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PubMed2004

Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors.

Hepatoblasts give rise to both mature hepatocytes and cholangiocytes. While Notch signaling has been implicated in the formation of bile ducts composed of cholangiocytes, little is known about the mechanism of lineage commitment of hepatoblasts. Here we describe the role of the Notch pathway in hepatoblast differentiation. Immunohistochemical analysis showed that Jagged1 was expressed in the cells surrounding the portal veins and Notch2 was expressed in most hepatic cells at mid gestation when ductal plates are formed surrounding the portal veins. Interestingly, the Jagged1+ cells were adjacent to ductal plates, suggesting that the Notch signaling is activated in hepatoblasts that undergo differentiation into cholangiocytes. In fact, expression of the Notch intracellular domain in Dlk+ hepatoblasts inhibited hepatic differentiation and significantly reduced the expression of albumin, a marker of both hepatoblasts and hepatocytes. Furthermore, the addition of Matrigel to the hepatoblast culture upregulated the expression of cytokeratin 7 and 19, integrin beta4, and HNF1beta, which are known to be expressed in cholangiocytes. By contrast, downregulation of the Notch signaling by siRNA specific for Notch2 mRNA as well as by the gamma-secretase inhibitor L-685,458 promoted the hepatic differentiation. Consistent with the previous finding that mature cholangiocytes strongly express HNF1beta, but barely express HNF1alpha, HNF4, and C/EBPalpha, activation of the Notch signaling upregulated HNF1beta expression, whereas it downregulated the expression of HNF1alpha, HNF4, and C/EBPalpha. These results suggest that the Notch signaling contributes to form a network of these transcription factors suitable for cholangiocyte differentiation.

Animals↗

PubMed2000

Expression of a highly conserved protein, p27BBP, during the progression of human colorectal cancer.

The highly conserved protein p27BBP is a cytoplasmic interactor of integrin beta4 expressed in epithelia. p27BBP is found in two pools: one nuclear pool enriched in the perinucleolar region, and one cytoplasmic pool. Deletion of p27BBP in yeast is lethal as a result of loss of the ribosomal 60S subunit. The aim of this study was to investigate the distribution of p27BBP in gut epithelium and its behavior during progression of human colorectal carcinomas. Results indicated that p27BBP is high in rapidly cycling cells and decreased in villous cells committed to apoptotic cell death. In dysplastic adenomas and carcinomas, p27BBP displayed a large increase of its nucleolar component that was superimposable to argyrophylic nucleolar organizing region-associated proteins and was associated with the nuclear matrix. Western blotting confirmed increased p27BBP in dysplastic adenomas and in carcinomas. In particular, p27BBP increased progressively from adenomas to carcinomas and, in the latter, was related to the tumor stage. The overexpression of p27BBP corresponded to mRNA up-regulation in carcinomas, supporting the idea of transcriptional or post-transcriptional regulation of its expression. Results suggested that p27BBP alterations are an early event in the transition from benign to malignant colorectal phenotypes and provide a novel tool in surgical pathology.

Adenoma↗

PubMed2004

L1CAM, INP10, P-cadherin, tPA and ITGB4 over-expression in malignant pleural mesotheliomas revealed by combined use of cDNA and tissue microarray.

