SEARCH · PubMed Health

Results for “Integrin alpha1beta1”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 199 records · Page 11Linked to original sources

PubMedDate not supplied

Collagen-receptor signaling in health and disease.

Collagens are not only essential for the mechanical resistance and resilience of multicellular organisms, but are also signaling molecules defining cellular shape and behavior. The communication between collagens and cells is achieved by cell surface receptors. Three types of cell surface receptors for collagen are known: integrins, discoidin domain receptors and glycoprotein VI. All three types independently trigger a variety of signaling pathways upon collagen-binding. Besides regulating numerous cellular responses, both integrin and discoidin domain receptors monitor the integrity of the collagenous extracellular matrix by triggering matrix degradation and renewal. Some recently discovered mechanisms of locally controlled expression of collagen, collagen-binding receptors and collagen-degrading proteases in the cellular microenvironment are described.

Collagen↗

PubMed1994

The role of the I domain in ligand binding of the human integrin alpha 1 beta 1.

We report here the analysis of potential ligand binding domains within the human integrin alpha 1 subunit, a known collagen/laminin receptor. This integrin is effectively blocked by the mouse monoclonal antibody 1B3.1. A truncated version of the alpha 1 subunit lacking the NH2-terminal half of the extracellular domain is not recognized by monoclonal antibody 1B3.1. Furthermore, we have isolated a cDNA containing the I domain from chicken alpha 1 bearing significant homology to the human and rat alpha 1 sequences. Replacing the human I domain with its chicken counterpart led to the surface expression of a functional heterodimer with endogenous mouse beta 1 on NIH 3T3 cells. However, 1B3.1 does not bind to the chicken/human chimera, demonstrating that the human alpha 1 I domain is required for epitope recognition. Mutation of Asp253 within the I domain to alanine resulted in surface expression of an alpha beta heterodimer recognized by 1B3.1 but with markedly reduced binding to collagen IV or laminin. Since a previously reported mutation of a homologous Asp in the Mac-1 I domain has similar consequences, these results suggest a central role for the I domain in ligand recognition for all integrin alpha subunits containing this domain.

3T3 Cells↗

PubMed1994

Transforming growth factor beta 1 suppresses transformation in hepatocytes by regulating alpha 1 beta 1 integrin expression.

We previously reported that (a) treatment of the ras-transformed hepatocyte cell line NR4 with transforming growth factor (TGF) beta 1 suppresses many characteristics associated with the transformed phenotype including altered morphology, actin cytoskeleton reorganization, and anchorage-independent growth such that the cells more closely resemble the immortalized CWSV1 parent cell line; (b) transformed NR4 cells expressed significantly less alpha 1 integrin RNA than the immortalized CWSV1 cells; and (c) TGF-beta 1 treatment of NR4 cells stimulated the expression of alpha 1 and beta 1 integrin RNAs. In this report, the role of the alpha 1 beta 1 integrin in TGF-beta 1-mediated suppression of the ras-transformed phenotype was investigated. We determined that (a) the cell surface integrin that increased in response to TGF-beta 1 treatment of NR4 cells was alpha 1 integrin; (b) TGF-beta 1 altered the ability of NR4 cells to attach to collagen and laminin, the extracellular matrix components that interact with the alpha 1 beta 1 integrin receptor; (c) TGF-beta 1 treatment resulted in relocalization of the alpha 1 integrin on the NR4 cell surface; and (d) TGF-beta 1-mediated inhibition of anchorage-independent growth was blocked by the presence of alpha 1 integrin antibody. A cell line that overexpresses alpha 1 integrin was derived from NR4 cells; characterization of these cells indicated that they continued to express H-ras RNA but were less transformed than the parent NR4 cells. Specifically, they had an altered morphology, an organized actin cytoskeleton, and reduced ability to demonstrate anchorage-independent growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Endometrial progesterone receptors and markers of uterine receptivity in the window of implantation.

