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K Rubin

Publications and source records attributed to K Rubin.

At least 37 records · Page 2Linked to original sources
PubMed1998

Cell interactions with collagen matrices in vivo and in vitro depend on phosphatidylinositol 3-kinase and free cytoplasmic calcium.

We have investigated the role of phosphatidylinositol 3-kinase (PI3-kinase) in cellular interactions with collagenous matrices. Platelet-derived growth factor-BB (PDGF-BB) elicited a mobilization of intracellular Ca2+ in pig aortic endothelial (PAE) cells transfected with wild type PDGF beta-receptor. This response was greatly reduced in PAE cells transfected with PDGF beta-receptors mutated at positions Y740 and Y751 to prevent PI3-kinase binding. The experimental drug 1D-myo-inositol 1,2,6-trisphosphate (alpha-trinositol) induced a rapid increase and subsequent oscillations of the cytoplasmic Ca2+ concentration in cultured fibroblasts. This response was not due to an effect of alpha-trinositol on inositol 1,4,5-trisphosphate (IP3) receptors. alpha-Trinositol did not influence PDGF-BB elicited chemotaxis through collagen-coated membranes of PAE cells transfected with the wild-type PDGF beta-receptor, but restored PDGF-BB elicited chemotaxis of PAE cells transfected with the PI3-kinase binding-site mutated PDGF beta-receptor. Collagen gel contraction has been suggested to serve as a model for cellular control of interstitial fluid pressure (PIF) in dermis. The PI3-kinase inhibitors wortmannin (50 nM) and LY294002 (5 microM) inhibited the stimulation of fibroblast-mediated collagen gel contraction by 0.4 nM PDGF-BB. Injection of wortmannin in rat paw skin induced a lowering of PIF, and this effect was abolished in animals pre-treated with alpha-trinositol. Pretreatment of rats with alpha-trinositol abolished the decrease in PIF induced by injecting monoclonal anti-rat alpha 2 beta 1 integrin IgG in rat paw skin. Taken together our data indicate that cell-collagen interactions in vivo and in vitro depend on PI3-kinase, and that this dependence can be bypassed by a drug eliciting intracellular Ca2+ mobilization.

Androstadienes↗
PubMed1998

Turner syndrome and osteoporosis: mechanisms and prognosis.

Despite only limited reports of a greater number of fractures during childhood or adulthood, osteoporosis historically has been described as a feature in Turner syndrome, because of the frequent observation of radiographic osteopenia and the coarse trabecular pattern of the carpal bones on radiographs. The pathogenesis of the skeletal demineralization remains unclear, but the data support the concept of an intrinsic bone defect that is then exacerbated by a number of hormonal factors, including the growth-regulating hormones, the gonadal steroids, and possibly the calcium-regulating hormones. The advent of more refined methods, such as single- and dual-photon absorptiometry and dual energy x-ray absorptiometry, has led to improved insights into bone mineral density (BMD) status in Turner syndrome (TS). A major limitation of these projection methods is that they report areal and not true volumetric BMD, resulting in an underestimation of the true BMD in smaller subjects. In assessing BMD in TS, various methods have been used to eliminate the confounding effect of bone size. Some consistent patterns do emerge in persons with TS who are not treated with long-term growth hormone (GH) or estrogen therapy. A significant deficit in cortical bone commonly appears in childhood and usually is associated with a low bone-turnover state. Significant osteopenia at predominantly trabecular sites develops during mid- to late adolescence and persists into adulthood, when it is associated with increased bone turnover. Preliminary BMD data on patients after long-term GH therapy show an absence of osteopenia. With respect to the impact of long-term estrogen therapy, the BMD deficit in adults with TS who have been treated adequately with estrogen, but who have not been treated with GH, is less than it is in those who have been insufficiently treated or not treated at all with estrogen. The available data indicate that long-term GH treatment during the prepubertal and early to midpubertal years optimizes BMD and improves the prognosis for adequate peak bone mass being achieved after a puberty that, most often, has been induced with exogenous estrogen. Long-term treatment with estrogen and progestin that is initiated during mid- to late adolescence and is continued throughout adulthood appears necessary for a normal peak bone mass to be achieved and the BMD to be preserved well beyond the time of peak bone mass. Additional measures to prevent osteoporosis must be used, such as ensuring adequate calcium intake and ample weight-bearing activities, focusing on preventing injuries and avoiding overtreatment with thyroid hormones. Long-term surveillance with measurement of BMD and of bone turnover in a large TS population into their later adult years is necessary before it can be concluded that the osteopenia observed in TS is a nonprogressive asymptomatic bone defect of no clinical consequences.

