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

Receptor tyrosine kinases are important in normal cellular physiology as well in the pathogenesis of a variety of tumors, including lung cancer. RTKs are a target for novel therapies currently being investigated. In the clinics, EGFR inhibitors and c-Kit inhibitors are already being utilized, and c-Met inhibitors are in development. Even though the RTK inhibitors provide a novel mechanism, it is important to realize that lung cancer etiology is a complex process, and eventually standard chemotherapy may need to be used in conjunction with these novel therapies to make an important difference in response rates.
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PMID:Role of receptor tyrosine kinases in lung cancer. 1241 90

Small-cell lung cancer (SCLC) is an aggressive, malignant neoplasm with a 5-year survival of less than 10%. This poor survival rate is related to a high propensity for recurrence and a high rate of metastases. Metastases initially occur in the lymph nodes and thereafter in other organs such as the lung itself, liver, adrenal glands, brain, bone, and bone marrow. The mechanisms of metastases have been better understood recently and are described in this review. Receptor tyrosine kinases (RTKs) have been identified as important therapeutic targets in non-small-cell lung cancer (such as the EGF-receptor). We have begun to identify RTKs in SCLC and have shown that c-Kit and c-Met are expressed and functional in SCLC. RTKs have also been shown to be important in the metastasis of cancer cells. The roles of RTKs in the mechanism of metastasis are detailed in this review, with special emphasis on downstream signal transduction from RTK signaling.
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PMID:Mechanisms of metastasis as related to receptor tyrosine kinases in small-cell lung cancer. 1452 91

Intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular and cholangiocarcinoma (HC-CC) are known to arise occasionally in hepatitis-related cirrhosis, although their clinicopathological features remain unclarified. In this study, we characterized the ICC (9 cases) and ICC elements of HC-CC (11 cases) arising in nonbiliary cirrhosis. Thirty-three hepatocellular carcinomas (HCC) associated with nonbiliary cirrhosis and 24 ICC without cirrhosis were used as controls. Prominent neutrophilic infiltration was frequent in ICC with cirrhosis (78%) and ICC elements of combined HC-CC (72%). Neutrophilic infiltration-related cytokines (interleukin 8, granulocyte colony-stimulating factor [G-CSF], and granulocyte macrophage colony-stimulating factor [GM-CSF]) were expressed frequently and intensely in carcinoma cells of ICC with cirrhosis (40%, 80%, and 60%, respectively) and in ICC elements of the combined one (13%, 38%, and 63%, respectively). Interleukin 8 was expressed in 18% of ICC without cirrhosis, irrespective of neutrophilic infiltration. Neutrophilic infiltration and expression of G-CSF and GM-CSF were in parallel (P < 0.05). G-CSF and GM-CSF mRNA were detected by RT-PCR in tissue specimens expressing G-CSF and GM-CSF at the protein level. Such neutrophilic infiltration and expression of G-CSF and GM-CSF were not evident in controls. The expressions of c-kit and c-Met, as a hematopoietic and hepatic stem cell marker, were seen frequently in ICC with cirrhosis (80% and 80%, respectively) and ICC elements of the combined one (63% and 50%, respectively). The present study revealed that the frequent expression of G-CSF and GM-CSF is a characteristic of ICC with cirrhosis and ICC in combined carcinoma, probably representing a phenotype of fetal hepatic parenchymal cell. The expression of these cytokines may be causally related to prominent neutrophilic infiltration.
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PMID:Intrahepatic cholangiocarcinoma in cirrhosis presents granulocyte and granulocyte-macrophage colony-stimulating factor. 1469 21

The liver is an organ with tremendous regenerative capacity. Hepatic stem cells, identified by flow cytometric sorting and single cell-based assays as c-Met (+)CD49f (+/low)c-Kit (-)CD45 (-)TER119 (-) cells in murine fetal livers, possess multilineage differentiation potential and self-renewing capability. These cells can differentiate in vitro as well as in vivo into some epithelia capable of reconstituting tissues within the liver, pancreas, and intestine following appropriate transplantation. The isolated fetal hepatic stem cells are also characterized by the ability to maintain their self-renewal capability in the developing liver. Thus, these cells may be ideal vehicles for delivering therapeutic genes to the liver. We also examined the relationship between fetal hepatic stem cells and hepatic oval cells in the adult liver. These two subtypes shared both multipotential capabilities of differentiation and surface marker expression profiles, suggesting that hepatic oval cells are probably the progeny of fetal hepatic stem cells. We also address the related topics of hepatocyte repopulation, exogenous hepatic stem cells, and transdifferentiation. Topics ranging from the fundamental properties and comprehensive descriptions of hepatic stem cells to current progress in the field are discussed in this brief article and our recent studies are addressed.
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PMID:Diversity of hepatic stem cells in the fetal and adult liver. 1472 11

