Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vast heterogeneity of endothelial cells (EC) in various organs necessitates isolation of EC from the relevant organs when defining mechanisms of site-specific pathologies. We report a novel finding that describes the presence of two heterogeneous populations of human nasal microvascular EC isolated from the inferior turbinate. Light and electron microscopy, flow cytometric analysis, and immunocytochemistry analysis demonstrated that one EC population exhibited the classic vascular endothelial markers with cobblestone-like morphology, whereas the other was sinusoidal with fusiform morphology. The sinusoidal EC (SEC) lacked surface expression of the endothelial markers CD31 and E-selectin, were discontinuous, showed fenestrae and pinocytic vesicles, and did not form tight junctions. Gene expression analysis using microarray revealed significant but limited heterogeneity between the two cell types. Immunohistochemical staining of normal nasal biopsies confirmed the presence of two distinct populations of EC. We found that CD31 was exclusively expressed on vascular EC (VEC), whereas the molecule L-SIGN was mainly expressed on SEC. Both cell types formed capillary-like tubules in matrigel in vitro. The two heterogeneous EC populations provide a unique in vitro system to study the biology of nasal VEC and SEC in normal conditions and in inflammatory processes in various nasal disorders.
Am J Respir Cell Mol Biol 2005 Jan
PMID:Heterogeneity of human nasal vascular and sinusoidal endothelial cells from the inferior turbinate. 1549 63

The effects of HER-2/neu overexpression on the tumor microenvironment in an aggressive breast cancer xenograft model were investigated. These studies focused on tumors derived following the subcutaneous injection of MDA-MB-435/LCC6 cells transfected with human c-erbB2 (LCC6(HER-2)) into SCID-Rag2M mice. LCC6(HER-2) tumors were more viable (H&E-stained tumor sections) than isogenic vector control tumors (LCC6(Vector)). Correspondingly, a 2.7-fold increase in trypan blue-excluding cells (P = 0.00056) and a 4.8-fold increase in clonogenic cells (P = 0.00146) were noted in cell suspensions derived from disaggregated LCC6(HER-2) versus LCC6(Vector) tumors. Tumor sections stained with the antibody detecting 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), a marker of hypoxia, showed a greater fraction of hypoxic tissue in LCC6(HER-2) tumors compared with control tumors. Flow cytometric analyses based on viable tumor cells (DNA content >/= 2N) in cell suspensions from disaggregated tumors confirmed that there were significantly more EF5-positive cells (i.e., hypoxic) in LCC6(HER-2) than in LCC6(Vector) tumors (16.41 +/- 8.1% and 5.96 +/- 4.1%, respectively; P = 0.0015). Protein levels of phosphorylated (Ser(536)) nuclear factor-kappaB p65 were significantly elevated in LCC6(HER-2) tumors (P = 0.00048), and a trend in increased hypoxia-inducible factor-1alpha protein levels was observed in LCC6(HER-2) compared with LCC6(Vector) tumors. Despite the substantial viable hypoxic cell fraction and a 1.7-fold increase of vascular endothelial growth factor protein (P = 0.05) in LCC6(HER-2) tumors, no significant differences were found (P > 0.05) between LCC6(HER-2) and LCC6(Vector) vasculature (CD31 staining and Hoechst 33342 perfusion). These results suggest that HER-2/neu overexpression may be linked with overall increased tumor viability and a significant increase in the population of viable hypoxic cells, which is not due to differences in tumor vascularization.
Mol Cancer Res 2004 Nov
PMID:HER-2/neu overexpression increases the viable hypoxic cell population within solid tumors without causing changes in tumor vascularization. 1556 77

The mda-7 gene (approved gene symbol IL24) is a novel tumor suppressor gene with tumor-apoptotic and immune-activating properties. We completed a Phase I dose-escalation clinical trial, in which a nonreplicating adenoviral construct expressing the mda-7 transgene (INGN 241; Ad-mda7) was administered intratumorally to 22 patients with advanced cancer. Excised tumors were evaluated for vector-specific DNA and RNA, transgenic MDA-7 expression, and biological effects. Successful gene transfer as assessed by DNA- and RT-PCR was demonstrated in 100% of patients evaluated. DNA analyses demonstrated a dose-dependent penetration of INGN 241 (up to 4 x 10(8) copies/mug DNA at the 2 x 10(12) vp dose). A parallel distribution of vector DNA, vector RNA, MDA-7 protein expression, and apoptosis induction was observed in all tumors, with signals decreasing with distance away from the injection site. Additional evidence for bioactivity of INGN 241 was illustrated via regulation of the MDA-7 target genes beta-catenin, iNOS, and CD31. Transient increases (up to 20-fold) of serum IL-6, IL-10, and TNF-alpha were observed. Significantly higher elevations of IL-6 and TNF-alpha were observed in patients who responded clinically to INGN 241. Patients also showed marked increases of CD3+CD8+ T cells posttreatment, suggesting that INGN 241 increased systemic TH1 cytokine production and mobilized CD8+ T cells. Intratumoral delivery of INGN 241 induced apoptosis in a large volume of tumor and elicited tumor-regulatory and immune-activating events that are consistent with the preclinical features of MDA-7/IL-24.
Mol Ther 2005 Jan
PMID:Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. 1558 17

