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)

The matricellular protein CCN2 (connective tissue growth factor, CTGF) has been previously implicated in tumorigenesis. In pancreatic cancer cells, CCN2 expression occurs downstream of ras/MEK/ERK. Direct evidence that CCN2 mediates tumor progression in pancreatic cancer has been lacking. An exciting recent report by Bennewith et al. (Cancer Res 69:775-784, 2009) has used shRNA knockdown of CCN2 to illustrate that CCN2 contributes to growth of pancreatic tumor cells, both in vitro and in vivo. This report briefly summarizes these findings.
 ...
PMID:Death of a tumor: targeting CCN in pancreatic cancer. 1926 21

Angiogenesis is a critical physiological process for cell survival and development. Endothelial cells, necessary for the course of angiogenesis, express several non-neuronal nicotinic acetylcholine receptors (AChRs). The most important functional non-neuronal AChRs are homomeric alpha7 AChRs and several heteromeric AChRs formed by a combination of alpha3, alpha5, beta2, and beta4 subunits, including alpha3beta4-containing AChRs. In endothelial cells, alpha7 AChR stimulation indirectly triggers the activation of the integrin alphavbeta3 receptor and an intracellular MAP kinase (ERK) pathway that mediates angiogenesis. Non-selective cholinergic agonists such as nicotine have been shown to induce angiogenesis, enhancing tumor progression. Moreover, alpha7 AChR selective antagonists such as alpha-bungarotoxin and methyllycaconitine as well as the non-specific antagonist mecamylamine have been shown to inhibit endothelial cell proliferation and ultimately blood vessel formation. Exploitation of such pharmacologic properties can lead to the discovery of new specific cholinergic antagonists as anti-cancer therapies. Conversely, the pro-angiogenic effect elicited by specific agonists can be used to treat diseases that respond to revascularization such as diabetic ischemia and atherosclerosis, as well as to accelerate wound healing. In this mini-review we discuss the pharmacological evidence supporting the importance of non-neuronal AChRs in angiogenesis. We also explore potential intracellular mechanisms by which alpha7 AChR activation mediates this vital cellular process.
 ...
PMID:Role of non-neuronal nicotinic acetylcholine receptors in angiogenesis. 1940 Nov 44

Bone sialoprotein (BSP) is a secreted glycoprotein found in mineralized tissues however, BSP is aberrantly expressed in a variety of osteotropic tumors. Elevated BSP expression in breast and prostate primary carcinomas is directly correlated with increased bone metastases and tumor progression. In this study, the intracellular signaling pathways responsible for BSP-induced migration and tumor survival were examined in breast and prostate cancer cells (MDA-MB-231, Hs578T and PC3). Additionally, the effects of exogenous TGF-beta1 and EGF, cytokines associated with tumor metastasis and present in high-levels in the bone microenvironment, were examined in BSP-expressing cancer cells. Expression of BSP but not an integrin-binding mutant (BSP-KAE) in tumor cell lines resulted in increased levels of alpha(v)-containing integrins and number of mature focal adhesions. Adhesion of cells to recombinant BSP or the expression of BSP stimulated focal adhesion kinase and ERK phosphorylation, as well as activated AP-1-family proteins. Activation of these pathways by BSP expression increased the expression of the matrix metalloproteinases MMP-2, MMP-9, and MMP-14. The BSP-mediated activation of the FAK-associated pathway resulted in increased cancer cell invasion in a Matrigel-coated Boyden-chamber assay and increased cell survival upon withdrawal of serum. Addition of EGF or TGF-beta1 to the BSP-expressing cell lines significantly increased ERK phosphorylation, AP-1 activation, MMP-2 expression, cell migration and survival compared to untreated cells expressing BSP. This study thus defines the cooperative mechanisms by which BSP can enhance specific factors associated with a metastatic phenotype in tumor cell lines, an effect that is increased by circulating TGF-beta1 and EGF.
 ...
PMID:Bone sialoprotein stimulates focal adhesion-related signaling pathways: role in migration and survival of breast and prostate cancer cells. 1949 34

