Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor beta 1 (TGF-beta 1) regulates a multitude of diverse biological functions in mammalian cells, and there is good evidence that aberrant expression of this growth factor can play an important role in mechanisms of malignant progression. We show that a TGF-beta 1-overexpressing mouse 10T1/2 cell line transfected with a TGF-beta 1 sequence that allows the synthesis of bioactive growth factor exhibits reduced sensitivity to the cytotoxic effects of the drug N-(phosphonacetyl)-L-aspartate (PALA) in colony-forming experiments. Furthermore, six independent 10T1/2 TGF-beta 1-transfected cell lines containing TGF-beta 1 gene expression under the control of a zinc sulfate-responsive metallothionein promoter were selected. In all cases, sensitivity to PALA cytotoxic effects was significantly reduced when cells were cultured under conditions that led to elevated levels of TGF-beta 1 gene expression when compared to cells containing basal levels of this growth factor. Fluctuation analysis to determine the rate of PALA resistance was performed with several TGF-beta 1-transfected cell lines in which growth factor expression was regulated by the metallothionein promoter. We observed significantly higher rates of PALA resistance/cell/generation in cell populations expressing high levels of TGF-beta 1 than in the same cells expressing relatively low levels of this growth factor. The only mechanism known for PALA resistance in mouse cells involves the amplification of the gene coding for the protein target of PALA, CAD, a multifunctional polypeptide containing carbamyl phosphate synthetase, aspartate transcarbamylase, and dihydroorotase. Southern blot analysis of colonies that survived normally cytotoxic concentrations of PALA exhibited CAD gene amplification. In total, these observations indicate that aberrant expression of TGF-beta 1 gene expression decreases the genetic stability of 10T1/2 cells, leading to increased rates of drug resistance and elevated gene amplification potential. The results of this study indicate a new malignancy related function for TGF-beta 1 alterations and suggest a novel role for aberrant expression of this growth factor in mechanisms of drug resistance and tumor progression.
 ...
PMID:Drug resistance and gene amplification potential regulated by transforming growth factor beta 1 gene expression. 771 85

Peptide regulatory factors, i.e. cytokines, are released spontaneously or upon induction by melanoma cells in culture. Among these cytokines there are factors such as Il-1, IL-6, IL-8, IL-10 as well as TGF-beta 1 which are basically acting as immunoregulatory molecules. However, their contribution to an augmentation and/or suppression of local or systemic immune response against melanoma cells in situ has not yet been elucidated. On the other hand, some of these molecules, e.g. IL-6 and TGF-beta 1, are growth inhibitors, especially in the early phases of melanoma development. During tumor progression, resistance to the inhibitory effect of these cytokines seems to take place. Whether this resistance is due to an excessive production of these cytokines or a downregulation or blockade of receptors is still controversial. The aberrant expression of bFGF in melanoma cells explains how melanoma cells in vitro and probably also in vivo acquire growth autonomy and the capacity of metastasis formation. The expression of bFGF by human melanoma cells and its activity as autocrine growth regulator imply that agents which interfere with heparin-binding growth factors such as Suramin or pentosan sulfate may be of clinical usefulness. Additionally, these latter agents have been shown to be potent anti-angiogenic factors. Their clinical efficacy, however, has to be established in phase I and II studies.
 ...
PMID:Production of polypeptide regulatory factors by human melanoma cells. 772 36

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in tumor progression by promoting angiogenesis or suppressing immune system. We reported previously that transforming growth factor-beta 1 (TGF-beta 1) is overproduced by human hepatocellular carcinoma (HCC) tissues and that plasma TGF-beta 1 levels are elevated in patients with HCC. In the present study, we investigated the relationship between plasma TGF-beta 1 levels and tumor vascularity as assessed by conventional celiac angiography in 17 patients with HCC. The plasma TGF-beta 1 level did not correlate with tumor size or underlying liver disease. However, we found that plasma TGF-beta 1 levels correlated positively with the tumor vascularity. These results suggest that excessive TGF-beta 1 production may contribute to tumor angiogenesis in HCC.
 ...
PMID:Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma. 788 1

To study the contribution of autocrine and paracrine TGF-beta 1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-beta 1 gene were initiated in vitro with the v-rasHa oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v-rasHa-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well-differentiated papillomas. Malignant progression was not associated with mutations in the c-rasHa gene, alterations in p53 protein, or loss of responsiveness to TGF-beta 1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-beta 1 null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-beta 1 from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-beta 1 positive even though they did not express TGF-beta 1 mRNA. These results demonstrate that autocrine TGF-beta 1 suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-beta 1 can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-beta 1 by a mechanism that operates in normal cells.
 ...
PMID:Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma. 795 7

