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

It has been reported that ectopically expressed interleukin-17 (IL-17) in tumor cells suppresses tumor progression through enhanced antitumor immunity in immune competent mice or promote tumor progression through an increase in inflammatory angiogenesis in immune-deficient mice. The role of endogenous IL-17 in tumor immunity remains undefined. Here we showed that tumor growth and lung metastasis were enhanced in IL-17-deficient mice, associated with decreased interferon-gamma(+) natural killer cells and tumor specific interferon-gamma(+) T cells in the tumor draining lymph nodes and tumors. Together with the published data showing that in vitro transforming growth factor-beta and IL-6-polarized Th17 cells induce tumor regression, our work supports the notion that endogenous IL-17 or/and Th17 cells may play a protective role in tumor immunity.
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PMID:Endogenous IL-17 contributes to reduced tumor growth and metastasis. 2033 8

During rodent mammary gland involution there is a dramatic increase in the expression of the transforming growth factor-beta isoform, TGF-beta3. The TGF-betas are multifunctional cytokines which play important roles in wound healing and in carcinogenesis. The responses that are activated in the remodeling of the gland during involution have many similarities with the wound healing process and have been postulated to generate a mammary stroma that provides a microenvironment favoring tumor progression. In this review we will discuss the putative role of TGF-beta during involution, as well as its effects on the mammary microenvironment and possible implications for pregnancy-associated tumorigenesis.
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PMID:Transforming growth factor-(beta)s and mammary gland involution; functional roles and implications for cancer progression. 1939 28

Inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors for more than a decade. Recent emerging results using siRNA and knockout mice are expanding the previous understanding of this protein family. The results of ING1 knockout mouse experiments revealed that ING1 has a protective effect on apoptosis. Our recent results showed that ING2 is overexpressed in colorectal cancer, and induces colon cancer cell invasion through an MMP13-dependent pathway. Knockdown of ING2 by siRNA induces premature senescence in normal human fibroblast cells, and apoptosis or cell cycle arrest in various adherent cancer cells. Taken together, these results suggest that ING2 may also have roles in cancer progression and/or malignant transformation under some conditions. Additionally, knockdown of ING4 and ING5 by siRNA shows an inhibitory effect on the transition from G(2)/M to G(1) phase and DNA replication, respectively, suggesting that these proteins may play roles during cell proliferation in some context. ING family proteins may play dual roles, similar to transforming growth factor-beta, which has tumor suppressor-like functions in normal epithelium and also oncogenic functions in invasive metastatic cancers. In the present article, we briefly review ING history and propose a possible interpretation of discrepancies between past and recent data.
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PMID:Reviewing the current classification of inhibitor of growth family proteins. 1943 90

By inducing epithelial-to-mesenchymal transition (EMT), transforming growth factor-beta (TGF-beta) promotes cancer progression and fibrosis. Here we show that expression of the TGF-beta receptor-associated protein, SARA (Smad anchor for receptor activation), decreases within 72 h of exposure to TGF-beta and that this decline is both required and sufficient for the induction of several markers of EMT. It has been suggested recently that expression of the TGF-beta signaling mediators, Smad2 and Smad3, may have different functional effects, with Smad2 loss being more permissive for EMT progression. We find that the loss of SARA expression leads to a concomitant decrease in Smad2 expression and a disruption of Smad2-specific transcriptional activity, with no effect on Smad3 signaling or expression. Further, the effects of inducing the loss of Smad2 mimic those of the loss of SARA, enhancing expression of the EMT marker, smooth muscle alpha-actin. Smad2 mRNA levels are not affected by the loss of SARA. However, the ubiquitination of Smad2 is increased in SARA-deficient cells. We therefore examined the E3 ubiquitin ligase Smurf2 and found that although Smurf2 expression was unaltered in SARA-deficient cells, the interaction of Smad2 and Smurf2 was enhanced. These results describe a significant role for SARA in regulating cell phenotype and suggest that its effects are mediated through modification of the balance between Smad2 and Smad3 signaling. In part, this is achieved by enhancing the association of Smad2 with Smurf2, leading to Smad2 degradation.
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PMID:Role of SARA (SMAD anchor for receptor activation) in maintenance of epithelial cell phenotype. 1962 Feb 43

