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Eect of TGFb1 on ®bronectin production in SKLMS/HGF cells. SK-LMS/HGF cells were exposed to 5 ng/mL TGFb1 or to control conditions for 24 h. Total cellular RNA isolated from these cells (HGF5) or from the parental SK-LMS cells (Control) was used for Northern blotting; the blot was probed sequentially with the indicated cDNA probes. The positions of the major ribosomal RNA species are indicated at the left
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The tyrosine kinase receptor Met and its ligand, hepatocyte growth factor (HGF)/scatter factor are involved in the etiology and progression of a number of human cancers. Coexpression of Met and HGF in mesenchymal cells increases the tumorigenic and metastatic potential of the cells. In the studies described here, we used differential display screen...
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... determine if TGFb1 levels did in¯uence ®bronectin levels in SK-LMS cells, cells expressing HGF/SF were exposed to exogenous TGFb1 for 24 h. Under these conditions, TGFb1 caused a partial restoration of ®bronectin production (Figure 2), suggesting that HGF/SF and TGFb1 acted as antagonistic factors in determining ®bronectin production, and that the eect of TGFb1 was dominant but not absolute. We measured Met levels in the cells following exposure to TGFb1, but they were not altered (data not shown). ...
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The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF), known to stimulate invasive growth of epithelial cells. MET is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. To investigate whether this oncogene is direc...
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... The role of FN1 in tumorigenesis and malignant progression has been highly controversial [26]. Taylor et al. reported that FN1 level was decreased in human and mouse tumor cell lines and its decrease was correlated with Met/HGF-mediated tumorigenesis, suggesting that FN1 acts as a tumor suppressive role [27]. On the contrary, evidence suggests that FN1 level was increased in many types of cancer [28][29][30]. ...
Colorectal cancer (CRC) is a major cause of cancer mortality. Currently used CRC biomarkers provide insufficient sensitivity and specificity; therefore, novel biomarkers are needed to improve the CRC detection. Label-free quantitative proteomics were used to identify and compare glycoproteins, enriched by wheat germ agglutinin, from plasma of CRC patients and age-matched healthy controls. Among 189 identified glycoproteins, the levels of 7 and 15 glycoproteins were significantly altered in the non-metastatic and metastatic CRC groups, respectively. Protein-protein interaction analysis revealed that they were predominantly involved in immune responses, complement pathways, wound healing and coagulation. Of these, the levels of complement C9 (C9) was increased and fibronectin (FN1) was decreased in both CRC states in comparison to those of the healthy controls. Moreover, their levels detected by immunoblotting were validated in another independent cohort and the results were consistent with in the study cohort. Combination of CEA, a commercial CRC biomarker, with C9 and FN1 showed better diagnostic performance. Interestingly, predominant glycoforms associated with acetylneuraminic acid were obviously detected in alpha-2 macroglobulin, haptoglobin, alpha-1-acid glycoprotein 1, and complement C4-A of CRC patient groups. This glycoproteomic approach provides invaluable information of plasma proteome profiles of CRC patients and identification of CRC biomarker candidates.
... However, the role of FN in tumorigenesis and malignant progression has been highly controversial [7,8]. On the one hand, it has been reported that FN expression in tumor cells plays a tumor suppressive role to prevent tumor transformation and to halt their early progression [9]. On the other hand, abundant evidence reveals that FN provokes late stages of cancer metastasis and is associated with poor prognosis when endogenously expressed in tumor cells. ...
The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies.
... Fibronectin expression reduces in children lungs with asthma, and this decrease can result in congenital abnormalities in bronchial epithelium (Lieberman, 2010). A reduction in fibronectin expression was reported in striae distensa disease (Lee et al., 1994), patients with hepatocyte carcinoma (Sell and Ruoslahti, 1982), mice and human tumoral cell lines (Taylor et al., 1998) and uterus cancer (Futyma et al., 2009). Therefore, decrease in fibronectin expression in emberyonic period may cause functional defects especially asthma during either childhood or puberty period. ...
