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PubMed1983

Transcriptional control of the fibronectin gene in chick embryo fibroblasts transformed by Rous sarcoma virus.

Rous sarcoma virus transformed-chick embryo fibroblasts contain decreased amounts of the adhesive protein fibronectin that results from a lowering of fibronectin mRNA levels (Fagan, J.B., Sobel, M.E., Yamada, K.M., de Crombrugghe, B., and Pastan, I. (1981) J. Biol. Chem. 256, 520-525). In the present study, nuclei isolated from chick embryo fibroblasts (CEF) and Rous sarcoma virus transformed-chick embryo fibroblasts (RSV-CEF) were used to measure relative rates of fibronectin RNA synthesis. [32P]RNA was synthesized by preinitiated endogenous RNA polymerases in nuclei, and the radioactive RNA was subsequently hybridized to DNA fragments spanning approximately 40 kilobase pairs (approximately 85%) of the fibronectin gene. Transformation of CEF by RSV resulted in a 7- to 8-fold reduction in the amount of 32P-labeled nuclear RNA hybridizing with fibronectin DNA sequences when the nuclei were incubated for either 3.5 or 45 min. These results indicate that decreased transcription and not reduced RNA stability plays a major role in lowering fibronectin mRNA levels in RSV-CEF. When nuclear RNA was transcribed in the presence of Sarkosyl, diminished RNA synthesis was still observed suggesting that reduced fibronectin transcription in RSV-CEF is not due to a block in RNA chain elongation. Our data indicate that transcriptional regulation of the fibronectin gene is an important mechanism of lowering steady state levels of fibronectin mRNA in RSV-CEF.

Animals↗
PubMed1984

Detection of autoantibodies and glomerular injury in rabbits immunized with denatured human fibronectin monomer.

Seven rabbits were studied after immunization with human plasma fibronectin which had been purified by preparative sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis run after reduction. Light- and electron-microscopic examination of kidneys revealed proliferative mesangial and capillary alterations in all of the rabbits immunized with fibronectin, but not in the rabbits immunized with fibrinogen or saline. In addition, one of the rabbits (Rabbit 4) also demonstrated dense deposits in a unique distribution within the glomerular basement membrane. Granular staining for rabbit IgG was present in the mesangium and along the basement membranes of the capillary loops of glomeruli from Rabbit 4 as detected by immunohistochemical methods. Sera from all of the rabbits immunized with human fibronectin contained IgG antibodies that reacted with rabbit fibronectin when tested by the Western blotting method. Preimmune sera and sera from rabbits immunized with fibrinogen or saline recognized neither human nor rabbit fibronectin. Although antibodies from several of the rabbits reacted with the 27,000-dalton, aminoterminal fragments of human fibronectin by the Western blotting method, only antibodies from Rabbit 4 recognized the 27,000-dalton fragment of rabbit fibronectin. These studies indicate that antibodies which recognize fibronectin of the host species and which are involved in the pathogenesis of glomerular injury can be induced by immunization with denatured heterologous fibronectin monomer.

Animals↗
PubMed1984

Fibronectin synthesized by a human hepatoma cell line.

Fibronectin is a family of immunologically similar glycoproteins which mediate a variety of cell-cell and cell-substratum interactions. It is a constituent of the extracellular matrix of connective tissue and circulates in plasma. When suspension and adherent cultures of a human hepatoma cell line (SK-HEP-1) were incubated in serum-free medium, the resulting conditioned medium contained material which was specifically immunoprecipitated by antisera to human plasma fibronectin. By double immunodiffusion, a component in the conditioned culture medium was shown to form a line of identity with fibronectin in human plasma and to migrate as an alpha 2- to beta-globulin during immunoelectrophoresis. Human fibronectin was quantified in conditioned medium by electroimmunodiffusion, and was found to increase for at least three days at about 0.1 micrograms/10(6) cells/day. Adherent cultures of SK-HEP-1 cells were incubated with L-[35S]methionine to label newly synthesized proteins. Labeled fibronectin in conditioned medium or in cell extracts comigrated with fibronectin in human plasma as shown by autoradiography following crossed-immunoelectrophoresis. Fibronectin was demonstrated in the extra-cellular matrix of adherent SK-HEP-1 cultures by immunofluorescence. We had shown previously that SK-HEP-1 cells synthesize alpha 1-protease inhibitor, one of the products of normal hepatocytes. The finding that these hepatoma cells also synthesize fibronectin supports the concept that the hepatocyte may be one source of circulating fibronectin, a possibility consistent with the established role of this cell type in blood plasma protein synthesis.