We have implemented a hybrid cellular automata model based on the structure of human prostate that recapitulates key interactions in nascent tumor foci between tumor cells and adjacent stroma. Model simulations show how stochastic interactions between tumor cells and stroma may lead to a structural suppression of tumor growth, modest proliferation, or unopposed tumor growth. The model incorporates key aspects of prostate tumor progression, including transforming growth factor-beta (TGF-beta), matrix-degrading enzyme activity, and stromal activation. It also examines the importance of TGF-beta during tumor progression and the role of stromal cell density in regulating tumor growth. The validity of one of the key predictions of the model about the effect of epithelial TGF-beta production on glandular stability was tested in vivo. These experimental results confirmed the ability of the model to generate testable biological predictions in addition to providing new avenues of experimental interest. This work underscores the need for more pathologically representative models to cooperatively drive computational and biological modeling, which together could eventually lead to more accurate diagnoses and treatments of prostate cancer.
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PMID:The role of transforming growth factor-beta-mediated tumor-stroma interactions in prostate cancer progression: an integrative approach. 1970 77

We were interested in developing oncolytic adenoviral vectors that can be administered systemically for the treatment of breast cancer. To restrict viral replication in breast tumor cells, we constructed mhTERTAd.sTbetaRFc, a 01/07-based adenoviral vector expressing the soluble form of transforming growth factor-beta (TGFbeta) receptor II fused with the human Fc IgG1 (sTGFbetaRIIFc) gene, in which viral replication is under the control of a modified human telomerase reverse transcriptase (mhTERT) promoter. In addition, mhTERTAd.sTbetaRFc-mediated sTGFbetaRIIFc production targets the TGFbeta pathway known to contribute to the tumor progression of breast cancer metastasis. We chose to use the mhTERT promoter because it was found to be relatively more active (approximately 20 times) in breast cancer cells compared with normal human cells. We showed that infection of MDA-MB-231 and MCF-7 breast cancer cells for 48 h with mhTERTAd.sTbetaRFc produced high levels of sTGFbetaRIIFc (greater than 1 microg ml(-1)) in the medium. Breast cancer cells produced nearly a 6000-fold increase in viral titers during the 48 h infection period. However, mhTERTAd.sTbetaRFc replication was attenuated in normal cells. Infection of breast cancer cells with a replication-deficient virus Ad(E1(-)).sTbetaRFc also produced high levels of sTGFbetaRIIFc, but under these conditions, no detectable viral replication was observed. Adenoviral-mediated production of sTGFbetaRIIFc was shown to bind with TGFbeta-1, and to abolish the effects of TGFbeta-1 on downstream SMAD-3 phosphorylation. The administration of mhTERTAd.sTbetaRFc intravenously into MDA-MB-231 human xenograft-bearing mice resulted in a significant inhibition of tumor growth and production of sTGFbetaRIIFc in the blood. Conversely, intravenous injection of Ad(E1(-)).sTbetaRFc did not show a significant inhibition of tumor growth, but resulted in sTGFbetaRIIFc in the blood, suggesting that viral replication along with sTGFbetaRIIFc protein production is critical in inducing the inhibition of tumor growth. These results warrant future investigation of mhTERTAd.sTbetaRFc as an antitumor agent in vivo.
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PMID:A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFbeta signaling for breast cancer therapy. 1979 22

Tumorigenesis and cancer progression are closely associated with the transforming growth factor-beta (TGF-beta) and its downstream component Smad. The TGF-beta/Smad signaling pathway, which is activated in prostate cancer, has a regulatory effect on cell adhesion, the actin filament system and cell cycle, as well as the expression of specific genes. Meanwhile, other protein signals such as MAPK and PI3K/Akt/mTOR and some genes may act on the expression of the TGF-beta/Smad pathway. This article updates recent researches on the expression, action and regulatory effect of the TGF-beta/Smad signaling pathway in prostate cancer.
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PMID:[TGF-beta/Smad in prostate cancer: an update]. 1994 72