Smoking during pregnancy may impair pulmonary function in infants and children. Nicotine is one of the chemical substances with high level of toxicity. It crosses the placenta and accumulates in the developing organs of fetus. Previous investigations indicated that maternal nicotine exposure induces abnormal collagen IV expression and causes defects in bronchopulmonary development. In this study, the effect of maternal nicotine exposure on fibronectin expression in the lungs of newborn mice has been evaluated. Female Balb/C mice were mated and positivity in vaginal plug was designated as day 0 of pregnancy. Pregnant mice were divided into 2 experimental and 2 control groups. The experimental group 1 received 3 mg/kg intra peritoneal (IP) nicotine from day 7 of gestation to the last day of pregnancy. Also, the same amount of nicotine was injected into experimental group 2 during the same gestational days as well as day 14 after birth (lactation). However, control groups received the same volume of normal saline during the same periods. At the end of exposure times, all of newborns were anesthetized and their lungs removed for Immunohistochemical method and real-time polymerase chain reaction (PCR). Our finding indicated that fibronectin mRNA expression in the lung of newborn during gestation and lactation period was decreased by 0.7-and 1-fold, respectively compared with control groups. Fibronectin immunoreactivity intensity was not similar in the different parts of the lungs including alveoli, bronchiole and small vessels, having a significant decrease in immunoreactivity of the experimental groups in contrast with the control groups. These data also indicate that maternal nicotine exposure may induce abnormal fibronectin expression which may cause defects in lung function during life time.
... Recent studies using human mesangial cells have also demonstrated that HGF can suppress TGF-β1 expression induced by a high concentration of glucose [14]. HGF also represses TGF-β1 production [25,26]. Thus, in our study, it seems that HGF alters TGF-β1 regulation at multiple levels. ...
Tubulointerstitial changes in the diabetic kidney correlate closely with renal fibrosis, and transforming growth factor-beta-1 (TGF-beta1) is thought to play a key role in this process. In contrast, hepatocyte growth factor (HGF) has shown therapeutic effects on injured renal tubules in animal models. This study was undertaken to test the hypothesis that the preventive effects of HGF may result from interventions in TGF-beta1-mediated signaling and collagen III secretion. We examined the expression of HGF/HGF receptor (c-Met) and TGF-beta1 in renal fibroblasts at multiple time points. The effects of recombinant human HGF on TGF-beta1 expression were studied by RT-PCR and Western blotting, and the levels of collagen III were measured by ELISA. In the high-glucose condition, the expression of HGF and c-Met in renal fibroblasts was detected as early as 6 hours following cell culture while the level of TGF-beta1 peaked at 96 hours. The addition of recombinant human HGF to the culture media dose-dependently inhibited TGF-beta1 mRNA expression and reduced collagen III secretion by 34%. These results indicate that, during hyperglycemia, HGF inhibits TGF-beta1 signaling and type III collagen activation in interstitial fibroblasts. Furthermore, we should recognize that changes in the balance between HGF and TGF-beta1 might be decisive in the pathogenesis of chronic renal fibrosis. Therefore, administration of HGF to restore this balance may offer a novel therapeutic intervention in managing renal fibrogenesis in diabetic nephropathy.
... Cellular surface FN functions as a cell-cell and cell-substrate binding molecule, facilitating cellular adhesion, attachment to extra cellular matrix macromolecules, and contact inhibition, among others (13,14). A major source of interest in FN derived from the finding that the expression of cellular surface FN is repressed after malignant transformation (15)(16)(17)(18)(19). However, in addition to the data connecting FN suppression to malignancy, Akiyama et al reported increased FN expression within tumorassociated fibroblasts actually enhancing tumor cell motility, cancer spread, and metastasis formation, which led to a controversial discussion on the role of FN in carcinogenesis (20). ...
... FN expression pattern in malignant tumors. FN suppression has been adopted into current models of cancer pathology by numerous authors (15)(16)(17)(18)26). Immunohistochemical studies were able to demonstrate strong negative correlations between tumor and normal nodal states comparing FN expression in cervical carcinoma (27) and pulmonary squamous cell carcinoma (28). ...
