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)

Autocrine motility factor (AMF) is a tumor-secreted cytokine that acts as a motogen as well as a mitogen via a receptor-mediated signaling pathway(s). Expression of the AMF receptor (AMF-R) in normal cells is regulated by cell contact whereas in transformed cells AMF-R is constitutively expressed irrespective of cell density. Here we have analyzed the regulation of AMF-R expression in a BALB/c angiosarcoma tumor system that allows investigation of cellular characteristics associated with tumor progression. The metastatic cell variant (A31-M) displayed a higher rate of unstimulated motility and responded to tumor-derived AMF locomotory stimulus as compared with the nonmetastatic cell variants (A31-TR and A31-TU) and, although a similar level of receptor expression was detected in cellular extracts from subconfluent cultures of these sublines, surface localization differed and cell contact down-regulated AMF-R expression in the normal but not the transformed cell counterparts. AMF promoted marked rearrangement of focal adhesion plaque proteins in the AMF migration-responsive cells exclusively. Reorganization of vinculin after AMF stimulation was paralleled by morphological redistribution of tyrosine-phosphorylated proteins and the tyrosine kinase pp125FAK in the migration-responsive cells; however, we did not observe a concomitant change in the pp125FAK phosphorylation state or the general level of cellular tyrosine phosphorylation in response to treatment, suggesting that the induction of cellular migration by AMF is independent of tyrosine phosphorylation events at the focal contacts and may therefore represent a novel pathway of cytokine-induced migration regulation.
 ...
PMID:Tumor autocrine motility factor responses are mediated through cell contact and focal adhesion rearrangement in the absence of new tyrosine phosphorylation in metastatic cells. 862 32

Megakaryocytic genes such as alphaIIbbeta3 can be expressed by malignant cells as part of the disturbances in their gene regulation. However, the function of the gene product greatly depends on the interaction of the ectopic protein with the new environment. The outside-in signaling of the ectopically expressed alphaIIbbeta3 integrin was studied in B16a murine melanoma cells using a monoclonal antibody, specifically directed to the activated conformation of alphaIIbbeta3, PAC-1 and the physiological ligand, fibrinogen. Ligation of alphaIIbbeta3 induced down-regulation of FAK but serine phosphorylation of three protein bands, 20/21, 85 and 140 kDa within 1-15 min. Flow cytometry indicated that the ligation of the receptor in B16a cells induces approximately 50% increase in phosphoserine positive cells within 5-15 min. 12-lipoxygenase is placed downstream in the signaling pathway, since ligation of alphaIIbbeta3 induces 12-HETE production within 5 min and pretreatment of tumor cells with select lipoxygenase inhibitior, Baicalein, prevents the increase in serine phosphorylation. Confocal microscopy of adherent tumor cells demonstrated rearrangement of actin filaments upon alphaIIbbeta3 ligation paralleled by downregulation of p125FAK and phoshotyrosine+ adhesion plaques and translocation of PKCalpha to stress fibers and cortical actin. PKC appears to be the major effector serine kinase of the alphaIIbbeta3-coupled signaling pathway, since pretreatment of tumor cells with a select PKC inhibitor, Calphostin C, prevents the ligation-induced serine phosphorylation. Previous studies have indicated a role for the 12-lipoxygenase-PKC signaling pathway in platelet aggregation as well as tumor invasion, therefore the involvement of this cascade in the signaling of the ectopic alphaIIbbeta3 integrin may partially explain its role in tumor progression.
 ...
PMID:Ectopic alphaIIbbeta3 integrin signaling involves 12-lipoxygenase- and PKC-mediated serine phosphorylation events in melanoma cells. 1143 81

Malignant melanoma cells show high aggressiveness and metastatic potential. Tumor cells as they become more metastatic, gradually lose their dependence on both adhesion and serum. Thus, in the process of tumor progression cells undergo series of changes that allow them to adapt to different tissue milieu. This implies that during this process, points on the integrin pathway may become constitutively activated. In the present study we investigated the possible role of FAK, being one of the key members of the integrin-signaling pathway, in the multistep progression towards a malignant phenotype in human melanoma. In our study we show that in melanoma cells there is neither an increase in the amount of FAK nor in its phosphorylation capacity, but rather in its levels of constitutive activation. Indeed, in all melanoma cells tested and not in nevus and neuroblastoma cells, we observed various degrees of constitutive activation of FAK. Our results also suggest that FAK constitutive activation is regulated at least in part by the cytoskeleton, implying that steps along the integrin signaling pathway involving FAK could be among the oncogenic mechanisms that operate in melanoma and may account for the highly aggressive, anchorage independent phenotype of this tumor.
 ...
PMID:The focal adhesion kinase (P125FAK) is constitutively active in human malignant melanoma. 1203 79

