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PubMed1995

Pathological and biological features of mammographically detected invasive breast carcinomas.

The pathological and biological features of a consecutive series of impalpable invasive breast carcinoma, detected by mammography in the prevalent round of the breast screening programme, have been compared with a clinically presenting group of carcinomas in age-matched patients. There was a significantly higher prevalence of tubular carcinomas as well-differentiated infiltrating ductal carcinomas in the mammographically detected group, and a lower prevalence of poorly differentiated infiltrating ductal carcinomas. Lymph node metastasis was found in 6.5% of the impalpable group compared with 53% of the clinical group. The prevalence of oestrogen receptor was much higher in the impalpable group (96%) than in the control group (67%), although there were no significant differences for progesterone receptor. The prevalence of pS2 was also much higher in the impalpable group, as was cathepsin D. This finding is surprising in view of the reported relationship between cathepsin D and poorer survival. p53 and c-erb-2 proteins were detectable in fewer impalpable carcinomas. The mean MIBI (Ki-67) index was lower in the impalpable group (11.6) than in the clinical group (15.25). Within the mammographically detected group there was a significant difference in the MIBI index between tubular carcinomas and the different grades of infiltrating ductal carcinomas, with a wide range in each category but no association with size. The impalpable carcinomas detected by mammography differ from clinically presenting carcinomas in many ways, raising the question of whether a proportion or all would progress (dedifferentiate) with time.

Aged↗
PubMed1995

Role of the PS integrins in Drosophila development.

The PS1 and PS2 integrins of Drosophila are heterodimers of alphaPS1betaPS and alphaPS2betaPS subunits, respectively, with very strong structural similarity to vertebrate integrins. Cell transfection experiments indicate that the PS integrins are receptors for extracellular matrix components and are functionally analogous to vertebrate integrins. Matrix ligands from Drosophila tissues have been identified for PS1 and PS2 integrins, using transformed cells and a cell-spreading assay. Mutations in all three subunit genes have been identified, and the phenotypes of mutants indicate that PS integrins are required for the proper morphogenesis of a number of embryonic tissues. Using methods to produce genetic mosaics and transformation of integrin transgenes into whole animals, integrin functions in adult morphogenesis also have been examined. In the pupal wing, integrins are critically required to maintain the connection between dorsal and ventral epithelia, and recent results suggest that in early pupal development, the integrins are acting as specific receptors, as opposed to a non-specific cell-matrix glue.

Animals↗
PubMed2002

T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?

Pancreatic cancer is an aggressive and potent disease, which is largely resistant to conventional forms of treatment. However, the discovery of antigens associated with pancreatic cancer cells has recently suggested the possibility that immunotherapy might become a specific and effective therapeutic option. T cells within many epithelia, including those of the pancreas, are known to express the alphaEbeta7-integrin adhesion molecule, CD103. The only characterised ligand for CD103 is E-cadherin, an epithelial adhesion molecule which exhibits reduced expression in pancreatic cancer. In our study, CD103 was found to be expressed only by activated T cells following exposure to tumour necrosis factor beta 1, a factor produced by many cancer cells. Significantly, the expression of this integrin was restricted mainly to class I major histocompatibility complex-restricted CD8+ T cells. The human pancreatic cancer cell line Panc-1 was transfected with human E-cadherin in order to generate E-cadherin negative (wild type) and positive (transfected) sub-lines. Using a sensitive flow cytometric adhesion assay it was found that the expression of both CD103 (on T cells) and E-cadherin (on cancer cells) was essential for efficient adhesion of activated T cells to pancreatic cancer cells. This adhesion process was inhibited by the addition of antibodies specific for CD103, thereby demonstrating the importance of the CD103-->E-cadherin interaction for T-cell adhesion. Using a 51Cr-release cytotoxicity assay it was found that CD103 expressing T cells lysed E-cadherin expressing Panc-1 target cells following T cell receptor stimulation; addition of antibodies specific for CD103 significantly reduced this lysis. Furthermore, absence of either CD103 from the T cells or E-cadherin expression from the cancer cells resulted in a significant reduction in cancer cell lysis. Therefore, potentially antigenic pancreatic cancer cells could evade a local anti-cancer immune response in vivo as a consequence of their loss of E-cadherin expression; this phenotypic change may also favour metastasis by reducing homotypic adhesion between adjacent cancer cells. We conclude that effective immunotherapy is likely to require upregulation of E-cadherin expression by pancreatic cancer cells or the development of cytotoxic immune cells that are less dependent on this adhesion molecule for efficient effecter function.