Malignant pleural mesothelioma (MM) is a rare tumour with high mortality, which can exhibit various morphologies classified as epithelioid, biphasic and sarcomatoid subtypes. To investigate the molecular changes in these tumours, we studied gene expression patterns by combined use of cDNA arrays and tumour tissue microarrays (TMA). Deregulation of the expression of 588 cancer-related genes was screened in 16 MM comprising all three subtypes and compared with references, i.e. normal mesothelial cell lines and pleural mesothelium. Array data were analysed using three statistical methods; principal component analysis (PCA), permutation test and receiver operating characteristic (ROC) curves. Eleven genes were verified by real-time RT-PCR. Genes encoding two adhesion molecules [COL1A2 and integrin beta4 (ITGB4)] and a chemokine (INP10) were up-regulated in MM compared with both the cell lines and pleural mesothelium. There was a type-specific up-regulation of semaphorin E, ITGB4 and P-cadherin in epithelioid MM, matrix metalloproteinase 9 (MMP9) and tissue-type plasminogen activator (tPA) in sarcomatoid MM and neural cell adhesion molecule L1 (L1CAM) and INP10 in biphasic MM. Immunohistochemistry on TMA containing 47 MM (26 epithelioid, 15 sarcomatoid and six biphasic) was performed for five proteins, ITGB4, P-cadherin, tPA, INP10 and L1CAM. INP10 expression was increased in MM in general compared with normal mesothelium, while increased expression of P-cadherin, L1CAM and ITGB4 was more specific in MMs exhibiting an epithelioid growth pattern. The over-expression of tPA was more frequent in epithelioid MM despite higher mRNA levels in sarcomatoid and biphasic MM. We conclude that several proteins, associated with cell adhesion either directly (ITGB4, L1CAM, P-cadherin) or as a regulatory factor (INP10), are differentially expressed in MM. In particular, INP10, ITGB4 and COL1A2 were up-regulated in MM compared with both reference sample types, suggesting a relationship with development of these tumours.

Cell Adhesion↗

PubMed2006

Adhesion structures of amniotic membranes integrated into human corneas.

PURPOSE: The aim of this study was to investigate the structural relationship between integrated amniotic membrane (AM) and corneal tissues in various integration patterns, focusing on adhesion structures along the interface. METHODS: Fourteen eyes of 14 patients (age, 65.8 +/- 13.5 years) underwent penetrating keratoplasty (PKP) 19.3 +/- 20.7 weeks after cryopreserved human AM transplantation (AMT). The corneal buttons (after PKP) and the corresponding original AM (before AMT) were examined with the use of transmission electron microscopy (TEM) and immunohistochemistry for integrin beta4, type VII collagen, and laminin. Main outcome measures included thickness of the corneal epithelium and AM, density of the epithelial desmosomes and hemidesmosomes, continuity, and thickness of the epithelial basement membrane. RESULTS: Integrated AM was found by slit lamp in only 2 of 14 patients, but histology and TEM revealed AM integration in 11 of 14 patients up to 77 weeks after AMT. No amniotic epithelial cell was detected in any cornea with integrated AM stroma. Three basic patterns of integration could be described: subepithelial, intraepithelial, and intrastromal. Hemidesmosomes anchored the corneal epithelial cells to the AM at a density up to 165.3 +/- 22.9 per 100 microm cell membrane length. Discontinuous basement membrane segments 17.2 +/- 4.9 nm thick could be detected. Desmosomes among recovered corneal epithelial cells were found at a density of 21.2 +/- 5.3 per 10 microm cell membrane length. CONCLUSIONS: The AM stroma can integrate into the host corneal tissue. Integration is associated with the formation of adhesion structures such as hemidesmosomes and desmosomes, which provide anchoring and stability of the regenerating corneal epithelium. The presence of integrated AM and adhesion structures with host corneal tissue supports the clinical experience obtained with AMT in ocular surface disease.

Aged↗

PubMed2000

Integrin alpha6beta4 as a suppressor and a predictive marker for peritoneal dissemination in human gastric cancer.

BACKGROUND & AIMS: Because alterations of integrin expression in cancers contribute to cancer cell biology, we analyzed the association between the potential for peritoneal dissemination and integrin expression. METHODS: The dissemination potential of 10 human gastric cancer cell lines in mice with severe combined immunodeficiency (SCID) was compared with the expression of various integrins. The relationship between integrin expression and peritoneal dissemination was also investigated in surgically resected gastric cancer cases. RESULTS: The level of integrin beta4 subunit expression was inversely correlated with dissemination potential. Introduction of a full-length complementary DNA (cDNA) for beta4 subunit into cancer cells showing negligible beta4 subunit expression markedly suppressed peritoneal dissemination and inhibition of endogenous integrin alpha6beta4 by introduction of a cytoplasmic domain-deleted beta4 subunit cDNA into cells showing high expression of beta4 subunit promoted peritoneal dissemination. Apoptosis, which was histologically evident in peritoneal nodules of SCID mice, was induced in the cells with high beta4 subunit expression by attachment to laminin and stimulation with growth factors in vitro. An immunohistochemical study of specimens from 120 cases of primary gastric cancer showed that patients with beta4 subunit-positive tumors exhibited peritoneal dissemination only infrequently (P < 0.0001) and had a better outcome (P < 0.01). CONCLUSIONS: These results indicate that integrin alpha6beta4 is both a suppressor and a predictive marker for peritoneal dissemination in gastric cancer.