Heparanase is an endo-beta-glucuronidase responsible for the cleavage of heparan sulfate, participating in extracellular matrix degradation and remodeling. Traditionally, heparanase activity was well correlated with the metastatic potential of a large number of tumor-derived cell types. More recently, heparanase up-regulation was detected in essentially all human tumors examined, correlating, in some cases, with poor postoperative survival and increased tumor vascularity. The role of heparanase in primary tumor progression is, however, poorly understood. Here, we overexpressed the human heparanase gene in a human glioma cell line, U87. We found that heparanase overexpression induces cell invasion, as might be expected. Surprisingly, elevated heparanase expression levels correlated with decreased proliferation rates and increased cell spreading and formation of a tight monolayer rather than large cell aggregates. This phenotypic appearance was accompanied by beta1-integrin activation, FAK and Akt phosphorylation, and Rac activation. In a xenograft tumor model, relatively moderate heparanase expression levels significantly enhanced tumor development and tumor vascularity, whereas high heparanase expression levels inhibited tumor growth. These results indicate that heparanase activates signal transduction pathways and, depending on its expression levels, may modulate tumor progression.
 ...
PMID:Heparanase affects adhesive and tumorigenic potential of human glioma cells. 1463 98

Progression of human colon cancer is often associated with elevated expression and activity of the Src family tyrosine kinase (SFK). SFK is ordinarily in equilibrium between inactive and primed states by a balance of negative regulatory kinase Csk and its counteracting tyrosine phosphatase(s), both of which act on the regulatory C-terminal tyrosine of SFK. To evaluate the contribution of the regulatory system of SFK in cancer progression, we here modulated the equilibrium status of SFK by introducing wild-type or dominant-negative Csk in human epithelial colon cancer cells, HCT15 and HT29. Overexpression of wild-type Csk induced decreased SFK activation, increased cell-cell contacts mediated by E-cadherin, decreased the number of focal contacts and decreased cell adhesion/migration and in vitro invasiveness. Conversely, expression of a dominant-negative Csk resulted in elevated SFK activation, enhanced phosphorylation of FAK and paxilllin, enhanced cell scattering, an increased number of focal contacts, dramatic rearrangement of actin cytoskeleton and increased cell adhesion/migration and in vitro invasiveness. In these scattered cells, however, localization, expression and phosphorylation of either E-cadherin or beta-catenin were not significantly affected, suggesting that the E-cadherin-mediated cell-cell contact is indirectly regulated by SFK. Furthermore, all these events occurred absolutely dependent on integrin-mediated cell adhesion. These findings demonstrate that Csk defines the ability of integrin-SFK-mediated cell adhesion signaling that influences the metastatic potential of cancer cells.
 ...
PMID:Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis. 1471 34

The nonreceptor tyrosine kinase c-Src is activated in most invasive cancers. Activated c-Src binds to FAK in the focal adhesion complex, resulting in the activation of the c-Src/FAK signaling cascade, which regulates cytoskeletal functions. However, the mechanisms by which c-Src/FAK signaling is regulated during conditions of anchorage-independent growth, a hallmark of tumor progression, are not clearly known. Here, an in vivo approach to measure c-Src activity was studied using phospho-specific antibodies against phosphorylated Y418 of c-Src (Src[pY418]), an autophosphorylation site of c-Src, and phosphorylated Y577 of FAK (FAK[pY577]), a known substrate of c-Src. Using genetic and pharmacological approaches to modulate c-Src activity, we showed that the levels of Src[pY418] and FAK[pY577], and the formation of a c-Src/FAK[pY577] complex correlated with the activation state of c-Src in adherent cells. Interestingly, both the in vivo level of Src[pY418] and in vitro c-Src kinase activity were increased in carcinoma cells following disruption of Ca(2+)-dependent cell-matrix adhesion. In contrast, the level of FAK[pY577] and its association with c-Src were reduced in suspended cells. The amount of FAK[pY577] in suspended cells was recovered following attachment of rounded cells to fibronectin-coated polystyrene beads, indicating that cell spreading was not required for phosphorylation of FAK. Moreover, cells expressing activated c-Src showed sustained Src[Y418] phosphorylation, but required Ca(2+)-dependent cell adhesion for phosphorylation of FAK[Y577] and association of c-Src with FAK[pY577]. These findings indicate an important role of integrin-based cell-matrix adhesion in regulating c-Src/FAK signaling under decreased anchorage conditions.
 ...
PMID:Disruption of Ca2+-dependent cell-matrix adhesion enhances c-Src kinase activity, but causes dissociation of the c-Src/FAK complex and dephosphorylation of tyrosine-577 of FAK in carcinoma cells. 1472 52