Antigens, CD↗
PubMed2003

Expression of CD18, CD49b, CD49c and CD49e on lens anterior capsules in human cataracts.

PURPOSE: To examine the lens epithelial cells obtained from the anterior lens capsules removed during cataract surgery and detect various subclasses of the cell surface adhesion molecules known as integrins. METHODS: The circular sections of anterior capsules with attached lens epithelial cells (LECs) were obtained during cataract surgery from 28 patients. The lens capsules were immunohistochemically stained. RESULTS: CD49b CD49c, CD49e, and CD18 were detected in varying degrees in specimens obtained from human cataractous lenses. The positive percentages were 33, 75, 33, and 20%, respectively. The most striking feature was the increasing staining profiles towards the edges of the capsules (away from the central part of the lens capsules) for CD49c, suggesting that the LECs showed higher immunoreactivity for this antibody. The immunoreactivity for CD49b and CD49e was weaker. This was absent for CD18 in the central part of the lens capsules. CONCLUSION: The positive expression of antibodies suggests that specific integrin subunits were expressed in LECs of human cataracts. These results suggest that lens epithelial cells expressing CD49b, CD49c, CD49e, and CD18 might be precursors in the process of anterior lens epithelial cell (A cell) adhesion, and hence play a role in anterior capsule opacification or in subsequent migration and a possible role in posterior capsule opacification.

Aged↗
PubMed1999

WT1 expression induces features of renal epithelial differentiation in mesenchymal fibroblasts.

The WT1 tumor suppressor gene, implicated in hereditofamilial and sporadic Wilms' tumor, is required for normal renal development and is up-regulated during the mesenchymal-epithelial transition. NIH3T3 fibroblasts overexpressing WT1 were less proliferative, larger in size and more firmly attached to tissue culture plastic, suggesting an alteration of their state of differentiation. These cells were studied in vivo by subcutaneous injection into nude mice. The resulting tumors exhibited epithelioid histopathology and formed desmosome-like structures. Molecular analyses of these WT1 expressing fibroblasts grown in culture and in nude mice revealed significant alterations in the expression of many kidney epithelial markers. These studies indicate that WT1 expression can initiate features of a program of epithelial differentiation consistent with a prominent role for WT1 in the mesenchymal epithelial transition that occurs during renal development. Through this work we identified a number of novel target genes for the WT1 transcription factor, including uvomorulin, integrin alpha8 and perlecan, and suggest that WTI may activate the IGF-II gene, also implicated in the development of Wilms' tumor.

3T3 Cells↗
PubMed2005

ADP-ribosylation of integrin alpha7 modulates the binding of integrin alpha7beta1 to laminin.

The extracellular domain of integrin alpha7 is ADP-ribosylated by an arginine-specific ecto-ADP-ribosyltransferase after adding exogenous NAD+ to intact C2C12 skeletal muscle cells. The effect of ADP-ribosylation on the structure or function of integrin alpha7beta1 has not been explored. In the present study, we show that ADP-ribosylation of integrin alpha7 takes place exclusively in differentiated myotubes and that this post-translational modification modulates the affinity of alpha7beta1 dimer for its ligand, laminin. ADP-ribosylation in the 37-kDa 'stalk' region of alpha7 that takes place at micromolar NAD+ concentrations increases the binding of the alpha7beta1 dimer to laminin. Increased in vitro binding of integrin alpha7beta1 to laminin after ADP-ribosylation of the 37-kDa fragment of alpha7 requires the presence of Mn2+ and it is not observed in the presence of Mg2+. In contrast, ADP-ribosylation of the 63-kDa N-terminal region comprising the ligand-binding site of alpha7 that occurs at approx. 100 microM NAD+ inhibits the binding of integrin alpha7beta1 to laminin. Furthermore, incubation of C2C12 myotubes with NAD+ increases the expression of an epitope on integrin beta1 subunit recognized by monoclonal antibody 9EG7. We discuss our results based on the current models of integrin activation. We also hypothesize that ADP-ribosylation may represent a mechanism of regulation of integrin alpha7beta1 function in myofibres in vivo when the continuity of the membrane is compromised and NAD+ is available as a substrate for ecto-ADP-ribosylation.

