Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD44 has been implicated in tumor progression and metastasis, but the mechanism(s) involved is as yet poorly understood. Recent studies have shown that CD44 isoforms containing the alternatively spliced exon v3 carry heparan sulfate side chains and are able to bind heparin-binding growth factors. In the present study, we have explored the possibility of a physical and functional interaction between CD44 and hepatocyte growth factor/scatter factor (HGF/SF), the ligand of the receptor tyrosine kinase c-Met. The HGF/SF-c-Met pathway mediates cell growth and motility and has been implicated in tumor invasion and metastasis. We demonstrate that a CD44v3 splice variant efficiently binds HGF/SF via its heparan sulfate side chain. To address the functional relevance of this interaction, Namalwa Burkitt's lymphoma cells were stably co-transfected with c-Met and either CD44v3 or the isoform CD44s, which lacks heparan sulfate. We show that, as compared with CD44s, CD44v3 promotes: (i) HGF/SF-induced phosphorylation of c-Met, (ii) phosphorylation of several downstream proteins, and (iii) activation of the MAP kinases ERK1 and -2. By heparitinase treatment and the use of a mutant HGF/SF with greatly decreased affinity for heparan sulfate, we show that the enhancement of c-Met signal transduction induced by CD44v3 was critically dependent on heparan sulfate moieties. Our results identify heparan sulfate-modified CD44 (CD44-HS) as a functional co-receptor for HGF/SF which promotes signaling through the receptor tyrosine kinase c-Met, presumably by concentrating and presenting HGF/SF. As both CD44-HS and c-Met are overexpressed on several types of tumors, we propose that the observed functional collaboration might be instrumental in promoting tumor growth and metastasis.
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PMID:Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met. 1003 43

Monoclonal antibody (mAb) 225 against the human epidermal growth factor receptor blocks activation of receptor tyrosine kinase. This retards or arrests cell cycle progression, with accumulation of cells in G1 phase. The mechanism of growth inhibition involves increased levels of p27KIP1 and inhibition of cyclin-dependent kinase-2 activity. mAb in combination with chemotherapy exhibits a synergistic antitumor activity, with successful eradication of well-established tumor xenografts that resist treatment with either mAb or drug alone. A Phase I clinical trial has established the safety of repeated administration of human:mouse chimeric mAb 225 at concentrations that maintain receptor-saturating blood levels for up to 3 months. Phase I trials exploring mAb 225 treatment in combination with doxorubicin, cisplatin, or paclitaxel are ongoing.
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PMID:Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. 1006 77

The prevalence of NTRK1 re-arrangement was determined in papillary thyroid carcinomas (PTCs) of children from Belarus who had been exposed to radioactive iodine after the Chernobyl reactor accident; 81 tumors were included, all of which were devoid of RET re-arrangement as analyzed in a current study on genomic alterations in PTC. Oncogenic fusion of the NTRK1 tyrosine kinase domain with the amino-terminal part of the tropomyosin gene (TPM3/NTRK1, trk) was observed in 5 tumors. A single tumor exhibited a TPR/NTRK1 fusion (TRK-T2). Reciprocal NTRK1/TPM3 transcripts were found in 4 of 5 tumors with TPM3/NTRK1 re-arrangement, indicating an intra-chromosomal balanced reciprocal inversion. No phenotypic differences from other post-Chernobyl childhood PTCs were detected. As compared with the high prevalence of RET re-arrangements reported for thyroid carcinomas of children after the Chernobyl reactor accident, NTRK1 re-arrangements appear rare. Our results confirm that activation of receptor tyrosine kinase genes plays the predominant role in post-Chernobyl childhood thyroid carcinogenesis.
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PMID:NTRK1 re-arrangement in papillary thyroid carcinomas of children after the Chernobyl reactor accident. 1007 15

Prostate cancer progresses from a hormone-sensitive, androgen-dependent stage to a hormone-refractory, androgen-independent tumor. The androgen receptor pathway functions in these androgen-independent tumors despite anti-androgen therapy. In our LAPC-4 prostate cancer model, androgen-independent sublines expressed higher levels of the HER-2/neu receptor tyrosine kinase than their androgen-dependent counterparts. Forced overexpression of HER-2/neu in androgen-dependent prostate cancer cells allowed ligand-independent growth. HER-2/neu activated the androgen receptor pathway in the absence of ligand and synergized with low levels of androgen to 'superactivate' the pathway. By modulating the response to low doses of androgen, a tyrosine kinase receptor can restore androgen receptor function to prostate cancer cells, a finding directly related to the clinical progression of prostate cancer.
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PMID:A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. 1008 74

