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PubMed2001

Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer.

We recently established a new human inflammatory breast cancer (IBC) xenograft (WIBC-9) originating from a patient with IBC. The graft was transplantable in BALB/c nude and severe combined immunodeficient (SCID) mice. WIBC-9 was frequently accompanied by lung metastasis and exhibited erythema of the overlying skin, reflecting its human counterpart. Histological study of the original tumor and WIBC-9 revealed invasive ductal carcinoma with a hypervascular structure of solid nests and marked lymphatic permeation in the overlying dermis. In the central part of the solid nests, absence of endothelial cells, central necrosis, and fibrosis were observed. In vitro, WIBC-9 formed tube-like structures and loops, reflecting its in vivo feature and its human counterpart. WIBC-9 exhibited aneuploidy, ErbB-2 gene amplification, and an absence of estrogen receptor and progesterone receptor, which is consistent with IBC. Comparative studies of WIBC-9, three established non-IBC xenografts, and a human breast cancer cell line (SK-BR3) by reverse transcription-PCR, ELISA, and immunohistochemistry indicated that certain human genes (interleukin 8, vascular epidermal growth factor, basic fibroblast growth factor, angiopoietin 13, Flt-1, Tie-2, and Tie-1) and certain murine genes (integrin alpha(v)beta3, flt-1, tie-2, vascular epidermal growth factor, and CD31) were overexpressed in exposure to tumor cells. The molecular basis and these unique histological features may be associated with aggressive IBC on angiogenic and nonangiogenic pathways.

Angiogenesis Inducing Agents↗
PubMed2003

A novel role of fibrin in epidermal healing: plasminogen-mediated migration and selective detachment of differentiated keratinocytes.

Recent studies have shown that fibrin promotes epidermal regeneration in vitro and maintains the stem cell population after transplantation of keratinocytes in vivo. As epidermal keratinocytes do not express integrin alpha(v)beta3, the receptor for fibrin and fibrinogen, the mechanism through which fibrin affects epidermal cells remains elusive. To investigate the role of fibrin in epidermal wound healing, we developed an in vitro model in which fibrin was added to the top of wounded keratinocyte monolayers grown on collagen. With this matrix topology, keratinocytes migrate between the collagen on their basal side and fibrin on their apical side mimicking migration of the epidermis in vivo. Using this model, we found that fibrin promoted keratinocyte migration in low and high calcium concentrations by exposing the cells to plasminogen. The migration rate depended strongly on the concentration of fibrinogen and the rate of plasmin-mediated fibrin degradation. Surprisingly, fibrin and fibrinogen caused significant detachment of keratinocytes which was prevented by the addition of calcium. Further examination using flow cytometry revealed that the detached cells were larger, more granular, and had very low levels of beta1 integrin, which are all signs of differentiated keratinocytes. Our results suggest a novel dual role of fibrin in epidermal healing. First, fibrin promotes keratinocyte migration indirectly by exposing plasminogen to migrating cells, and second, fibrin selectively disrupts adhesion of differentiated keratinocytes. Our data are novel and may have important implications in understanding wound healing and in the use of fibrin as a biomaterial for protein and gene delivery.

Calcium↗
PubMed2001

Integrin alpha(v)beta1 is an adenovirus coreceptor.

The human embryonic kidney (HEK293) cell line, commonly used for recombinant adenovirus (Ad) propagation, does not express the Ad coreceptor alpha(v)beta3 or alpha(v)beta5 integrins, yet these cells are efficiently infected by Ad vectors. Here we demonstrate that Ad binds to HEK293 cells via the fiber receptor CAR and is subsequently internalized via interaction with integrin alpha(v)beta1. Function-blocking antibodies directed against alpha(v) or beta1, but not beta3, beta5, or alpha5, integrin subunits block Ad infection and viral endocytosis. Therefore, alpha(v)beta1 serves as a coreceptor for Ad infection, and the lack of beta3 and/or beta5 but the relatively high expression of alpha(v)beta1 integrins on certain tumor cell types may explain why these cells are readily transduced by Ad vectors.

Adenoviridae↗
PubMed2004

Urokinase-type plasminogen activator receptor is involved in mediating the apoptotic effect of cleaved high molecular weight kininogen in human endothelial cells.