Adenosine Diphosphate Ribose↗
PubMed1998

Stimulation of thrombocytopoiesis decreases platelet beta2 but not beta1 or beta3 integrins.

The expression of CD29, CD61, CD18 and CD11a on platelets was examined by flow cytometry in mice treated with leukaemia inhibitory factor (LIF) or megakaryocyte growth and development factor (PEG-rHuMGDF or mpl-ligand). Treatment for 7-14 d with PEG-rHuMGDF or LIF increased the number of platelets in peripheral blood from 0.9 up to <2.0 x 10(6)/microl. These treatments decreased the expression of CD11a and CD18, whereas that of CD29 or CD61 was not markedly changed. Study after various doses or times of PEG-rHuMGDF administration indicated that a decrease of CD18 expression occurred when platelet counts started to rise. Platelet RNA content was increased in mice treated with PEG-rHuMGDF but double staining indicated that expression of CD18 was not correlated with RNA content. To evaluate integrin expression as a function of time in circulation, platelets were biotinylated in vivo. In normal or PEG-rHuMGDF-treated mice, the expression of CD29 or CD61 did not change, whereas that of CD18 decreased significantly as a function of time in circulation. These findings indicate, firstly, that stimulation of thrombocytopoiesis leads to the release of platelets with a low content of beta2 integrin and, secondly, that this integrin is also selectively lost while in the circulation.

Animals↗
PubMed1996

Circulating immunoglobulin-secreting cells are heterogeneous in their expression of maturation markers and homing receptors.

Immunoglobulin-secreting cells (ISC) in the peripheral blood are active effectors of the human immune defence system on their way to their site of action. We combined immunomagnetic cell separation and ELISPOT to study the expression of maturation markers and homing receptors (HR) on these cells in healthy volunteers. The results revealed that although highly differentiated, peripheral blood ISC are remarkably heterogeneous both with respect to their expression of maturation markers and HR. Moreover, significant differences were demonstrated between the various isotypes. Fewer IgA-secreting cells expressed both markers of early maturation (HLA-DR, HLA-DQ, CD20, and CD21) and of more mature B cells or plasma cells (CD28, CD38, and alpha-syndecan) compared with IgG- and IgM-secreting cells. IgA-secreting cells also showed the lowest proportion of cells positive for the peripheral lymph node HR, L-selectin, or the skin HR, cutaneous lymphocyte antigen (CLA). By contrast, the expression of mucosal HR on IgA-secreting cells did not reveal a more pronounced homing attitude to mucosal tissues than IgG- or IgM-secreting cells. We conclude that peripheral blood ISC are a heterogeneous cell population and that IgA-secreting cells seem to differ from the other isotypes both in respect of expression of HR and the various maturational markers studied.

Adult↗
PubMed2001

Distribution of lymphocytes of the alpha(E)beta(7) phenotype and E-cadherin in normal human urothelium and bladder carcinomas.