Animals↗

PubMed1999

Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells.

Laminin 5 regulates anchorage and motility of epithelial cells through integrins alpha6beta4 and alpha3beta1, respectively. We used targeted disruption of the LAMA3 gene, which encodes the alpha3 subunit of laminin 5 and other isoforms, to examine developmental functions that are regulated by adhesion to the basement membrane (BM). In homozygous null animals, profound epithelial abnormalities were detected that resulted in neonatal lethality, consistent with removal of all alpha3-laminin isoforms from epithelial BMs. Alterations in three different cellular functions were identified. First, using a novel tissue adhesion assay, we found that the mutant BM could not induce stable adhesion by integrin alpha6beta4, consistent with the presence of junctional blisters and abnormal hemidesmosomes. In the absence of laminin 5 function, we were able to detect a new ligand for integrin alpha3beta1 in the epidermal BM, suggesting that basal keratinocytes can utilize integrin alpha3beta1 to interact with an alternative ligand. Second, we identified a survival defect in mutant epithelial cells that could be rescued by exogenous laminin 5, collagen, or an antibody against integrin alpha6beta4, suggesting that signaling through beta1 or beta4 integrins is sufficient for survival. Third, we detected abnormalities in ameloblast differentiation in developing mutant incisors indicating that events downstream of adhesion are affected in mutant animals. These results indicate that laminin 5 has an important role in regulating tissue organization, gene expression, and survival of epithelium.

Ameloblasts↗

PubMed2006

Transcriptomes of human prostate cells.

BACKGROUND: The gene expression profiles of most human tissues have been studied by determining the transcriptome of whole tissue homogenates. Due to the solid composition of tissues it is difficult to study the transcriptomes of individual cell types that compose a tissue. To overcome the problem of heterogeneity we have developed a method to isolate individual cell types from whole tissue that are a source of RNA suitable for transcriptome profiling. RESULTS: Using monoclonal antibodies specific for basal (integrin beta4), luminal secretory (dipeptidyl peptidase IV), stromal fibromuscular (integrin alpha 1), and endothelial (PECAM-1) cells, respectively, we separated the cell types of the prostate with magnetic cell sorting (MACS). Gene expression of MACS-sorted cell populations was assessed with Affymetrix GeneChips. Analysis of the data provided insight into gene expression patterns at the level of individual cell populations in the prostate. CONCLUSION: In this study, we have determined the transcriptome profile of a solid tissue at the level of individual cell types. Our data will be useful for studying prostate development and cancer progression in the context of single cell populations within the organ.

Bone Morphogenetic Proteins↗

PubMed2000

Evidence for differential signaling in human conjunctival epithelial cells adherent to laminin isoforms.