Bone Demineralization, Pathologic↗
PubMed1997

Introduction.

Explore the source record for details and available documents.

Journal Article↗
PubMed1997

Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer--a predictor of tumour stage.

The aim of this study was to investigate whether immunohistochemical staining patterns of tissue inhibitor of metalloproteinases TIMP-2 and matrix metalloproteinases MMP-2 and MMP-9 can be predictors of tumour stage and survival time in colorectal cancer. Frozen tumour sections from 212 patients operated on between January 1987 and November 1990 were investigated. Three mouse monoclonal antibodies--T2-101 against TIMP-2, CA-4001 against MMP-2 and GE-213 against MMP-9--were used. Positive expression of TIMP-2 (a) in basement membranes and (b) diffusely in stroma with (c) subglandular enhancement was found significantly (P < 0.01, P < 0.05, P < 0.05) more often in localized tumours than in tumours with regional or distant metastases. Neither pattern correlated with tumour differentiation. Patterns (a) and (c) correlated with longer survival time (P < 0.05); (b) reached near significance (P < 0.07). When the survival analyses were restricted to potentially cured patients, neither pattern could foretell death from cancer. Positive expression of MMP-2 in tumour epithelium and of MMP-9 in tumour-infiltrating macrophages were both independent of tumour stage and were without correlation with survival time. A large number of MMP-9-positive macrophages correlated (P < 0.05) with poor tumour differentiation, whereas weak or absent epithelial MMP-2 staining reached near significance (P < 0.08). Exploration of TIMP-2 expression is valuable for the discrimination between macroscopically localized and metastatic colorectal cancer, but it cannot predict which of the potentially cured patients are likely to have micrometastases. MMP-2 and MMP-9 stainings are of minor value in staging and prognostic prediction.

Adult↗
PubMed1997

Tumor cell and connective tissue cell interactions in human colorectal adenocarcinoma. Transfer of platelet-derived growth factor-AB/BB to stromal cells.

Mechanisms underlying stimulation of platelet-derived growth factor (PDGF) beta-receptors expressed on connective tissue cells in human colorectal adenocarcinoma were investigated in this study. PDGF-AB/BB, but not PDGF receptors, was expressed by tumor cells in situ, as well as in tumor cell isolates of low passage from human colorectal adenocarcinoma. In an experimental co-culture system, conditioned medium from tumor cells only marginally activated PDGF beta-receptors expressed on fibroblasts. In contrast, co-culturing of the two cell types led to a marked PDGF beta-receptor activation. Functional PDGF-AB/BB was found to be associated with heparinase-I-sensitive components on the tumor cell surface. PDGF-AB/BB, isolated from heparinase-I-sensitive cell surface components, induced a marked activation of PDGF beta-receptors. Furthermore, co-culturing tumor cells together with fibroblasts led to a sustained activation of PDGF beta-receptors expressed on fibroblasts. Double immunofluorescence staining of tissue sections from human colorectal adenocarcinoma, combined with computer-aided image analysis, revealed that nonproliferating tumor cells were the predominant cellular source of PDGF-AB/BB in the tumor stroma. In addition, PDGF-AB/BB-expressing tumor cells were found juxtapositioned to microvascular cells expressing activated PDGF beta-receptors. Confocal microscopy revealed a cytoplasmic and cell-membrane-associated expression of PDGF-AB/BB in tumor cells situated in the stroma. In contrast, epithelial cells situated in normal or tumorous acinar structures revealed only a cell-membrane-associated PDGF-AB/BB expression. The is vitro and in situ results demonstrate that tumor cells not only facilitate but also have the ability to modulate connective tissue cell responsiveness to PDGF-AB/BB in a paracrine fashion, through direct cell-cell interactions in human colorectal adenocarcinoma.

