Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stem cell factor (SCF) plays important roles in tumor growth and angiogenesis. However, its regulatory mechanism remains largely undefined. Here, we report that hypoxia upregulated the expression of SCF in MCF-7 breast cancer cells in both messenger RNA and protein levels. When hypoxia-inducible factor (HIF)-1 alpha expression was knocked down by RNA interference, the MCF-7 cell expression of SCF was decreased significantly. Furthermore, the SCF receptor, c-kit phosphorylation was significantly strengthened by the condition culture media from hypoxic MCF-7 and MCF-7-c cells. The survival of A549 cells was more dependent on SCF under hypoxia. Analysis of SCF promoter 5'-flanking region revealed a potential hypoxia-response element (HRE; 5'-GCGTG-3') located at -68 to -64 relative to the transcriptional start site. Chromatin immunoprecipitation assay demonstrated that HIF-1 alpha directly bound to this region under normoxia, and this binding activity was significantly enhanced under hypoxia. Overexpression of HIF-1 alpha significantly upregulated the expression of luciferase reporter gene under control of the SCF promoters in both MCF-7 cells and human embryonic kidney 293 cells, but mutation of the HRE site completely blocked this effect. Epidermal growth factor was also able to enhance the SCF expression under normoxia in MCF-7 cells, which was dependent on HIF-1 alpha. Taken together, our data demonstrated that HIF-1 alpha was a key regulator of SCF expression in breast cancer cells. Hypoxia and epidermal growth factor receptor signal coexisted in the tumor microenvironment and might promote angiogenesis through HIF-1 alpha-mediated upregulation of SCF and other angiogenic factors.
 ...
PMID:Hypoxia-inducible factor (HIF)-1 alpha directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF). 1833 85

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Angiogenesis, primarily mediated through vascular endothelial growth factor (VEGF), is one of the key steps in tumor growth and metastasis. VEGF is now a validated target for NSCLC based on the results of the Eastern Cooperative Oncology Group trial E4599 which showed that the addition of bevacizumab, a VEGF monoclonal antibody, to cytotoxic chemotherapy improves survival compared with chemotherapy alone in patients with metastatic NSCLC. As NSCLC has complex and integrated signaling pathways, a rational approach is to target more than one of these pathways concurrently. Sorafenib, which is approved for the treatment of renal cell carcinoma, is a multitargeted signal transduction inhibitor that inhibits raf-kinases, VEGF receptor-2, platelet derived growth factor receptor-B, and c-kit. In a phase II monotherapy trial in patients with previously treated NSCLC, sorafenib demonstrated activity with a disease control rate and survival rate comparable to other small molecules. Additionally, sorafenib has shown preliminary activity in combination with chemotherapy and with epidermal growth factor receptor inhibitors. Future directions will include the development of rational combinations either with cytotoxic compounds or biologically targeted compounds and the identification of subsets of patients that might benefit from the other targets of sorafenib.
 ...
PMID:Sorafenib in lung cancer: clinical developments and future directions. 1852 Feb 94

Despite the evidence for the role of inflammation in cancer initiation, promotion, and progression, the precise mechanism by which the inflammation within tumor is orchestrated by inflammatory cells remains to be determined. Here, we report that tumor-infiltrating mast cells remodel tumor microenvironment and promote tumor growth. Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. Low concentrations of SCF efficiently induced the chemotactic migration of mast cells. Tumor-infiltrating mast cells, activated by higher concentrations of SCF, expressed multiple proinflammatory factors and increased IL-17 expression in tumors. The activity of NF-kappaB and AP-1 in tumor cells was intensified in the mast cell-remodeled inflammatory microenvironment. SCF-activated mast cells also exacerbated tumor immunosuppression by releasing adenosine and increasing T regulatory cells, which augmented the suppression of T cells and natural killer cells in tumors. These findings emphasize that the remodeling of the tumor microenvironment can actually be initiated by tumor cell-released SCF and suggest that mast cells are not only a participator but also a critical regulator of inflammation and immunosuppression in the tumor microenvironment.
 ...
PMID:SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. 1852 89

Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors of the gastrointestinal tract, the diagnosis of which is difficult. The presence of membrane receptor c-KIT on GIST cells implies their origin from a precursor of interstitial cells of Cajal. Mutations in the c-kit gene result in the constitutive ligand-independent activation of the c-KIT receptor and, consequently, aberrant cell division and tumor growth. Imatinib (STI571), used in the treatment of unresectable GIST, selectively inhibits the enzymatic activity of the tyrosine kinase c-KIT. However, it is known that some mutations in the c-kit gene lead to resistance to imatinib. Therefore, the search for new effective agents is being continued. In this paper the clinical and molecular characterization of the GIST is presented as well as data related to imatinib in the treatment of GIST. Moreover, novel agents for the treatment of patients with advanced GIST are described.
 ...
PMID:[Clinical and molecular characterization of gastrointestinal stromal tumors (GIST)]. 1854 42

The incorporation of new anti-cancer kinase inhibitors within cancer management is rapidly increasing. Mast cells are sensitive to several of these new anti-cancer agents most notably to c-Kit inhibitors. As a result, studies investigating the role of mast cells in tumors may have direct clinical relevance and consequently, important clinical implications. Here we review some of the basic attributes of mast cells, especially those related to the new "targeted" drugs. Mast cell roles such as modulators of regulatory T-cells, inducers of angiogenesis and promoters of clot formation are discussed. We also review recent mouse tumor models and human pathological data which implicate mast cells as having both pro- and anti-tumor growth properties. These studies expose a complex, emerging picture of mast cell involvement in tumor biology. It seems that mast cell modulator drugs may improve the efficacy of anti-tumor therapy under certain circumstances, whilst under others, may negatively affect drug efficacy.
 ...
PMID:Mast cells and cancer--no longer just basic science. 1863 84

Pazopanib, which is being developed by GlaxoSmithKline plc, is an oral, second-generation multi-targeted tyrosine kinase inhibitor that targets VEGFR, platelet-derived growth factor receptor and c-kit, key proteins responsible for tumor growth and survival. Pazopanib exhibited good potency against all of the human VEGFRs and closely related tyrosine receptor kinases in vitro, and demonstrated antitumor activity in several human tumor xenografts, including renal cell carcinoma (RCC), and breast and lung cancer. In phase I and II clinical trials, pazopanib was generally well tolerated with the main side effects being hypertension, fatigue or gastrointestinal disorders. Pazopanib alone caused a decrease in tumor size and stable disease in a significant number of patients, including those with RCC, NSCLC and gynecological tumors. The combination of pazopanib with lapatinib was effective in patients with breast cancer. At the time of publication, pazopanib monotherapy was being evaluated in phase III trials in patients with RCC and as combination therapy with lapatinib in patients with breast cancer. In addition, phase I and II trials were being conducted to assess pazopanib alone or in combination with a range of chemotherapeutics in patients with solid tumors or multiple myeloma.
 ...
PMID:Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. 1903 39

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Current therapeutic options include surgery and targeted molecular approaches such as imatinib and sunitinib. Our aim was to establish patient-derived GIST xenografts for the use of screening new drugs and improving current treatment regimens used in GIST. In this present study, we investigate the antitumor activity of sorafenib against patient-derived GIST xenografts. Murine xenograft models were given two oral doses of sorafenib daily for 30 days and growth of established tumor xenografts was monitored at least twice weekly by vernier caliper measurements. Western blotting was then used to determine changes in proteins in these xenografts before and after sorafenib therapy. Apoptotic and cell proliferation were analyzed by immunohistochemisty. Our data found that oral administration of sorafenib to mice, bearing patient-derived GIST xenografts, resulted in dose-dependent inhibition of tumor growth. Sorafenib-induced growth inhibition was associated with decreased cell proliferation, increased apoptosis, and reduction in tumor angiogenesis. Western blot analysis revealed that sorafenib inhibited C-Raf, phospho-extracellular signal-regulated kinase 1/2, and phospho-MEK1 (Thr286) slightly as well as phospho-c-Kit (Tyr568/Tyr570), phospho- platelet-derived growth factor receptor beta (Tyr1021), and phospho-Flk1 (Tyr951), suggesting that sorafenib inhibited GIST growth by blocking the Raf/MEK/extracellular signal-regulated kinase pathway and angiogenesis. Sorafenib also induced cell cycle arrest, evident through increased levels of p15 and p27 and decreased levels of p21, cyclin A, cyclin B1, and cdc-2. Our study provides a strong rationale for the clinical investigation of sorafenib in patients with GIST as well as an established platform for further drug evaluation studies using GIST xenograft models.
 ...
PMID:Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor. 1913 24

