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PubMed1991

Modulation of monocyte chemotactic function in inflammatory lesions. Role of inflammatory mediators.

Monocyte recruitment and accumulation in the synovial tissue is pivotal in the evolution of rheumatoid arthritis (RA). In the present study we examined the chemotactic potential of monocytes obtained from synovial fluid (SF) of patients with RA. Functionally, SF monocytes exhibited greatly diminished chemotactic activity to C5a compared with monocytes from the peripheral blood. In contrast, their chemotactic responsiveness to the synthetic peptide, FMLP, was nearly normal. To define a mechanism for this differential chemotactic dysfunction, cell-surface receptors for C5a (C5aR) and FMLP (FMLP-R) were evaluated. Whereas FMLP-R expression was similar on both blood and inflammatory monocytes, C5aR expression was markedly reduced on SF cells. Because decreased C5a binding in certain RA SF samples could not be attributed to free C5a, known or suspected components of inflammatory SF were evaluated for their ability to modulate chemotactic ligand receptors. Bacterial products including LPS and streptococcal cell walls, which are potent monocyte activators, down-regulated C5aR without affecting FMLP-R. Moreover, the cytokines IFN-gamma and granulocyte-macrophage-CSF selectively decreased C5aR in parallel with decreased in vitro chemotactic activity to C5a. Thus, these data indicate that 1) synovial effusions may contain C5a and/or inflammatory mediators that modulate phenotypic and functional changes in monocytes, 2) chemotactic ligand receptors are independently regulated in inflammatory lesions, and 3) decreased C5aR expression and chemotactic potential likely provide a mechanism whereby monocyte-macrophages persist within the inflamed synovium.

Adult↗
PubMedDate not supplied

Early ionic events associated with phorbol ester induced differentiation and inhibition of cell growth in hematopoietic tumor cell lines.

The effects of 12-O-tetradecanoylphorbol-13 acetate (TPA) on DNA synthesis, phenotypic expression, cytoplasmic Ca2+ (Ca2+i), intracellular pH (pHi) and membrane potential were studied in the monoblastic U-937 and the erythroleukemic K-562 cells. In both cell lines DNA synthesis was inhibited and in the U-937 cells this was accompanied by the appearance of macrophage differentiation markers. The erythroid characteristics of K-562 cells, on the other hand, were markedly suppressed. Intracellular pH (pHi) was increased by TPA treatment; however, while the alkalinization of K-562 cells was dependent on the presence of extracellular Na+, the response of U-937 cells was unaffected by the removal of this cation. In each cell type the protein kinase C (PKC) inhibitor H-7 largely attenuated the TPA induced increase of pHi. Moreover, the alpha-stereoisomer of TPA, which does not activate PKC, had no effects. TPA caused a dose-dependent decrease in Ca2+i which was more pronounced in U-937 cells. Measurements of membrane potential revealed a marked TPA depolarization of the K-562 cells, but no such effects were observed in the U-937 cell line. The depolarizing response of K-562 cells could be abolished by substituting extracellular Na+ with choline+, indicating the presence of a TPA sensitive Na+ permeability. The results show that the phorbol ester TPA, which inhibits proliferation and causes phenotypic modulation, also induced a number of early, apparently PKC dependent and cell type specific, changes of intracellular ion activities. The possible role of intracellular ion fluxes in the regulation of cell growth and differentiation is discussed.

Calcium↗
PubMed1989

Comparative growth dynamics and actin concentration between cultured human myofibroblasts from granulating wounds and dermal fibroblasts from normal skin.

