducible alterations in the expression of alpha6-integrin. In the presence of LM-1, the UVB-induced down-regulation of alpha6-integrin in melanocytes was significantly reduced. Moreover, LM-1 increased the resistance of melanocytes to UVB-induced cell death, as measured by annexinV-binding analysis. This effect was reversed by preincubation with an alpha6-integrin-blocking antibody. By immunofluorescence, we could demonstrate that UVB leads to a dose-dependent internalization of alpha6-integrin, providing an obvious explanation for the down-regulation on the outer cell surface observed by flow cytometry. We suggest that adhesion to LM-1 through alpha6-integrin represents a protective mechanism for melanocytes to withstand UVB damage. Through alpha6-integrin internalization, sunburns might alter the interaction between melanocytes and the BM, resulting in apoptosis induced by loss of anchorage (anoikis). Repeated sunburns may then lead to the selection of a population of melanocytes which are capable of anchorage-independent survival, culminating in solar nevogenesis and melanoma development.

Annexin A5↗

PubMed2002

EGF and beta1 integrin convergently regulate migration of A431 carcinoma cell through MAP kinase activation.

We found that the convergently epidermal growth factor (EGF)-induced signal and the collagen-induced signal activate mitogen-activated protein kinase (MAPK), which induces migration. We examined the signaling mechanisms of EGF-induced cell migration on collagen using the A431 carcinoma cell. EGF (10 ng/ml) induced migration on collagen, but inhibited proliferation. Using a MAPK cascade inhibitor, PD98059, it was shown that EGF-induced migration on collagen was mediated by MAPK whereas EGF-induced migration on fibronectin and vitronectin was not. PD98059 also showed that activation of MAPK induced by EGF enhanced the adhesiveness of A431 cells to collagen. By Western blotting analysis, the kinetics of MAPK phosphorylation induced by EGF and collagen was examined separately, and convergently. First of all, EGF without collagen caused transient MAPK phosphorylation. Collagen without EGF caused MAPK to be immediately and transiently dephosphorylated, and rephosphorylated followed by sustained hyperphosphorylation. EGF together with collagen caused an immediate, and sustained, hyperphosphorylation. These facts suggest that the transient MAPK dephosphorylation induced by collagen is required for migration in order to maintain an appropriate level of sustained phosphorylation. Furthermore, we found that adhesion of A431 cells to collagen was blocked by the anti-beta1 integrin antibody or by the mixed antibodies composed of anti-alpha1, -alpha2, and -alpha3 antibodies, indicating that collagen-induced MAPK phosphorylation was mediated through alpha1beta1, alpha2beta1, and alpha3beta1 integrins.

Cell Movement↗

PubMed2005

Laminins 2 (alpha2beta1gamma1, Lm-211) and 8 (alpha4beta1gamma1, Lm-411) are synthesized and secreted by tooth pulp fibroblasts and differentially promote neurite outgrowth from trigeminal ganglion sensory neurons.

The tooth pulp innervation originates from the trigeminal ganglion (TG) and represents an illustrative example of tissue targeting by sensory nerves. Pulpal fibroblasts strongly promote neurite outgrowth from TG neurons in vitro. In the present study, we have investigated the possible participation of laminins (LNs), potent neuritogenic extracellular matrix components. Immunohistochemistry of human tooth pulp demonstrated expression of LN alpha1, alpha2, alpha4, alpha5, beta1 and gamma1, and laminin-binding integrin alpha3, alpha6, beta1 and beta4 chains in nerves. Though faintly stained for laminins in situ, pulpal fibroblasts reacted, once cultured and permeabilized, with antibodies to LN alpha2, alpha4, beta1 and gamma1 chains by flow cytometry. The cells also expressed the corresponding mRNAs and were able to assemble and secrete LN-2 (alpha2beta1gamma1, Lm-211) and LN-8 (alpha4beta1gamma1, Lm-411). LN-8 displayed a chondroitin sulphate (CS) modification in its alpha4 chain. In functional assays, mouse LN-1 (alpha1beta1gamma1, Lm-111) and recombinant human (rh) LN-8, but not native or rhLN-2, strongly promoted neurite outgrowth from TG neurons, mimicking the effect of cultured pulp fibroblast. Altogether, the results indicate that LN-2 and LN-8 are synthesized by tooth pulp fibroblasts and differentially promote neurite outgrowth from TG neurons. LN-8 may contribute to sensory innervation of teeth and other tissues during development and/or regeneration.

Adolescent↗

PubMed2004

Differential gene expression in ovarian carcinoma: identification of potential biomarkers.

Ovarian cancer remains the fifth leading cause of cancer death for women in the United States. In this study, the gene expression of 20 ovarian carcinomas, 17 ovarian carcinomas metastatic to the omentum, and 50 normal ovaries was determined by Gene Logic Inc. using Affymetrix GeneChip HU_95 arrays containing approximately 12,000 known genes. Differences in gene expression were quantified as fold changes in gene expression in ovarian carcinomas compared to normal ovaries and ovarian carcinoma metastases. Genes up-regulated in ovarian carcinoma tissue samples compared to more than 300 other normal and diseased tissue samples were identified. Seven genes were selected for further screening by immunohistochemistry to determine the presence and localization of the proteins. These seven genes were: the beta8 integrin subunit, bone morphogenetic protein-7, claudin-4, collagen type IX alpha2, cellular retinoic acid binding protein-1, forkhead box J1, and S100 calcium-binding protein A1. Statistical analyses showed that the beta8 integrin subunit, claudin-4, and S100A1 provided the best distinction between ovarian carcinoma and normal ovary tissues, and may serve as the best candidate tumor markers among the seven genes studied. These results suggest that further exploration into other up-regulated genes may identify novel diagnostic, therapeutic, and/or prognostic biomarkers in ovarian carcinoma.

Adenocarcinoma, Papillary↗