We describe here the establishment of a new synovial sarcoma cell line, SYO-1, derived from a biphasic synovial sarcoma that developed in the groin of a 19-year-old female. The cell line was maintained for more than 70 passages (more than 24 months) in vitro. The SYO-1 cells in monolayer culture exhibited a spindle shape without conspicuous pleomorphism. Immunohistochemically, the cells were positive for vimentin, type IV collagen, S-100, mdm2, bcl-2, c-Met and c-Kit. Tumors developed by their implantation in nude mice histologically showed biphasic features that were composed of areas of fascicles of spindle cells and areas of compact proliferation of polygonal to ovoid cells, which occasionally formed epithelial plaque and expressed cytokeratin and EMA. SYO-1 cells harbored the characteristic t(X;18)(p11.2;q11.2) translocation by chromosome analysis and SYT-SSX2 chimeric transcript by RT-PCR. The SYO-1 cells, the first characterized cell line derived from biphasic synovial sarcoma retaining the characteristic genetic and phenotypic features of the tumor, will be useful for various investigations on synovial sarcoma, especially for its epithelial differentiation.
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PMID:Establishment and characterization of a biphasic synovial sarcoma cell line, SYO-1. 1474 40

During pancreatic development, neogenesis, and regeneration, stem cells might act as a central player to generate endocrine, acinar, and duct cells. Although these cells are well known as pancreatic stem cells (PSCs), indisputable proof of their existence has not been reported. Identification of phenotypic markers for PSCs leads to their prospective isolation and precise characterization to clear whether stem cells exist in the pancreas. By combining flow cytometry and clonal analysis, we show here that a possible pancreatic stem or progenitor cell candidate that resides in the developing and adult mouse pancreas expresses the receptor for the hepatocyte growth factor (HGF) c-Met, but does not express hematopoietic and vascular endothelial antigens such as CD45, TER119, c-Kit, and Flk-1. These cells formed clonal colonies in vitro and differentiated into multiple pancreatic lineage cells from single cells. Some of them could largely expand with self-renewing cell divisions in culture, and, following cell transplantation, they differentiated into pancreatic endocrine and acinar cells in vivo. Furthermore, they produced cells expressing multiple markers of nonpancreatic organs including liver, stomach, and intestine in vitro. Our data strongly suggest that c-Met/HGF signaling plays an important role in stem/progenitor cell function in both developing and adult pancreas. By using this antigen, PSCs could be isolated prospectively, enabling a detailed investigation of stem cell markers and application toward regenerative therapies for diabetes.
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PMID:Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. 1527 99

Lung cancer is a deadly disease with high mortality and morbidity. Most cases of lung cancer are due to non-small cell carcinoma, with 16% of cases being small cell carcinoma. The biology at a cellular level is of interest at many levels. Knowing cellular pathways helps to further enhance our knowledge of how lung cancer cells survive, proliferate, and metastasize. The receptor tyrosine kinases (RTKs) located at the cellular membrane are becoming of great interest as sites for targeted therapies for lung cancers. This review will discuss the RTKs that are involved in lung cancers and the newer therapies that are being tested. We will specifically discuss receptors such as epidermal growth factor receptor, c-Kit receptor, VEGF receptor, c-Met receptor, insulin growth factor receptor, and Eph receptor. The inhibitors against the specific RTKs are in various preclinical and clinical trials, and this will be detailed.
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PMID:Receptor tyrosine kinases and inhibitors in lung cancer. 1534 2