OBJECTIVE: To compare the expression of endometrial P receptors (PR) levels with markers of endometrial receptivity during the window of implantation. DESIGN: Prospective, controlled study to examine endometrial PR and three cycle-specific integrins in endometrial biopsies obtained during the window of implantation. SETTING: An academic teaching hospital. PATIENTS: One hundred seventy-five endometrial biopsies from regularly cycling women with luteal phase defect (LPD; group 1; n = 80), medically treated LPD (group 2; n = 16), minimal and mild endometriosis with aberrant alpha v beta 3 expression (group 3; n = 21), fertile controls (group 4; n = 26), and infertile controls (group 5; n = 32). MAIN OUTCOME MEASURE: Immunohistochemical staining intensity of each antigen using the semi-quantitative grading system (HSCORE), compared using analysis of variance with Scheffe's correction. RESULTS: Among the five groups studied, nuclear PR expression was significantly elevated in glandular epithelial cells from tissue samples with histologic delay > or = 3 days consistent with luteal phase deficiency (LPD; group 1). Failure of PR down-regulation was associated with aberrant alpha v beta 3 integrin expression. Medical correction of LPD was associated with return of normal endometrial histology, normal integrin expression, and the loss of epithelial PR, similar to controls. The other two cycle-dependent integrin markers, alpha 1 beta 1 and alpha 4 beta 1, were not different between groups. In women with aberrant alpha v beta 3 and "in phase" endometrium, epithelial PR expression was not different from controls. CONCLUSIONS: The establishment of normal endometrial receptivity appears to be tightly associated with the down-regulation of epithelial PR. Histologic delay, consistent with LPD, is associated with a failure of PR down-regulation and the lack of normal markers of endometrial receptivity. Occult uterine receptivity defects (aberrant beta 3 expression in otherwise normal histology) are regulated differently, suggesting alternate mechanisms also exist which influence endometrial receptivity.

Adult↗

PubMed1996

Altered integrin expression in rheumatoid synovial lining type B cells: in vitro cytokine regulation of alpha 1 beta 1, alpha 6 beta 1, and alpha v beta 5 integrins.

OBJECTIVE: We recently showed that in rheumatoid arthritis (RA) the extracellular matrix around the lining cells is similar to the matrix seen in osteoarthritis, whereas the cellular adhesion apparatus is very different. In hyperplastic synovial membrane there is very little of alpha 6, alpha v, and beta 5 integrin subunits, whereas in noninflammatory synovial membrane these integrins are well expressed. We studied how expression of these cell adhesion molecules is regulated in RA in vitro. METHODS: The integrin expression in 6 different synovial fibroblast strains representing the type B cells and in THP-1 cell line was examined by immunoprecipitation, flow cytometry, and Northern hybridization. RESULTS: Proinflammatory cytokines, especially interleukin 1 beta, increased the expression of alpha 1 integrin in synovial fibroblasts. When the monocyte-like THP-1 cells were induced to differentiate to adherent macrophages they started to express alpha 6 and beta 5 integrin subunits. In adherent THP-1 cells the expression of integrin alpha 6 subunit was strongly enhanced by transforming growth factor-beta and downregulated by the combination of tumor necrosis factor-alpha and interferon-gamma. CONCLUSION: Cytokines regulate the cell adhesion molecules of synovial fibroblasts and mononuclear phagocytes in vitro causing alterations in integrin expression similar to the ones seen in rheumatoid synovium in vivo.

Adult↗

PubMed1997

Blocking of alpha 1 beta 1 integrin strongly improves survival of hepatocytes in allogeneic transplantation.