The receptor tyrosine kinase Flt3 is expressed on the blasts of a high proportion of AML cases. We were interested in the expression and function of Flt3 on various human tumors. human tumor cell lines were tested for Flt3 expression by northern blot analysis and RT-PCR using head/neck (n=3), breast (n=4), ovarian (n=4), small cell lung (n=2), non-small cell lung (n=2), gastric (n=1), colon (n=3), pancreatic (n=1) and prostate carcinoma (n=1), choriocarcinoma (n=1), glioblastoma (n=5), neuroblastoma (n=1), melanoma (n=3), lymphoma (n=1), Hodgkin's disease (n=2), and leukemic (n=6) cell lines. With no expression on the other cell samples, 3 of 6 leukemic cell lines showed expression of Flt3 mRNA. The cDNA region corresponding to the juxtamembrane domain did not show any mutation as determined by sequence analysis. In all 3 positive cell lines, protein expression was verified by immunoprecipitation followed by immunoblot analysis. Although Flt3 is functional in these cell lines, as judged by ligand-dependent receptor autophosphorylation, it only mediates a proliferative response in 2 of the 3 cell lines. In conclusion, Flt3 is expressed exclusively in hematopoietic malignancies. Although early signalling events are detectable in all Flt3-positive cell lines tested, the expression of Flt3 does not predict a proliferative response of the cell lines. No internal tandem duplication of the juxtamembrane domain can be observed.
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PMID:Expression and function of Flt3/flk2 in human tumor cell lines. 1008 27

Hepatocyte growth factor (HGF) is a multifunctional cytokine which is believed to have important roles in tissue development and regeneration, and tumor progression. It is indistinguishable from scatter factor (SF), a motility factor. HGF/SF is believed to be a mesenchymal cell-derived cytokine acting for epithelial cells bearing its receptor tyrosine kinase, c-Met. Recently, we found that glioblastoma multiforme (GBM), a highly malignant brain tumor of astrocytic origin, concomitantly express HGF/SF and c-Met. This finding indicates a presence of autocrine loop of HGF/SF signaling pathway in GBM. Moreover, GBM cells also co-express HGF activator, a recently identified serine proteinase having efficient HGF/SF activating activity. The expression of HGF/SF and c-Met was low or hardly detectable in low-grade astrocytoma, and c-Met immunoreactivity was correlated with the histological grade of the tumor suggesting that the creation of HGF/SF autocrine loop occurs along with the progression of astrocytic brain tumors. Experimental evidence indicated that HGF/SF exhibits potent migration/invasion-inducing activity for GBM cells bearing c-Met receptor. It is also a significant angiogenesis factor in GBM, and may serve as a cellular growth factor for certain GBM cells. These lines of evidence suggest that HGF/SF signaling pathway may serve as a promising new target of therapeutic intervention of GBM.
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PMID:Expression of hepatocyte growth factor/scatter factor and its receptor c-Met in brain tumors: evidence for a role in progression of astrocytic tumors (Review). 1020 87

The tumour suppressor gene PTEN (also called MMAC1 or TEP1) is somatically mutated in a variety of cancer types [1] [2] [3] [4]. In addition, germline mutation of PTEN is responsible for two dominantly inherited, related cancer syndromes called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome [4]. PTEN encodes a dual-specificity phosphatase that inhibits cell spreading and migration partly by inhibiting integrin-mediated signalling [5] [6] [7]. Furthermore, PTEN regulates the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by specifically dephosphorylating position 3 on the inositol ring [8]. We report here that the dauer formation gene daf-18 is the Caenorhabditis elegans homologue of PTEN. DAF-18 is a component of the insulin-like signalling pathway controlling entry into diapause and adult longevity that is regulated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI 3-kinase [9]. Others have shown that mutation of daf-18 suppresses the life extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Similarly, we show that inactivation of daf-18 by RNA-mediated interference mimics this suppression, and that a wild-type daf-18 transgene rescues the dauer defect. These results indicate that PTEN/daf-18 antagonizes the DAF-2-AGE-1 pathway, perhaps by catalyzing dephosphorylation of the PIP3 generated by AGE-1. These data further support the notion that mutations of PTEN contribute to the development of human neoplasia through an aberrant activation of the PI 3-kinase signalling cascade.
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PMID:Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. 1020 98