Adenocarcinoma↗
PubMed1996

Recruitment of type I collagen producing cells from the microvasculature in vitro.

We have previously suggested that microvascular pericytes can differentiate into fibroblast-like, type I collagen-producing cells during excessive dermal scarring in vivo (Sundberg, C., Ivarsson, M., Gerdin, B., and Rubin, K., Lab. Invest. 74, 454-468, 1996). Here we have investigated to what extent pericytes derived from microvessels of full-term human placenta exhibited this capacity in vitro. Vascular fragments of human term placenta were isolated by enzymatic digestion and separation in Percoll. Their microvascular origin was ascertained by confocal microscopy using antibodies specific for endothelial cells (PAL-E) and pericytes (high-molecular-weight-melanoma-associated antigen). When vascular fragments were cultured in vitro, large cells with irregular edges migrated out from the fragments. After 4-6 days in culture, these cells started to proliferate and reached near confluence after approximately 8 days. The cultures were not overgrown by clones of cells with a high proliferative capacity, as demonstrated by cell membrane fluorescence staining and Ki67 expression. Expression of PAL-E, high-molecular-weight-melanoma-associated antigen, smooth muscle alpha-actin, desmin, and collagen synthesis (prolyl-4-hydroxylase and type I procollagen, as well as collagen pro-alpha1(I) mRNA) were followed during a culture period of 8 days. The cells were PAL-E negative but expressed high-molecular-weight-melanoma-associated antigen, smooth muscle alpha-actin, and desmin. Based on morphology and expression of the various markers, the outgrowing cells were identified as pericytes. With time in culture the cells decreased their expression of all these markers and increased their expression of prolyl-4-hydroxylase, type I procollagen, and collagen pro-alpha1(I) mRNA. Metabolic labeling and SDS-PAGE analysis of labeled proteins revealed that type I collagen was the major collagen species synthesized in the cultures. Our results support the hypotheses that pericytes can leave the vasculature and differentiate into collagen-producing cells and that cultured "fibroblasts" are derived from pericytes.

Actins↗
PubMed1996

A novel physiological function for platelet-derived growth factor-BB in rat dermis.

1. The present experiments describe a role for platelet-derived growth factor-BB and cellular adhesion receptors towards extracellular matrix molecules (beta 1-integrins) in control of interstitial fluid pressure (Pif). 2. Pif was measured in rat skin with sharpened glass capillaries (3-7 microns) connected to a servocontrolled counter-pressure system. 3. The collagen and laminin-binding alpha 2 beta 1-integrin is involved in the control of Pif since subdermal injection (5 microliters) of monoclonal hamster anti-rat alpha 2 beta 1-integrin IgG (anti-alpha 2 beta 1) resulted in increased negativity of Pif. Control Pif averaged -0.88 +/- 0.23 mmHg (+/- S.D.) and decreased to -2.50 +/- 0.35 mmHg (P < 0.05) and -3.88 +/- 1.45 mmHg (P < 0.05) at anti-alpha 2 beta 1 concentrations of 0.56 and 1.12 mg ml-1, respectively. 4. The effect of anti-alpha 2 beta 1 was abolished when platelet-derived growth factor-BB (PDGF-BB) (200 ng ml-1) was injected together with anti-alpha 2 beta 1. 5. The time- and dose-responses of PDGF-BB to counteract increased negativity of Pif were studied further using dextran anaphylaxis as an experimental model inducing increased negativity of Pif in skin. Control Pif averaged -0.33 +/- 0.43 mmHg and fell to -4.10 +/- 1.47 mmHg within 10 min after dextran (P < 0.01). Subsequent subdermal injection of PDGF-BB at 200 ng ml-1 normalized Pif in 10-20 min which became -1.37 +/- 1.23 mmHg (P < 0.01 versus dextran, P > 0.05 versus control). PDGF-BB had little or no effect at 50 ng ml-1. PDGF-AA and basic fibroblast growth factor had no effect on Pif. 6. The in vivo function reported for PDGF-BB has not been described previously and provides further evidence for active participation of connective tissue cells in control of Pif by altering tension on extracellular matrix structures.

