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Biomedical subjects

L C Andersson

Publications and source records attributed to L C Andersson.

At least 55 records · Page 3Linked to original sources
PubMed1997

2,6-Bis((3,4-dihydroxyphenyl)-methylene)cyclohexanone (BDHPC)-induced apoptosis and p53-independent growth inhibition: synergism with genistein.

Estrogen binds to two classes of proteins in the cells, the high-affinity estrogen receptor (ER) as well as a low affinity estrogen type II binding site (EBS-II). Methyl p-hydroxyphenyllactate (MeHPLA) is an endogenous ligand for EBS-II. Binding of MeHPLA to EBS-II has a growth regulatory effect in estrogen-responsive cells, and levels of MeHPLA are decreased in breast cancer due to degradation by a specific esterase. 2,6-bis((3, 4-dihydroxyphenyl)-methylene) cyclohexanone (BDHPC) is an esterase-resistant analogue of MeHPLA which binds irreversibly to EBS-II and inhibits growth of breast cancer cells. In the present study, we analyzed the mechanism of growth inhibition by BDHPC. Treatment with BDHPC resulted in accumulation of cells in G1 phase and apoptosis. The G1 accumulation was not dependent on a functional p53 gene. The G1-specific growth inhibition by BDHPC was found to act synergistically with the G2/M-specific inhibition induced by the tyrosine kinase inhibitor genistein, suggesting this drug combination could be effectively used in cancer treatment.

Antineoplastic Agents↗
PubMed1997

Human ornithine decarboxylase-overproducing NIH3T3 cells induce rapidly growing, highly vascularized tumors in nude mice.

Overexpression of human ornithine decarboxylase (ODC) under the control of strong promoters induces morphological transformation of immortalized NIH3T3 and Rat-1 fibroblasts [M. Auvinen et al., Nature (Lond.), 360: 355-358, 1992]. We demonstrate here that ODC-overproducing NIH3T3 cells are tumorigenic in nude mice, giving rise to rapidly growing, large fibrosarcomas at the site of inoculation. The tumors are capable of invading host fat and muscle tissues and are vascularized abundantly. To disclose the molecular mechanism(s) driving the tumorigenic, invasive, and angiogenic phenotype of the tumors, the ODC-overproducing cell lines and tumor tissues were analyzed for the expression of various potential regulators and mediators of cell proliferation, matrix degradation, and angiogenesis. The tumorigenicity of ODC transformants was associated with elevated polyamine levels and down-regulated growth factor receptors. The invasiveness of the ODC-induced tumors could not be attributed to overexpression of various known extracellular matrix-degrading proteases or matrix metalloproteinases. The induction of the tumor neovascularization proved not to be elicited by vascular endothelial growth factor or basic fibroblast growth factor. Instead, the ODC-overexpressing cells appeared to secrete a novel angiogenic factor(s) that was able to promote migration of bovine capillary endothelial cells in collagen gels and increase the proliferation of human endothelial cells in vitro. In parallel, ODC-transformed cells displayed down-regulation of thrombospondin-1 and -2, the negative regulators of angiogenesis. Thus, the induction of the angiogenic phenotype of the ODC transformants is likely due both to increased expression and secretion of the new angiogenesis-stimulating factor(s) and decreased production and release of the antiangiogenic thrombospondins.

3T3 Cells↗
PubMed1997

Expression of glycodelin in MCF-7 breast cancer cells induces differentiation into organized acinar epithelium.