The survival rate of hepatocytes after allogeneic hepatocyte transplatation (HTX) is low, possibly because of formation of intravascular hepatocyte aggregates. The aim of this study was to determine the role of integrins in intravascular aggregation and intraparenchymal survival of transplanted hepatocytes in a fully allogeneic rat model. First, the expression profile of various integrins was determined on both isolated hepatocytes in vitro and on hepatocyte aggregates in recipient livers after intraportal transplantation of allogeneic hepatocytes. Next, the role of these integrins in hepatocyte aggregation was determined in an in vitro attachment assay on liver sections with function-blocking anti-integrin monoclonal antibodies (mAb). The results showed that anti-alpha 1 beta 1 integrin mAb significantly block hepatocyte attachment to vessel walls and liver parenchyma in vitro. Subsequently, the effect of preincubation of hepatocytes with anti-integrin mAb on their intravascular aggregation and on intraparenchymal survival was studied in an allogeneic HTX model. Preincubation with anti-leukocyte function-associated antigen-1 alpha or anti-beta 2 mAb significantly intravascular hepatocyte aggregation, and anti-leukocyte function-associated antigen-1 alpha mAb enhanced intraparenchymal survival. Preincubation with anti-alpha 1 or anti-beta 1 mAb did not inhibit aggregation but significantly improved survival from 2% to up to 45% at Day 2 after transplantation (p < 0.001). In conclusion, our results suggest that the blocking of alpha 1 beta 1 integrin significantly improves survival of allotransplanted hepatocytes.

Animals↗

PubMed2001

A comparison of ocular melanocyte and uveal melanoma cell invasion and the implication of alpha1beta1, alpha4beta1 and alpha6beta1 integrins.

BACKGROUND/AIMS: Posterior uveal melanoma is the most common intraocular tumour in adults, responsible for the death of approximately 35% of patients. Hepatic metastases are most frequent, and once diagnosed survival is usually less than 1 year. The beta1 family of integrins, alphavbeta3 and MMP-2 and MMP-9 have been implicated in the metastasis of several types of tumour. To study their involvement in uveal melanoma we analysed the expression of the beta1 integrins, alphavbeta3, MMP-2, and MMP-9 in 10 primary posterior uveal melanomas, and correlated expression with invasive potential in vitro. Comparable studies were undertaken on cultures of melanocytes. METHODS: Expression of integrins was studied by immunohistochemistry, secretion of MMP-2 and MMP-9 by zymography, and the invasive potential was assessed using a transwell model. RESULTS: MMP-2 was secreted by all uveal melanomas and seven of 10 secreted MMP-9. Among uveal melanoma, invasion levels of 4-25% were observed and the major integrins expressed were alpha1beta1, alpha2beta1, alpha3beta1, alpha5beta1, and avbeta3. Melanocytes did not express alpha1beta1, alpha4beta1, and alpha6beta1. CONCLUSION: The laminin binding alpha6beta1 integrin was not expressed by either melanocytes or tumours with spindle morphology, which are considered to have a better prognosis. It is possible that expression of the alpha6beta1 integrin may prove useful as a prognostic indicator.

Adult↗

PubMed2000

The collagen receptor integrins have distinct ligand recognition and signaling functions.

Distinct collagen subtypes are recognized by specific cell surface receptors. Two of the best known collagen receptors are members of the integrin family and are named alpha1beta1 and alpha2beta1. Integrin alpha1beta1 is abundant on smooth muscle cells, whereas the alpha2beta1 integrin is the major collagen receptor on epithelial cells and platelets. Many cell types, such as fibroblasts, osteoblasts, chondrocytes, endothelial cells, and lymphocytes may concomitantly express both of the receptors. We have studied the cell biology of these integrins at two levels. First, we have analyzed their ligand binding mechanism and specificity. Second, we have studied their signaling function inside three-dimensional collagen gels. This mini-review summarizes our most recent results. In conclusion, our data indicate that alpha1beta1 and alpha2beta1 integrins have differences in their ligand binding specificity. Furthermore, the two receptors are connected to distinct signaling pathways and their ligation may lead to opposite cellular responses.

Animals↗

PubMed1996

Interactions of human skin fibroblasts with monomeric or fibrillar collagens induce different organization of the cytoskeleton.

