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)

Tumor-associated macrophages may influence tumor progression, angiogenesis and invasion. To investigate mechanisms by which macrophages interact with tumor cells, we developed an in vitro coculture model. Previously we reported that coculture enhanced invasiveness of the tumor cells in a TNF-alpha- and matrix metalloprotease-dependent manner. In this report, we studied intracellular signaling pathways and induction of inflammatory genes in malignant cells under the influence of macrophage coculture. We report that coculture of macrophages with ovarian or breast cancer cell lines led to TNF-alpha-dependent activation of JNK and NF-kappaB pathways in tumor cells, but not in benign immortalized epithelial cells. Tumor cells with increased JNK and NF-kappaB activity exhibited enhanced invasiveness. Inhibition of the NF-kappaB pathway by TNF-alpha neutralizing Abs, an NF-kappaB inhibitor, RNAi to RelA, or overexpression of IkappaB inhibited tumor cell invasiveness. Blockade of JNK also significantly reduced invasiveness, but blockade of p38 MAPK or p42 MAPK had no effect. Cocultured tumor cells were screened for the expression of 22 genes associated with inflammation and invasion that also contained an AP-1 and NF-kappaB binding site. EMMPRIN and MIF were up-regulated in cocultured tumor cells in a JNK- and NF-kappaB-dependent manner. Knocking down either MIF or EMMPRIN by RNAi in the tumor cells significantly reduced tumor cell invasiveness and matrix metalloprotease activity in the coculture supernatant. We conclude that TNF-alpha, via NF-kappaB, and JNK induces MIF and EMMPRIN in macrophage to tumor cell cocultures and this leads to increased invasive capacity of the tumor cells.
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PMID:Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. 1600 23

To determine the effects of expression of mutant Ki-ras on lung tumorigenesis, we developed a bitransgenic mouse model that expresses the human Ki-ras(G12C) allele in alveolar type II and/or Clara cells in a tetracycline-inducible, lung-specific manner. Expression of Ki-ras(G12C) caused multiple, small lung tumors over a 12-month time period. Although tumor multiplicity increased upon continued Ki-ras expression, most lung lesions were hyperplasias or well-differentiated adenomas. This is in contrast to the more severe phenotypes observed in other transgenic mouse models in which different mutant Ki-ras alleles were expressed in the lung. Expression of Ki-ras(G12C) was associated with a 2-fold increase in the activation of the Ras and Ral signaling pathways and increased phosphorylation of Ras downstream effectors, including Erk, p90 ribosomal S6 kinase, ribosomal S6 protein, p38 and MAPKAPK-2. In contrast, expression of the transgene had no effect on the activation of the JNK and Akt signaling pathways. Withdrawal of doxycycline for 1 month resulted in almost a complete absence of proliferative pulmonary lesions, suggesting tumor regression in the absence of Ki-ras expression. Mutant Ki-ras(G12C) expression was sufficient for initial lung tumor transformation, required for maintenance of tumor phenotype, and induced transformation of lung epithelial cells by the activation of multiple effector pathways. These results describe a novel mouse lung tumor model demonstrating benign tumor development in the absence of tumor progression, which will provide a new tool for understanding the early stages of lung tumor pathogenesis.
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PMID:Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model. 1605 43