Glycodelin, a 28-kd human glycoprotein found in glandular epithelial cells of endometrium and seminal vesicle, was originally considered specific for the reproductive tract. Glycodelin has significant amino-acid sequence homology with beta-lactoglobulins from various species. We report herein the expression of glycodelin in normal and neoplastic glandular epithelia outside the reproductive tract including breast, sweat glands, parabronchial glands, hidradenoma, and pancreatic cystadenoma. The localization of glycodelin in highly differentiated acinar epithelia led us to investigate a possible role for glycodelin in epithelial organization. Transfection of glycodelin cDNA into MCF-7 breast cancer cells induced a dramatically altered growth behavior with formation of acinar configurations and an inability to grow in semisolid media because of apoptosis. The glycodelin-expressing cells also displayed strongly up-regulated expression of markers of organized epithelia, such as cytokeratins 8 and 18 as well as E-cadherin, and changes in intracellular distribution of beta-catenin. The rate of proliferation was also suppressed. These results show that, besides being a product of glandular epithelial cells, expression of glycodelin is accompanied by the acquisition of a phenotype of organized glandular epithelium.

Breast Neoplasms↗
PubMed1997

Tumor size-related DNA copy number changes occur in solitary fibrous tumors but not in hemangiopericytomas.

Solitary fibrous tumor (SFT) presenting in the pleura and other soft tissue sites and hemangiopericytoma (HPC) presenting at various soft tissue sites are mesenchymal tumors that share many histologic and immunohistochemical features. This raises the questions of whether these tumors are related and whether they belong within the spectrum of a single biologic entity. The behavior of both SFTs and HPCs is difficult to predict histologically. The genetic background of both SFTs and HPCs is poorly known, but it could be helpful in the evaluation of malignancy and could give clues to their possible relationship. In this study, we analyzed 15 SFTs and 11 HPCs by comparative genomic hybridization (CGH), a powerful molecular cytogenetic tool that can be applied to DNA extracted from formaldehyde-fixed and paraffin-embedded tissue. All of these tumors were immunohistochemically similar and showed reactivity for CD34-antigen but not for keratins, desmin, or muscle actins. Only 1 SFT smaller than 10 cm showed DNA copy number changes (a single loss in chromosome 13), but 7 of 8 SFTs larger than 10 cm (including all 4 tumors with more than 4 mitoses per 10 high power fields) showed changes, mostly chromosomal gains in 5q 7, 8, 12, and 18. Four cases showed losses, two of them in chromosome 13 and two others in 20q. These findings suggest that CGH might be useful in the evaluation of malignant transformation in SFT. The most common change, gain of the entire chromosome 8, seen in two cases as the only change, suggests trisomy 8 and parallels a similar finding previously described in other fibrous tumors, such as subsets of desmoid fibromatosis and infantile fibrosarcoma. In contrast, HPCs, including large and mitotically active tumors, showed no DNA copy number changes on CGH. This suggests that HPC is genetically different from SFT.

Adult↗
PubMed1996

Analysis of novel apolipoprotein B mutations using a modified U937 cell line LDL binding assay.

The U937 myelomonocyte proliferation assay can be used to detect patients with familial defective apolipoprotein B-100 (FDB). Previous studies have employed electronic cell counting to assess cell proliferation. We simplified the assay using 3H-thymidine incorporation DNA analysis to measure cell growth. We tested the modified method by analyzing the effects of different concentrations of native low density lipoproteins (LDL), methylated LDL, as well as LDLs obtained from patients with FDB on cell growth. Methylation of LDL to various degrees reduced cell proliferation correspondingly, and LDLs obtained from FDB patients decreased cell growth confirming that the modified method was able to detect binding defective species of LDL. We applied this method to analyze three novel apoB polymorphisms recently characterized in this laboratory (apoB His1896-->Arg, apoB Asn1887-->Ser, apoB Ala4454-->Thr), which did not significantly alter U937 cell proliferation. Our results show that this simplified assay can be used for screening for LDL variants with defective binding.

Alleles↗
PubMed1996

2-Methoxyestradiol arrests cells in mitosis without depolymerizing tubulin.