Fibrillar collagens represent the most abundant extracellular matrix components surrounding fibroblasts. Although there is a large heterogeneity in the collagen composition and in the physiological functions of different tissues, interactions between cells and native collagens monomers are mediated by only two integrins, the alpha1beta1 and alpha2beta1 integrins. In tissue, fibroblasts are exposed to collagen polymers, supramolecular assemblies which might play a role on the availability of the cell-binding sites at the surface of the fibrils. We have addressed this issue by investigating the patterns of adhesion structures in normal human skin fibroblasts exposed to collagen monomers or polymers. Our results showed that cell morphology, cell adhesion pattern, actin organization, and distribution of integrin subunits, talin, vinculin, and phosphotyrosine-containing proteins are dependent on the supramolecular organization of the collagens. In particular, compared to monomers, collagen polymers induced a looser organization of the actin network and a linear clustering of integrins, talin, vinculin, and phosphotyrosine-containing proteins. These results emphasize the role of the physical state of collagen on cellular interactions and underline the role of the extracellular matrix in the phenotypic modulation of fibroblasts. Furthermore, our studies suggest the existence of a local heterogeneity in the biological activity of collagen fibrils.

Actins↗

PubMed2004

VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins.

Vascular endothelial growth factor-A (VEGF-A) is strongly up-regulated in wounded cutaneous tissue and promotes repair-associated angiogenesis. However, little is known about its role in lymphatic regeneration of the healing skin. We studied wound healing in transgenic mice that overexpress VEGF-A specifically in the epidermis and in wild-type mice in the absence or presence of inhibitors of VEGF-A signaling. Surprisingly, transgenic overexpression of VEGF-A in the skin promoted lymphangiogenesis at the wound healing site, whereas systemic blockade of VEGFR-2 prevented lymphatic vessel formation. Studies in cultured lymphatic endothelial cells revealed that VEGF-A induced expression of the alpha1 and alpha2 integrins, which promoted their in vitro tube formation and their haptotactic migration toward type I collagen. VEGF-A-induced lymphatic endothelial cord formation and haptotactic migration were suppressed by anti-alpha1 and anti-alpha2 integrin blocking antibodies, and systemic blockade of the alpha1 and alpha2 integrins inhibited VEGF-A-driven lymphangiogenesis in vivo. We propose that VEGF-A promotes lymphatic vasculature formation via activation of VEGFR-2 and that lineage-specific differences of integrin receptor expression contribute to the distinct dynamics of wound-associated angiogenesis and lymphangiogenesis.

Animals↗

PubMed2001

Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix.

To date, the precise interactions between bone marrow stromal cells and the extracellular matrix that govern stromal cell development remain unclear. The integrin super-family of cell-surface adhesion molecules represents a major pathway used by virtually all cell types to interact with different extracellular matrix components. In this study, purified populations of stromal precursor cells were isolated from the STRO-1-positive fraction of normal human marrow, by fluoresence-activated cell sorting, and then assayed for their ability to initiate clonogenic growth in the presence of various integrin ligands. Bone marrow-derived stromal progenitors displayed differential growth to fibronectin, vitronectin, and laminin, over collagen types I and III, but showed a similar affinity for collagen type IV. The integrin heterodimers alpha1beta1, alpha2beta1, alpha5beta1, alpha6beta1, alpha(v)beta3, and alpha(v)beta5 were found to coexpress with the STRO-1 antigen on the cell surface of CFU-F, using dual-color analysis. Furthermore, only a proportion of stromal precursors expressed the integrin alpha4beta1, while no measurable levels of the integrin alpha3beta1 could be detected. Subsequent adhesion studies using functional blocking antibodies to different integrin alpha/beta heterodimers showed that stromal cell growth on collagen, laminin, and fibronectin was mediated by multiple beta1 integrins. In contrast, cloning efficiency in the presence of vitronectin was mediated in part by alpha(v)beta3. When human marrow stromal cells were cultured under osteoinductive conditions, their ability to form a mineralized matrix in vitro was significantly diminished in the presence of a functional blocking monoclonal antibody to the beta1 integrin subunit. The results of this study indicate that beta1 integrins appear to be the predominant adhesion receptor subfamily utilized by stromal precursor cells to adhere and proliferate utilizing matrix glycoproteins commonly found in the bone marrow microenvironment and bone surfaces. Furthermore, these data suggest a possible role for the beta1 integrin subfamily during the development of stromal precursor cells into functional osteoblast-like cells.