Carcinoma, Hepatocellular↗
PubMed1983

Plasma fibronectin is synthesized and secreted by hepatocytes.

Primary cultures of hepatocytes of rats and hamsters were established and examined for the synthesis and secretion of fibronectin. Hepatocytes of both species secreted fibronectin as a soluble dimeric protein which could be purified by its affinity for gelatin and using specific antisera. Plasma and cellular fibronectins could be clearly resolved on two-dimensional gels. In both species, the majority of the fibronectin secreted by hepatocytes was of the plasma type, as shown by analyses on one- and two-dimensional gels. The secretion of plasma fibronectin increased with time in culture, both in absolute terms and relative to the secretion of albumin. Even during the first day of culture, the secretion of fibronectin relative to that of albumin appeared to be sufficient to account for the relative levels of these two proteins in plasma. Hepatocytes of both species secreted preferentially the chain of plasma fibronectin with higher apparent molecular weight, although the faster migrating chain was also secreted. In addition, hamster hepatocytes cultured for 2 or more days appeared to secrete a cellular form of fibronectin. Possible origins for the different chain types of cellular and plasma fibronectins are discussed.

Animals↗
PubMed1984

Flow kinetics of fibronectin secretion by livers of young preweanling rats.

Fibronectin is a high molecular weight adhesive glycoprotein present both on the cell surface (cellular fibronectin) and circulating free in the plasma (plasma fibronectin). To investigate the cellular origins of plasma fibronectin, monoclonal antibodies prepared against purified plasma fibronectin of the rat were used in both in vivo and in vitro pulse-chase experiments comparing livers of animals of different ages. For in vitro analyses, slices were pulsed with 3H-leucine and purified fractions of endoplasmic reticulum, Golgi apparatus and plasma membrane were prepared at various times post-chase and characterized morphologically. The total protein was solubilized with NP-40, and incorporation into fibronectin was determined from PAGE analysis of immunoprecipitates. Incorporation was greatest in 5-day-old animals, representing greater than 0.3% of the total radioactivity and was least in adults animals. Label appeared in fibronectin associated with the plasma membrane within 60 min. At earlier times, labeled fibronectin appeared first in the endoplasmic reticulum (30 min) and then in the Golgi apparatus (45 min). The findings demonstrate synthesis of fibronectin by rat liver and evidence for participation of liver endomembranes in its secretion.

Animals↗
PubMed1984

Fibronectin enhancement of directed migration of B16 melanoma cells.

The migration of B16 melanoma cells into porous nitrocellulose filters fitted between the upper and lower compartments of blindwell chemotactic chambers was examined by light microscopy. Human plasma fibronectin placed in the lower compartment of such chambers enhanced in a time-, temperature-, and dose-dependent manner the directed migration of B16 cells into the filter. Fibronectin placed either in the upper compartment alone or in equal concentrations in both compartments did not result in a significant increase in B16 cell migration, indicating that a positive gradient of fibronectin is required. Pretreatment of filters with fibronectin to establish a gradient of bound fibronectin also stimulated the directed migration of B16 cells. The response to fibronectin appeared to be specific, since other plasma proteins and reduced fibronectin or trypsin-digested fibronectin failed to enhance the migration over base-line values. These results suggest that a specific haptotactic-chemotactic response to fibronectin was responsible for enhanced B16 cell migration.