c-erbB-2-positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1alpha (HIF1alpha) production (Laughner et al., Mol Cell Biol 2001;21:3995-4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1alpha expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2-positive and 90 c-erbB-2-negative carcinomas) were stained immunohistochemically for HIF1alpha and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1alpha protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1alpha expression. If activation of c-erbB-2 in humans results in overexpression of HIF1alpha independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2-positive breast tumors.
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PMID:c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent. 1558 32

Stromal stem cells proliferate in vitro and may be differentiated along several lineages. Freshly isolated, these cells have been too few or insufficiently pure to be thoroughly characterized. Here, we have isolated two populations of CD45-CD34+CD105+ cells from human adipose tissue which could be separated based on expression of CD31. Compared with CD31+ cells, CD31- cells overexpressed transcripts associated with cell cycle quiescence and stemness, and transcripts involved in the biology of cartilage, bone, fat, muscle, and neural tissues. In contrast, CD31+ cells overexpressed transcripts associated with endothelium and the major histocompatibility complex class II complex. Clones of CD31- cells could be expanded in vitro and differentiated into cells with characteristics of bone, fat, and neural-like tissue. On culture, transcripts associated with cell cycle quiescence, stemness, certain cytokines and organ specific genes were down-regulated, whereas transcripts associated with signal transduction, cell adhesion, and cytoskeletal +CD105+CD31- cells from human adipose tissue have stromal stem cell properties which may make them useful for tissue engineering.
Mol Biol Cell 2005 Mar
PMID:Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture. 1563 89

Antiangiogenesis is a promising strategy of cancer treatment. Vascular endothelial growth factor receptor [fetal liver kinase/kinase-inserting domain-containing receptor (KDR)] is a tyrosine kinase receptor and has been strongly implicated in tumor angiogenesis. In this study, we report that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (ON-III), extracted from the dried flower Cleistocalyx operculatus, used in traditional Chinese medicine, reversibly inhibited KDR tyrosine kinase phosphorylation, but epidermal growth factor receptor tyrosine kinase phosphorylation was unaffected under the same concentrations of ON-III. ON-III also inhibited mitogen-activated protein kinase (MAPK) and AKT activation of KDR signal transduction in downstream molecules without reduced total MAPK and AKT. The results in vitro showed that ON-III inhibited growth of human vascular endothelial HDMEC cells in the presence of VEGF preferentially, compared with epidermal growth factor. Systemic administration of ON-III at nontoxic doses in nude mice resulted in inhibition of subcutaneous tumor growth of human hepatocarcinoma Bel7402 and lung cancer GLC-82 xenografts. The tumor vessel density decreased, as determined by immunohistochemical staining, for CD31 after ON-III treatment. These results indicated that ON-III inhibited KDR tyrosine kinase, shut down KDR-mediated signal transduction, and inhibited tumor growth of human xenografts in vivo.
Mol Pharmacol 2005 May
PMID:Blockade of vascular endothelial growth factor receptor signal pathway and antitumor activity of ON-III (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone), a component from Chinese herbal medicine. 1570 76