Antibodies, Monoclonal↗

PubMed2004

Regulation of human beta-cell adhesion, motility, and insulin secretion by collagen IV and its receptor alpha1beta1.

Collagens have been shown to influence the survival and function of cultured beta-cells; however, the utilization and function of individual collagen receptors in beta-cells is largely unknown. The integrin superfamily contains up to five collagen receptors, but we have determined that alpha(1)beta(1) is the primary receptor utilized by both fetal and adult beta-cells. Cultured beta-cells adhered to and migrated on collagen type IV (Col-IV), and these responses were mediated almost exclusively by alpha(1)beta(1). The migration of cultured beta-cells to Col-IV significantly exceeded that to other matrix components suggesting that this substrate is of unique importance for beta-cell motility. The interaction of alpha(1)beta(1) with Col-IV also resulted in significant insulin secretion at basal glucose concentrations. A subset of beta-cells in developing islets was confirmed to express alpha(1)beta(1), and this expression co-localized with Col-IV in the basal membranes of juxtaposed endothelial cells. Our findings indicate that alpha(1)beta(1) and Col-IV contribute to beta-cell functions known to be important for islet morphogenesis and glucose homeostasis.

Aged↗

PubMed2003

Adhesion of human fibroblasts to root-end-filling materials.

This study evaluated the attachment of cultured explants of human periodontal ligament fibroblasts and gingival fibroblasts to different root-end-filling materials. Although periodontal ligament and gingival fibroblasts initially attached avidly to Geristore, these same cells displayed no significant attachment to ProRoot, Tytin amalgam, or SuperEBA. With further incubation on Geristore, the attachment of both periodontal ligament and gingival fibroblasts improved and these cells proliferated. In contrast, no improvement in attachment or proliferation was observed for cells incubated for greater times with ProRoot, Tytin amalgam, or SuperEBA. Because the attachment characteristics of these two groups of fibroblasts were identical, we examined the potential role of the extracellular matrix family of receptors (integrins) on the attachment of gingival fibroblasts. Gingival fibroblast attachment to collagen type I was determined to be dependent on alpha1beta1 and alpha2beta1 integrins, whereas their attachment to the RGD-binding sequence of fibronectin and vitronectin was partially inhibited by antibodies to the beta1 and alphaV integrin subunits. However, attachment of gingival fibroblasts to Geristore was not reduced by the addition of any of the attachment-perturbing anti-integrin antibodies examined. Thus, gingival fibroblasts attach to Geristore, but this attachment was mediated by mechanisms other than integrins.

Aluminum Compounds↗

PubMed2004

The fibril-associated collagen IX provides a novel mechanism for cell adhesion to cartilaginous matrix.

Collagen IX is the prototype fibril-associated collagen with interruptions in triple helix. In human cartilage it covers collagen fibrils, but its putative cellular receptors have been unknown. The reverse transcription-PCR analysis of human fetal tissues suggested that based on their distribution all four collagen receptor integrins, namely alpha1beta1, alpha2beta1, alpha10beta1, and alpha11beta1, are possible receptors for collagen IX. Furthermore primary chondrocytes and chondrosarcoma cells express the four integrins simultaneously. Chondrosarcoma cells, as well as Chinese hamster ovary cells transfected to express alpha1beta1, alpha2beta1, or alpha10beta1 integrin as their only collagen receptor, showed fast attachment and spreading on human recombinant collagen IX indicating that it is an effective cell adhesion protein. To further study the recognition of collagen IX we produced recombinant alphaI domains in Escherichia coli. For each of the four alphaI domains, collagen IX was among the best collagenous ligands, making collagen IX exceptional compared with all other collagen subtypes tested so far. Rotary shadowing electron microscopy images of both alpha1I- and alpha2I-collagen IX complexes unveiled only one binding site located in the COL3 domain close to the kink between it and the COL2 domain. The recognition of collagen IX by alpha2I was considered to represent a novel mechanism for two reasons. First, collagen IX has no GFOGER motif, and the identified binding region lacks any similar sequences. Second, the alpha2I domain mutations D219R and H258V, which both decreased binding to collagen I and GFOGER, had very different effects on its binding to collagen IX. D219R had no effect, and H258V prevented type IX binding. Thus, our results indicate that collagen IX has unique cell adhesion properties when compared with other collagens, and it provides a novel mechanism for cell adhesion to cartilaginous matrix.