The normal contraction of open wounds and many forms of pathologic contracture are related by the presence of a contractile fibroblast known as a myofibroblast. The function of this cell has been postulated as a result of previous pharmacological, immunological, and biochemical testing on strips of contracted connective tissue. The purpose of this study was to develop a specific assay that could measure the concentration of one contractile element (actin) within cultured myofibroblasts isolated from a contracting wound and in normal fibroblasts from uninjured dermis. Rates of growth and actin concentration through 15 days of culture were compared among populations of paired control fibroblasts from normal dermis and granulating wound myofibroblasts from three patients. Growth curves showed that myofibroblasts always grew slower than fibroblasts. An enzyme-linked immunosorbent assay showed that actin concentration was generally greater in mass cultures of granulating wound myofibroblasts than in fibroblasts from uninjured dermis. During exponential growth (1-6 days) the average actin concentration among myofibroblast lines ranged from 24 to 62 pg/cell. Average actin levels among control fibroblasts ranged from 3 to 47 pg/cell during the same interval. After 15 days of culture, actin concentration peaked twice. The first actin peak occurred within the period of exponential growth. At confluency, cellular actin levels dropped. Superconfluent cultures exhibited a second actin peak that displayed an irregular pattern of actin concentration. The latter observation suggested an artifact that might be the result of three-dimensional matrix of cells that altered points of cell adhesion and produced an irregular pattern of actin concentration. These data show that the phenotype of increased actin in cultured myofibroblasts was carried over by myofibroblasts from contracted skin wounds to culture. Because of a higher concentration of actin in myofibroblasts than in undifferentiated fibroblasts, these data suggest that the differentiation process of myofibroblasts may be associated with an increased availability of monomeric actin for filament synthesis. This study demonstrates that the use of tissue culture and our enzyme-linked immunosorbent assay will be a useful method to study factors affecting myofibroblast phenotypic modulation. Future studies should be directed toward developing procedures for isolation of pure populations of myofibroblasts as well as extracellular matrices that would maintain the morphology of both differentiated myofibroblasts and normal undifferentiated fibroblasts.

Actins↗
PubMed1988

Proliferative changes in the pulmonary arterial wall during short-term hyperoxic injury to the lung.

Injury to the lung during in vivo exposure to hyperoxia results in vascular restructuring and pulmonary hypertension. This study reports the pattern of cellular proliferation that occurs in proximal intrapulmonary arteries over time during vessel wall injury and adaptation to increased partial pressures of oxygen. Although the remodeling of the capillary bed has been emphasized particularly during oxygen injury to the lung, this report identifies significant proliferative changes within the vessel wall of proximal arterial segments isolated from rats exposed to 85% oxygen. An increased incorporation of 3H-thymidine by endothelial cells is the earliest and most dramatic vessel wall response. The labeling index of these cells is increased more than tenfold by the end of 7 days in hyperoxia. Proliferation of medial smooth muscle cells and adventitial fibroblasts is also significantly increased. The increased cell number within these compartments is noted especially for its contribution to the overall vessel wall hypertrophy observed in chronic hyperoxic pulmonary hypertension. This general proliferative response is accompanied by specific shifts in the relative percentages of different actin protein isoforms as identified by two-dimensional gel electrophoresis. Changes in the distribution of actin isoforms are discussed as potential markers of a phenotypic modulation among vascular smooth muscle cells that occurs during the progression of pulmonary vessel wall remodeling.

Animals↗
PubMed1986

Acute lymphoblastic leukemia at relapse in a child with acute myeloblastic leukemia.

We describe a child diagnosed as having acute myelogenous leukemia (AML) at 25 months of age who relapsed with acute lymphoblastic leukemia (ALL) 1 year later. The AML was morphologically M2 by the French-American-British classification, periodic acid Schiff (PAS) stain negative and peroxidase positive. The ALL was L1 by this classification, PAS positive, and peroxidase negative. The initial AML was associated with a small segment deletion of the long arm of chromosome 11 [46, XY, de (11) (q23)] not seen in the relapse ALL, which had a normal karyotype. The child was rapidly reinduced with vincristine and prednisone, and remains in remission on maintenance lymphoma type (LSA2-L2) therapy more than 2 years later. These findings suggest the development of a new leukemic clone, rather than a phenotypic modulation of the initial leukemia.

Bone Marrow↗
PubMed1986

In vitro production of glycosaminoglycans by retinal microvessel cells and lens epithelium.

Analysis of bovine lens capsules and retinal microvessel basement membranes by cellulose acetate electrophoresis, together with treatment by specific enzymes or by nitrous acid, reveals that heparan sulfate is the only demonstrable glycosaminoglycan (GAG), consistent with the observations of most other investigators on basement membrane preparations from several different tissues. When bovine retinal microvessel pericytes or endothelial cells or bovine lens epithelial cells are grown in culture in the presence of [35S]-sulfate or [3H]-glucosamine, however, both cellulose acetate electrophoresis and gel filtration chromatography reveal that the cultured pericytes synthesize primarily chondroitin sulfate, whereas the lens epithelial cells and microvascular endothelial cells produce a mixture of GAGs consisting of approximately 60% heparan sulfate and 40% chondroitin sulfate. The chondroitin sulfate chains have an Mr of 70,000, but the Mr of the heparan sulfate chains is 10,000, based on gel filtration chromatography on Sepharose CL-6B. Hence, cell culture conditions may produce phenotypic modulation of the biosynthetic capacities of these cells for GAGs. However, the difference between the in vitro and in vivo findings may in part be explained if many of the chondroitin sulfate GAGs synthesized in vitro are cell associated and are not incorporated into the basement membrane.