Both the laminin composition of the basement membrane and the keratin intermediate filament composition of the epithelial cell differs between cornea and conjunctiva, suggesting that at least some aspects of ocular surface epithelial cell differentiation may be regulated by extracellular matrix. The purpose of this study was to analyse the role of beta1 integrin in intracellular signaling pathways in human conjunctival epithelial cells adherent to laminin. In addition, the purpose was to compare the phosphorylation kinetics of signaling intermediates in cells adherent to different laminin isoforms. Cell adhesion assays, integrin clustering experiments, and integrin function blocking experiments demonstrated that beta1 but not beta4 integrin mediated human conjunctival epithelial cell adhesion to placental laminin isoforms (laminin-10/11) and induced focal adhesion kinase (FAK) tyrosine phosphorylation. Western blot analysis of cell lysates adherent to placental laminin showed that the tyrosine phosphorylation of p130Cas and FAK was maximally above constitutive levels after 60 min. In cells adherent to EHS laminin (laminin-1), the tyrosine phosphorylation kinetics of tensin, p130Cas, FAK and unknown proteins of 138 kDa and 110 kDa were similar, and peaked above constitutive levels after 30 min. Tyrosine phosphorylation of a 70 kDa protein was induced by cell adhesion to EHS laminin after 5 min, and phosphorylation peaked at 15 min. In contrast, the tyrosine phosphorylation of the 70 kDa protein was undetected in cells adherent to placental laminin. Erk-1 phosphorylation and activation was not differentially modulated by conjunctival epithelial cell adhesion to laminins. However, phosphorylation and activation kinetics of Erk-2 in cells adherent to placental laminin was similar to that observed for FAK and p130Cas. Erk-2 phosphorylation and activation was essentially undetectable in cells adherent to EHS laminin. These observations suggest that human conjunctival epithelial cell adhesion to different laminin isoforms activates different intracellular signaling pathways, and provides support for the hypothesis that extracellular matrix molecules can modulate ocular surface epithelial cell differentiation via alternate signaling pathways.

Antibodies, Monoclonal↗

PubMed1999

Laminin mediates tethering and spreading of colon cancer cells in physiological shear flow.

Under the physiological shear condition, cultured colon cancer cells bound to laminin (LM), but not to fibronectin or vitronectin. Most of the tethered cells did not roll, but arrested immediately and spread within 10-30 min on LM under the continuous presence of shear flow. The tethering of Colo201 was partially inhibited by monoclonal antibodies (mAbs) to alpha6 integrin and a combination of mAbs to beta1 and beta4 integrins, but not by mAb to 67KD laminin receptor. Some Colo201 cells still tethered at 4 degrees C. This suggests that alpha6beta1 and alpha6beta4 integrins participate in Colo201 tethering on LM, although other non-integrin molecules play roles. In contrast, the spread of Colo201 was effectively inhibited by the mAbs to integrin alpha2, alpha6 and beta1 chains. The effect of anti-alpha2 plus anti-alpha6 mAbs was almost equal to anti-beta1, suggesting that Colo201 cells mainly use alpha2beta1 and alpha6beta1 integrins for spreading on LM. When the cells were perfused on subconfluent endothelial cells (HUVEC) cultured on LM, they did not tether on HUVEC but did on coated LM exposed at intercellular gap area. Immunohistochemistry revealed that LM abundantly existed in the cytosol of human portal and hepatic vein endothelial cells. These data suggest that LM can mediate from tethering to spreading of colon cancer cells under the blood flow and plays an essential role in haematogeneous metastasis.

Antibodies, Monoclonal↗

PubMed2004

Protein kinase C alpha/beta inhibitor Go6976 promotes formation of cell junctions and inhibits invasion of urinary bladder carcinoma cells.

Changes in activation balance of different protein kinase C (PKC) isoenzymes have been linked to cancer development. The current study investigated the effect of different PKC inhibitors on cellular contacts in cultured high-grade urinary bladder carcinoma cells (5637 and T24). Exposure of the cells to isoenzyme-specific PKC inhibitors yielded variable results: Go6976, an inhibitor of PKCalpha and PKCbeta isoenzymes, induced rapid clustering of cultured carcinoma cells and formation of an increased number of desmosomes and adherens junctions. Safingol, a PKCalpha inhibitor, had similar but less pronounced effects. In contrast, a PKCdelta inhibitor, rottlerin, had an opposite effect on cell clustering and caused dissociation of cell junctions. A broad-spectrum PKC inhibitor bisindolylmaleimide I did not have any apparent effect on the morphology of the cultures or on the number of cell junctions. Additional studies with Go6976 demonstrated that inhibition of PKCalpha and beta isoenzymes induced translocation of beta1-integrin from the cell-matrix junctions and that beta4-integrin was translocated to face the culture substratum. Go6976 was also highly effective in inhibiting migration of carcinoma cells and inhibited invasion through artificial basement membrane. Our results on urinary bladder carcinoma cells emphasize that Go6976 is a potential anticancer drug due to its effects on cell-cell and cell-matrix junctions, migration, and invasion. Furthermore, the results may be explained by changes in PKC activation balance promoted by inhibition of PKCalpha/beta.