Amino Acid Sequence↗

PubMed1999

Collagen integrin receptors regulate early osteoblast differentiation induced by BMP-2.

Studies in several cell types indicate that the actions of integrin receptors for extracellular matrix and receptors for growth factors are synergistic in regulating cellular differentiation and function. We studied the roles of the alpha1beta1 and alpha2beta1 integrin collagen receptors in regulating the differentiation of 2T3 osteoblastic cells in response to bone morphogenetic protein (BMP)-2. The immortalized 2T3 cell line was established from the calvaria of mice transgenic for a BMP-2 promoter driving SV40 T-antigen. These cells require exogenous BMP-2, as well as ascorbic acid and beta-glycerolphosphate, for expression of a mature osteoblast phenotype and formation of a mineralized matrix. To determine how integrin receptors for collagen-I affect BMP-2 signaling, function-perturbing anti-rat alpha1 and/or alpha2 integrin subunit, or anti-type I collagen (Col-I), antibodies were added to human recombinant (hr)BMP-2-treated 2T3 cultures at confluence (C0) or at 4 or 8 days postconfluence (C4, C8). After 4 days of exposure to the antibodies, cultures were assayed for alkaline phosphatase (ALP) mRNA levels and enzyme activity and for cAMP production in response to parathyroid hormone. Addition of anti-collagen-I or both anti-integrin-alpha1 and -alpha2 antibodies to C0 cultures blocked expression of these early osteoblast markers by more than 90%, and also blocked mineralization (0.5-1.8% control) of these cells. In all cases, adding anti-alpha1 or anti-alpha2 antibodies separately produced partial effects, while their combined effect approached that of anti-collagen-I. When antibodies were added to more differentiated 2T3 cells, the inhibitory effects decreased. 2T3 cells carrying constitutively active BMP receptor (caBMPR-IB) showed elevated ALP activity without hrBMP-2; this constitutive activity was also suppressed by alpha1 and alpha2 integrin antibodies and by anti-Col-I antibody. Together, our data suggest that a signal(s) from collagen integrin receptors regulates the response to BMP downstream of BMPR-IB and upstream of the regulation of ALP mRNA and other early markers of osteoblast differentiation.

Alkaline Phosphatase↗

PubMed2004

Transforming growth factor-beta1 stimulates collagen matrix remodeling through increased adhesive and contractive potential by human renal fibroblasts.

Renal tubulointerstitial fibrosis is the common final pathway leading to end-stage renal failure. Tubulointerstitial fibrosis is characterized by fibroblast proliferation and excessive matrix accumulation. Transforming growth factor-beta1 (TGF-beta1) has been implicated in the development of renal fibrosis accompanied by alpha-smooth muscle actin (alpha-SMA) expression in renal fibroblasts. To investigate the molecular and cellular mechanisms involved in tubulointerstitial fibrosis, we examined the effect of TGF-beta1 on collagen type I (collagen) gel contraction, an in vitro model of scar collagen remodeling. TGF-beta1 enhanced collagen gel contraction by human renal fibroblasts in a dose- and time-dependent manner. Function-blocking anti-alpha1 or anti-alpha2 integrin subunit antibodies significantly suppressed TGF-beta1-stimulated collagen gel contraction. Scanning electron microscopy showed that TGF-beta1 enhanced the formation of the collagen fibrils by cell attachment to collagen via alpha1beta1 and alpha2beta1 integrins. Flow cytometry and cell adhesion analyses revealed that the stimulation of renal fibroblasts with TGF-beta1 enhanced cell adhesion to collagen via the increased expression of alpha1 and alpha2 integrin subunits within collagen gels. Fibroblast migration to collagen was not up-regulated by TGF-beta1. Furthermore, TGF-beta1 increased the expression of a putative contractile protein, alpha-SMA, by human renal fibroblasts in collagen gels. These results suggest that TGF-beta1 stimulates fibroblast-collagen matrix remodeling by increasing both integrin-mediated cell attachment to collagen and alpha-SMA expression, thereby contributing to pathological tubulointerstitial collagen matrix reorganization in renal fibrosis.