Cleaved high molecular weight kininogen (HKa) has been shown to inhibit in vivo neovascularization and induce apoptosis of endothelial cells. We have shown that HKa-induced apoptosis correlated with its antiadhesive effect and was regulated by extracellular matrix (ECM) proteins. In this study, we identified the urokinase-type plasminogen activator receptor (uPAR) as a target of HKa activity at the endothelial cell surface. Anti-uPAR antibodies blocked the apoptotic effect of HKa. Further studies revealed that uPAR formed a signaling complex containing integrin alpha(v)beta3 or alpha5beta1, caveolin, and Src kinase Yes in endothelial cells. HKa physically disrupted the formation of this complex in a manner that paralleled its apoptotic effect. For the first time, our results provide a mechanistic explanation for the previous observation that HKa selectively induces apoptosis of endothelial cells grown on vitronectin, but not cells grown on fibronectin. These data also resolve the controversial role of uPAR in mediating the apoptotic and antiadhesive activities of HKa.

Antibodies, Monoclonal↗
PubMed2001

Autologous antileukemic immune response induced by chronic lymphocytic leukemia B cells expressing the CD40 ligand and interleukin 2 transgenes.

Although the B cells of chronic lymphocytic leukemia (B-CLL cells) express both tumor-specific peptides and major histocompatibility complex (MHC) class I antigens, they lack the capacity for costimulatory signaling, contributing to their protection against host antitumor immunity. To stimulate CLL-specific immune responses, we sought to transfer the human CD40 ligand (hCD40L) gene to B-CLL cells, using an adenoviral vector, in order to upregulate costimulating factors on these cells. Because efficient gene transduction with adenoviral vectors requires the expression of virus receptors on target cells, including the coxsackievirus B-adenovirus receptors (CAR) and alpha(v) integrins, we cocultured B-CLL cells with human embryonic lung fibroblasts (MRC-5 line). This exposure led to increased expression of integrin alpha(v)beta3 on B-CLL cells, which correlated with higher transduction rates. Using this novel prestimulation system, we transduced B-CLL cells with the hCD40L gene. The Ad-hCD40L-infected cells had higher expression of B7 molecules and induced activation of autologous T cells in vitro, but these T cells could not recognize parental leukemic cells. By contrast, an admixture of Ad-hCD40L-positive cells and leukemic cells transduced with the human interleukin 2 (IL-2) gene produced greater T cell activation than did either immunostimulator population alone. Importantly, this combination generated autologous T cells capable of specifically recognizing parental B-CLL cells. These findings suggest that the combined use of genetically modified CD40L-expressing B-CLL cells in combination with IL-2-expressing B-CLL cells may induce therapeutically significant leukemia-specific immune responses.

Adenoviridae↗
PubMed2006

Homologous peptide of connective tissue growth factor ameliorates epithelial to mesenchymal transition of tubular epithelial cells.

The hallmark of failing renal transplants is tubular atrophy and interstitial fibrosis. The cytokine connective tissue growth factor (CTGF or CCN2) plays an important role in epithelial-mesenchymal transition (EMT) of tubular epithelial cells (TECs). A unique domain within CTGF (IRTPKISKPIKFELSG) which binds to its potential receptor integrin alpha v beta3 has been identified. This study was carried out to further characterize a synthetic hexadeca-peptide (P2) homologous to this domain and to determine its effect on CTGF-mediated solid phase cell adhesion, EMT induction and fibrogenesis in rat renal NRK-52E cells. Results showed that both P2 and recombinant CTGF bound to NRK-52E cells. Unlike CTGF, P2 had little effect on EMT induction including cytoskeleton remodeling and expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin, nor did it have effect on fibrogenic induction including alternation of extracellular matrix (ECM) proteins, collagen type I and IV at gene and protein levels. All data showed that P2 bound preferably on the surface of NRK-52E cells and inhibited the effect of CTGF on EMT induction and cell fibrogenesis, probably by occupying the binding sites of CTGF within its potential receptors. Therefore, P2 may be used as a potential anti-fibrotic agent.

Actins↗
PubMed1997

Resistance to IL-1 anti-proliferative effect, accompanied by characteristics of advanced melanoma, permits invasion of human melanoma cells in vitro, but not metastasis in the nude mouse.