Animals↗
PubMed1996

Colon-cancer cell variants producing regressive tumors in syngeneic rats, unlike variants yielding progressive tumors, attach to interstitial collagens through integrin alpha2beta1.

Nine clones of tumor cells, derived from a single rat colon carcinoma, were analyzed for their adhesive properties and in vivo growth patterns. Four clones (denoted REG) gave rise to regressively growing tumors. Cells from the 4 REG clones attached significantly better to collagen types I and III than did cells from the 5 clones (denoted PRO) which grew progressively in vivo. In contrast, REG and PRO clones did not differ in their attachment to collagen type IV, laminin or fibronectin. The attachment of REG cells to collagen was dependent on Mg2+, but not Ca2+. Monospecific rabbit IgG to rat integrin beta 1-chain inhibited REG cell attachment to collagen, demonstrating involvement of a beta 1 integrin in this process. PRO and REG cells expressed an underglycosylated beta 1 chain (Mr approximately 105,000) that was somewhat smaller than beta 1-chains described previously on rat fibroblasts and hepatocytes (Mr approximately 115,000). Monoclonal IgG to rat integrin alpha 2 beta 1, but not to alpha 1 beta 1, readily inhibited REG cell attachment to collagen, demonstrating the involvement of integrin alpha 2 beta 1. However, beta 1 and alpha 2 integrin subunits were found in purified glycoproteins from both PRO and REG cells. This suggests that alpha 2 beta 1 integrin is expressed by both cell variants, but is functional as a collagen receptor on REG cells only. In this system of tumor-cell variants, the clear-cut differences in attachment to interstitial collagens of the 9 clones suggest a possible relationship between this attachment and the capacity to induce progressive or regressive tumors.

Amino Acid Sequence↗
PubMed1996

Stimulation of beta1 integrins on fibroblasts induces PDGF independent tyrosine phosphorylation of PDGF beta-receptors.

We report that integrin-mediated signaling induces a rapid and transient tyrosine phosphorylation of platelet-derived growth factor (PDGF) beta-receptors in human diploid foreskin AG 1518 fibroblasts. A transient tyrosine phosphorylation of PDGF beta-receptors was evident one and two hours after cells had been plated on collagen type I and fibronectin, as well as on immobilized anti-integrin subunit IgG, but not on poly-L-lysine. In contrast EGF or PDGF alpha-receptors were not phosphorylated on tyrosine residues under these conditions. Tyrosine phosphorylation of PDGF beta-receptors induced by plating on collagen type I was inhibited by cytochalasin D and herbimycin A, unaffected by cycloheximide and enhanced by orthovanadate. Furthermore, a transient phosphorylation of PDGF beta-receptors occurred when AG 518 fibroblasts were cultured in three-dimensional collagen lattices or exposed to external strain exerted through centrifugation. The latter effect was evident already after two minutes. Clustering of cell surface beta1 integrins led to PDGF beta-receptor phosphorylation both in suspended and firmly attached AG 1518 fibroblasts. Plating of cells on collagen type I, fibronectin, and anti-beta1-integrin IgG resulted in the formation of PDGF beta-receptor aggregates as detected by immunofluorescence. Suramin or anti-PDGF-BB IgG had no effect on the plating-induced tyrosine phosphorylation of PDGF beta-receptors. PDGF-B chain mRNA, or protein, were not detected in AG 1518 fibroblasts. Our data suggest that a ligand-independent PDGF beta-receptor activation during cell adhesion and early phases of cell spreading is involved in integrin-mediated signaling in fibroblasts, and constitutes parts of a mechanism for cells to respond during the dynamic phases of externally applied tension as well as fibroblast-mediated tension during cell adhesion and collagen gel contraction.