Actinin↗

PubMed2005

Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy.

BACKGROUND: Tumor development remains one of the major obstacles following organ transplantation. Immunosuppressive drugs such as cyclosporine and tacrolimus directly contribute to enhanced malignancy, whereas the influence of the novel compound mycophenolate mofetil (MMF) on tumor cell dissemination has not been explored. We therefore investigated the adhesion capacity of colon, pancreas, prostate and kidney carcinoma cell lines to endothelium, as well as their beta1 integrin expression profile before and after MMF treatment. METHODS: Tumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 microM MMF and compared to unstimulated controls. beta1 integrin analysis included alpha1beta1 (CD49a), alpha2beta1 (CD49b), alpha3beta1 (CD49c), alpha4beta1 (CD49d), alpha5beta1 (CD49e), and alpha6beta1 (CD49f) receptors, and was carried out by reverse transcriptase-polymerase chain reaction, confocal microscopy and flow cytometry. RESULTS: Adhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 muM MMF. This effect was accompanied by down-regulation of alpha3beta1 and alpha6beta1 surface expression and of alpha3beta1 and alpha6beta1 coding mRNA. Adhesion of the prostate tumor cell line DU-145 was blocked dose-dependently by MMF. In contrast to MMF's effects on HT-29 cells, MMF dose-dependently up-regulated alpha1beta1, alpha2beta1, alpha3beta1, and alpha5beta1 on DU-145 tumor cell membranes. CONCLUSION: We conclude that MMF possesses distinct anti-tumoral properties, particularly in colon and prostate carcinoma cells. Adhesion blockage of HT-29 cells was due to the loss of alpha3beta1 and alpha6beta1 surface expression, which might contribute to a reduced invasive behaviour of this tumor entity. The enhancement of integrin beta1 subtypes observed in DU-145 cells possibly causes re-differentiation towards a low-invasive phenotype.

Cell Adhesion↗

PubMedDate not supplied

Vascular integrins in tumor angiogenesis: mediators and therapeutic targets.

The notion that tumor angiogenesis may have therapeutic implications in the control of tumor growth was introduced by Dr. Judah Folkman in 1971. The approval of Avastin in 2004 as the first antiangiogenic systemic drug to treat cancer patients came as a validation of this visionary concept and opened new perspectives to the treatment of cancer. In addition, this success boosted the field to the quest for new therapeutic targets and antiangiogenic drugs. Preclinical and clinical evidence indicate that vascular integrins may be valid therapeutic targets. In preclinical studies, pharmacological inhibition of integrin function efficiently suppressed angiogenesis and inhibited tumor progression. alphaVbeta3 and alphaVbeta5 were the first vascular integrins targeted to suppress tumor angiogenesis. Subsequent experiments revealed that at least four additional integrins (i.e., alpha1beta1, alpha2beta1, alpha5beta1, and alpha6beta4) might be potential therapeutic targets. In clinical studies low-molecular-weight integrin inhibitors and anti-integrin function-blocking antibodies demonstrated low toxicity and good tolerability and are now being tested in combination with radiotherapy and chemotherapy for anticancer activity in patients. In this article the authors review the role of integrins in angiogenesis, present recent development in the use of alphaVbeta3 and alpha5beta1 integrin antagonists as potential therapeutics in cancer, and discuss future perspectives.

Animals↗