Animals↗
PubMedDate not supplied

[Molecular heterogeneity of the collagen from the skin of white rats in the early postnatal period].

Content and biosynthesis of collagens of I and III types were studied in skin of 5 and 50 days old rats. The ratio of collagens of the I and III types was equal to 17.84 in the skin of 5 days old rats and to -- 13.42 in the tissue of 50 days old rats. The collagen biosynthesis was studied using 14C-glycine incorporation. The ratio of 14C-collagens of the I and III types was equal to 47.53 and 50.03 in the skin of 5- and 50 days old animals, respectively. The data obtained showed occurrence of collagen III biosynthesis of comparatively low rate in rat skin within the postnatal period. The phenotypic modulation of biosynthesis of these collagen types exhibited the step-like pattern in the change from embryogenesis to postnatal development of rats.

Aging↗
PubMed1995

Overexpression of c-met protooncogene product and raised Ki67 index in hepatocellular carcinomas with respect to benign liver conditions.

The c-met protooncogene encodes a 190-kd transmembrane tyrosine kinase. This molecule is the receptor for the hepatocyte growth factor (HGF), which is an important mitogen for hepatocytes both in vitro and in vivo. In experimental models, the c-met transcripts appeared strongly expressed by actively proliferating oval cells (OCs). We evaluated the phenotypic modulation of the c-met protooncogene product (c-met pp), in 10 hepatocellular carcinomas (HCCs), 5 focal nodular hyperplasias (FNHs), 4 cases of fulminant hepatitis (FH), and 1 regenerated liver, selected to include the different biological states of hepatocyte (mature normal hepatocytes, transformed ones, and OCs). The supposed mitogenic effect of HGF was analyzed by comparing c-met pp overexpression with the Ki67 index, whereas anti-OV-6 antibody was used for comparison with the presence of OCs. The anti-c-met pp showed a typical plasma membrane-specific staining in all cases. The signal was much stronger in the HCCs than in the benign conditions. The anti-OV-6 monoclonal antibody showed positive immunostaining in many of the cells expressing c-met pp. The percentage of Ki67+ nuclei in high-grade HCCs paralleled c-met protooncogene overexpression. The c-met pp in OV-6+ cells suggests that the paracrine mechanism postulated in experimental models could also apply to human liver.

Biomarkers, Tumor↗
PubMed1994

Clusterin expression in differentiating smooth muscle cells.

Clusterin is a heterodimeric glycoprotein, expressed by various cell types and shown to have activity in cell-cell adhesion. Cultured porcine smooth muscle cells (SMC) undergo morphological and phenotypic modulation associated with a change from a substrate-attached monolayer culture to a nodular culture in which most of the cells are present in multicellular aggregations (nodules). During that transition from monolayer to nodular cell culture (> 8 days) the expression of an mRNA and protein with significant homology to rat and human clusterin is increased. Clusterin expression continues in the nodular cell cultures and it is secreted at 0.3 micrograms/ml/24 h as a protein with an apparent molecular mass = 80 kDa. In the presence of beta-mercaptoethanol the molecular mass is approximately 40 kDa. SMC clusterin expression is regulated by culture conditions that also affect culture morphology. SMC cultures seeded on a preformed extracellular matrix composed of Matrigel form nodules within 24 h and cultures seeded on a collagen gel form nodules in 48-72 h. We establish here that Matrigel contains clusterin and propose that endogenous clusterin supports the rapid formation of nodules. The collagen gel does not contain clusterin but facilitates clusterin expression by smooth muscle cells. Nodule formation in SMC cultures growing on collagen gel is inhibited by the addition of anticlusterin antibody to SMC growing on collagen gels and the antibody effect is eliminated by preincubation with purified plasma clusterin. These results demonstrate differential expression of SMC clusterin and suggest that clusterin has a functional role in SMC modulation.

Animals↗
PubMed1994

Development-related changes in matrix metalloproteinase expression in human aortic smooth muscle cells.