Animals↗
PubMed1982

Reversible binding of a guinea-pig lymphokine to gelatin and fibrinogen: possible relationship of macrophage agglutination factor and fibronectin.

Macrophage agglutination factor (MAggF) is a T-cell-dependent guinea-pig lymphokine with pH stability, heat stability and isoelectric point similar to fibronectin (see preceeding paper for details). Further observations confirm the similarity between MAggF and fibronectin. MAggF in unconcentrated lymph node cell culture supernatants bound reversibly to gelatin and fibrinogen. On gel filtration chromatography, most MAggF activity in a pooled concentrated lymphokine preparation was associated with molecules of 370,000 Daltons; lesser amounts of activity were found at 240,000 and 50,000 Daltons. All molecular weight forms of MAggF bound reversibly to gelatin. Guinea-pig plasma fibronectin prepared by affinity chromatography over gelatin had a molecular weight of about 450,000, a sub-unit on reduction of about 240,000 Daltons, and showed partial antigenic identity with human plasma fibronectin. Human and guinea-pig fibronectin preparations showed MAggF activity when tested using guinea-pig peritoneal macrophages, but their potencies relative to a culture supernatant standard did not correlate with the content of immunoprecipitable fibronectin measured by anti-human fibronectin antiserum. However, anti-human fibronectin immunoadsorbents specifically and reversibly bound MAggF activity in culture supernatants. On the basis of our observations, we suggest MAggF is a guinea-pig tissue fibronectin.

Animals↗
PubMed1983

Amplification of the opsonic activity of fibronectin by a plasma factor lacking gelatin affinity.

The opsonic activity of plasma fibronectin is important in modulating the reticuloendothelial system (RES) phagocytic removal of a variety of endogenous and exogenous particulate material from the vascular compartment. Purification of plasma-opsonic fibronectin by affinity chromatography with gelatin-Sepharose revealed that although in vitro hepatic Kupffer cell phagocytosis was absolutely dependent upon the presence of fibronectin, the purified fibronectin evaluated in concentrations similar to that found in plasma (350-450 micrograms/ml) supported phagocytosis at a level two- to threefold less than that observed in whole plasma. In contrast, the combination of purified fibronectin with small aliquots of opsonically inactive fibronectin-free plasma restored normal opsonic activity as assessed by liver slice bioassay and enhanced fibronectin-mediated attachment of gelatinized particulate to isolated Kupffer cells in vitro. Evidence is presented in this study that there exists in plasma a macromolecular species that amplifies the opsonic activity of fibronectin in a dose-related manner. This amplification or cofactor activity is nondialysable and has a molecular weight greater than 12,000. Inactivation of the amplification activity present in affinity-absorbed plasma can be achieved by heating the fibronectin-free plasma at 60 degrees C for 20 min, supporting the hypothesis that the cofactor is a protein. The amplification response is dose related, suggesting that the mechanism of its action is stoichiometric rather than catalytic. Evidence is presented that partial purification of the cofactor can be achieved by (NH4)2SO4 precipitation at 4 degrees C. Purification of this cofactor will provide an opportunity to evaluate its role in the altered opsonic states known to exist after trauma, burn, and sepsis.

Animals↗
PubMed1981

Fibronectin in von Willebrand's disease and thrombasthenia: role in platelet aggregation.