The primary aim of this work was to survey normal urothelium and transitional cell carcinoma (TCC) for the presence of T lymphocytes expressing the intraepithelial, CD103(+) phenotype. This antigen defines the alpha(E)beta(7)-integrin. The adhesive counter-receptor for alpha(E)beta(7) is E-cadherin, which is down-regulated during cancer progression. The secondary aim was to determine the pattern of distribution of CD103(+) lymphocytes in relation to E-cadherin expression in bladder cancer. Cryostat sections of normal bladder and TCC were treated with antibodies specific for human CD103, CD3, CD8 and E-cadherin. Visualization was performed by immunoperoxidase or alkaline phosphatase development with light and confocal microscopy. Dual staining and serial sections were used to assess the relationship between these antigens. Four samples of normal bladder and 26 TCC samples were assessed. Occasional T lymphocytes (CD3(+)) were seen in normal urothelium and lamina propria. In the urothelium the majority of these T lymphocytes (71%) were also CD8(+) and of these 68% expressed the CD103 marker. In the lamina propria 62% of the T lymphocytes were CD8(+) and 56% of these expressed the CD103 marker. In carcinomas significantly greater numbers of CD103(+) T lymphocytes were present in the surrounding stroma rather than infiltrating the carcinomas (P = 0.0006). Of those T lymphocytes infiltrating the tumours, 71% were CD8(+) and of these 58% expressed CD103. In the surrounding stroma 52% of lymphocytes were CD8(+) and 82% of this subset expressed CD103. Infiltration by CD103(+) lymphocytes was not related to the intensity of E-cadherin expression. T lymphocytes of the CD103(+) phenotype are present in normal urothelium where they may play a role in immunosurveillance. Rather than infiltrating into carcinomas, these cells predominate in the surrounding stroma which could suggest a failure of immune function.

Antigens, CD↗
PubMed2002

Interaction between apterous and early expression of vestigial in formation of the dorso-ventral compartments in the Drosophila wing disc.

BACKGROUND: Compartment formation is a developmental process that requires the existence of barriers against intermixing between cell groups. In the Drosophila wing disc, the dorso-ventral (D/V) compartment boundary is defined by the expression of the apterous (ap) selector gene in the dorsal compartment. AP activity is under control of dLMO which destabilizes the formation of the AP-CHIP complex. RESULTS: We report that D/V boundary formation in the wing disc also depends on early expression of vestigial (vg). Our data suggest that vg is already required for wing cell proliferation before D/V compartmentalization. In addition, we show that over-expression of vg can, to some extent, rescue the effect of the absence of ap on D/V boundary formation. Early VG product regulates AP activity by inducing dLMO and thus indirectly regulating ap target genes such as fringe and the PSalpha1 and PSalpha2 integrins. CONCLUSION: Normal cell proliferation is necessary for ap expression at the level of the D/V boundary. This would be mediated by vg, which interacts in a dose-dependent way with ap.

Animals↗
PubMed2001

Beta-integrin of Anopheles gambiae: mRNA cloning and analysis of structure and expression.

We have isolated an mRNA encoding a beta integrin subunit of the malaria mosquito Anopheles gambiae. Our analysis predicts a protein that is very similar to betaPS, the fruitfly orthologue. The gene is expressed during all developmental stages and it is found in all body parts, including the midgut. Finally, the expression of the gene does not seem to be modulated during blood meals, except for a substantial increase 48 h posthaematophagy, when digestion is nearly complete.

Amino Acid Sequence↗
PubMed2003

Haemocytes from Pseudoplusia includens express multiple alpha and beta integrin subunits.

Cellular immune responses such as encapsulation involve the adhesion of one or more classes of haemocytes. How insect haemocytes recognize encapsulation targets as foreign or the identity of the molecules regulating haemocyte adhesion is unknown. One of the most important classes of adhesion receptors in mammalian immune cells is the integrins, which form functional heterodimers through different combinations of alpha and beta subunits. Prior studies with the moth Pseudoplusia includens indicated that encapsulation depends on two classes of haemocytes called granulocytes and plasmatocytes. Here we report the cloning and identification of three alpha integrin subunits (alphaPi1-3) and one beta subunit (betaPi1) from P. includens. Northern blot analysis indicated that all four subunits are expressed in granulocytes and that three of the four subunits are expressed in plasmatocytes. Quantification of transcription patterns using real-time PCR revealed that expression of alphaPi2 and betaPi1 increased in granulocytes and plasmatocytes when binding to a foreign surface or forming a capsule. alphaPi2 transcription in plasmatocytes was further increased by granulocyte conditioned medium, plasmatocyte spreading peptide, and the integrin recognition peptide RGD. Collectively, these results suggest that one or more integrins play an important role in regulating haemocyte adhesion during encapsulation.