Activating mutations in the K-ras gene are genetic alterations frequently found in human carcinomas, particularly in pancreatic adenocarcinomas. Mutation of the K-ras gene is thought to be an early and important event in pancreatic tumor initiation, but the precise role of the mutant K-Ras proteins in neoplastic progression is still unknown. In the present study, we have characterized the influence of oncogenic K-Ras on the phenotype and on the signal transduction of epitheloid PANC-1 pancreatic carcinoma cells by generating PANC-1 cell clones, which stably express EGFP(enhanced green fluorescent protein)-K-Ras (V12). EGFP-K-Ras (V12)-expressing cells exhibited a more fibroblastoid cellular phenotype with irregular cell shape and disorganized cytokeratin filaments. Moreover, these cells showed a marked enhancement of their migratory and invasive properties. Stable expression of EGFP-K-Ras (V12) down-regulated the activity of Rac1 and RhoA, resulting in reduced subcortical actin filaments and stress fibers, which might contribute to the epithelial dedifferentiation. Characterization of the activity of mitogen-activated protein kinases revealed that EGFP-K-Ras (V12) enhanced the activity of p38, but did not affect the activities of the Raf/MEK/ERK cascade and JNK. While inhibition of either MEK or JNK activity had no effect on EGFP-K-Ras (V12)-induced migration, inhibition of p38 activity markedly reduced EGFP-K-Ras (V12)-induced migration. Collectively, the results suggest that oncogenic K-Ras enhances the malignant phenotype and identify the mitogen-activated protein kinase p38 as a target to inhibit oncogenic K-Ras-induced pancreatic tumor cell migration.
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PMID:Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38. 1625 81

Unfolded protein response (UPR) is an important genomic response to endoplasmic reticulum (ER) stress. The ER chaperones, GRP78 and Gadd153, play critical roles in cell survival or cell death as part of the UPR, which is regulated by three signaling pathways: PERK/ATF4, IRE1/XBP1 and ATF6. During the UPR, accumulated unfolded protein is either correctly refolded, or unsuccessfully refolded and degraded by the ubiquitin-proteasome pathway. When the unfolded protein exceeds a threshold, damaged cells are committed to cell death, which is mediated by ATF4 and ATF6, as well as activation of the JNK/AP-1/Gadd153-signaling pathway. Gadd153 suppresses activation of Bcl-2 and NF-kappaB. UPR-mediated cell survival or cell death is regulated by the balance of GRP78 and Gadd153 expression, which is coregulated by NF-kappaB in accordance with the magnitude of ER stress. Less susceptibility to cell death upon activation of the UPR may contribute to tumor progression and drug resistance of solid tumors.
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PMID:Role of the unfolded protein response in cell death. 1637 48

ARHI is a maternally imprinted tumor suppressor gene that is downregulated in 60% of ovarian and breast cancers. Loss of ARHI expression is associated with tumor progression in breast cancer and decreased disease-free survival in ovarian cancer. ARHI encodes a 26-kDa protein with 55-62% homology to Ras and Rap. In contrast to Ras, ARHI inhibits growth, motility, and invasion. ARHI contains a unique 34 amino-acid extension at its N-terminus and differs from Ras in residues critical for GTPase activity and for its putative effector function. Deletion of ARHI's unique N-terminal extension markedly reduces its inhibitory effect on cell growth. The gene maps to chromosome 1p31 at a site of LOH in 40% of ovarian and breast cancers. Mutations have not been detected, but the remaining allele is silenced by methylation in approximately 10-15 % of cases. In the remaining cancers, ARHI is downregulated by transcriptional mechanisms that involve E2F1 and E2F4, as well as by the loss of RNA binding proteins that decrease the half-life of ARHI mRNA. Transgenic expression of human ARHI in mice produces small stature, induces ovarian atrophy, and prevents postpartum milk production. Reexpression of ARHI in cancer cells inhibits signaling through Ras/Map and PI3 kinase, upregulates P21(WAF1/CIP1), downregulates cyclin D1, induces JNK, and inhibits signaling through STAT3. Marked overexpression of ARHI with a dual adenoviral vector induces caspase-independent, calpain-dependent apoptosis. When ARHI is expressed from a doxycycline-inducible promoter at more physiological levels, autophagy is induced, rather than apoptosis. Growth of ovarian and breast cancer xenografts is reversibly suppressed by ARHI, but expression of the NTD mutant produced only a limited inhibitory effect on growth of xenografts.
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PMID:Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. 1675 45