Gastric cancer is a deadly disease for which current therapeutic options are extremely limited. Vascular endothelial growth factor receptors and platelet-derived growth factor receptors regulate gastric cancer cell proliferation, invasion, and tumor angiogenesis. In the present study, we report that sorafenib therapy effectively inhibited tumor growth and angiogenesis in tumor xenografts. These were associated with reduction in the phosphorylation of vascular endothelial growth factor receptor-2 Tyr951, c-Kit Tyr568/570, platelet-derived growth factor receptor-beta Tyr1021, and Akt Ser473 and Thr308, down-regulation of positive cell cycle regulators, increased apoptosis, and up-regulation of p27. Sorafenib treatment also caused up-regulation of p-c-Raf Ser338 and p-extracellular signal-regulated kinase (ERK) Thr202/Tyr204 in gastric cancer xenografts. The combination of sorafenib and MAP/ERK kinase inhibitor AZD6244 enhances the effectiveness of each compound alone. Potential effect of sorafenib/AZD6244 included increase in proapoptotic Bim. Our data show that MAP/ERK kinase inhibition enhances the antitumor activity of sorafenib in vivo, supporting a rationale for multitargeted suppression of the angiogenesis and ERK signaling network in gastric cancer therapy.
 ...
PMID:AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer. 1972 82

Hepatocellular carcinoma (HCC) is associated with a high morbidity and mortality due to its high rate of recurrence. However, little is known about the biological characteristics of recurrent HCC cells. A single patient's primary and recurrent HCC-derived cell lines, Hep-11 and Hep-12, respectively, were established by primary culture. These two cell lines have the same hepatitis B virus integration site and share many common amplifications and deletions, which suggest that they have the same clonal origin. While Hep-11 cells were non-tumorigenic at 16 weeks following injection of up to 10 000 cells, injection of only 100 Hep-12 cells was sufficient to initiate tumor growth, and all single Hep-12 clones were tumorigenic in immunodeficient mice. Compared with Hep-11, Hep-12 cells expressed the oval cell markers AFP, NCAM/CD56, c-kit/CD117, as well as multiple stem cell markers such as Nanog, OCT4 and SOX2. In addition, >90% of Hep-12 cells were aldehyde dehydrogenase positive. They were also less resistant to paclitaxel, but more resistant to doxorubicin, cisplatin and hydroxycamptothecin (HCPT), which had been administrated to the patient. Furthermore, Hep-12 cells expressed higher levels of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) than Hep-11, and PARP-1 inhibition potentiated the sensitivity to HCPT in Hep-12 cells but not in Hep-11 cells. These results indicate that a large population of the recurrent HCC-derived Hep-12 cells were tumor-initiating cells and that elevated expression of PARP-1 was related to their resistance to HCPT.
 ...
PMID:The properties of tumor-initiating cells from a hepatocellular carcinoma patient's primary and recurrent tumor. 1989 2

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in a variety of cancer cells. The addition of ligand activates the receptor by inducing a conformational change in the receptor, which can be recapitulated by mutation. To investigate the role of activated PPARgamma signaling in breast cancer, we compared the function of a constitutively active PPARgamma (PgammaCA) mutant with the wild-type PPARgamma in ErbB2-induced mammary tumorigenesis in vivo. Tumor cells transduced with either PPARgamma or PgammaCA were implanted into immunocompetent FVB mice. Enhanced tumor growth was observed in PgammaCA-transduced cells, which was associated with increased angiogenesis and endothelial stem cells as evidenced by increased number of cells stained with von Willebrand factor, c-Kit, CD133, and CD31. Genome-wide expression profiling identified a group of genes within the angiogenesis pathway, including Angptl4, as targets of activated PPARgamma; PgammaCA also induced Angptl4 protein secretion in ErbB2-transformed mammary epithelial cells. Angptl4 promoted vascular endothelial cell migration; conversely, immunodepletion of Angptl4 reduced PgammaCA-mediated cellular migration. Collectively, these studies suggest that activated PPARgamma induces Angptl4 to promote tumor growth through enhanced angiogenesis in vivo.
 ...
PMID:Activating peroxisome proliferator-activated receptor gamma mutant promotes tumor growth in vivo by enhancing angiogenesis. 1993 21


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