We reported earlier that IL-1 inhibits the growth of human melanoma cells (A375-6), and that these cells become resistant to IL-1 after prolonged periods of culture. The resistant cells constitutively produce IL-alpha and IL-6 with IL-6 production was induced by endogenous IL-1 in an autocrine manner. The cells are also resistant to IL-6 anti-proliferative effects. In the present study, we show that the resistant clones exhibited up-regulated expression of intercellular-adhesion molecule 1 (ICAM-1) and vitronectin receptor (integrin alpha(v)beta3) when compared with the IL-1-sensitive clone, A375-6. Moreover, these IL-1-resistant clones exhibited many other metastatic characteristics, such as expression of IL-8 mRNA, production of matrix metalloproteinases (MMP-2 and MMP-9), and augmented invasion activity. However, contrary to our expectations, the IL-1-resistant cells did not exhibit experimental metastasis in a nude-mouse model, similarly to the IL-1-sensitive parental A375-6 cell line. In contrast, the highly metastatic clone A375-SM exhibited alpha(v)beta3 expression at a level comparable to that of the IL-1-resistant cells, but expressed low or no ICAM-1, metalloproteinase and displayed little in vitro invasion activity. These results show that the metastatic characteristics of IL-1-resistant cells are not sufficient to produce metastasis in vivo and suggest that these resistant clones may provide a good model system for characterizing the molecular mechanisms of metastasis.

Animals↗
PubMed2001

Expression in Pichia pastoris and characterization by circular dichroism and NMR of rhodostomin.

Rhodostomin (Rho) is a snake venom protein isolated from Calloselasma rhodostoma. Rho is a disintegrin that inhibits platelet aggregation by blocking the binding of fibrinogen to the integrin alpha(IIb)beta3 of platelets. Rho produced in Escherichia coli inhibited platelet aggregation with a K(I) value of 263 nM. Although functional, Rho produced in E. coli is misfolded based on our 2D and 3D NMR studies. In order to correct the folding problem, Rho was expressed in Pichia pastoris. The recombinant Rho expressed in P. pastoris inhibited platelet aggregation with a resulting K(I) value of 70 nM. This is the same potency as that of native Rho. CD analysis showed that the secondary structures of Rho are pH-independent and contain 3.5-7.9% alpha-helix, 48.2-50.5% beta-structures, and 42.3-47% coil. The sequential assignment and structure analysis of Rho were obtained using 2D and 3D 15N-edited NMR spectra. These results provide the first direct evidence that highly disulfide-bonded disintegrin can be expressed in P. pastoris with the correct fold. This evidence may serve as the basis for exploring the structure and function relationships as well as the dynamics of disintegrin and its variants.

Amino Acid Sequence↗
PubMed2005

Bovine adenovirus type 3 internalization is independent of primary receptors of human adenovirus type 5 and porcine adenovirus type 3.

Usefulness of adenoviral vectors derived from human adenovirus (HAd) type 5 (HAd5) is mainly limited by wide prevalence of preexisting anti-HAd5 immunity as well as non-specific tissue tropism of these vectors. As an alternative, non-human adenoviral vectors including bovine adenovirus type 3 (BAd3) are currently being investigated. Non-prevalence of BAd3 in humans and its ability to evade preexisting HAd immunity are some of the features that make BAd3 a promising vector for human gene delivery. BAd3 appears to have a tissue tropism distinct from that of HAd5 and also the repertoire of cells efficiently transduced by BAd3 is different. We performed antibody-mediated receptor blocking experiments to show that BAd3 internalization was independent of coxsackievirus-adenovirus receptor, the primary determinant of HAd5 tropism, or integrin alpha(v)beta3, a secondary molecule involved in HAd5 entry. Using homologous and heterologous knob-mediated competition assays with recombinant knobs of HAd5, porcine adenovirus type 3 (PAd3), or BAd3, we observed that BAd3 internalization was independent of the primary receptors of HAd5 and PAd3. These results provide support for further exploration of BAd3 vectors for designing targeted vectors for human gene therapy.

Adenoviridae↗
PubMed2006

Novel biomarkers in malignant melanoma.