Cell Adhesion↗
PubMed1996

Pericytes as collagen-producing cells in excessive dermal scarring.

Immunohistochemistry and image analysis were performed on sections from excessive dermal scar formation to investigate the potential of pericytes to differentiate into collagen-producing cells. Expression of the prolyl-4-hydroxylase beta-subunit (P-4-H) was used as a marker for collagen synthesis as the distribution of this protein was identical to the distribution of procollagen type I C-propeptide and similar to the distribution of cells expressing pro alpha 1(I) collagen mRNA. Double immunofluorescence stainings using combinations of monoclonal antibodies specific for activated pericytes in vivo (high molecular weight-melanoma associated antigen (HMW-MAA)), P-4-H, smooth muscle alpha-actin (SMA), endothelial cells (PAL-E), platelet-derived growth factor (PDGF) beta-receptor, and the integrin alpha 5 subunit were performed. Stained sections were analyzed by computerized image analysis allowing for a quantification of the degree of colocalization between pairs of antigens on the same tissue section. Four different subpopulations of HMW-MAA expressing cells were discerned. The first subpopulation corresponded to intramural pericytes, juxtapositioned to the endothelium, that expressed HMW-MAA, SMA, integrin alpha 5 subunit and the PDGF beta-receptor, but not P-4-H. The second subpopulation was partly dissociated from the microvascular wall and exhibited a similar antigen expression except for a decrease in expression of SMA. Cells in the third subpopulation were located in the perivascular space and expressed P-4-H, integrin alpha 5 subunit, the PDGF beta-receptor and, albeit less pronounced, HMW-MAA, but not SMA. The fourth subpopulation expressed integrin alpha 5 subunit, HMW-MAA and the PDGF beta-receptor, no expression of SMA and a strong expression of P-4-H. Moreover, an in vitro analysis of cells derived from isolated microvascular fragments from human dermis revealed a similar pattern of phenotypical change. Taken together the data suggest that a population of intramural pericytes migrate into the perivascular space and develop into collagen-synthesizing fibroblasts during fibrosis.

Basement Membrane↗
PubMed1994

Purification of a bone sialoprotein-binding protein from Staphylococcus aureus.

Bone sialoprotein (BSP) is selectively bound by Staphylococcus aureus cells isolated from patients suffering from infections of bone and joint tissues [Rydén C., Maxe, I., Franzén, A., Ljungh, A., Heinegård, D. & Rubin, K. (1987) Lancet II, 515]. We now report on the purification of a cell-wall protein from Staphylococcus aureus, strain O24, that possesses affinity for bone sialoprotein. Staphylococcal cell-wall components with capacity to inhibit binding of 125I-labeled BSP to staphylococcal cells were solubilized with LiCl (1.0 M, pH 5.0). Preparative SDS/PAGE and protein-overlay experiments revealed that inhibitory activity present in LiCl extracts resided in a fraction of polypeptides with M(r) 75,000-110,000. Staphylococcal proteins solubilized with LiCl were chromatographed on a Mono-Q anion-exchange column. Inhibitory activity was eluted at 0.6-0.8 M NaCl and could be further purified by affinity chromatography on BSP-Sepharose. Elution of the affinity matrix with 0.1 M glycine, pH 3.0, specifically eluted inhibitory activity. Analysis by SDS/PAGE revealed a single M(r) 97,000 polypeptide in the eluate. The purified M(r) 97,000 protein bound BSP in protein-overlay experiments. LiCl extracts from S. aureus, strain E514 or Staphylococcus epidermidis, strain 7686, both lacking the capacity to bind BSP did not contain the M9r) 97,000 protein. Our data demonstrate the presence of a S. aureus cell-surface BSP-binding protein. This protein could be involved in bacterial tropism in osteomyelitis.