Upon cancer progression in mouse models of prostate cancer, the heat shock transcription factor Hsf1 becomes strongly upregulated, especially in metastases. We hypothesized that Hsf1 plays a role in cell migration, a process necessary for metastases. Using a cell culture model of migration in a scratch, we found that immortalized MEF cells derived from hsf1-/- animals were deficient in both basal and EGF-induced migration. MEF cell migration was dependent on JNK and ERK signaling, since inhibition of these pathways blocked EGF-stimulated cell migration. ERK was activated at the edge of the scratch in parental cells, and this activity was further increased after addition of EGF. Both basal and EGF-stimulated ERK activation were suppressed in hsf1-/- cells at the edge of the scratch. Furthermore, activation of ERK and JNK pathways by EGF was reduced in hsf1-/- cells. The impairment of MAP kinase signaling in hsf1-/- cells was partly due to the reduced expression of EGFR1. In addition, knockout of Hsf1 gene caused a second defect in MAP kinase signaling probably at the level of Ras. We conclude that HSF1 is necessary for MAP kinase signaling which in turn affects the EGF-induced cell migration.
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PMID:Heat shock transcription factor (HSF1) plays a critical role in cell migration via maintaining MAP kinase signaling. 1685 93

Because increased transforming growth factor-beta (TGFbeta) production by tumor cells contributes to cancer progression through paracrine mechanisms, identification of critical points that can be targeted to block TGFbeta production is important. Previous studies have identified the precise signaling components and promoter elements required for TGFbeta induction of TGFbeta1 expression in epithelial cells (Yue, J., and Mulder, K. M. (2000) J. Biol. Chem. 275, 30765-30773). To determine how regulation of TGFbeta3 expression differs from that of TGFbeta1, we identified the precise signaling pathways and transcription factor-binding sites that are required for TGFbeta3 gene expression. By using mutational analysis in electrophoresis mobility shift assays (EMSAs), we demonstrated that the c-AMP-responsive element (CRE) site in the TGFbeta3 promoter was required for TGFbeta-inducible TGFbeta3 expression. Electrophoresis mobility supershift assays indicated that CRE-binding protein 1 (CREB1) and Smad3 were the major components present in this TGFbeta-inducible complex. Furthermore, by using chromatin immunoprecipitation assays, we demonstrated that CREB-1, ATF-2, and c-Jun bound constitutively at the TGFbeta3 promoter (-100 to +1), whereas Smad3 bound at this site only after TGFbeta stimulation. In addition, inhibition of JNK and p38 suppressed TGFbeta induction of TGFbeta3 transactivation, whereas inhibition of ERK and protein kinase A had no effect. Small interfering RNA-CREB1 and small interfering RNA-Smad3 significantly inhibited TGFbeta stimulation of TGFbeta3 promoter reporter activity and TGFbeta3 production. Our results indicate that TGFbeta activation of the TGFbeta3 promoter CRE site, which leads to TGFbeta3 production, is required for TGFbetaRII, JNK, p38, and Smad3 but was independent of protein kinase A, ERK, and Smad4.
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PMID:Requirement of Smad3 and CREB-1 in mediating transforming growth factor-beta (TGF beta) induction of TGF beta 3 secretion. 1689 11

The objective of this study was to compare the expression of the nerve growth factor (NGF) receptors TrkA and p75 in ovarian borderline tumors, International Federation of Gynecology and Obstetrics (FIGO) stage I carcinomas and advanced-stage (FIGO stage III-IV) carcinomas, and to assess a possible association between NGF receptor expression and mitogen-activated protein kinase (MAPK) activation in borderline tumors and FIGO stage I carcinomas. Sections from 119 borderline tumors, 57 FIGO stage I invasive ovarian carcinomas, and 56 advanced-stage carcinomas were evaluated for expression of activated phospho-TrkA (p-TrkA) and p75 using immunohistochemistry. MAPK activation was analyzed in stage I carcinomas and borderline tumors using phospho-specific antibodies against the extracellular-regulated kinase (p-ERK), the high osmolarity glycerol response kinase (p-p38), and the c-jun amino-terminal kinase (p-JNK). p-TrkA membrane expression was significantly more frequent in advanced-stage carcinomas compared with both borderline and stage I carcinomas (P < .001). p75 membrane expression was comparable in the 3 groups (P > .05). p-ERK and p-p38 expression was comparable in borderline and stage I carcinomas, whereas p-JNK was more frequently expressed in stage I ovarian carcinomas (P < .001). NGF receptor expression showed no association with MAPK activation in borderline and stage I carcinomas. In conclusion, expression of biologically active p-TrkA receptor at the cell membrane is up-regulated along tumor progression in ovarian carcinoma, whereas p75 expression remains unaltered. These data provide further evidence regarding the clinical role of p-TrkA in ovarian carcinoma. NGF receptors probably signal via MAPK-independent pathways in ovarian carcinoma.
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PMID:The activated nerve growth factor receptor p-TrkA is selectively expressed in advanced-stage ovarian carcinoma. 1699 70