Cutaneous malignant melanoma remains the leading cause of skin cancer death in industrialized countries. Melanoma progression is well defined in its clinical and histopathological aspects (Breslow's index, tumour size, ulceration, or vascular invasion), which also give hints to prognosis of the patient. Use of molecular markers should therefore give additional information which cannot be determined by routine histopathology. Markers showing only a correlation to Clark level or tumour size are not useful. Several molecules influencing invasiveness and metastatic dissemination of melanoma have been identified. Expression of these molecules has been studied in primary melanoma and correlated with prognosis. Moreover, several tumour suppressors and oncogenes have been shown to be involved in melanoma pathogenesis, including CDKN2A, PTEN, TP53, RAS and MYC, but have not been related to melanoma subtypes or validated as prognostic markers. In the past, in melanoma, an increase in the number of positive tumour cells for Ki67 (detected by Mib1), cyclin A, cyclin D, MMP-2, integrins beta1 and beta3 or osteonectin were considered as factors of poor prognosis as well as the decrease in p16, p27, and Melan A. However, only a small subset of these proteins has a prognostic value independent of tumour thickness. The recent development of high-throughput technologies analyzing global molecular profiles of cancer is bringing up previously unknown candidate genes involved in melanoma, such as Wnt-5A and B-raf. Here, recently published data related to new genes involved in melanoma pathogenesis, which may represent important biomarkers for the identification of genetic profiles or indication of progression of melanoma, are reviewed.

Animals↗
PubMed2004

Tumor-stromal cell contact promotes invasion of human uterine cervical carcinoma cells by augmenting the expression and activation of stromal matrix metalloproteinases.

OBJECTIVE: The augmentation of the expression and activation of matrix metalloproteinases (MMPs) is associated with tumor invasion and metastasis. In addition, tumor-stromal cell contact provides a crucial signal for regulating the pericellular proteolysis for the progression of tumor invasiveness. The present study evaluates the regulation of the expression and activation of MMPs and tissue inhibitors of metalloproteinases (TIMPs) by tumor-stromal cell contact in an in vitro co-culture model of human uterine cervical carcinoma cells and human uterine cervical fibroblasts. METHODS: When human uterine cervical carcinoma SKG-II cells were co-cultured with human uterine cervical fibroblasts (HUCFs), the invasive activity of SKG-II cells was analyzed using an in vitro invasion assay using Matrigel. The production, mRNA expression and activation of MMPs and TIMPs were monitored by Western blot and Northern blot analyses and gelatin zymography. RESULTS: SKG-II cells, which constitutively produced membrane-type 1 MMP (MT1-MMP) and a trace of proMMP-2 but neither TIMP-1 nor TIMP-2, showed poor invasiveness in vitro. Upon co-culturing with HUCFs, SKG-II cells were found to transform to the invasive phenotype by enhancing the production and mRNA expression of tumoral MT1-MMP. In addition, a sequential increase in the activation of fibroblast proMMP-2 was observed along with the formation of an MT1-MMP-TIMP-2-proMMP-2 complex on the tumor cell surface. Furthermore, the production and gene expression of fibroblast proMMP-1 and proMMP-3 were augmented under co-culture conditions, whereas mRNA expression of proMMP-2, TIMP-1 and TIMP-2 was unchanged. Moreover, we demonstrated the partial involvement of tumor-cell-derived soluble factors in the augmentation of the production of proMMP-1 and proMMP-3 in HUCFs. However, anti-integrin beta1 and beta3 antibodies failed to abolish the augmentation of fibroblast proMMP-3 production and proMMP-2 activation in the co-culture. CONCLUSION: Cell-cell contact between cervical carcinoma cells and peripheral stromal fibroblasts augments the production and activation of MMPs, and therefore the subsequent imbalance between MMPs and TIMPs may result in the progression of invasiveness of cervical carcinoma cells in vivo.

Cell Communication↗
PubMed2002

Sustained activation of MEK1-ERK1/2 pathway in membrane skeleton occurs dependently on cell adhesion in megakaryocytic differentiation.