Epithelial cellular fibronectin is frequently repressed after malignant transformation in a variety of cancers. This change has been associated with a loss of contact inhibition. To determine if these findings are unique to malignant processes and to identify mechanisms responsible for fibronectin suppression, we investigated fibronectin expression patterns in 46 head and neck carcinomas, 16 samples of adenoid tissue, and 10 benign mucosal biopsies. We report fibronectin suppression in 78% of the head and neck cancer samples, occurring most prominently within tumor cells, as opposed to the adjacent stroma which exhibited abundant fibronectin. Interestingly, fibronectin was also strongly repressed in chronically inflamed adenoid samples. We showed that fibronectin suppression is mediated by different mechanisms in both benign as well as malignant scenarios: In adenoids, macrophages and T-cells were visualized throughout epithelium that has lost its tight cellular array, allowing leukocyte passage. We have shown that tumor necrosis factor-alpha secreted by macrophages is capable of inducing epithelial derangement via activator protein-1 and nuclear factor-kappaB mediated fibronectin suppression. In head and neck carcinomas, we identified human papilloma virus early protein-2 as a fibronectin transcription inhibitor. We conclude that epithelial fibronectin suppression may not be a hallmark of malignancy, because it can concur with benign processes that involve leukocyte migration. Furthermore, our data suggest that the pattern of fibronectin suppression within the tumor structure largely depends on the cancer cell-stroma relation, which could explain previous conflicting reports on its repression or overexpression along with malignant transformation. In addition, our data support an involvement of human papilloma virus as a mechanism of carcinogenesis mediated via a loss of fibronectin gene expression.
... DAB2 is of particular interest since it suppresses signaling from the growth factor signal transduction pathway to AP-1 (33,104) and is down regulated in a variety of human tumors (11,23). Other known tumor suppressor genes, those for thrombospondin 1 (63,78), RECK (69,81,99), TIMP1 (77), IGSF4 (25), gremlin/ CKTSF1B1 (10), sFRP1 (49,98), IGFBP7/MAC25 (96), fibronectin 1 (52,73,101), STAT1 (38), and FAT (21), and some purported tumor suppressor genes, those for brush-1/WASF3 (87), TES (102), and WNT5A (39), are all down-regulated in Tif-Fos cells. The number of tumor suppressor genes that are down-regulated in Tif-Fos cells and their breadth of activities (ECM components, transcription regulators, signal transducers, and protease inhibitors) reflect the complexity of the invasion program and the many aspects of cell biology that are engaged during invasion. ...
Invasion is generally perceived to be a late event during the progression of human cancer, but to date there are no consistent reports of alterations specifically associated with malignant conversion. We provide evidence that the v-Fos oncogene induces changes in gene expression that render noninvasive normal human diploid fibroblasts highly invasive, without inducing changes in growth factor requirements or anchorage dependence for proliferation. Furthermore, v-Fos-stimulated invasion is independent of the pRb/p16(INK4a) and p53 tumor suppressor pathways and telomerase. We have performed microarray analysis using Affymetrix GeneChips, and the gene expression profile of v-Fos transformed cells supports its role in the regulation of invasion, independent from proliferation. We also demonstrate that invasion, but not proliferation, is dependent on the activity of the up-regulated epidermal growth factor receptor. Taken together, these results indicate that AP-1-directed invasion could precede deregulated proliferation during tumorigenesis and that sustained activation of AP-1 could be the epigenetic event required for conversion of a benign tumor into a malignant one, thereby explaining why many malignant human tumors present without an obvious premalignant hyperproliferative dysplastic lesion.
... Although a basal level of Rac activity is necessary for cytoskeleton reorganization and disconnection of intercellular contacts required for locomotion [132] , neither PKB/Akt nor Rac can cause the motogenic effect [130]. Decrease of fibronectin gene expression is one of the most important effects induced by HGF/SF in soft tissue sarcoma cells; this can alter adhesion interactions with matrix and locomotion [133]. Mutations in HGF/SF receptor gene (protooncogene Met) leading to permanent stimulation of its tyrosine kinase activity are oncogenic: they can induced morphologic transformation of cultivated cells in vitro [134] . ...