The transforming growth factor-beta (TGF-beta) maintains epithelial homeostasis and suppresses early tumor formation, but paradoxically at later stages of tumor progression, TGF-beta promotes malignancy. TGF-beta activates phosphorylation of Smad2 and -3 effectors. Smad2 and -3 are known to have different functions, but differential regulation of their phosphorylation has not been described. Here we show that upon hypoxia, the TGF-beta-induced phosphorylation of Smad3 was inhibited, although Smad2 remained phosphorylated. The inhibition of Smad3 phosphorylation was not due to TGF-beta receptor inactivation. We show that Smad3 was dephosphorylated by PP2A (protein phosphatase 2A) specifically under hypoxic conditions. The hypoxic Smad3 dephosphorylation required intact expression of the essential scaffold component PR65 of PP2A. PP2A physically interacted with Smad3 that occurred only in hypoxia. Accordingly, Smad3-associated PP2A activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of TGF-beta-induced Smad3 but did not affect Smad2. Moreover, the influence of TGF-beta on a set of Smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical PP2A inhibition. Our data demonstrate the existence of a Smad3-specific phosphatase and identify a novel role for PP2A. Moreover, our data implicate a novel mechanism by which hypoxia regulates growth factor responses.
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PMID:Hypoxia-activated Smad3-specific dephosphorylation by PP2A. 1995 45

Loss of expression of the type III transforming growth factor-beta receptor (TbetaRIII or betaglycan), a transforming growth factor-beta (TGF-beta) superfamily co-receptor, is common in human breast cancers. TbetaRIII suppresses cancer progression in vivo by reducing cancer cell migration and invasion by largely unknown mechanisms. Here, we demonstrate that the cytoplasmic domain of TbetaRIII is essential for TbetaRIII-mediated downregulation of migration and invasion in vitro and TbetaRIII-mediated inhibition of breast cancer progression in vivo. Functionally, the cytoplasmic domain of TbetaRIII is required to attenuate TGF-beta signaling, whereas TbetaRIII-mediated attenuation of TGF-beta signaling is required for TbetaRIII-mediated inhibition of migration and invasion. Mechanistically, both TbetaRIII-mediated inhibition of TGF-beta signaling and TbetaRIII-mediated inhibition of invasion occur through the interaction of the cytoplasmic domain of TbetaRIII with the scaffolding protein GAIP-interacting protein C-terminus (GIPC). Taken together, these studies support a functional role for the TbetaRIII cytoplasmic domain interacting with GIPC to suppress breast cancer progression.
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PMID:The type III TGF-beta receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-beta signaling. 1995 93

The identification of genes involved in carcinogenesis and tumor progression is of great interest since these genes might be feasible as candidates for new tumor-targeted therapy strategies. Chimeric tumor suppressor-1 (CTS-1), an artificial synthetic variant of p53, resists common p53 inactivation and could therefore be defined as a dominant-positive p53 variant. Overexpression of CTS-1 induces caspase-independent cell death. We used whole-genome microarray expression analysis in a parental (229(P)) and a CTS-1-resistant glioma cell line (229(Res)) to analyze alterations in gene expression in Ad-CTS-1-infected and in uninfected parental and resistant cells. In total, 700 genes were differentially expressed in infected and 313 genes in uninfected 229(Res) versus 229(P) cells. Ingenuity Pathway Analysis determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of intracellular networks with central tumor-involved players such as nuclear factor-kappaB (NFkappaB), protein kinase B/AKT or transforming growth factor-beta. Here we focused on the function of NFkappaB in Ad-CTS-1-mediated cell death in glioma. NFkappaB was activated in Ad-CTS-1-infected 229(P) but not 229(Res) cells. NFkappaB activation was accompanied by the induction of cell death in parental cells. Inhibition of NFkappaB activity by expression of an IkappaB super repressor or upregulation of the NFkappaB-linked gene Bex protected parental cells to Ad-CTS-1-induced cell death, whereas knockdown of Bex sensitized both parental and resistant cells. Taken together, these data suggest that activation of the normally antiapoptotic protein NFkappaB does not always necessarily protect cells from apoptosis but, in the glioma cell lines tested so far, and in an environment where p53 is constitutively active, also leads to the induction of cell death.
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PMID:Gene expression profile in a glioma cell line resistant to cell death induced by the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53--the role of NFkappaB. 2001 65


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