Fibronectin is involved in cell-cell and cell-substratum adhesion processes. Since von Willebrand's disease and thrombasthenia are characterized, respectively, by platelet-substratum and platelet-platelet adhesion anomalies, we investigated the state of fibronectin in platelets and plasma of these two disorders as well as the role of plasma fibronectin in platelet aggregation. The levels of platelet and plasma fibronectin in three cases of von Willebrand's disease and in three cases of thrombasthenia did not show statistically significant differences as compared with the normal controls. Immunofluorescent staining intensity and patterns of disease-derived and normal platelets, studied with anti-fibronectin antibodies, were similar. Furthermore, 125I-labeled protein A binds to anti-fibronectin-treated platelets from the two diseases investigated in the same fashion as in normal controls. No role for plasma fibronectin was detected in platelet aggregation induced by ADP, thrombin, collagen, epinephrine, and arachidonic acid. Thus our results do not indicate a direct quantitative role of fibronectin in the adhesion anomalies encountered in these diseases. However, fibronectin may still be important to platelet adhesion and normal hemostasis processes through interactions with the plasma von Willebrand factor and the membrane glycoproteins IIb and III, which have been shown to be deficient in von Willebrand's disease and thrombasthenia, respectively.

Blood Platelets↗
PubMed1980

Ascorbate-induced fibroblast cell matrix: reaction of antibodies to procollagen I and III and fibronectin in an axial periodic fashion.

Fibronectin and procollagen types I and III are constituents of the extracellular matrix of human fibroblasts. Ultrastructural immunocytochemistry using the peroxidase anti-peroxidase method showed fibronectin and procollagen antibodies reacting in continuous fashion on 10 nm diameter extracellular fibrils on human fibroblasts. Intracellular localization showed an intense accumulation of procollagen within cells cultured under routine conditions. This accumulation appeared almost as if there were a blockade in secretion of procollagen under routine culture conditions. Cells treated with ascorbic acid do not have the dense intracellular accumulation of procollagens seen with the apparent blockade of secretion in cells cultured under routine conditions. Ascorbate treated cells also have a more pronounced extracellular accumulation of matrix fibronectin and procollagen constituents. At the electromicroscopic level a new 40 nm diameter fibril is formed after ascorbic acid treatment of human fibroblasts. Antibody to fibronectin and procollagen I and III are seen binding to the 40 nm diameter fibrils in a periodic or stuttered appearance. The fibronectin and procollagen antibodies react with a 70 nm axial repeat along these 40 nm fibrils formed after ascorbate treatment. These studies suggest that under routine culture conditions "precursor" fibrils of fibronectin and procollagen are formed. Ascorbic acid treatment leads to enhanced matrix formation. Ultrastructural studies clearly show antibodies to fibronectin bind to fibronectin on native collagen fibrils formed by human fibroblasts cultured with ascrobic acid. Lastly there is an asymmetric or 70 nm axial periodic distribution of fibronectin along these definitive or mature collagen fibrils formed after ascorbic acid treatment.

Antibodies↗
PubMed1981

Interactions of normal, dysplastic, and malignant mammary epithelial cells with fibronectin in vivo and in vitro.

Previous studies have demonstrated that normal and malignant mouse mammary cells are indistinguishable in many surface-related properties that often denote transformation of other cell types such as fibroblasts. In the present investigation, the interactions of normal, dysplastic, and malignant mammary epithelial cells with fibronectin in tissues and cultures were examined by indirect immunofluorescence. Cells lining the lumina of ducts and alveoli in normal and dysplastic mouse and human mammary tissues abutted a layer of fibronectin along their basal surfaces that included the region of the basement membrane and the underlying stroma. Moreover, double staining for keratin and fibronectin revealed that myoepithelial cells were surrounded by the matrix protein. In contrast, tumor cells in adenocarcinomas and ductal carcinomas were not directly associated with fibronectin. The accumulation of fibronectin in primary cultures prepared from mouse mammary tissues paralleled the distribution seen in vivo. A matrix of fibronectin formed beneath normal and preneoplastic mammary cells within 4 to 6 days after plating, whereas tumor cells were negative, regardless of the age or density of the culture. This correlation with in vivo results did not extend to cells of established mammary tumor culture lines which readily accumulated pericellular networks of fibronectin. Addition of exogenous fibronectin to primary cultures enhanced formation of a basal matrix by normal cells but had no effect on the negative status of the tumor cells. The results indicate that mammary tumor cells in tissues and in primary cultures have an altered capacity to interact with fibronectin. However, this alteration is not necessarily expressed by established mammary tumor cell lines.