BACKGROUND: It is known that extracellular matrix-degrading enzymes play an important role in tissue remodeling and that large amounts of structural proteins including types I, III, IV, and V collagens and elastin are produced by smooth muscle cells (SMC) in the arterial wall. We have recently shown that matrix metalloproteinases (MMPs) produced by human aortic medial smooth muscle cells are closely related to the proliferation of the cells, leading to the formation of atherosclerotic plaques, characteristic of intimal remodeling. For a better understanding of the mechanism of atherogenesis, therefore, it is important to clarify the relationship between the production of matrix-degrading enzymes and artery development. EXPERIMENTAL DESIGN: In vivo or in vitro synthesis of MMPs by SMC was analyzed by immunohistochemistry and immunoblotting. Elastase activity in the culture medium was also estimated. RESULTS: Production of proMMP 1, 2, and 3 was detected in cultured SMC isolated from the aortas of both neonates and fetuses; in medial SMC cultured from young individuals, production of proMMP-1 and -3 was extremely decreased, but was apparent in intimal SMC. Immunohistochemical observation indicated that in the media of fetal or neonatal aorta, SMC synthesized large amounts of the three proMMPs; in aortas from older individuals, proMMP-2, but not proMMP-1 and -3, was detected in the media, and relatively large amounts of proMMP-1, -2, and -3 were produced by SMC in the slightly thickened intima. Assay of elastase activity in the culture medium gave results similar to those for MMPs. CONCLUSIONS: We conclude that the production of proMMP-1 and -3 is associated with phenotypic modulation of SMC to a "synthetic" state, and that the ability of SMC to produce MMPs plays an important role in the development and/or aging of the human aorta through remodeling of the extracellular matrix; furthermore elastase is also involved in these processes in the arterial wall.

Adolescent↗
PubMed1993

[Molecular basis for cardiac functions].

Cardiac functions are regulated by both contractile proteins and calcium regulatory proteins. Alterations of these are considered involved in impaired contractile and diastolic functions in hypertrophied hearts. In this study, we analyzed molecular changes during the development of cardiac hypertrophy. Cardiac hypertrophy was induced by constricting the pulmonary artery in rabbits or the aorta in rats. In rabbit right ventricular hypertrophy, protein synthesis was increased to 1.8 times the control 2-4 days after pulmonary constriction. This increase in protein synthesis could be classified as an increase in both capacity and efficiency of synthesis. beta-cardiac myosin heavy chain (beta-MHC) isoform was predominantly expressed and alpha-MHC was suppressed in pressure overload hypertrophy. The switch from alpha- to beta-MHC occurred at the mRNA level. Ca(2+)-ATPase of sarcoplasmic reticulum (SR) is important because it regulates intracellular Ca2+ levels during relaxation. In pressure-overload hypertrophy, the SR Ca(2+)-ATPase was markedly decreased in both the enzyme activities and mRNA levels, while in thyrotoxic hearts both were increased. Interstitial cells also undergo phenotypic modulation which was demonstrated by the induction of nonmuscle-type MHC in pressure-overload hypertrophy. The signal transduction system in cardiac hypertrophy was examined by stretching cardiac myocytes grown on deformable membranes. In our analysis, stretching myocytes stimulated protein kinase C, MAP-II kinase and S6 kinase, all of which may lead to the induction of fetal-type cardiac genes and accelerated protein synthesis. These analyses of subcellular adaptation in cardiac hypertrophy provide important insights into understanding molecular mechanisms of cardiac functions.

Animals↗
PubMed1996

Allograft vascular disease: comparison of heart and other grafted organs.

A striking resemblance exists between the vasculopathy in several different allografts. The arteriopathy of epicardial coronary arteries is diffuse, involving proximal, distal, and small branch segments in a generally concentric pattern of intimal thickening. Smooth muscle cells in a lipid- and glycosaminoglycan-rich matrix are the predominant components of this expanded intima. Varying amounts of collagen are present, more being present late posttransplant. A superficial and, to a lesser degree, deep, bandlike infiltrate of T cells and macrophages is uniformly present, although it is somewhat more prominent in early lesions as compared to more severely narrowed arteries from longer-term, susceptible grafts. The media is likewise altered by areas of lipid and glycosaminoglycan deposition associated with smooth muscle cell loss and phenotypic modulation. The media is altered in an outside-to-inside direction, with percolation of adventitial leukocytes into the outer media. Virtually all of the coronary features are seen in the medium to large arteries of liver, pancreas, and kidney allografts. Chronic rejection in lung allografts is manifest by obliterative bronchiolitis; vascular changes, although architecturally similar, are somewhat less common and result in less-severe luminal narrowing. The role of allograft vasculopathy in chronic lung rejection is thus less certain. A finding perhaps unique to epicardial coronary arteries of heart allografts is the presence of eccentric lesions more typical of native atherosclerosis. Many of the latter grafts probably have preexistent, undetected donor disease. Sequential evaluation of vascular changes is limited in human biopsy material by their general absence in endomyocardial or core liver needle specimens. Fortunately, vascular changes can be detected in some renal and pancreas core needle biopsies, and these findings may provide an avenue for monitoring the effectiveness of immunosuppressive therapy, antiviral or lipid-altering therapies, or modifications of smooth muscle cell proliferation and glycosaminoglycan deposition yet to be developed.