A human megakaryoblastic cell line, CMK, was treated with 12-o-tetradecanoylphorbol-13-acetate (TPA) for differentiation-induction. We examined TPA-induced activation of the MEK1-ERK1/2 pathway in the 100,000g Triton X-insoluble fraction of CMK cells as the membrane skeleton and researched the relation of the MEK1-ERK1/2 activation with integrin expression. We found that this activation was divided into two phases: the first activation occurred transiently in the membrane skeleton fraction of the suspended cell status and diminished after 1h; and the second sustained activation was maintained by cell adhesion. TPA-treated CMK cells revealed increased expression of integrins alphaIIb and beta3 only when the cell adhesion persisted, regardless of the difference of culture substratum. Sustained activation of the MEK1-ERK1/2 pathway is generated in the membrane skeleton by continuous cell adhesion and seems to be essential to TPA-induced megakaryocytic differentiation of CMK cells.

Butadienes↗
PubMed2002

Emergency contraception with mifepristone and levonorgestrel: mechanism of action.

OBJECTIVE: To study the effect of mifepristone and levonorgestrel on ovarian function and endometrial development in doses effective as emergency contraception. METHODS: Twelve fertile women were treated with either 10 mg of mifepristone as a single dose (n = 6) or two doses of 0.75 mg of levonorgestrel, 12 hours apart (n = 6) before and after ovulation. An endometrial biopsy performed during the implantation period was analyzed for endometrial maturation and expression of markers of endometrial receptivity. The markers tested for were integrin alpha4 and beta3, cyclooxygenase-1 and -2, progesterone receptors, Dolichos biflorus agglutinin lectin binding, and pinopodes. Urinary excretion of luteinizing hormone, estrone, and pregnanediol were also determined. RESULTS: Treatment with mifepristone and levonorgestrel before ovulation inhibited the luteinizing hormone surge showing no significant differences between the means of luteinizing hormone measurements. When mifepristone was administered in the early luteal phase, downregulation of progesterone receptors was inhibited in five of six women. No significant alteration was found in any of the remaining markers of endometrial receptivity. CONCLUSION: The mode of action of emergency contraception with mifepristone or levonorgestrel is primarily due to inhibition of ovulation rather than inhibition of implantation.

Adult↗
PubMed1999

Vitronectin receptors are expressed by macaque trophoblast cells and play a role in migration and adhesion to endothelium.

The objective of this work was to develop an in vitro system that would extend the usefulness of the macaque as a model for studying trophoblast invasion and spiral artery modification. We sought to determine whether trophoblast cells isolated from early gestation macaque placentas expressed vitronectin receptors and tested the idea that these receptors play a role in trophoblast migration and adhesion. Cytotrophoblast cells were isolated from 40-100 day macaque placentas, cultured, and characterized by immunofluorescence microscopy and flow cytometry. The cells expressed alphaV, beta3, and beta1 integrins on their surfaces. Immunohistochemical analysis of early gestation placentas and decidua basalis confirmed that intravascular trophoblast cells express alphaVbeta3/beta5. Using migration chambers we found that the trophoblast cells migrated towards vitronectin but not towards bovine serum albumin. This specific migration was blocked by preincubating the trophoblast cells with anti-vitronectin receptor (alphaVbeta3/beta5) antibodies. In other experiments, macaque trophoblast cells adhered to myometrial endothelial cells in a time-dependent manner and adhesion was significantly blocked by antibodies against alphaVbeta3/beta5 integrin. The results suggest that vitronectin receptors expressed by macaque trophoblast cells play a role in the migratory activity of these cells and may also be important in mediating attachment to endothelium.

Animals↗
PubMed2000

Severe and relapsing upper gastrointestinal bleeding in a patient with Glanzmann's thrombasthenia.

Glanzmann's thrombasthenia (GT) is a rare familial thrombocytic disease inherited as an autosomal recessive disorder that can induce hemorrhages due to a defect of platelet aggregation, resulting from the absence or reduced concentration of the membrane glycoproteic receptor binding the fibrinogen (integrin alpha(IIb)beta3). The gastrointestinal tract is the site of bleeding in only about 10% of cases but the related mortality is high (12.8%). Among the deaths due to hemorrhage, digestive bleeding causes 57.1%. According to reported data, the source of bleeding may be from preexisting gastroduodenal chronic and acute lesions. We report a case of severe and relapsing upper digestive bleeding in a woman with GT and coexisting thrombocytopenia (from HCV-related liver cirrhosis) and H. pylori-positive duodenal ulcer.