Radioresistance markedly impairs the efficacy of tumor radiotherapy and involves antiapoptotic signal transduction pathways that prevent radiation-induced cell death. The majority of human prostate cancers overexpress the important antiapoptotic proteins Bcl-2 and/or Bcl-xL, which render tumors resistant to radiation therapy. (-)-Gossypol, a natural polyphenol product from cottonseed, has recently been identified as a potent small molecule inhibitor of both Bcl-2 and Bcl-xL. In the current study, we investigated the antitumor activity of (-)-gossypol in prostate cancer and tested our hypothesis that (-)-gossypol may improve prostate cancer's response to radiation by potentiating radiation-induced apoptosis and thus making cancer cells more sensitive to ionizing radiation. Our data show that (-)-gossypol potently enhanced radiation-induced apoptosis and growth inhibition of human prostate cancer PC-3 cells, which have a high level of Bcl-2/Bcl-xL proteins. Our in vivo studies using PC-3 xenograft models in nude mice show that orally given (-)-gossypol significantly enhanced the antitumor activity of X-ray irradiation, leading to tumor regression in the combination therapy. In situ terminal deoxynucleotidyl transferase-mediated nick end labeling staining showed that significantly more apoptotic cells were induced in the tumors treated with (-)-gossypol plus radiation than either treatment alone. Anti-CD31 immunohistochemical staining indicates that (-)-gossypol plus radiation significantly inhibited tumor angiogenesis. Our results show that the natural polyphenol inhibitor of Bcl-2/Bcl-xL, (-)-gossypol, can radiosensitize prostate cancer in vitro and in vivo without augmenting toxicity. (-)-Gossypol may improve the outcome of current prostate cancer radiotherapy and represents a promising novel anticancer regime for molecular targeted therapy of hormone-refractory prostate cancer with Bcl-2/Bcl-xL overexpression.
Mol Cancer Ther 2005 Feb
PMID:(-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. 1571 91

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1alpha, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12-24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.
Am J Physiol Lung Cell Mol Physiol 2005 Jul
PMID:Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus. 1579 65

Side population (SP) cells are a select cell population identified by a capacity to efflux Hoechst dye that are highly enriched for stem/progenitor cell activity. In this study, we found that SP cells comprised of CD45(+) and CD45(-) subtypes are present in the embryonic lung (E-SP) at levels varying with gestational age. Long-term in vivo competitive blood reconstitution studies demonstrated that hematopoeitic stem cell capacity resided within the CD45(+) E-SP cell subset. Immunophenotyping of CD45(-) E-SP cells determined that this population consists of two subtypes: CD31(-) and CD31(+). Limited gene expression profiling indicated that CD45(-)/CD31(-) E-SP cells have features of smooth muscle precursors, and give rise to smooth muscle in culture. On the other hand, CD45(-)/CD31(+) E-SP cells express genes characteristic of endothelium, but by themselves do not grow or differentiate in culture. Co-culture of CD45(-)/CD31(+) and CD45(-)/CD31(-) E-SP cells, however, resulted in the formation of complex tubular networks that express markers of endothelium. Together, these findings illustrate that embryonic lung SP cells are heterogeneous, composed of hematopoeitic and nonhematopoeitic progenitors, and may play a key role in the formation of the lung vasculature.
Am J Respir Cell Mol Biol 2005 Jul
PMID:Embryonic lung side population cells are hematopoietic and vascular precursors. 1580 52

Germinal centers within the lymph node follicles are T-cell-dependent, antigen-driven B-cell proliferations that develop from the rapid clonal expansion of a few founder cells. The end results of this B-cell expansion are memory B cells or plasma cells. Two morphologic forms of plasma cell can be recognized in the germinal center: classic plasma cells, characterized morphologically by peripherally clumped arrangement of nuclear chromatin, and cells with a nuclear morphology more resembling that of the centrocytes, which the authors have termed "centrocytoid plasma cells." In this study the authors examined the distribution and immunohistochemical characteristics of these two populations of germinal center plasma cells. The centrocytoid plasma cells were arranged in a band stretching from the junction of the dark and light zone to the periphery of the germinal centers, while the classic plasma cells were mainly present at the germinal center periphery. Both marked with CD38, CD138, and VS38c, recognized markers for plasma cells; however, EMA and CD31 were present only in the classic form of plasma cell. The proliferation marker Ki67 was present in less than 1% of the cells labeling with CD138. Others have demonstrated Ki67 in 50% of the cells labeled with Blimp-1, which is consistent with Blimp-1 appearing earlier than CD138 in ontogeny. CD10 is co-expressed with CD138 in about 10% of cells and CD45 with CD138 in about 5% of cells. Their topographic features, together with the progressive acquisition of plasma cell markers, suggest that the centrocytoid plasma cells may be the precursors of the classic plasma cells. Of note, both the forms of plasma cell were absent in follicles of follicular lymphoma, which supports the concept that in this disease, lymphocytes fail to differentiate and mature beyond the centrocyte stage.
Appl Immunohistochem Mol Morphol 2005 Jun
PMID:Centrocytoid plasma cells of the germinal center. 1589 23


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