Actins↗

PubMed2004

Human intestinal epithelial crypt cell survival and death: Complex modulations of Bcl-2 homologs by Fak, PI3-K/Akt-1, MEK/Erk, and p38 signaling pathways.

To investigate the mechanisms responsible for survival and apoptosis/anoikis in normal human intestinal epithelial crypt cells, we analyzed the roles of various signaling pathways and cell adhesion on the expression of six Bcl-2 homologs (Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, Bad) in the well established HIEC-6 cell model. Pharmacological inhibitors and/or dominant-negative constructs were used to inhibit focal adhesion kinase (Fak) and p38 isoforms, as well as the phosphatidylinositol 3'-kinase (PI3-K)/Akt-1 and mitogen-activated protein kinase [MAPK] kinase (MEK)/extracellular regulated kinases (Erk) pathways. Cell adhesion was disrupted by antibody-inhibition of integrin binding or forced cell suspension. The activation levels of studied kinase pathways were also analyzed. Herein, we report that beta1 integrins, Fak, and the PI3-K/Akt-1 pathway, but not beta4 integrins or the MEK/Erk pathway, are crucial for the survival of HIEC-6 cells. Conversely, p38beta, but not p38alpha or gamma, is required for the induction of apoptosis/anoikis in HIEC-6 cells. However, each of the signaling molecules/pathways analyzed were found to affect distinctively the individual expression of the Bcl-2 homologs studied. For example, the inhibition of the PI3-K/Akt-1 pathway down-regulated Bcl-XL, Mcl-1, and Bad, while at the same time up-regulating Bax, whereas the inhibition of Fak up-regulated both Bax and Bak, down-regulated Bad, and did not affect the other Bcl-2 homologs analyzed. These results indicate that integrins, Fak, PI3-K/Akt-1, MEK/Erk, and p38 isoforms perform distinct roles in the regulation of HIEC-6 cell survival and/or death. In addition, our data show that the functions performed by these molecules/pathways in promoting cell survival or apoptosis/anoikis translate into complex, differential modulations of individual Bcl-2 homologs.

Apoptosis↗

PubMed2005

Ascites induces modulation of alpha6beta1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma.

Interactions between cancer cells and the surrounding medium are not fully understood. In this study, we demonstrate that ascites induces selective changes in the expression of integrins and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) in ovarian cancer cells. We hypothesise that this change of integrin and uPA/uPAR expression triggers signalling pathways responsible for modulating phenotype-dependent functional changes in ovarian cancer cells. Human ovarian surface epithelial (HOSE) cell lines and epithelial ovarian cancer cell lines were treated with ascites for 48 h. Ascites induced upregulation of alpha6 integrin, without any change in the expression of alphav, beta1 and beta4 integrin subunits. Out of the four ovarian cancer cell lines studied, ascites induced enhancement in the expression of uPA/uPAR in the more invasive OVCA 433 and HEY cell lines without any change in the noninvasive OVHS1 and moderately invasive PEO.36 cell lines. On the other hand, no change in the expression of alpha6 integrin or uPAR, in response to ascites, was observed in HOSE cells. In response to ascites, enhancement in proliferation and in adhesion was observed in all four ovarian cancer cell lines studied. In contrast, no significant increase in proliferation or adhesion by ascites was observed in HOSE cells. Ascites-induced expression of uPA/uPAR correlated with the increased invasiveness of HEY and OVCA 433 cell lines but was not seen in OVHS1, PEO.36 and HOSE cell lines. Upregulation of alpha6 integrin and uPA/uPAR correlated with the activation of Ras and downstream Erk pathways. Ascites-induced activation of Ras and downstream Erk can be inhibited by using inhibitory antibodies against alpha6 and beta1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and invasive functions of ovarian cancer cell lines. Based on these findings, we conclude that ascites can induce selective upregulation of integrin and uPA/uPAR in ovarian cancer cells and these changes may modulate the functions of ovarian carcinomas.