Female↗
PubMed2001

The role of osteopontin in breast cancer: clinical and experimental studies.

Osteopontin (OPN) is a secreted, integrin-binding protein which has been implicated in cancer, as well as other pathologies and some aspects of normal development. Here we focus on the role of OPN in breast cancer. We describe studies that have shown that OPN plays a role in normal mammary gland development as well as in progression of breast cancer. We also summarize studies that have shown that OPN can play a functional role in malignancy of breast cancer. At least some of these effects are mediated by specific cell surface integrins (alpha(v)beta3 vs. alpha(v)beta1 and alpha(v)beta5) and lead to increased cell migration, activation of growth factor/receptor pathways (e.g. HGF and EGF), and increased proteolytic enzyme activity (e.g. uPA). We also summarize clinical studies that show that OPN levels in tumors and blood are elevated in women with metastatic breast cancer and may offer promise as prognostic markers in breast cancer.

Animals↗
PubMed2002

In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways.

Most small cell lung cancer (SCLC) patients relapse within 12 months of starting combination chemotherapy plus radio-therapy, due to the development of acquired chemo- and radio-resistance. This phenomenon relates to the induction of tumour differentiation, resulting in apoptosis-resistant, morphologically variant (v-SCLC) cells, which lack the neuroendocrine expression of classic (c-) SCLC cells. In this study spontaneously adherent SCLC sublines were shown by differential gene expression analysis to provide an in vitro model of variant differentiation in SCLC, with down-regulation of neuroendocrine markers and up-regulation of epithelial differentiation markers cyclin D1, endothelin, the cell adhesion molecules CD 44 and integrin subunits alpha2, beta3 and beta4. The sensitivity of adherent SCLC sublines to etoposide, cyclophosphamide and gamma radiation was significantly diminished relative to parent suspension cell lines. Western blot analysis using phosphorylation-specific antibodies to Akt and MAP kinase revealed markedly elevated activation in adherent SCLC sublines, paralleled by increased levels of phosphorylated Bad protein and activated NF-kappaB. Subcultivation of the adherent sublines on uncoated surfaces reversed their adherent phenotype immediately and under these conditions Akt activity reverted to low levels. These results suggest that c-SCLC cells can differentiate spontaneously to v-SCLC and that the associated cellular adhesion may trigger Akt-dependent inhibition of apoptosis in SCLC cells, thus leading to acquired chemo- and radio-resistance.

Antineoplastic Agents↗
PubMed2001

Selective inactivation of Von Willebrand factor binding to glycoprotein IIb/IIIa and to inhibitor monoclonal antibody 9 by site-directed mutagenesis.

INTRODUCTION: The purpose of this study was to assess the requirement for the RGD sequence of von Willebrand factor (VWF) for its binding to the beta3 chain of integrins and the structural basis for the specificity of monoclonal antibody (MoAb) 9 which specifically binds to VWF and inhibits this interaction. MATERIAL AND METHODS: : Seven point mutations were introduced into VWF by site-directed mutagenesis. Mutated recombinant VWF were tested for their multimeric pattern and their ability to bind to purified GPIIb/IIIa, thrombin-activated platelets and MoAb 9. RESULTS: All recombinant VWF were fully multimerized. The conservative Arg 1744 to Lys substitution into the RGD sequence resulted in an 80% loss of function whereas the Arg to Ala change led to a total loss of function. The two substitutions however did not impair the binding to MoAb 9. In contrast Arg 1715 to Ala substitution had no effect on the binding to GPIIb/IIIa but the binding of the corresponding mutated recombinant VWF to MoAb 9 was strikingly decreased. CONCLUSION: Direct evidence of the role of the structure and the charge of Arg 1744 into the RGD sequence were established by changing Arg to Lys (KGD) and to Ala (AGD). Our results also demonstrate that Arg 1715 is not essential in the function but it is necessary for maintaining the conformation recognized by MoAb 9 specific for the GPIIb/IIIa-binding domain of VWF.

Amino Acid Substitution↗