Ki-1 (CD30)+ cutaneous T-cell lymphomas CTCLs) are slowly progressive lymphomas in which initial spontaneous regression is often observed. To better understand the mechanisms of spontaneous regression and eventual tumor progression in Ki-1+ CTCLs, type beta transforming growth factor (TGF-beta)-mediated growth inhibition of clonally related cell lines derived from two time points, before and after tumor progression, was studied. TGF-beta 1 inhibited colony-forming efficiency (CFE) of a cell line (Mac-1) derived from clinically indolent Ki-1+ CTCLs but failed to inhibit CFE of Mac-2A and -2B cell lines from advanced CTCLs. To determine the basis for TGF-beta 1 resistance in advanced CTCL cells, we looked for possible defects in the expression of cell surface TGF-beta receptors. Mac-1 cells were found to express TGF-beta receptors I and II, which mediate growth inhibition, and the TGF-beta-binding proteoglycan betaglycan. In contrast, receptors I and II were not detected in CTCL lines Mac-2A and -2B even though these cell lines did express betaglycan. Various treatments that unmask or induce TGF-beta receptors in other cells failed to show evidence for these receptors in advanced CTCL cells. Loss of TGF-beta receptor expression in these cells correlated with a marked decrease in TGF-beta receptor II mRNA levels. Loss of cell surface TGF-beta receptors was also found in two of five other patients with T-cell lymphomas including the Sezary syndrome and a noncutaneous T-cell lymphoma, suggesting that loss of TGF-beta receptor expression may be a recurrent feature of human T-cell malignancies.
 ...
PMID:Loss of receptors for transforming growth factor beta in human T-cell malignancies. 801 5

Transforming growth factor (TGF)-beta 1, whose gene is located on mouse chromosome 7, has been proposed to be involved in skin carcinogenesis. In the study presented here, we demonstrated that single topical treatments with different types of tumor promoters, i.e., the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 micrograms); the non-protein kinase C activators anthralin (22.6 micrograms), benzoyl peroxide (20 mg), and cumene hydroperoxide (1.2 mg); the first-stage tumor promoters 4-O-methyl-TPA (500 micrograms) and A23187 (166 micrograms); and the second-stage tumor promoter mezerein (2 micrograms) produced transient induction of TGF-beta 1 mRNA in SSIN (inbred SENCAR) mouse skin. The time of maximum induction varied from 3 to 12 h; the relative extent of induction was ranked as cumene hydroperoxide > benzoyl peroxide > anthralin > TPA > 4-O-methyl-TPA > mezerein > A23187. These findings suggested that TGF-beta 1 mRNA induction is a common response of skin to several types of complete and stage-specific promoters; however, the extent of induction did not correlate with the reported hyperplastic activity of single applications of these promoters. We also demonstrated that TGF-beta 1 mRNA expression in papillomas of SENCAR mice generally correlated with expression levels of cyclin D1, another gene on chromosome 7, and with stage of tumor progression. TGF-beta 1 mRNA expression was constitutively elevated in most squamous cell carcinomas from either initiation-promotion or complete carcinogenesis protocols. Cell lines established from carcinomas also overexpressed TGF-beta 1 mRNA. Immunohistochemical staining of tissue sections of normal and TPA-treated skin revealed the presence of extracellular TGF-beta 1 protein in the dermis and intracellular TGF-beta 1 protein in the epidermis, especially in the suprabasal layers. The staining patterns of papillomas varied, with 62 +/- 13% of the tissue showing strong intracellular staining but only 25 +/- 8% of the connective tissue staining for extracellular TGF-beta 1. Variable staining patterns were also found in carcinomas; some areas stained heavily for both the intracellular and extracellular forms of TGF-beta 1. Overall, 28 +/- 6% of the tissue of the 12 analyzed carcinomas stained for the intracellular form and 18 +/- 5% for the extracellular form of TGF-beta 1.
 ...
PMID:Altered expression of transforming growth factor-beta 1 mRNA and protein in mouse skin carcinogenesis. 814 55