CXCR1 and CXCR2 are receptors for CXCL-8 and are differentially expressed on melanoma and endothelial cells. In this study, we determined the functional role of these receptors in melanoma progression. We stably knock-down the expression of CXCR1 and/or CXCR2 in A375-SM (SM; high metastatic) human melanoma cells by short-hairpin RNA transfection. Cell proliferation, migration, invasion, ERK phosphorlyation and cytoskeletal rearrangements were carried out in vitro. In vivo growth was evaluated using murine subcutaneous xenograft model. Our data demonstrate that knock-down of CXCR1 and/or CXCR2 expression, inhibited melanoma cell proliferation, survival, migration and invasive potential in vitro. Moreover, we also observed inhibition of ERK phosphorylation and cytoskeltal rearrangement in SM-shCXCR1, SM-shCXCR2 and SM-shCXCR1/2 cells. Furthermore, when SM-shCXCR1 or SM-shCXCR2 cells implanted in nude mice, tumor growth, proliferation and microvessel density was significantly inhibited as compared to SM-control cells. In addition, we observed a significant increase in melanoma cell apoptosis in SM-shCXCR1 and SM-shCXCR2 tumors compared to SM-control tumors. Together, these data demonstrate that CXCR1 and CXCR2 expression play a critical role in human melanoma tumor progression and, functional blockade of CXCR1 and CXCR2 could be potentially used for future therapeutic intervention in malignant melanoma.
 ...
PMID:Small interfering RNA-mediated CXCR1 or CXCR2 knock-down inhibits melanoma tumor growth and invasion. 1958 80

Alpha-dystroglycan (alpha-DG) represents a highly glycosylated cell surface molecule that is expressed in the epithelial cell-basement membrane (BM) interface and plays an essential role in epithelium development and tissue organization. The alpha-DG-mediated epithelial cell-BM interaction is often impaired in invasive carcinomas, yet roles and underlying mechanisms of such an impaired interaction in tumor progression remain unclear. We report here a suppressor function of laminin-binding glycans on alpha-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, laminin-binding glycans are dramatically decreased, although the amount of alpha-DG and beta-dystroglycan is maintained. The decrease of laminin-binding glycans and consequent increased cell migration were associated with the decreased expression of beta3-N-acetylglucosaminyltransferase-1 (beta3GnT1). Forced expression of beta3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. beta3GnT1 was found to be required for laminin-binding glycan synthesis through formation of a complex with LARGE, thus regulating the function of LARGE. Interaction of the laminin-binding glycans with laminin and other adhesive molecules in BM attenuates tumor cell migratory potential by antagonizing ERK/AKT phosphorylation induced by the components in the ECM. These results identify a previously undescribed role of carbohydrate-dependent cell-BM interaction in tumor suppression and its control by beta3GnT1 and LARGE.
 ...
PMID:Tumor suppressor function of laminin-binding alpha-dystroglycan requires a distinct beta3-N-acetylglucosaminyltransferase. 1958 35

Parathyroid hormone-related protein (PTHrP), a paraneoplastic protein expressed by two-thirds of human non-small cell lung cancers, has been reported to slow progression of lung carcinomas in mouse models and to lengthen survival of patients with lung cancer. This study investigated the effects of ectopic expression of PTHrP on proliferation and cell cycle progression of two human lung adenocarcinoma cell lines that are normally PTHrP negative. Stable transfection with PTHrP decreased H1944 cell DNA synthesis, measured by thymidine incorporation, bromodeoxyuridine uptake, and MTT proliferation assay. A substantial fraction of PTHrP-positive cells was arrested in or slowly progressing through G1. Cyclin D2 and cyclin A2 protein levels were 60-70% lower in PTHrP-expressing cells compared with control cells (P < 0.05, N = 3 independent clones per group), while expression of p27(Kip1), a cyclin-dependent kinase inhibitor, was increased by 35 +/- 9% (mean +/- SE, P < 0.05) in the presence of PTHrP. Expression of other cyclins, including cyclins D1 and D3, and cyclin-dependent kinases was unaffected by PTHrP. PTHrP did not alter the phosphorylation state of Rb, but decreased cyclin-dependent kinase (CDK) 2-cyclin A2 complex formation. Ectopic expression of PTHrP stimulated ERK phosphorylation. In MV522 cells, PTHrP had similar effects on DNA synthesis, cyclin A2 expression, pRb levels, CDK2-cyclin A2 association, and ERK activation. In summary, PTHrP appears to slow progression of lung cancer cells into S phase, possibly by decreasing activation of CDK2. Slower cancer cell proliferation could contribute to slower tumor progression and increased survival of patients with PTHrP-positive lung cancer.
 ...
PMID:Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma. 1963 68