The endogenous estrogen metabolite 2-methoxyestradiol (2-MeOE2) suppresses experimental tumor growth in vivo and inhibits angiogenesis activity in vitro. Moreover, 2-MeOE2 has been observed to block mitosis in cell cultures. As high concentrations of 2-MeOE2 prevent microtubule assembly in vitro, the mitotic arrest has been attributed to inhibition of tubulin polymerization. Here we report that concentrations of 2-MeOE2 that cause complete metaphasal arrest do not inhibit the assembly of mitotic spindles. In contrast to the chromosomal dispersal seen in cells arrested by the tubulin depolymerizing drug colcemid, the chromosomes of cells treated with 2-MeOE2 remained in the metaphasal plate indicating a functional defect of the mitotic spindle. The 2-MeOE2 arrest resembles those induced by compounds affecting microtubule dynamics such as taxol and vinblastine. The 2-MeOE2 block is also similar to that induced by several anti-calmodulin agents. Given that metaphase to anaphase transition is a calmodulin-dependent step and our observation that 2-MeOE2 inhibits calmodulin activity in vitro, we suggest that the 2-MeOE2 metaphasal arrest may occur via inhibition of calmodulin.

2-Methoxyestradiol↗
PubMed1996

DNA copy number losses in chromosome 14: an early change in gastrointestinal stromal tumors.

The DNA copy number changes were investigated in 13 malignant, 3 borderline, and 16 benign gastrointestinal stromal tumors (GISTs) by comparative genomic hybridization. A consistent finding was the loss of DNA copy numbers in chromosome 14q. This was detected in 75% of the benign tumors, in 62% of the malignant tumors, and in two out of the three borderline tumors with a minimal overlapping region located to 14q22. Losses of DNA copy numbers were more frequent than gains, with 2-10 changes in malignant GISTs and 1-3 changes in benign tumors. High-level DNA amplifications, detected only in malignant GISTs, were assigned to 3q26-q29 (40%), 5p (30%), and 8q22-24 (40%). Our results indicate that copy number losses in 14q are an early change during oncogenesis of GISTs and suggest the possibility that a new tumor suppressor gene at 14q22 might be involved in the regulation of differentiation or proliferation of such mesenchymal cells.

Adult↗
PubMed1996

BCL2 regulates neural differentiation.

A main function attributed to the BCL2 protein is its ability to confer resistance against apoptosis. In addition to the constitutively high expression of BCL2, caused by gene rearrangement in follicular lymphomas, elevated expression of the BCL2 gene has been found in differentiating hematopoietic, neural, and epithelial tissues. To address the question of whether the expression of BCL2 is a cause or consequence of cell differentiation, we used a human neural-crest-derived tumor cell line, Paju, that undergoes spontaneous neural differentiation in vitro. The Paju cell line displays moderate expression of BCL2, the level of which increases in parallel with further neural differentiation induced by treatment with phorbol 12-myristate 13-acetate. Transfection of normal human BCL2 cDNA in sense and antisense orientations had a dramatic impact on the differentiation of the Paju cells. Overexpression of BCL2 cDNA induced extensive neurite outgrowth, even in low serum concentrations, together with an increased expression of neuron-specific enolase. Paju cells expressing the anti-sense BCL2 cDNA construct, which reduced the endogenous levels of BCL2, did not undergo spontaneous neural differentiation. These cells acquired an epithelioid morphology and up-regulated the intermediate filament protein nestin, typically present in primitive neuroectodermal cells. The manipulated levels of BCL2 did not have appreciable impact on cell survival in normal culture. Our findings demonstrate that the BCL2 gene product participates in the regulation of neural differentiation.

Adolescent↗
PubMed1996

Cervical necrotising fasciitis with pharyngeal perforation: treatment and reconstruction.

We present a case of life-threatening necrotising fasciitis of the neck with acute pharyngeal perforation following a parapharyngeal abscess caused by tonsillitis. The joint occurrence of cervical necrotising fasciitis and acute pharyngeal perforation has not been previously reported. A new way of reconstructing the pharyngeal defect using an islanded submental perforator flap is presented.