Bacterial Proteins↗
PubMed1994

Vitronectin in colorectal adenocarcinoma--synthesis by stromal cells in culture.

We have investigated the expression and cellular source of vitronectin in colorectal adenocarcinoma. Immunofluorescence staining of tissue sections revealed the presence of vitronectin in the stroma of the 11 tumors studied, but not in adjacent normal colon. A method was devised for the isolation from colorectal adenocarcinomas of fibroblast-like cells that stained positive for vimentin but negative for cytokeratin. These tumor-derived stromal cells synthesized and secreted vitronectin, as revealed by metabolic labeling and immunoprecipitation. This was confirmed by Southern blot analysis of polymerase chain reaction amplification products from reverse-transcribed RNA. Normal skin fibroblasts did not synthesize vitronectin. Immunofluorescence staining showed vitronectin deposited at focal contact sites in the tumor-derived cells, where it colocalized with vinculin and the alpha v integrin subunit. The deposition of vitronectin into focal contact sites was not dependent on the presence of serum. The finding that vitronectin can be synthesized and secreted by tumor-derived fibroblast-like cells in culture indicates that vitronectin expression can be promoted by as yet unknown signals provided in disease states, such as cancer.

Adenocarcinoma↗
PubMed1994

Platelet-derived growth factor-BB stimulates synthesis of the integrin alpha 2-subunit in human diploid fibroblasts.

Platelet-derived growth factor (PDGF)-BB stimulates fibroblast-mediated contraction of collagen gels, as well as migration of fibroblasts through collagen-coated membranes. In the present study we examined effects of PDGF-BB stimulation on the synthesis of collagen-binding beta 1 integrins by human diploid fibroblasts (AG 1518). PDGF-BB stimulation led to an increase in the rare of integrin alpha 2-subunit synthesis. In contrast, synthesis of the integrin alpha 1- or alpha 3-subunits were not affected by PDGF-BB stimulation. Furthermore, levels of alpha 2-subunit mRNA relative to levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA increased after PDGF-BB stimulation. The latter finding is compatible with PDGF-BB stimulating transcription of the alpha 2-subunit gene. PDGF-BB stimulation did not influence the relation between levels of integrin beta 1-subunit mRNA and GAPDH mRNA. In addition, the rate of synthesis or post-translational processing of the integrin beta 1-subunit were not, or only marginally, affected by PDGF-BB stimulation. It is likely that the motility response elicited in fibroblasts by PDGF-BB involves such alterations in the synthesis of the alpha 2-subunit of the alpha 2 beta 1 collagen-binding integrin.

Becaplermin↗
PubMed1994

The anti-inflammatory agent alpha-trinositol exerts its edema-preventing effects through modulation of beta 1 integrin function.

Edema formation in acute inflammation can be induced through lowering of interstitial fluid pressure (Pif) and seems to involve dynamic beta 1 integrin-mediated interactions between dermal cells and extracellular matrix fibers. The present experiments investigate the role of beta 1 integrins in the control of Pif. The anti-inflammatory drug alpha-trinositol (1,2,6-D-myo-inositol trisphosphate) stabilizes Pif in acute inflammation. Pretreatment with 5 mg IV alpha-trinositol in pentobarbital-anesthetized rats inhibited the lowering in Pif and the edema formation induced by subdermal injection of anti-beta 1 integrin IgG. This stabilization of the beta 1 integrin function in vivo was paralleled by effects of alpha-trinositol on contraction of fibroblast-populated three-dimensional collagen lattices in vitro. alpha-Trinositol was additive to the known stimulatory effect of platelet-derived growth factor-BB on the final gel size in the collagen gel contraction assay. Furthermore, alpha-trinositol counteracted the inhibitory effect of anti-beta 1 integrin Fab fragments on collagen gel contraction. Finally, subdermal injection of dibutyryl-cAMP (db-cAMP) induced increased negativity of Pif to the same extent as did anti-beta 1 integrin antibodies, and in vitro db-cAMP reduced the ability of fibroblasts to contract collagen gels. The latter effect was opposed by alpha-trinositol. The data demonstrate that alpha-trinositol modulates beta 1 integrin function and may do so via intracellular pathways in turn affecting the function and/or cell surface expression of beta 1 integrins and suggest that alpha-trinositol can serve as a tool to study integrin function. Furthermore, the data indicate that the collagen contraction assays may provide important information of the control of Pif in vivo.