Changes in expression of protooncogenes and tumor suppressor genes play a key role in oncogenesis. Dysfunction of their protein products leads to abnormal regulation of signaling pathways, which control the cell cycle, apoptosis, genetic stability, cell differentiation, and morphogenetic reactions. Changes in these important physiological processes are obviously responsible both for initial steps of neoplastic cell transformation and for determination of subsequent tumor progression resulting in the development of malignant tumors.
... Constitutive expression of HGF/SF in renal epithelial cells stimulated expressions of its specific receptor gene c-met and also FN gene, which was totally blocked by incubation with a neutralizing anti-HGF/SF but not an anti-TGF- antibody (34). On the other hand, in human and mouse tumor cell lines, HGF/SF-Met signaling resulted in a great decrease in FN expression at both mRNA and protein levels (35). Cell density influences FN protein production (36) and also FN splicing at the EDA region in fibroblasts (28). ...
EDA-containing fibronectin (EDA + FN) is selectively produced under several physiological and pathological conditions requiring tissue remodeling, where cells actively proliferate and migrate. Only a few growth factors, such as transforming growth factor (TGF)-beta1, have been reported to regulate FN splicing at the EDA region. In the present study, we showed for the first time that hepatocyte growth factor/scatter factor (HGF/SF), which is mainly produced by mesenchymal cells and functions as a motogenic and mitogenic factor for epithelial cells, modulates FN splicing at the EDA region in MDCK epithelial cells. HGF/SF treatment increased the ratio of EDA + FN mRNA to mRNA of FN that lacks EDA (EDA - FN) (EDA+/EDA- ratio) more than TGF-beta1 treatment did: at a range from 0.02 to 20 ng/ml, HGF/SF increased the ratio in a dose-dependent manner by up to 2. 1-fold compared with nontreated control, while TGF-beta1 stimulated the EDA+/EDA- ratio by 1.5-fold at the optimum dose of 10 ng/ml. However, TGF-beta1 increased total FN mRNA levels by 3-fold at 10 ng/ml, but HGF/SF did not. We previously demonstrated that fibroblasts cultured at low cell density expressed more EDA + FN than those at high cell density. The same effect of cell density was also observed in MDCK cells. Furthermore, at low cell density, HGF/SF stimulated EDA inclusion into FN mRNA more effectively than did TGF-beta1, whereas at high cell density, TGF-beta1 was more potent than HGF/SF. Simultaneous treatment of cells with HGF/SF and TGF-beta1 synergistically stimulated EDA inclusion into FN mRNA. This stimulation of EDA inclusion into FN mRNA by HGF/SF led to increased EDA + FN protein production and secretion by cells, which was demonstrated by immunoblotting. Thus, our studies have shown that HGF/SF is an enhancer of EDA inclusion into FN mRNA as is TGF-beta1. However, these two factors were different in their effects at low and high cell densities and also in their effects on total FN mRNA levels.
The extracellular matrix (ECM) is a complex network of proteins and glycans, dynamically remodeled and specifically tailored to the structure/function of each organ. The malignant transformation of cancer cells is determined by both cell intrinsic properties, such as mutations, and extrinsic variables, such as the mixture of surrounding cells in the tumor microenvironment and the biophysics of the ECM. During cancer progression, the ECM undergoes extensive remodeling, characterized by disruption of the basal lamina, vascular endothelial cell invasion, and development of fibrosis in and around the tumor cells resulting in increased tissue stiffness. This enhanced rigidity leads to aberrant mechanotransduction and further malignant transformation potentiating the de-differentiation, proliferation and invasion of tumor cells. Interestingly, this fibrotic microenvironment is primarily secreted and assembled by non-cancerous cells. Among them, the cancer-associated fibroblasts (CAFs) play a central role. CAFs massively produce fibronectin together with type I collagen. This review delves into the primary interactions and signaling pathways through which fibronectin can support tumorigenesis and metastasis, aiming to provide critical molecular insights for better therapy response prediction.