Acute Disease↗
PubMed1996

Dorsocranial liver resection and direct hepatoatrial anastomosis for hepatic venous outflow obstruction: long-term outcome and functional results.

OBJECTIVES: The management of hepatic venous outflow obstruction, usually known as Budd-Chiari syndrome, remains complex despite a variety of treatments. METHODS: We present the results from 16 patients with Budd-Chiari syndrome who underwent dorsocranial liver resection and direct hepatoatrial anastomosis over a 10-yr period. The inferior caval vein was occluded in 10 patients. RESULTS: Operative mortality was 12.5% (2/16). During a mean follow-up of 7.2 yr, three patients required reoperation, two of whom had veno-occlusive disease. The late mortality was 14% (2/14). Clinical status improved in terms of: abdominal pain, 81 versus 14%; lower limb edema, 56 versus 14%; hematemesis, 19% versus 0%; hepatomegaly, 94 versus 36%; esophageal varices, 56 versus 7%; splenomegaly, 56 versus 21%; and ascites, 87 versus 29%. Mean serum bilirubin (micromol/l) fell from 40.2 to 27.1 (p = 0.005), and serum albumin remained unchanged. A patent hepatoatrial anastomosis was demonstrated in 10/12 survivors. The actuarial survival rate was 74.2% at 5 and 10 yr. CONCLUSIONS: Thus, in patients with outflow obstruction of the major hepatic veins, transcaval dorsocranial liver resection and direct hepatoatrial anastomosis recreate an adequate hepatic runoff. Moreover, this procedure is appropriate for patients with occlusion of the inferior caval vein, obviates or defers the need for liver transplantation, and prevents recurrence of thrombosis.

Adolescent↗
PubMed1995

Abnormal distributions of T-lymphocyte subsets in the cerebrospinal fluid of patients with acute schizophrenia.

We analysed the percentages of CD4+ and CD8+ T lymphocytes in the cerebrospinal fluid (CSF) from 31 acutely ill schizophrenic patients. The psychotic patients had in their CSF clearly altered proportions of CD4+ and/or CD8+ T cells. As compared to the distribution of T cell subsets in the CSF from non-psychotic controls, the schizophrenic patients displayed both abnormally high and abnormally low frequencies of CD4+ and/or CD8+ cells. Changes in the distribution of T cell subsets corresponding to those seen in the CSF were not observed in paired blood samples from schizophrenic patients.

Acute Disease↗
PubMed1995

Ornithine decarboxylase- and ras-induced cell transformations: reversal by protein tyrosine kinase inhibitors and role of pp130CAS.

We have found that overexpression of human ornithine decarboxylase (ODC) induces cell transformation in NIH 3T3 and Rat-1 cells (M. Auvinen, A. Paasinen, L. C. Andersson, and E. Hölttä, Nature (London) 360:355-358, 1992). The ODC-transformed cells display increased levels of tyrosine phosphorylation, in particular of a cluster of 130-kDa proteins. Here we show that one of the proteins with enhanced levels of tyrosine phosphorylation in ODC-overexpressing cells is the previously described p130 substrate of pp60v-src, known to associate also with v-Crk and designated p130CAS. We also studied the role of protein tyrosine phosphorylation in the ODC-induced cell transformation by exposing the cells to herbimycin A, a potent inhibitor of Src-family kinases, and to other inhibitors of protein tyrosine kinases. Treatment with the inhibitors reversed the phenotype of ODC-transformed cells to normal, with an organized, filamentous actin cytoskeleton. Coincidentally, the tyrosine hyperphosphorylation of p130 was markedly reduced, while the level of activity of ODC remained highly elevated. A similar reduction in pp130 phosphorylation and reversion of morphology by herbimycin A were observed in v-src- and c-Ha-ras-transformed cells. In addition, we show that expression of antisense mRNA for p130CAS resulted in reversion of the transformed phenotype of all these cell lines. An increased level of tyrosine kinase activity, not caused by c-Src or c-Abl, was further detected in the cytoplasmic fraction of ODC-transformed cells. Preliminary characteristics of this kinase are shown. These data indicate that p130CAS is involved in cell transformation by ODC, c-ras, and v-src oncogenes, raise the intriguing possibility that p130CAS may be generally required for transformation, and imply that there is at least one protein tyrosine kinase downstream of ODC that is instrumental for cell transformation.

