Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have established hepatoma clones from benzopyrene-treated liver cells, one of which (G-5) shows extensive metastasis to the lung when injected subcutaneously into mice [Tanigaki, Y. et al. (1995) Invasion Metastasis 15, 70-80]. In the present study, we performed in vitro assays suitable for examination of the adhesive and invasive properties of the highly metastatic cells. G-5 cells efficiently entered the pores of fibronectin-coated filters. Treatment of the cells with an inhibitor of phosphoinositide 3-kinase (PI 3-kinase), wortmannin, significantly impaired the invasive activity. A structurally unrelated inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) also prevented invasion. Both inhibitors suppressed cell adhesion to fibronectin-coated dishes. G-5 cells were next transfected with a mutant regulatory subunit (Deltap85) of PI 3-kinase, which was expected to impair the function of PI 3-kinase. The transfectants showed suppressed adhesion to the dishes and did not efficiently migrate into the filters. The lower adhesive ability of the transfected cells was not further affected by inhibitors of PI 3-kinase. Thus, PI 3-kinase activity contributes significantly to the adhesive and invasive properties of G-5 cells.
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PMID:Involvement of phosphoinositide 3-kinase in regulation of adhesive activity of highly metastatic hepatoma cells. 979 28

Small cell lung cancer (SCLC) is characterized by early and widespread metastases. Anchorage-independent growth is pivotal to the ability of tumor cells to survive and metastasize in vivo and, under in vitro conditions, allows transformed cells to form colonies in semisolid medium. Here, we report that of five SCLC cell lines tested, all exhibited high basal constitutive phosphoinositide 3-kinase (PI 3-kinase) activity, which results in high basal protein kinase B (PKB) and ribosomal p70 S6 kinase activity (p70s6k). Inhibition of PI 3-kinase activity markedly inhibited SCLC cell proliferation in liquid culture as a result of stimulating apoptosis and promoting cell cycle delay in G1. Furthermore, PI 3-kinase inhibition reduced basal SCLC cell colony formation in agarose semisolid medium that could not be overcome by the addition of neuropeptide growth factors. Thus, constitutive PI 3-kinase activity in SCLC cells plays an important role in promoting the growth and anchorage independence of SCLC. This is not due to activating ras mutations or increased basal src or focal adhesion kinase activity. These data represent the first description of constitutively activated PI 3-kinase/PKB in any human cancer. Constitutive activation of these integrin-dependent signaling events provides a molecular explanation for the anchorage-independent growth of SCLC cells and may account for the nonadherent phenotype and highly metastatic nature of this aggressive cancer. Up-regulation of the PI 3-kinase/PKB pathway may, therefore, represent a novel target for therapeutic intervention in SCLC.
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PMID:The presence of a constitutively active phosphoinositide 3-kinase in small cell lung cancer cells mediates anchorage-independent proliferation via a protein kinase B and p70s6k-dependent pathway. 982 38

The functions of NK cells are regulated by the balance of activating and inhibitory signals. The inhibitory NK cell receptors are well understood; however, less is known about the activating signaling pathways. To explore whether a costimulatory receptor, inducible costimulator (ICOS), is involved in NK cell function, we assessed the role of ICOS in NK cell-mediated cytotoxicity and cytokine production. In addition, to determine whether ICOS contributes to the elimination of tumors in vivo, we examined the tumor growth survival of mice injected with a tumor expressing the ICOS ligand, B7RP-1. We found that ICOS was up-regulated by cytokine stimulation in murine NK cells. Consistent with ICOS expression on activated NK cells, ICOS-dependent cytotoxicity and IFN-gamma production were observed, and appeared to require signaling through the phosphoinositide 3-kinase pathway. Interestingly, ICOS-mediated stimulation allowed activated NK cells to kill more efficiently tumor cells expressing MHC class I. Furthermore, fewer metastases appeared in the liver and spleen of mice injected with the ICOS ligand-expressing tumor compared with mice bearing the parental tumor. These results indicate that NK cell functions are regulated by ICOS.
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PMID:Inducible costimulator costimulates cytotoxic activity and IFN-gamma production in activated murine NK cells. 1224 60