Transforming growth factor beta 1 (TGF-beta1) is a potent tumor suppressor but, paradoxically, TGF-beta1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-beta type I receptor, ALK5, and three mitogen-activated protein kinases (MAPKs) in metastasis by breast cancer cell line MDA-MB-231. We show that autocrine TGF-beta signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinase-inactive ALK5 reduces tumor invasion and formation of new blood vessels within the tumor orthotopic xenografts in severe combined immunodeficiency (SCID) mice. In contrast, constitutively active ALK5-T204D enhances tumor invasion and angiogenesis by stimulating expression of matrix metalloproteinase MMP-9/gelatinase-B. Ablation of MMP-9 in ALK5-T204D cells by RNA interference (RNAi) reduces tumor invasion and tumor growth. Importantly, RNAi-MMP-9 reduces tumor neovasculature and increases tumor cell death. Induction of MMP-9 by TGF-beta-ALK5 signaling requires MEK-ERK but not JNK, p38 MAPK or Smad4. Dominant-negative MEK blocks and constitutively active MEK1 enhances MMP-9 expression. However, all three MAPK cascades (ERK, JNK and p38 MAPK) are required for TGF-beta-mediated cell migration. Collectively, our results show that TGF-beta-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.
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PMID:ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. 1707 48

IL-22 is a recently discovered cytokine of the IL-10 family that binds to a class II cytokine receptor composed of IL-22R1 and IL-10R2(c) and influences a variety of immune reactions. As IL-22 has also been shown to modulate cell cycle and proliferation mediators such as ERK1/2 and JNK, we studied the role of IL-22 in proliferation, apoptosis, and cell cycle regulation in EMT6 murine breast cancer cells in vitro and in vivo. In this study, we report that murine breast cancer cells express functional IL-22R as indicated by RT-PCR studies, immunoblotting, and STAT3 activation assays. Importantly, IL-22 exposure of EMT6 cells resulted in decreased levels of phosphorylated ERK1/2 and AKT protein kinases, indicating an inhibitory effect of IL-22 on signaling pathways promoting cell proliferation. Furthermore, IL-22 induced a cell cycle arrest of EMT6 cells in the G(2)-M phase. IL-22 reduced EMT6 cell numbers and the proliferation rate by approximately 50% as measured by [(3)H]thymidine incorporation. IL-22 treatment of EMT6 tumor-bearing mice lead to a decreased tumor size and a reduced tumor cell proliferation in vivo, as determined by 3'-deoxy-3'-fluorothymidine-positron emission tomography scans. Interestingly, IL-22 did not induce apoptosis, as determined in annexin V binding assay and caspase-3 activation assay and had no effect on angiogenesis in vivo. In conclusion, our results indicate that IL-22 reduced tumor growth by inhibiting signaling pathways such as ERK1/2 and AKT phosphorylation that promote tumor cell proliferation in EMT6 cells. Therefore, IL-22 may play a role in the control of tumor growth and tumor progression.
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PMID:IL-22-mediated tumor growth reduction correlates with inhibition of ERK1/2 and AKT phosphorylation and induction of cell cycle arrest in the G2-M phase. 1711 5


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