Ascites↗

PubMed2006

Comparison of reactivity and epitope recognition between sera from American and Italian patients with oral pemphigoid.

Mucous membrane pemphigoid (MMP) (also known as cicatricial pemphigoid) is a rare autoimmune mucocutaneous blistering disease that affects mucous membranes derived from stratified squamous epithelium and the skin. A subset of MMP affects only the oral cavity and is referred to as the oral pemphigoid (OP). MMP and OP are characterized by subepithelial vesicles on histology and in vivo deposition of immunoglobulins and complement at the basement membrane zone (BMZ) on immunopathology. Previous studies have shown that sera of patients with MMP bind to human integrin beta4, while sera of patients with oral pemphigoid bind to the integrin alpha6 component of the heterodimer. The prognosis in MMP is grave but excellent in OP. In this study we compare the binding of sera from patients with OP from Boston, MA, USA to Naples, Italy, and attempt to identify an epitope to which the anti-integrin alpha6 human autoantibody binds. Our results indicate that the sera from Boston and Naples are identical in their reactivity. They recognize a fragment I (AA 23-462) and its subfragment IB (AA 217-462) only, in the human integrin alpha6 molecule. Blocking studies, immunoprecipitation and immunoabsorbtion studies confirm the presence of this single 245 AA region. Antibodies to subfragment IB cause BMZ separation in organ culture using normal human oral mucosa as substrate. This preliminary study indicates that patients on both continents may have similar reactivity and suggests that an intercontinental study group could be established to advance our understanding of the pathogenesis of OP and the biology of anti-alpha6 integrin autoantibodies.

Animals↗

PubMed2001

Human papillomavirus type 6b virus-like particles are able to activate the Ras-MAP kinase pathway and induce cell proliferation.

The initial step in viral infection is the attachment of the virus to the host cell via an interaction with its receptor. We have previously shown that a receptor for human papillomavirus is the alpha6 integrin. The alpha6 integrin is involved in the attachment of epithelial cells with the basement membrane, but recent evidence suggests that ligation of many integrins results in intracellular signaling events that influence cell proliferation. Here we present evidence that exposure of A431 human epithelial cells to human papillomavirus type 6b L1 virus-like particles (VLPs) results in a dose-dependent increase in cell proliferation, as measured by bromodeoxyuridine incorporation. This proliferation is lost if VLPs are first denatured or incubated with a monoclonal antibody against L1 protein. The MEK1 inhibitor PB98059 inhibits the VLP-mediated increase in cell proliferation, suggesting involvement of the Ras-MAP kinase pathway. Indeed, VLP binding results in rapid phosphorylation of the beta4 integrin upon tyrosine residues and subsequent recruitment of the adapter protein Shc to beta4. Within 30 min, the activation of Ras, Raf, and Erk2 was observed. Finally, the upregulation of c-myc mRNA was observed at 60 min. These data indicate that human papillomavirus type 6b is able to signal cells via the Ras-MAP kinase pathway to induce cell proliferation. We hypothesize that such a mechanism would allow papillomaviruses to infect hosts more successfully by increasing the potential pool of cells they are able to infect via the initiation of proliferation in resting keratinocyte stem and suprabasal cells.

Adaptor Proteins, Signal Transducing↗

PubMed2000

CD46 (membrane cofactor protein) associates with multiple beta1 integrins and tetraspans.

The tetraspans associate with a large number of surface molecules, including a subset of beta1 integrins and, indirectly through CD19, with the complement receptor CD21. To further characterize the tetraspan complexes we have raised and selected monoclonal antibodies (mAb) for their ability to immunoprecipitate a molecule associated with CD9. A unique mAb was identified which recognizes the complement regulator CD46 (membrane cofactor protein). CD46 associated in part with several tetranspans and with all beta1 integrins that were tested (CD29/CD49a, CD29/CD49b, CD29/CD49c, CD29/CD49e, CD29/CD49f) but not with beta4 integrins. These data, together with cross-linking experiments showing the existence in living cells of CD46/integrin complexes, suggest that CD46 associates directly with beta1 integrins and indirectly with tetraspans. CD46 also acts as a receptor for measles virus; however, mAb to various integrins and tetraspans did not modify the virus fusion entry step.