Animals↗
PubMed1981

Spatiotemporal patterns of fibronectin distribution during embryonic development. II. Chick branchial arches.

It has recently been demonstrated with the chick limb in ovo that successive nonrandom patterns of fluorescent staining with specific antibodies to fibronectin indicate the cartilagenous primordia prior to overt chondrogenesis. Given the apparent nonequivalence of embryonic cartilages, the purpose of this study was to determine whether this phenomenon was unique to developing chick limbs or is a more general characteristic of chondrogenesis. The appearance and distribution of fibronectin during chick first and second branchial arch development in ovo was investigated by indirect immunofluorescence techniques in H.H. stages 15-26. Fibronectin can be detected in early stages in areas presumed to be composed mainly of ectomesenchyme. During later stages of development, successive nonrandom patterns of fibronectin distribution appear to precede overt chondrogenesis as demonstrated by alcian blue staining. Pretreatment of cartilage with testicular hyaluronidase, prior to fibronectin staining, revealed that fibronectin was still present, suggesting that it was masked by proteoglycans. Fibronectin was also detected in the developing membrane bones of the mandible. The nonrandom patterning of fibronectin distribution in ovo in chick branchial arches and limb buds, respectively derived from neural crest and somatic mesoderm, were similar. It appears that specific patterns of fibronectin distribution were characteristic of chondrogenesis, regardless of the embryonic origin of the cartilage. This phenomenon may prove to be an extremely useful probe for early developmental skeletal abnormalities.

Animals↗
PubMed1982

Fibronectin fragment(s) are chemotactic for human peripheral blood monocytes.

Both plasma-derived and cell-derived fibronectin are deposited at sites of inflammation and wound healing and are associated with migrating cell populations including monocytes/macrophages. We found that fibronectin fragments generated by endogenous protease(s) are potent chemoattractants for human peripheral blood monocytes, whereas intact fibronectin has no activity. Fibronectin preparations produced by gelatin affinity chromatography in the absence of protease inhibitors contained 90 to 220 kd fragments and had potent chemotactic and chemokinetic activity for monocytes but no activity for human neutrophils or lymphocytes. The addition of phenylmethylsulfonyl fluoride to plasma reduced but did not eliminate the recovery of fibronectin fragments and likewise reduced the chemotactic activity. When the preparations were further purified by DEAE ion exchange and Sepharose 4B molecular sieve chromatography, however, intact fibronectin was recovered that lacked both chemotactic and chemokinetic activity. When fragment-poor fibronectin was allowed to sit at 25 degrees C in NaN3 but without protease inhibitors, increased fragmentation and increased chemotactic activity were noted. In addition, chemotactically active small m.w. fragments arose from high m.w. fragments or from intact fibronectin as demonstrated by rechromatography experiments over Sephadex G-150. These findings suggest that proteolytic cleavage of fibronectin during inflammatory processes produces fragments that selectively augment the recruitment of monocytes into tissue sites of inflammation.

Cells, Cultured↗
PubMed1994

Expression of antisense fibronectin RNA in human colon carcinoma cells disrupts the regulation of carcinoembryonic antigen by transforming growth factor beta 1.

Transforming growth factor beta 1 regulates the expression of extracellular matrix adhesion molecules and the carcinoembryonic antigen gene family of glycoproteins in the Moser colon carcinoma cell line. Expression of fibronectin antisense RNA in the Moser cells down-regulated fibronectin mRNA expression and blocked the ability of transforming growth factor beta 1 to stimulate fibronectin secretion. Cells expressing antisense fibronectin RNA exhibited a higher rate of proliferation, changed their morphology, and produced more laminin in response to treatment with transforming growth factor beta 1. The stimulation of carcinoembryonic antigen secretion by transforming growth factor beta 1 (which normally lagged 10-16 h behind that of fibronectin secretion stimulated by transforming growth factor beta 1) was blocked by the expression of antisense fibronectin RNA. Thus, the stimulation of fibronectin secretion by transforming growth factor beta 1 was a prerequisite for subsequent stimulation of carcinoembryonic antigen secretion. In addition, the stimulation of the cellular expression of carcinoembryonic antigen and three carcinoembryonic antigen cross-reactive species of glycoproteins by transforming growth factor beta 1 was down-modulated in cells expressing antisense fibronectin RNA. We therefore conclude that fibronectin may play an important role in the mechanisms of transforming growth factor beta 1 regulation of the expression of carcino-embryonic antigen gene family of glycoproteins.