Amino Acid Sequence↗
PubMed1997

Localization of integrin beta 1, alpha 1, alpha 5 and alpha 9 subunits in the rat testis.

Very late activation (VLA, beta 1; alpha 1; alpha 5, alpha 9) integrins were studied by immunoblotting and immunohistochemistry in the testes of sexually mature rats. All integrin subunits were present in membrane fractions of homogenized testes. Immunohistochemistry revealed that the anti beta 1 antibody recognized peritubular cells and the basement membrane of blood vessels. Immunoreactivity was also demonstrated in the lamina propria, basement membrane, and the basal cytoplasm of Sertoli cells. In elongating spermatids, beta 1 integrin was localized to the acrosome. The alpha 1 subunit was expressed in peritubular cells and in the lamina propria. In the adluminal compartment, round spermatids were stained diffusely for the alpha 1 subunit. Immunoreactivity for alpha 1 integrin was found additionally in the acrosomes of elongating spermatids shortly before their release into the seminiferous tubule lumen. The alpha 5 subunit was expressed in the acrosomes of elongating spermatids as well as in their distal cytoplasm during stages III-VI; the cytoplasmic lobes of elongate spermatids and/or residual bodies also appeared to be immunostained in seminiferous tubules at stages VII-VIII. The alpha 9 subunit was immunolocalized only in the basement membrane and in peritubular cells. These data suggest that integrins are involved in spermatogenesis, in particular in the process of spermatid maturation.

Animals↗
PubMed2003

Delayed behavioural aging and altered mortality in Drosophila beta integrin mutants.

The genetic basis for aging is being intensely investigated in a variety of model systems. Much of the focus in Drosophila has been on the molecular-genetic determinants of lifespan, whereas the molecular-genetic basis for age-related functional declines has been less vigorously explored. We evaluated behavioural aging and lifespan in flies harbouring loss-of-function mutations in myospheroid, the gene that encodes betaPS, a beta integrin. Integrins are adhesion molecules that regulate a number of cellular processes and developmental events. Their role in aging, however, has received limited attention. We report here that age-related declines in locomotor activity are ameliorated and that mean lifespan is increased in myospheroid mutants. The delayed functional senescence and altered mortality in myospheroid flies are independent of changes in body size, reproduction or stress resistance. Our data indicate that functional senescence and age-dependent mortality are influenced by beta integrins in Drosophila.

Animals↗
PubMed2003

Mechanism of beta 1-integrin-mediated hepatoma cell growth involves p27 and S-phase kinase-associated protein 2.

Although cooperative interactions between growth factors and integrins, cell surface receptors for extracellular matrices (ECM), have been reported, little is known about the interaction between hepatocyte growth factor (HGF) and integrin in hepatoma cells. We investigated the effects and mechanisms of integrin on the proliferation of hepatoma cells regulated by HGF. Human HepG2 hepatoma cells stably transfected with beta 1-integrin were treated with HGF and compared with parental and mock-transfected control cells. Cell proliferation and expression of cyclin-dependent kinase (Cdk) inhibitors and S-phase kinase-associated protein 2 (Skp2), were investigated. HGF dose-dependently suppressed the proliferation of parental and mock-transfected HepG2 cells. However, cells overexpressing beta 1-integrin exhibited increased proliferation in response to HGF. Although HGF increased p27 and decreased Skp2 expression in the parental and mock-transfected cells, the p27 and Skp2 levels in cells overexpressing beta 1-integrin were not altered by HGF. Interestingly, HepG2 cells overexpressing beta 1-integrin showed increased Skp2 expression. Furthermore, HGF did not reduce the proliferation of HepG2 cells transfected with antisense p27 or sense Skp2. Thus, HGF suppresses HepG2 cell proliferation by directly increasing p27 expression and indirectly decreasing Skp2 expression, and beta 1-integrin modulates the responsiveness of hepatoma cells to HGF via a p27-dependent manner by increasing Skp2. In conclusion, these results strongly suggest that integrin-mediated signals from the ECM can modulate growth factor-mediated signals in hepatoma cells, and may contribute to the growth of hepatocellular carcinomas.