Acute Disease↗
PubMed1994

Anti-beta 1 integrin IgG inhibits pulmonary macrometastasis and the size of micrometastases from a murine mammary carcinoma.

In the present report, we investigated the possible importance of beta 1 integrins in the growth and metastasis of a murine mammary carcinoma, SP1, and a metastatic variant, SP1-3M in vivo. CBA/J female mice bearing SP1 tumor transplants were injected with anti-beta 1 integrin IgG or control nonimmune IgG (200 micrograms per mouse; i.p.) every two days. Animals received anti-CD4 antibody (100 micrograms per mouse) at time zero to suppress immunity against rabbit IgG. Outgrowth of macroscopic metastases from SP1, but not from SP1-3M primary tumors, was markedly inhibited in animals receiving anti-beta 1 integrin IgG but not nonimmune IgG. To assess the stage(s) in the metastatic cascade affected, we examined the number and diameter of micrometastatic nodules in treated and untreated groups. The diameter of micrometastases was significantly reduced in SP1-tumor-bearing mice treated with anti-beta 1 integrin IgG compared to control IgG, although the number of nodules per cm2 of lung sections examined remained unchanged. No change in the number or size of micrometastases in SP1-3M tumor-bearing mice was observed. No difference in the binding, or complement-mediated and antibody-dependent cell-mediated cytotoxicity of anti-beta 1 integrin IgG with SP1 and SP1-3M cells was detected. The results suggest that under these conditions anti-beta 1 integrin inhibits metastatic tumor growth in lung tissue, but has minimal effect on intravasation, adhesion to target organs and extravasation.

Animals↗
PubMed1994

Collagen type I is not under autocrine control by transforming growth factor-beta 1 in normal and scleroderma fibroblasts.

BACKGROUND: The ability of transforming growth factor-beta (TGF-beta) to induce synthesis of extracellular matrix proteins stimulated this study in which we address the hypothesis that TGF-beta can induce, in normal fibroblasts, the sustained, elevated collagen synthesis characteristic of the scleroderma fibroblast. EXPERIMENTAL DESIGN: Fibroblasts were studied for synthesis of and responsiveness to TGF-beta. Secreted TGF-beta levels were determined in a bioassay and at the transcriptional level in a series of scleroderma (SSc) and normal fibroblasts. The ability of cells to interact functionally with a 3-dimensional collagen matrix after TGF-beta treatment was examined. The kinetics of TGF-beta-induced fibrosis in fibroblasts was studied. RESULTS: SSc fibroblasts were not characterized by elevated TGF-beta synthesis. There was no evidence of coordinate regulation of TGF-beta and collagen over passage number. Repeated pulses of 200 pM of TGF-beta did not significantly induce sustained procollagen alpha 1(I) mRNA synthesis in normal fibroblasts, and this treatment did not significantly alter the characteristics of normal fibroblasts in a collagen gel. mRNA for both collagen and TGF-beta type II receptor was induced by TGF-beta in both SSc and control cells. SSc fibroblasts were found to have an impaired ability to activate the small latent complex of TGF-beta. CONCLUSIONS: Our data give no support to the hypothesis that TGF-beta can maintain the SSc phenotype in vitro or that it is able to induce this phenotype. The inducibility of TGF-beta receptor mRNA in SSc fibroblasts after exposure to TGF-beta suggests that the lack of sustained elevation in collagen synthesis is not due to lack of responsiveness by the fibroblasts but is rather a reflection of the transient nature of TGF-beta-induced fibrosis.

Cell Division↗