Binding of epidermal growth factor (EGF) to the EGF receptor is known to trigger a number of biological responses in the target cells including EGF receptor phosphorylation and stimulation of DNA synthesis leading to cell proliferation. Agents that bind to the EGF receptors could have a significant role in the therapy of tumors that express increased numbers of receptors by blocking the stimulatory effect of EGF. Different monoclonal antibodies (MAbs) directed to the EGF receptor have been generated that inhibit EGF binding and do not induce activation of the receptor tyrosine kinase. When there is sufficient uptake these antibodies can be used for immunotherapy and, after labeling with an appropriate radionuclide, also for radioimmunotherapy. For evaluation of a ligand as a therapeutic agent, it is necessary to investigate its binding characteristics in tumor cells and experimental tumors in vivo. Because the effectiveness of the antitumor activity of the MAb is dependent upon the amount of receptors in the tissue and the penetration of the MAb into the tissue, the receptor density, biokinetics, and tumor distribution of the MAb or its fragments were evaluated in different tumor models. The results of the experimental studies with tumor cell spheroids and different xenotransplanted human tumors have shown that the uptake and distribution in the tumor tissue is dependent on the molecular weight of the ligand. The correlation between the uptake of the substances and the receptor density is an indication for a noninvasive scintigraphic characterization of human tumors using radiolabeled compounds with specific binding to the tumor receptor and for selection of an optimal therapeutic regimen or radionuclide targeting of the tumor.
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PMID:Binding of EGF peptide and EGF receptor antibodies and its fragments in different tumor models. 1021 85

The ErbB2 receptor tyrosine kinase is often overexpressed in human malignancies and causally involved in transformation. High levels of ErbB2 in tumor cells correlate with an unfavorable prognosis. This makes the ErbB2 receptor an interesting target for tumor therapy, and several strategies have been designed to direct drugs to ErbB2-expressing cells. We established a novel cellular model that allows preclinical evaluation of ErbB2-directed drugs in immunocompetent animals. Renal carcinoma (Renca) cells are an established tumor cell line that originated in Balb/c mice. Upon intravenous transplantation, these cells form pulmonary metastases in Balb/c mice. The transforming genetic lesions in these cells are not fully characterized, but do not seem to involve alterations in ErbB2 gene expression. We transfected Renca cells with the gene encoding the human ErbB2 receptor to provide a target structure for specific drugs and with the bacterial lacZ gene to provide a sensitive means of detection of the tumor cells in the transplanted animals. These genetically modified cells form lung metastasis and can be easily visualized on the surface of lung tissue by staining with an X-gal solution. This allows a quantitative analysis of the number of ErbB2-expressing pulmonary metastasis. We previously used these Renca cells to evaluate the efficacy of an ErbB2-specific tumor toxin on pulmonary metastases in an adjuvant and a palliative treatment setting. In both cases, we achieved a dramatic reduction of disseminated lung lesions. Here we show that even at an advanced stage of metastasis formation, the ErbB2-specific toxin is able to efficiently reduce the number of pulmonary tumors.
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PMID:A novel animal model for the evaluation of the efficacy of drugs directed against the ErbB2 receptor on metastasis formation. 1021 91

Melanoma formation in the teleost fish Xiphophorus is caused by the uncontrolled activity of the genetically defined tumor locus Tu. The critical component of this locus is the Xmrk oncogene encoding a subclass I receptor tyrosine kinase. Overexpression and constitutive activation of the Xmrk receptor triggers a set of specific signal transduction events eventually resulting in the malignant phenotype. We have identified a melanoma-specific DNA-protein complex which seems to depend on Xmrk activation as shown in a heterologous cell system. The critical component of this complex, which directs transcriptional activation in the melanoma cells, proved to be a fish homologue of STAT5. Two other STAT factors, STAT1 and STAT3, implied in signaling by the Xmrk-related EGF receptor, were not activated in this particular cell type. Thus, Xmrk initiates very specific signaling pathways and transcriptional responses in Xiphophorus melanoma.
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PMID:Specific activation of a STAT family member in Xiphophorus melanoma cells. 1036 20


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