Previously, we found that hepatocyte growth factor receptor (c-Met)-and alpha-fetoprotein (AFP)-expressing cells were present in adult rat bone marrow, and that these cells also expressed hematopoietic stem cell markers, such as CD34, Thy-1, and c-Kit. When bone marrow cells were cultured in a hepatocyte growth medium (HGM) with HGF and EGF, colonies composed of polygonal cells resembling mature hepatocytes appeared by 2 weeks and grew very slowly because of overgrowth of stromal cells. At days 34-41, 2-mm2 sheets of hepatocyte-like cells were cut out of their colonies by scratching with an injection needle under observation with a phase contrast microscope, transferred into wells of 24-well plates, and cultured in the HGM medium in the presence or absence of HGF and EGF. When cells reached confluence, cells were detached with trypsin and EDTA and transferred step by step into bigger culture vessels. Thus, hepatocyte-like cells were expanded 1000-fold during less than 4 months. These cells were immunocytochemically stained for albumin and also for AFP and the hematopoietic stem cell markers described above, showing characteristics of oval cells. By RT-PCR, we detected mRNAs of tryptophan-2,3-dioxygenase and tyrosine aminotransferase, markers of hepatocytes at a terminal differentiation stage. The present culture system may be useful for supply of hepatocyte resources for cell transplantation therapy.
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PMID:Propagation of adult rat bone marrow-derived hepatocyte-like cells by serial passages in vitro. 1546 80

This study determines the effect of hepatocyte growth factor (HGF) on post-infarction left ventricular (LV) remodeling and cardiac function. In mice, on day 1 after myocardial infarction (MI), HGF (0.45 mg/kg per day) was injected into the tail vein for 7 days (n = 12). In the control mice (n = 12), 0.9% sodium chloride was injected instead of HGF. Hemodynamic data were obtained in vehicle treated control and HGF-treated hearts 4 weeks after the onset of MI. In the HGF-treated group, cardiac function was well preserved as indicated by LV pressure-volume relationship. These mice exhibited better LV systolic and diastolic function. The infarcted LV wall in HGF-treated heart was thicker as compared to vehicle treated group. Fibrosis and infarct size of the ventricular wall was significantly reduced in the HGF-treated hearts. 5-Bromo-2'-deoxy-uridine (BrdU) and Ki67 positive cardiomyocytes were observed in the border area of the HGF-treated infarcted hearts. c-Met and c-kit positive cardiomyocytes were observed in the border area and epicardium. Angiogenesis was significantly enhanced in HGF-treated hearts as determined by vessel density per unit area. A significant reduction in apoptosis in the HGF-treated hearts was observed compared with control hearts, and was strongly associated with increased Akt activation. Treatment with HGF improved heart function through angiogenesis, ventricular wall thickening, and hypertrophy of cardiomyocytes. The antiapoptotic effect of HGF was mediated by activation of PI3-kinase/Akt pathway.
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PMID:Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis. 1552 81

Pigmented neurofibroma (PNF) is a rare variant of neurofibroma showing melanin production. To clarify the clinicopathologic features of PNF and to characterize melanogenesis in PNF, 12 cases of PNF were examined in comparison with schwannoma (SCH, n = 16) and neurofibroma (NF, n = 26). The PNF patients were all Japanese including 7 men and 5 women, and patient age ranged from 11 to 71 years (median, 23.5 years). They showed strong a predisposition for neurofibromatosis type 1. Their tumor size was large, and tumors arose from various sites of skin. Histologically, clusters of epithelioid, dendritic, and spindle melanin-producing cells with faint pigmentation had a tendency to locate in deep dermis and subcutis, which seems to be a characteristic pattern of melanogenesis. There was a transition between melanin-producing cells and Schwann cells. Immunohistochemical examination included known melanogenic markers, microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis, and 2 tyrosine kinase receptors, c-Met and c-Kit, which regulate the development of melanocytes. In PNF, melanin-producing cells were S100 (+), MITF (+), Melan-A (+), tyrosinase (+/-), HMB45 (+/-), c-Met (+), and c-Kit (-). Schwann cells were S100 (+), MITF (-), Melan-A (-), tyrosinase (-), HMB45 (-), c-Met (-), and c-Kit (-), and intermediate spindle cells were S100 (+), MITF (+), Melan-A (+), tyrosinase (-), HMB45 (-), c-Met (+), and c-Kit (-). When compared with SCH and NF, MITF was weakly expressed in a part of tumor cells of SCH, whereas no definite staining was found in NF. c-Met expression was very weak in a scattered manner in SCH (10/15 cases) and NF (10/26 cases). These results suggest that PNF is a unique tumor that shows differentiation toward mature melanin production, but ability of melanin synthesis seems to be impaired. There may be a close relationship between up-regulated MITF and c-Met and the peculiar melanogenic nature of PNF, and both of these are useful diagnostic tools for distinguishing PNFs with less melanin production from NFs.
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PMID:Pigmented neurofibroma: review of Japanese patients with an analysis of melanogenesis demonstrating coexpression of c-met protooncogene and microphthalmia-associated transcription factor. 1611 3


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