Grb7 is an adaptor molecule that mediates signal transduction from multiple cell surface receptors to various downstream signaling pathways. Grb7 and its related family member Grb10 and Grb14 share a conserved molecular architecture including an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes a PH domain and shares sequence homology with the Caenorhabditis elegans protein, Mig-10, and a carboxyl-terminal SH2 domain. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues, although the functional significance of such phosphorylation is incompletely understood. Grb7/10/14 family proteins are mainly localized in the cytoplasm, but have been observed at the plasma membrane, focal contacts, or mitochondria under certain conditions. A large number of receptor tyrosine kinases and other signaling molecules can associate with Grb7/10/14 family proteins, mostly through the SH2 domains, although the functional consequences of such interactions have not been well characterized in most cases. Recent studies have suggested that various isoforms of Grb10 play important roles in mediating insulin/insulin-like growth factor regulation of cell proliferation and apoptosis, whereas Grb7 mediates signaling pathways from FAK and EphB1 receptor to regulate cell migration, which is also implicated in tumor progression. This review will discuss the current understanding of Grb7 mediated signal transduction pathways and their role in the regulation of various cellular functions.
 ...
PMID:Grb7 in intracellular signaling and its role in cell regulation. 1476 59

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is one representative of the natural matrix metalloproteinase (MMP) inhibitor family, encompassing four members. It inhibits all MMPs, except several MT-MMPs, and a disintegrin with a metalloproteinase domain (ADAM)-10 with Kis < nM. Unexpectedly, its upregulation was associated to poor clinical outcome for several cancer varieties. Such finding might be related to the growth-promoting and survival activities of TIMP-1 for normal and cancer cells. In most cases, such properties are MMP-independent and binding of TIMP-1 to an unknown receptor system can trigger JAK (or FAK)/PI3 kinase/Akt/bad-bclX2 (erythroid, myeloid, epithelial cell lines) or Ras/Raf1/FAK (osteosarcoma cell line) signaling pathways. The relationship between viral infection and TIMP-1 expression is here underlined. Thus, TIMP-1 might display a dual influence on tumor progression; either beneficial by inhibiting MMPs as MMP-9 and by impairing angiogenesis or detrimental by favoring cancer cells growth or survival. We consider that the proMMP-9/TIMP-1 balance is of critical importance in early events of tumor progression, and might show promise as diagnostic and prognostic marker of malignancy.
 ...
PMID:Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression. 1578 25

ICAM-3 interacts with LFA1, and is involved in the intercellular adhesion of leukocytes as well as in the mainenance of cell survival. It has also been suggested to induce cancer cell proliferation but the precise signaling pathway is unclear. The aim of this study was to determine the ICAM-3-activated downstream pathway in H1299 lung cancer cells. The level of ICAM-3-induced cell growth was examined using BrdU incorporation, which is a colony-forming assay, FACS analysis, and cell counting. The results showed that ICAM-3 expression induces cancer cell proliferation. In addition, FAK, Akt, PDK1, GSK-3beta, BAD, and PTEN were phosphorylated by ICAM-3-overexpression, resulting in enhanced cell proliferation. In conclusion, ICAM-3 expression induces cancer cell proliferation, and an increase in ICAM-3 expression can contribute to cancer progression.
 ...
PMID:ICAM-3-induced cancer cell proliferation through the PI3K/Akt pathway. 1613 25

Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT1 receptor (AT1R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT1R activation via Gq/11 stimulates phospholipases A2, C, and D, and activates inositol trisphosphate/Ca2+ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-kappaB pathway. The AT1R also signals via Gi/o and G11/12 and stimulates G protein-independent signaling pathways, such as beta-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT1R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT1R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT1R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT1R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II's pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT1R antagonists, in addition to their established therapeutic actions in essential hypertension.
 ...
PMID:Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. 1614 58


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