Dysregulated signaling contributes to altered cellular growth, motility, and survival during cancer progression. We have evaluated the ability of several factors to stimulate migration in WM1341D, a cell line derived from an invasive human vertical growth phase melanoma. Basic fibroblast growth factor, hepatocyte growth factor, interleukin-8, and CCL27 each slightly increased migration. Insulin-like growth factor I (IGF-I), however, stimulated a 15-fold increase in migration. This response required the IGF-I receptor, which activates phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways. Both pathways have been implicated in migration in a variety of cell types, but the signaling required for IGF-I-induced melanoma cell migration is not well defined. IGF-I-stimulated activation of MAPK/ERK signaling in WM1341D cells was inhibited by U0126, but a 33-fold higher dose of U0126 was needed to inhibit IGF-I-stimulated cellular migration. In contrast, similar concentrations of either wortmannin or LY294002 were required to inhibit both IGF-I-induced PI3K activation and migration. These results indicate that IGF-I-stimulated migration of WM1341D cells requires PI3K activation but is independent of MAPK/ERK signaling. Determining the contributions of IGF-I signaling pathways to migration will help us to understand melanoma progression and may lead to new therapeutic targets of this highly metastatic cancer.
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PMID:Insulin-like growth factor I-stimulated melanoma cell migration requires phosphoinositide 3-kinase but not extracellular-regulated kinase activation. 1272 1

Inappropriate alpha6beta4 integrin expression correlates with a high risk of tumour progression in stratified squamous epithelia. Targeted expression of alpha6beta4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the beta4 cytoplasmic domain. Suprabasal alpha6beta4 also perturbed transforming growth factor beta (TGFbeta) signalling as demonstrated by decreased nuclear Smad2 in transgenic epidermis and tumours. In cultured keratinocytes, suprabasal alpha6beta4 relieved TGFbeta-mediated growth inhibition and blocked nuclear translocation of activated Smad2/3. Responsiveness to TGFbeta could be restored by inhibiting cadherin-mediated cell-cell adhesion or phosphoinositide 3-kinase (PI3-K) activity, but not by inhibiting mitogen-activated protein kinase (MAPK) activity. These data suggest that suprabasal alpha6beta4 promotes tumourigenesis by preventing TGFbeta from suppressing clonal expansion of initiated cells in the epidermal basal layer.
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PMID:Suprabasal alpha6beta4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFbeta signalling. 1290 6

Metastasis in breast cancer significantly increases morbidity and mortality. The 5-year survival rate reduces from 90% for localised disease to about 20% once metastasis has taken place. The phosphoinositide 3-kinase/Akt signalling pathway has an important role in cell motility, invasion and metastasis. However, the precise contribution of the Akt kinase family members, Akt1, Akt2 and Akt3, in mediating these processes is unclear. The possibility that they have distinct functions in tumour progression is particularly interesting.
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PMID:Akt2: a role in breast cancer metastasis. 1468 Apr 86

Squamous cell carcinoma of the head and neck (SCCHN) tends to run an aggressive course and the prognosis has remained virtually unchanged in recent decades. The development of novel therapeutic strategies to improve patient outcome centres on the biology of the disease, namely the pivotal c-erbB family of growth factor receptors. c-erbB1 (or epidermal growth factor receptor, EGFR), is key to the pathogenesis of SCCHN and plays a central role in a complex network of downstream integrated signalling pathways. EGFR overexpression, detected in up to 90% of SCCHN, correlates with an increased risk of locoregional tumour relapse following primary therapy and relative resistance to treatment. The biological sequelae of erbB receptor activation are not simply cell proliferation, but also inhibition of apoptosis, enhanced migration, invasion, angiogenesis and metastasis: the 'hallmarks of cancer' [1]. As EGFR overexpression is associated with a poor clinical outcome in SCCHN, this receptor is attractive as a therapeutic target and the successful development of targeted therapies represents a paradigm shift in the medical approach to head and neck cancer. However, the extensive cross talk between signalling pathways, the multiple molecular aberrations and genetic plasticity in SCCHN all contribute to inherent and acquired resistance to both conventional and novel therapies. Understanding the cancer cell biology, in particular the significance of co-expression of c-erbB (and other) receptors, and the cell survival stimuli from (for example) activation of the phosphoinositide 3-kinase (PI3-kinase) cascade is fundamental to overcome current limitations in biologically targeted therapies.
Cancer Metastasis Rev 2005 Jan
PMID:Biological significance of c-erbB family oncogenes in head and neck cancer. 1578 72