Heart Transplantation↗
PubMed1997

Differentiating agent, hexamethylene bisacetamide, inhibits neointimal formation after vascular injury.

BACKGROUND: Hexamethylene bisacetamide (HMBA), a potent differentiating agent of transformed cell lines, has been reported to affect phenotypic modulation and suppress proliferation of vascular smooth muscle cells (VSMCs). The effects of HMBA on the growth of VSMCs were studied in the rat carotid injury model. METHODS: HMBA was added to culture medium of VSMCs explanted from aorta of Sprague Dawley rats and the cell number was counted after 5 days of incubation. The carotid artery of Sprague Dawley rats was denuded with a balloon embolectomy catheter. The rats were treated with continuous infusion of HMBA (1 g/day) or saline for 7 days after injury. RESULTS: HMBA inhibited VSMC proliferation in a dose-dependent manner (at a HMBA concentration of 1-5 mM). Plasma concentration of HMBA during continuous infusion was in the range 0.8-1.0 mM. Immunohistochemistry of proliferating cell nuclear antigen showed that HMBA inhibited VSMC proliferation after vascular injury. Cell number in the intima and neointimal thickening were significantly reduced in HMBA-treated rats at 14 days after injury. CONCLUSIONS: Systemic administration of HMBA inhibited VSMC proliferation in the rat carotid injury model.

Acetamides↗
PubMed1996

Naked cDNA encoding secreted proteins for intra-arterial and intramuscular gene transfer.

Experience with intra-arterial and intramuscular gene transfer of VEGF illustrates in prototypical fashion how features of the gene, protein, and target tissue may all contribute to phenotypic modulation of the host despite the low transfection efficiency typical of naked plasmid DNA. These features include the fact that VEGF is naturally secreted, binds to cell-surface heparan sulfates, is generated by hypoxic endothelial cells, reduces apoptosis, and binds to high-affinity receptors that are upregulated by hypoxia. Thus the success of gene therapy is not solely a function of vectors or transfection efficiency.

Animals↗
PubMed1998

Physical effects of cholesterol on arterial smooth muscle membranes: evidence of immiscible cholesterol domains and alterations in bilayer width during atherogenesis.

Small angle X-ray diffraction was used to examine arterial smooth muscle cell (SMC) plasma membranes isolated from control and cholesterol-fed (2%) atherosclerotic rabbits. A microsomal membrane enriched with plasma membrane obtained from animals fed cholesterol for up to 13 weeks showed a progressive elevation in the membrane unesterified (free) cholesterol:phospholipid (C/PL) mole ratio. Beyond 9 weeks of cholesterol feeding, X-ray diffraction patterns demonstrated a lateral immiscible cholesterol domain at 37 degrees C with a unit cell periodicity of 34 A coexisting within the liquid crystalline lipid bilayer. On warming, the immiscible cholesterol domain disappeared, and on cooling it reappeared, indicating that the immiscible cholesterol domain was fully reversible. These effects were reproduced in a model C/PL binary lipid system. In rabbits fed cholesterol for less than 9 weeks, lesser increases in membrane C/PL mole ratio were observed. X-ray diffraction analysis demonstrated an increase in membrane bilayer width that correlated with the C/PL mole ratio. This effect was also reproduced in a C/PL binary lipid system. Taken together, these findings demonstrate that in vivo, feeding of cholesterol causes cholesterol-phospholipid interactions in the membrane bilayer that alter bilayer structure and organization. This interaction results in an increase in bilayer width peaking at a saturating membrane cholesterol concentration, beyond which lateral phase separation occurs resulting in the formation of separate cholesterol bilayer domains. These alterations in structure and organization in SMC plasma membranes may have significance in phenotypic modulation or aortic SMC during early atherogenesis.