3T3 Cells↗
PubMed1994

Metastasizing neuroblastomas in mice transgenic for simian virus 40 large T (SV40T) under the olfactory marker protein gene promoter.

The olfactory marker protein (OMP) is a M(r) 19,000 polypeptide originally considered a selective marker for differentiated olfactory receptor neurons. In an attempt to induce neoplastic proliferation in the olfactory cells, we made mice transgenic for the simian virus 40 large T-antigen gene linked to the OMP gene promoter. Four independent lines of transgenic mice were established. Despite a high expression of the transgene in the olfactory receptor neurons, no evidence of tumor growth was observed. Instead, starting from an age of 4 months, animals of all four lines presented with highly metastatic tumors originating in the adrenal medullas or sympathetic ganglia. The histological, ultrastructural, and immunohistochemical features of the tumors were identical to those of human infant neuroblastoma. Five independent neuroblastoma cell lines were established from tumors of different transgenic animals. All cell lines constitutively express the endogenous OMP gene. The transgene product, simian virus 40 large T-antigen, associates with the product of the anti-oncogene p53 in these cell lines. This transgene system not only offers a biologically faithful model for investigations on the pathogenesis of neuroblastoma, the most common solid neoplasia of infancy, it also raises intriguing questions about the role of the OMP gene for the differentiation of the sympathetic neurons.

Animals↗
PubMed1994

Progesterone-associated endometrial protein--a constitutive marker of human erythroid precursors.

Progesterone-associated endometrial protein (PAEP/PP14) is a 28-kD glycoprotein with sequence homology to beta-lactoglobulins containing a retinol-binding motif. PAEP/PP14 is present at nanomolar concentrations in human serum. It is produced by secretory and decidualized endometrium in women and by seminal vesicle epithelium in men. We report here that PAEP mRNA is constitutively expressed in normal hematopoietic tissue. Western immunoblotting of bone marrow cells with rabbit antibodies to PAEP gave a band at 28 kD, and immunocytochemical staining with monoclonal antibodies localized PAEP into the cytoplasm of erythroid precursors representing different stages of the normoblast series. PAEP was not detected in mature red blood cells, platelets, or in cells of the myeloid lineage. Untreated K562 leukemia cells did not contain PAEP, whereas treatment of the cells with tetradecanoylphorbol acetate (TPA) induced strong expression of PAEP mRNA and synthesis of the intact protein that was found both in the cytoplasm of the differentiating cells and in the supernatant of TPA-treated cultures. These findings add a new member to the growing family of genes that are constitutively expressed both in the reproductive tract and in the hematopoietic system.

Base Sequence↗
PubMed1994

Triggering of human natural killer cells through CD16 induces tyrosine phosphorylation of the p72syk kinase.

Activation of protein tyrosine kinases (PTK) is an initial and obligatory event for the triggering of human natural killer (NK) cells to cytotoxicity. Of the different PTK detected in NK cells, only p56lck has previously been shown to participate in NK cell activation. Here we present evidence that another PTK, p72syk, is involved in activation of NK cells. Stimulation with a monoclonal antibody to to the Fc gamma RIII receptor (CD16) induced an increased tyrosine phosphorylation of p72syk. This phosphorylation correlated with an increased tyrosine kinase activity of p72syk towards a synthetic peptide substrate. A severalfold increase in the catalytic activity of p72syk was also seen after treatment of NK cells with an inhibitor of phosphotyrosine phosphatases, pervanadate. We conclude that triggering of the cytotoxic response in NK cells is associated with activation of p72syk.

Amino Acid Sequence↗