Carcinoma, Hepatocellular↗
PubMed2002

Hoxa 11 is upstream of Integrin alpha8 expression in the developing kidney.

Mutation of the functionally redundant Hoxa 11/Hoxd 11 genes gives absent or rudimentary kidneys resulting from a dramatic reduction of the growth and branching of the ureteric bud. To understand better the molecular mechanisms of Hoxa 11/Hoxd 11 function in kidney development, it is necessary to identify the downstream target genes regulated by their encoded transcription factors. To this end, we conducted a screen for Hoxa 11-responsive genes in two kidney cell lines. HEK293 cells, which usually do not express Hoxa 11, were modified to allow inducible Hoxa 11 expression. The mK10 cells, derived specifically for this study from Hoxa 11/Hoxd 11 double-mutant mice, were also modified to give cell populations with and without Hoxa 11 expression. Differential display, Gene Discovery Arrays, and Affymetrix genechip probe arrays were used to screen for genes up- or down-regulated by Hoxa 11. Nine genes, PDGF A, Cathepsin L, annexin A1, Mm.112139, Est2 repressor factor, NrCAM, ZNF192, integrin-associated protein, and GCM1, showed reproducible 3-fold or smaller changes in gene expression in response to Hoxa 11. One gene, the Integrin alpha8, was up-regulated approximately 20-fold after Hoxa 11 expression. The Integrin alpha8 gene is expressed together with Hoxa 11 in metanephric mesenchyme cells, and mutation of Integrin alpha8 gives a bud-branching morphogenesis defect very similar to that observed in Hoxa 11/Hoxd 11 mutant mice. In situ hybridizations showed a dramatic regional reduction in Integrin alpha8 expression in the developing kidneys of Hoxa 11/Hoxd 11 mutant mice. This work suggests that the Integrin alpha8 gene may be a major effector of Hoxa 11/Hoxd 11 function in the developing kidney.

Animals↗
PubMed1995

Processing of ADP-ribosylated integrin alpha 7 in skeletal muscle myotubes.

Integrin alpha 7 is a major substrate in skeletal muscle cells for the cell surface, glycosylphosphatidylinositol-anchored, arginine-specific ADP-ribosyltransferase. Since ADP-ribosylarginine hydrolase, the enzyme responsible for cleavage of the ADP-ribosylarginine bond and a component with the transferase of a putative ADP-ribosylation cycle, is cytosolic, the processing of ADP-ribosylated integrin alpha 7 was investigated. Following incubation of differentiated mouse C2C12 myoblasts with [adenylate-32P]NAD and analysis by SDS-polyacrylamide gel electrophoresis under reducing conditions, two [32P]ADP-ribosylated forms of integrin alpha 7 were resolved. By pulse-chase and purification of the radiolabeled proteins on a laminin affinity column, it was demonstrated that a 105-kDa ADP-ribosylated form originated from a mono-ADP-ribosylated 102-kDa form and represented integrin alpha 7 modified at more than one site. The additional site(s) of modification, utilized at higher NAD concentrations, were located in the 63-kDa N-terminal segment of integrin alpha 7. Both [32P]ADP-ribosylated integrins were loosely associated with the cytoskeleton, bound to laminin affinity columns, and immunoprecipitated with antibodies to integrin beta 1. 32P label was rapidly removed from [32P]ADP-ribosylated integrin alpha 7 at either site of modification, a process inhibited by free ADP-ribose or p-nitrophenylthymidine-5'-monophosphate, an alternative substrate of 5'-nucleotide phosphodiesterase. The processed integrin alpha 7 was unavailable for subsequent ADP-ribosylation, although the amount of surface integrin alpha 7 remained constant. During the processing, no loss of label was observed from integrin alpha 7 radiolabeled with [14C]NAD, containing 14C in the nicotinamide proximal ribose, consistent with degradation of the ADP-ribose moiety by a cell surface 5'-nucleotide phosphodiesterase. Thus, cell surface ADP-ribosylation, in contrast to intracellular ADP-ribosylation, is not readily reversed by ADP-ribosylarginine hydrolase and seems to operate outside the postulated ADP-ribosylation cycle.

ADP Ribose Transferases↗