Animals↗

PubMed2005

Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility.

PURPOSE: Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor. We recently reported that after protein kinase C activation, colocalization of alpha6beta4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors. EXPERIMENTAL DESIGN: Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility. RESULTS: The majority of pancreatic and colorectal tumors expressed the alpha2, alpha3, alpha6, beta1, and beta4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of alpha6beta4 and CO-029 was restricted to tumor cells, whereas alpha1, alpha2, alpha3, alpha6, beta1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and beta1 expression was observed at comparably high levels in healthy pancreatic tissue. alpha3beta1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas alpha6beta4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with beta4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration. CONCLUSION: alpha6beta4 is selectively up-regulated in pancreatic and colorectal cancer. The association of alpha6beta4 with CD151 and CO-029 correlates with increased tumor cell motility.

Adenocarcinoma↗

PubMed2006

Ultraviolet B radiation suppresses Langerhans cell migration in the dermis by down-regulation of alpha4 integrin.

BACKGROUND/PURPOSE: Ultraviolet B (UVB) radiation affects the migration and function of epidermal Langerhans cells (LC) and causes immunosuppression of contact hypersensitivity. It is known that LC leaves the epidermis after exposure to UVB. To know the behavior of LC in the dermis after UVB radiation, we studied the effect of UVB radiation on the expression of integrin families on freshly isolated or cultured murine LC. We also examined whether UVB radiation affects the migration of LC to secondary lymphoid tissue chemokine (SLC/6Ckine). METHODS: Integrin expressions of murine LC cultured in epidermal cell suspension were analyzed using flowcytometry. We used murine LC sorted flowcytometrically for binding assay to extracellular matrix and for migration assay to chemokine. Skin explant assay and immnohistochemical staining for 'cords formation' were performed as previously described. RESULTS: Twenty and 40 mJ/cm2 of UVB radiation down-regulated the expression of alpha4 integrin on 24 h-cultured LC, but not that of alpha6, beta1, or beta4 integrin. The number of cultured LC adhered to fibronectin, a ligand for alpha4 integrin, was decreased after UVB irradiation, while that to laminin, a ligand for alpha6 integrin, was not influenced. UVB radiation reduced the number of migrating LC to SLC. Furthermore, skin sheet explant experiments showed that UVB radiation inhibited the 'cords' formation in dermal vessels of the 48 h-cultured skin. CONCLUSIONS: These data suggest that UVB radiation may suppress the migration of LC from the dermis to lymphatic vessels. UVB radiation may downregulate the adherence of LC to dermal fibronectin and migration to SLC, and consequently suppress the migration of LC from the UVB-irradiated dermis to lymphatics.

Animals↗

PubMed2005

Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration.

In this study we analyzed the proteolytic activity of MMP-19 and its impact on keratinocyte migration. In the HaCaT keratinocyte cell line overexpressing wild-type MMP-19 (HaCaT-WT), transmigration through fibrin and type IV collagen matrices was significantly increased compared to cells harboring a catalytically inactive mutant (HaCaT-EA). Studying the expression of MMP-19 in early stages of squamous cell cancer (SCC), we found co-localization of MMP-19 and laminin 5 at the invading tumor front but not in suprabasal epidermis of the tumor. Examination of laminin 5 processing revealed increased processing of the gamma2 chain in the medium and matrix of HaCaT-WT cells and degradation by recombinant human MMP-19 to 105-kDa and 80-kDa fragments. Parental HaCaT grown on the matrix of HaCaT-WT and HaCaT-EA cells displayed differential tyrosine phosphorylation. Using integrin blocking and stimulating antibodies we could attribute these differences to a shift from beta4-integrin-dependent signaling on the HaCaT-EA matrix toward alpha3-integrin-dependent signaling on the HaCaT-WT matrix. As a consequence, parental HaCaT showed increased migration on the matrix of HaCaT-WT cells. These data suggest that the MMP-19-dependent processing of the gamma2 chains leads to the integrin switch favoring epithelial migration and that MMP-19 actively participates in the early stages of SCC invasion.

Cell Movement↗