Carcinoembryonic Antigen↗
PubMed1994

Role of the integrin alpha v beta 6 in cell attachment to fibronectin. Heterologous expression of intact and secreted forms of the receptor.

The integrin alpha v beta 6 has been shown to be a fibronectin-binding protein. To determine whether the cytoplasmic and transmembrane domains of alpha v beta 6 are necessary for binding to fibronectin, a truncated, secreted form of the integrin lacking these domains was engineered and expressed in Chinese hamster ovary cells. Fibronectin affinity chromatography demonstrated that the secreted integrin, like its full-length counterpart, was capable of binding fibronectin. Monoclonal antibodies were made to secreted alpha v beta 6 and to beta 6-transfected NIH 3T3 cells. In experiments designed to determine whether alpha v beta 6 can mediate cell attachment to fibronectin, full-length human beta 6 was expressed in Chinese hamster ovary cells and in the human colon carcinoma cell line SW480. beta 6-expressing cells were identified by alpha v beta 6-specific antibodies, and the beta 6-transfectants were used in cell-adhesion assays. In Chinese hamster ovary cells, human beta 6 associated with hamster alpha v but was incapable of mediating cell attachment to fibronectin. However, expression of beta 6 in these cells had the dominant negative effect of decreasing alpha v beta 5-dependent adhesion to vitronectin. In SW480 cells, beta 6 expression conferred the ability to bind to fibronectin even in the presence of inhibitory antibodies against beta 1 integrins. In such cells, fibronectin binding ability could be blocked by an antibody to alpha v integrins. These results constitute the first direct evidence that alpha v beta 6 mediates cell attachment to fibronectin.

3T3 Cells↗
PubMed1993

Corneal epithelial cell attachment with endogenous laminin and fibronectin.

PURPOSE: To evaluate the role of endogenously produced laminin and fibronectin as well as the effect of exogenous laminin and fibronectin in the attachment of human corneal epithelial cells in vitro. METHODS: Primary cultured human corneal epithelial cells labeled with 3H-thymidine were seeded onto plates coated with laminin or fibronectin, or onto uncoated bacteriologic plates. Attachment of cells was measured in the presence or absence of antisera against laminin or fibronectin, by counting radioactivity. RESULTS: Human corneal epithelial cells attached to plates coated with human laminin or human fibronectin in a dose-dependent manner, with 69% and 50% of cells attached to the wells coated with 40 micrograms/ml of laminin and fibronectin, respectively (P < 0.001). The percentage of attachment to uncoated bacteriologic plates increased from 1.2% at 45 min of incubation to 6.7% at 90 min, 22.2% at 3 hr, and 40.1% at 6 hr of incubation. Cycloheximide, a protein synthesis inhibitor, completely inhibited cell attachment. Rabbit antiserum against human fibronectin reduced cell attachment to the uncoated plates to 67% of the control value (P < 0.01), whereas rabbit antiserum against human laminin decreased the attachment to 52% of the control (P < 0.01). A combination of these two antisera reduced cell attachment to 46% of the control (P < 0.01). CONCLUSIONS: Endogenous laminin and fibronectin as well as exogenous laminin and fibronectin play significant roles in the attachment of human corneal epithelial cells in culture.

Autoradiography↗
PubMed1993

Role of the cyclic AMP response element in rat fibronectin gene expression.