Type 1 transforming growth beta (TGF-beta 1) is a multifunctional regulator of cellular differentiation, motility and growth. It is capable of inhibiting or stimulating these processes depending on cell type, cell density, culture conditions and TGF-beta 1 concentration. TGF-beta 1 regulates growth, in part, by inducing the expression and secretion of various types of collagen, which participate in the control of cell adhesion and migration, as well as growth. TGF-beta 1 also regulates cell growth by controlling the response to epidermal growth factor (EGF) and other growth factors, in ways that can either decrease or increase their growth-promoting effects. Alterations in both negative and positive growth responses to TGF-beta 1 play important roles in tumor progression. Loss of sensitivity to growth inhibition by TGF-beta 1 can occur as a result of decreased expression of collagen. Acquisition of sensitivity to growth stimulation, and autocrine transformation by TGF-beta 1, are associated with aberrant EGF receptor regulation. Aberrant growth factor receptor regulation by TGF-beta 1 may be mediated by a protein kinase C (PKC)-dependent pathway which inhibits degradation of growth factor receptor/ligand complexes. The evidence reviewed is consistent with a minimal two-step mechanism for autocrine transformation, which involves production of growth factor and enhanced cellular response as a result of aberrant membrane traffic. Defects in membrane traffic regulation may provide an explanation for common alterations in tumor cell response to both multiple growth inhibitors and growth stimulators, and may also suggest novel approaches to cancer chemotherapy.
 ...
PMID:Transforming growth factor beta and the cell surface in tumor progression. 828 11

Neuroendocrine tumors of the digestive system are slow growing neoplasms which often present with pronounced fibrosis around tumor cells and in the peritoneal cavity. In this report 30 midgut carcinoids and endocrine pancreatic tumors were examined for the expression of peptide growth factors and their receptors, both by immunohistochemistry and in situ hybridization. Our data indicate that multiple peptide growth factors, PDGF, TGF-beta, and bFGF are expressed by these tumors. PDGF was expressed on tumor cells and stroma in 70% of tissues examined. PDGF alpha-receptor was seen on clusters of tumor cells and occasionally on adjacent stroma, whereas PDGF beta-receptor was seen only in the stroma. Our data suggest that PDGF may be involved in the autocrine stimulation of tumor cells and stimulation of stromal cell growth through paracrine and possibly autocrine mechanism. In addition, tumor tissues express all three isoforms of TGF-beta in more than half of the tissues examined. Tumor cells produce small latent complexes causing an escape from potent inhibitory effect of TGF-beta and stimulation of stromal cell growth and matrix deposition through paracrine mechanism. bFGF, a potent stimulant of endothelial cell growth, was expressed by all tumor tissues examined. Our data suggest that multiple peptide growth factors may have an important role in tumor progression and desmoplastic reaction accompanying these tumors.
 ...
PMID:Expression of growth factor peptides and their receptors in neuroendocrine tumors of the digestive system. 839 29

The effects of insulin on cell growth control by transforming growth factor beta 1 (TGF-beta 1) in human hepatoma cell lines were studied. TGF-beta 1 inhibited cell growth and DNA synthesis of Hep3B cells but not that of HA22T/VGH cells. The cell cycle-dependent p34cdc2 kinase activity was inhibited by TGF-beta 1 in a dose-dependent manner in Hep3B cells. In contrast, the p34cdc2 kinase activity of HA22T/VGH cells was not regulated by TGF-beta 1. When insulin (10(-7) M) was added simultaneously with TGF-beta 1, we found that the inhibitory effects of TGF-beta 1 on cell growth and DNA synthesis in Hep3B cells was completely blocked and the p34cdc2 kinase activity of Hep3B cells was recovered after insulin administration. Thus, cell growth inhibition by TGF-beta 1 in Hep3B hepatoma cells can be antagonized by insulin and their interaction may play an important role in the tumor progression stage of hepatocarcinogenesis.
 ...
PMID:Effects of insulin on TGF-beta 1-induced cell growth inhibition in the human hepatoma cell lines. 840 23

Thrombospondin (TSP-1) is a large glycoprotein secreted by platelets and synthesized by many cell types, including endothelial and tumor cells. Although controversy exists about the biological function of TSP-1, the following observations suggest that TSP-1 may potentiate tumor progression. (1) Tumor metastases in mice are promoted by TSP-1 and inhibited by anti-TSP-1 antibodies. (2) TSP-1 promotes tumor cell adhesion, migration and invasion. (3) TSP-1 promotes angiogenesis in the rat aorta model. (4) TSP-1 up-regulates the plasminogen activator system through a mechanism involving the activation of TGF-beta 1. (5) Human tumors express increased levels of the CSVTCG-specific TSP-1 receptor. (6) Tumor stroma is enriched in TSP-1. (7) Cancer patients have high blood levels of TSP-1. (8) Poor patient survival correlates with a higher expression of the CSVTCG-specific TSP-1 receptor on tumor cells. In this paper we discuss the evidence that TSP-1 promotes tumor progression and present a hypothetical scheme for its mechanism of action.
 ...
PMID:The role of thrombospondin-1 in tumor progression and angiogenesis. 859 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>