Transforming growth factor-beta (TGF-beta) is involved in actin cytoskeleton reorganization and tumor progression. Fascin1, an actin-binding protein, increases cell invasiveness and motility in various transformed cells. To determine whether fascin1 is an important mediator of the tumor response to TGF-beta, we applied the small interfering RNA (siRNA) technique to silence fascin1 in gastric cancer (GC) cells MKN45. Results showed that the effects of TGF-beta1 on GC cells invasion and metastasis were mediated by tumor production of fascin1; furthermore, it was found that TGF-beta1- induced fascin1 expression was suppressed by the specific inhibitors of JNK and ERK pathways, SP6001125 and PD98059, respectively, but not by transient transfection of Smad2 and Smad4 siRNA. Our data for the first time demonstrated that fascin1 is an important mediator of TGF-beta1-induced invasion and metastasis of GC cells, which involves JNK and ERK signaling pathways.
 ...
PMID:TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. 1965 66

An effective Th1 type cell-mediated immune response against cancer cells is critical in limiting cancer progression. Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma. In addition, mRNA of T-bet and Eomes were reduced in Gadd45b(-/-) CD8(+) T cells, supporting a critical role of Gadd45b in shaping the Th1 fate. More importantly, the tumor vaccination, which is effective in WT mice, failed in Gadd45b/Gadd45g doubly deficient mice. Collectively, these data demonstrate that members of the Gadd45 gene family are important for anti-tumor immune responses.
 ...
PMID:Gadd45b and Gadd45g are important for anti-tumor immune responses. 1968 43

The approval of sorafenib and active development of many other molecularly targeted agents in hepatocellular carcinoma (HCC) have presented a challenge to understand the mechanism of action of sorafenib and identify predictive biomarkers to select patients more likely to benefit from sorafenib. The preclinical study by Zhang and celleagues published this month in BMC Medicine provides preliminary evidence that baseline phosphorylated extracellular signaling-regulated kinase (pERK) may be a relevant marker to reflect the level of constitutive activation of the RAF/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway and has the potential value in predicting response to sorafenib. The clinical data from the initial single arm phase II study and preliminary report from the randomized phase III study also suggest the correlation of baseline archived tumor pERK levels and time to tumor progression in HCC patients. Whether baseline pERK will prove to be a useful predictive biomarker of response and clinical benefits for sorafenib in HCC will need to be validated in future large prospective studies.
 ...
PMID:Predicting the response to sorafenib in hepatocellular carcinoma: where is the evidence for phosphorylated extracellular signaling-regulated kinase (pERK)? 1970 70

Phylogenetic studies had shown that evolution of mitochondria occurred in parallel with the maturation of kinases implicated in growth and final size of modern organisms. In the last years, different reports confirmed that MAPKs, Akt, PKA and PKC are present in mitochondria, particularly in the intermembrane space and inner membrane where they meet mitochondrial constitutive upstream activators. Although a priori phosphorylation is the apparent aim of translocation, new perspectives indicate that kinase activation depends on redox status as determined by the mitochondrial production of oxygen species. We observed that the degree of mitochondrial oxidation of ERK Cys(38) and Cys(214) discriminates the kinase to be phosphorylated and determines translocation to the nuclear compartment and proliferation, or accumulation in mitochondria and arrest. Otherwise, transcriptional gene regulation by Akt depends on Cys(60) and Cys(310) oxidation to sulfenic and sulfonic acids. It is concluded that the interactions between kinases and mitochondria control cell signaling pathways and participate in the modulation of cell proliferation and arrest, tissue protection, tumorigenesis and cancer progression.
 ...
PMID:Mitochondrial kinases in cell signaling: Facts and perspectives. 1973 3


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