Fibronectin expression is of considerable importance in normal and fibrotic liver. Plasma fibronectin levels are correlated with good prognosis in liver failure, and cellular fibronectin plays a crucial role in fibrogenesis. In this study, we observed that the H4II rat hepatoma cell line does not express fibronectin. Furthermore, a recombinant vector (pFGH) containing the promoter elements of the fibronectin gene showed no promoter function when transfected into this cell line. However, pFGH was actively expressed in L-cells and rat skin fibroblasts, cell types that express large amounts of endogenous fibronectin. To study the mechanisms regulating fibronectin expression, we evaluated the transcriptional regulatory elements of the rat fibronectin gene by mutational analysis and DNA-protein binding studies. Deletional mutation analysis showed that the sequences between positions -164 and -90 are essential for promoter activity. This region contains the consensus binding sites for CCAAT and the cyclic AMP-responsive element. Gel retardation assays demonstrated that although the binding activity to the CCAAT site at -140 was essentially the same as that in extracts from L-cells, hepatoma cells and rat livers, substantially greater amounts and different patterns of binding to the adjacent cyclic AMP-responsive element were observed in the extracts from the expressing L-cells and rat livers compared with those in the nonexpressing hepatoma cell nuclear extracts. Furthermore, mutagenesis of the cyclic AMP-responsive element site dramatically reduced promoter activity in transient transfection assays. The cyclic AMP-responsive element at position -160 appears to play an important role in the constitutive expression of the rat fibronectin gene.

Animals↗
PubMed1995

TGF beta and bFGF synthesis and localization in Dupuytren's disease (nodular palmar fibromatosis) relative to cellular activity, myofibroblast phenotype and oncofetal variants of fibronectin.

Nodular palmar fibromatosis is a self-limited proliferation of fibro-/myofibroblasts associated with growth factor synthesis and abundant fibronectin extracellular matrix deposition. bFGF and TGF beta are potent modulators of fibro-/myofibroblast proliferation and differentiation. Moreover, in vitro investigations evidenced a TGF beta 1-dependent regulation of alternative splicing of fibronectin mRNA. To investigate a possible implication of these growth factors in the tissue formation process of palmar fibromatosis, TGF beta 1/2 and bFGF synthesis, as well as TGF beta 1/3 and bFGF tissue distribution, is demonstrated by RNA in situ hybridization and/or immunohistochemistry in relation to myofibroblast phenotype development (alpha-smooth muscle actin, desmin immunohistochemistry), expression of different fibronectin isoforms (ED-A+, ED-B+ and oncofetal glycosylated fibronectin immunohistochemistry, fibronectin RNA in situ hybridization) and cellular activity (cyclin RNA in situ hybridization, Ki-67 immunolabelling). The myofibroblast phenotype (alpha-smooth muscle actin, desmin), the growth factor synthesis (TGF beta 1 and 2, bFGF), fibronectin matrix synthesis (RNA in situ hybridization with cDNA) and ED-A+, ED-B+ and oncofetal glycosylated fibronectin immunostaining are exclusively localized in the active proliferative nodules (Ki-67 immunolabelling and cyclin mRNA demonstration). Whereas the growth factor synthesis is restricted to the proliferative areas of the fibromatosis only, TGF beta 1, TGF beta 3 and bFGF proteins can also be detected immunohistochemically with a lower intensity in the surrounding aponeurotic tissue. The spatial correlation of myofibroblast phenotype, TGF beta and bFGF synthesis and the occurrence of the oncofetal molecular fibronectin variants (ED-B+ and oncofetal glycosylated fibronectin) in the active proliferative fibromatosis nodules suggests a pathogentic role of these growth factors and matrix components in the tumorous tissue formation process. The presence of the bFGF and TGF beta 1/3 proteins in fibroblasts neighbouring the proliferative nodules may point to a recruitment of quiescent aponeurotic fibroblasts in the fibromatous tissue formation process.

DNA, Complementary↗