Animals↗
PubMed1999

The apolipoprotein B R3531C mutation. Characteristics of 24 subjects from 9 kindreds.

Familial ligand-defective apolipoprotein B (apoB) is a group of disorders caused by mutations in the apoB gene. In this report the R3531C mutation is characterized further using a monoclonal antibody MB19/dynamic laser light scattering technique to measure ratios of Cys(3531) to normal low density lipoprotein (LDL) particles. All six subjects studied showed a preferential accumulation of particles carrying the defective apoB allotype. We determined binding properties of LDL from R3531C heterozygotes by measurement of high-affinity binding to LDL receptors on fibroblasts and its ability promote growth of U937 cells. LDL from R3531C heterozygotes, compared to normal LDL, had 49.3% of the binding affinity and was 74% as effective in a U937 cell proliferation assay. To identify new probands, we screened 2570 subjects for the R3531C mutation. Nine probands were found with 15 affected relatives. Of the seven haplotypes we uncovered, two were novel, while five were identical to one initially reported as associated with Cys3531. Three silent mutations were detected also: T3540T, N3542N and T3552T. Analysis of lipid profiles of R3531C families showed, as with the R3500Q mutation, variable expression of the phenotype, modulated by environmental and other genetic factors. Both mutations tend to produce lower plasma levels of LDL in affected subjects than do defects of the LDL receptor (familial hypercholesterolemia, FH). This study shows that the Cys(3531) LDL particles are not only defective at binding to the LDL receptor, as determined by two separate methods, but that in all cases they accumulate preferentially compared to the normal allotype.-Pullinger, C. R., D. Gaffney, M. M. Gutierrez, M. J. Malloy, V. N. Schumaker, C. J. Packard, and J. P. Kane. Apolipoprotein B R3531C mutation: characteristics of 24 subjects from 9 kindreds. .

Adolescent↗
PubMed1985

Ectopic peptides released by a human melanoma cell line that modulate the transformed phenotype.

Cells derived from a human melanoma strain by low serum selection in monolayer were found to be capable of growth in semi-solid medium, forming colonies ranging from tight, to loose, or dispersed. These phenotypes were found to be stable on cloning and retesting. Examination of the serum-free media conditioned by these clones indicates that the clones release activities capable of inducing agar colonies, in an indicator cell line (NRK, 49F), that express phenotypes similar to those of the melanoma clones used to produce the serum-free conditioned media (SF-CM). These SF-CM contained a transforming growth factor (TGF) beta (apparent Mr 14 700) and a single, apparently high Mr TGF-alpha species. Co-eluting with the TGF-alpha at an Mr of approximately 22 500 was a previously undescribed activity capable of modulating the phenotype of the NRK agar colonies induced by the combination of TFGs alpha and beta. This new activity can modulate the usual tight colony to express a loose or dispersed phenotype characteristic of the producer cells. The possible role these ectopic peptides play in the expression of the transformed phenotype by the tumour cells producing them, and the possible correlation between the 22 500 Mr EGF-like peptide (TGF-alpha) released by this particular tumour line and high Mr EGF-like peptides found in the urine of cancer patients, are both discussed.

Animals↗
PubMed1985

Ectopic peptides released by a human melanoma cell line that modulate the transformed phenotype.

Cells derived from a human melanoma strain by low-serum selection in monolayer were found to be capable of growth in semisolid medium, forming colonies ranging from tight to loose or dispersed. These phenotypes were found to be stable after cloning and retesting. Examination of the biological activities of ectopic peptides produced by a clone that gives rise to loose dispersed colonies revealed the presence of a transforming growth factor beta (TGF-beta; apparent Mr 14,700) and a single TGF-alpha species produced at an unusually high concentration (2.2 ng/ml). Coeluted with the TGF-alpha at approximately 22,500 was a mitogenic activity and a previously undescribed activity capable of modulating the phenotype of induced normal rat kidney fibroblast (NRK-49F) colonies in semisolid medium. This activity can modulate the usual tight colony to express a loose or dispersed phenotype characteristic of the producer cells. Both the possible role these ectopic peptides play in the expression of the transformed phenotype by the tumor cells producing them and the possible correlation between the Mr 22,500 epidermal growth factor-like peptide released by this particular tumor line and high molecular weight epidermal growth factor-like peptides found in the urine of cancer patients are discussed.

Animals↗