Identification of specific genes or signaling pathways involved in development of melanoma could lead to new therapies that target and correct these defects. Recent studies have revealed deregulation of the Akt signaling pathway occurring in 43-67% of melanomas. Akt kinase family members, Akt1/PKBalpha, Akt2/PKBbeta and Akt3/PKBgamma, share extensive structural similarity and perform common as well as unique functions within cells. The Akt signaling cascade initiates at the cell surface when growth factors or other extracellular stimuli activate phosphoinositide 3-kinase (PI3K). Activated PI3K generates a lipid second messenger, phosphatidylinositol-3,4,5-trisphosphate (PIP3), causing translocation of Akt to the plasma membrane where it becomes phosphorylated and activated. The balance of cellular PIP3 is regulated primarily by a phosphatase called PTEN that reduces PIP3 levels thereby lowering Akt activity. In melanomas, decreased PTEN activity elevates PIP3 levels resulting in Akt activation. Active Akt then phosphorylates downstream cellular proteins that promote melanoma cell proliferation and survival. Recently, Akt3 was discovered to be the predominant isoform activated in sporadic melanomas. Levels of activity increased during melanoma progression with metastatic melanomas having the highest activity. Although mechanisms of Akt3 activation remain to be fully characterized, overexpression of Akt3 and decreased PTEN activity play important roles in this process. Targeted reduction of Akt3 activity decreased survival of melanoma tumor cells leading to inhibition of tumor development, which may be therapeutically effective for shrinking tumors in melanoma patients. This review surveys recent developments in Akt deregulation in melanoma and its potential as a selective therapeutic target in patients in the advanced stages of this disease.
Cancer Metastasis Rev 2005 Jun
PMID:Functional and therapeutic significance of Akt deregulation in malignant melanoma. 1598 37

Squamous cell carcinoma of the head and neck (SCCHN) is associated with high morbidity and mortality. Despite significant surgical advances and refinement in the delivery of chemotherapy and radiotherapy, prognosis has improved little in recent decades. Better local control has led to the late presentation of distant metastases and novel therapeutic agents are urgently required to prevent relapse, control disseminated disease and thus improve survival. PIK3CA encodes the p110alpha isoform of phosphoinositide 3-kinase (PI3-K) and is important in SCCHN, aberrations in its activity occurring early in the oncogenic process. PI3-K signalling promotes cell survival, proliferation, invasion and angiogenesis, all contributing to tumour progression. Activation of the PI3-K pathway may also mediate resistance to chemotherapy, radiotherapy and novel therapeutic agents such as epidermal growth factor receptor inhibitors. Elements of this signalling matrix, therefore, offer attractive therapeutic targets in SCCHN as inhibition of many malignant characteristics, as well as sensitisation to multiple treatment modalities, could be anticipated.
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PMID:The phosphoinositide 3-kinase signalling pathway as a therapeutic target in squamous cell carcinoma of the head and neck. 1608 42

Here, we report the identification of a metastasis promoting factor by a forward genetic screen in mice. A retroviral cDNA library was introduced into the nonmetastatic cancer cell line 168FARN, which was then orthotopically transplanted into mouse mammary fat pads, followed by selection for cells that metastasize to the lung. The genes encoding the disulfide isomerase ERp5 and beta-catenin were found to promote breast cancer invasion and metastasis. Disulfide isomerases (thiol isomerases), which catalyze disulfide bond formation, reduction, and isomerization, have not previously been implicated in cancer cell signaling and tumor metastasis. Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. These effects were shown to involve activation of ErbB2 and phosphoinositide 3-kinase (PI3K) pathways through dimerization of ErbB2. Activation of ErbB2 and PI3K subsequently stimulates RhoA and beta-catenin, which mediate the migration and invasion of tumor cells. Inhibition of ErbB2 and PI3K reverses the phenotypes induced by ERp5. Finally, ERp5 was shown to be up-regulated in human surgical samples of invasive breast cancers. These data identify a link between disulfide isomerases and tumor development, and provide a mechanism that modulates ErbB2 and PI3K signaling in the promotion of cancer progression.
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PMID:In vivo selection for metastasis promoting genes in the mouse. 1742 Apr 53


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