Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinoid tumors of the midgut type are slowly growing neoplasms which often present clinically and histologically pronounced fibrosis around the tumors. Cryosections from 41 neuroendocrine tumors (31 midgut carcinoid tumors, 8 endocrine pancreatic carcinomas, 1 parathyroid carcinoma, and 1 pheochromocytoma) and 22 nonneuroendocrine carcinomas were examined for the presence of platelet-derived growth factor (PDGF) beta-receptor by immunohistochemistry using the monoclonal antibody PDGFR-B2. Twenty midgut carcinoid tumor tissues (66%) and 4 endocrine pancreatic carcinomas (50%) and the parathyroid carcinoma stained positively with the antibody. In contrast, only 2 nonneuroendocrine tumor tissues (10%) were stained, and the staining in these cases was weak. The immunoreaction in the carcinoid tumors was observed in connective tissue cells adjacent to tumor cell clusters but not in the tumor cells themselves. The degree of positive PDGF beta-receptor expression in the carcinoid tissues seems to correlate positively with the presence of macrophages as determined by the monoclonal antibody anti-Leu-M5, but not with other infiltrated lymphocytes identified with the monoclonal antibody anti-Leu-4, or with anti-HLA-DR antibodies. Stromal cells adjacent to tumor cells, including small capillaries, stained more strongly than the stromal cells which were distant from tumor cell clusters. Furthermore, carcinoid tumor metastases from lymph nodes as well as from liver showed stronger immunoreactivity in the stromal cells with the PDGF beta-receptor antibody than the corresponding primary tumors. Our data suggest that carcinoid tumor cells may directly or indirectly induce expression of PDGF beta-receptor on adjacent stromal cells in the tumor tissue, which may contribute to the fibrosis that is often seen around carcinoid tumors.
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PMID:Expression of platelet-derived growth factor beta-receptors on stromal tissue cells in human carcinoid tumors. 215 46

Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.
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PMID:Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy. 1118 30

Pilocytic astrocytomas are the most common childhood glioma. Most children with pilocytic astrocytomas survive many years with their tumor, but alternative treatment approaches are needed for those with refractory or metastatic disease. Signaling by the platelet-derived growth factor tyrosine kinase receptor pathways have been postulated to contribute to the development of gliomas. The authors treated a single patient with refractory, metastatic pilocytic astrocytoma with the tyrosine kinase inhibitor imatinib mesylate and observed marked, transient regression of tumor during treatment. Immunohistochemistry was used to assess expression of reported target genes of imatinib mesylate in this patient's tumor tissue and of the PDGFR in pilocytic astrocytomas from 19 other patients. Immunohistochemistry showed that the patient's tumor cells did not express any of the reported target molecules inhibited by imatinib mesylate. PDGFR expression was detected in tumor vasculative in the panel of 20 tumors, and not in the tumor cells. The authors suggest that the PDGFR-signaling pathway postulated to contribute to the development of gliomas in adults might not contribute to pilocytic astrocytomas in children, and that treatment with imatinib mesylate should be considered in patients with refractory pilocytic astrocytoma.
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PMID:Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (STI-571, Gleevec): a case report and laboratory investigation. 1290 20

Prostate adenocarcinoma metastasizes to the skeleton more frequently than any other organ. An underlying cause of this phenomenon may be the ability of bone-produced factors to specifically select disseminated prostate cancer cells that are susceptible to their trophic effects. Platelet-derived growth factor (PDGF), a potent mitogen for both normal and tumor cells, is produced in several tissues including bone, where it is synthesized by both osteoblasts and osteoclasts. Here, we show that PDGF causes a significantly stronger activation of the Akt/PKB survival pathway in bone-metastatic prostate cancer cells compared to nonmetastatic cells. Normal prostate epithelial cells and DU-145 prostate cells, originally derived from a brain metastasis, are not responsive to PDGF. In contrast, epidermal growth factor stimulates Akt to the same extent in all prostate cells tested. This difference in PDGF responsiveness depends on the higher expression of alpha-PDGFR in bone-metastatic compared to nonmetastatic prostate cells and the lack of alpha-PDGFR expression in normal and metastatic prostate cells derived from tissues other than bone. Thus, alpha-PDGFR expression might identify prostate cancer cells with the highest propensity to metastasize to the skeleton.
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PMID:Bone-metastatic potential of human prostate cancer cells correlates with Akt/PKB activation by alpha platelet-derived growth factor receptor. 1600 72

The conventional form of renal cell carcinoma (RCC) is a highly vascular tumour with an extremely poor prognosis in the presence of metastases. Significant progress has recently been made in the understanding of the molecular mechanisms leading to the vascular phenotype of renal cancer In particular, VHL disease constitutes a useful study model, as inactivation of the VHL gene leads to accumulation of HIF factor, inducing activation of genes such as: VEGF, PDGF, EPO, CaIX and TGF-alpha. The fact that VHL inactivation has been found in about 70% of sporadic renal cancers constitutes the best rationale to target the products of these genes. Candidate drugs currently target VEGF, VEGFR, PDGFR and tyrosine kinase receptors, which are necessary for intracellular signal transduction. The preliminary results of phase II trials in metastatic renal cancer, usually as second-line therapy, are very encouraging. The results of phase III trials will soon be available, but many studies are already evaluating these drugs either as first-line or in combination. Urologists have an opportunity to become familiar with these drugs by actively participating in trials of adjuvant therapy that will be initiated in the near future.
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PMID:[Molecular pathways of tumour angiogenesis and new targeted therapeutic approaches in renal cancer]. 1673 53

Metastasis is the major cause of cancer morbidity, but strategies for direct interference with invasion processes are lacking. Dedifferentiated, late-stage tumor cells secrete multiple factors that represent attractive targets for therapeutic intervention. Here we show that metastatic potential of oncogenic mammary epithelial cells requires an autocrine PDGF/PDGFR loop, which is established as a consequence of TGF-beta-induced epithelial-mesenchymal transition (EMT), a faithful in vitro correlate of metastasis. The cooperation of autocrine PDGFR signaling with oncogenic Ras hyperactivates PI3K and is required for survival during EMT. Autocrine PDGFR signaling also contributes to maintenance of EMT, possibly through activation of STAT1 and other distinct pathways. Inhibition of PDGFR signaling interfered with EMT and caused apoptosis in murine and human mammary carcinoma cell lines. Consequently, overexpression of a dominant-negative PDGFR or application of the established cancer drug STI571 interfered with experimental metastasis in mice. Similarly, in mouse mammary tumor virus-Neu (MMTV-Neu) transgenic mice, TGF-beta enhanced metastasis of mammary tumors, induced EMT, and elevated PDGFR signaling. Finally, expression of PDGFRalpha and -beta correlated with invasive behavior in human mammary carcinomas. Thus, autocrine PDGFR signaling plays an essential role during cancer progression, suggesting a novel application of STI571 to therapeutically interfere with metastasis.
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PMID:Autocrine PDGFR signaling promotes mammary cancer metastasis. 1674 76

Cancer of unknown primary site (CUP) ranks as the fourth most common cause of cancer deaths. Regression of the primary, early development of systemic metastases and resistance to therapy are hallmarks of this heterogeneous clinical entity. Targeted therapy offers promise for improvement of outcome of such patients, but it is currently hindered by lack of known molecular targets on which tumours are dependent for growth. In this review, we present the gene and protein profiling studies done on expression of oncogenes, tumour-suppressor genes and angiogenesis effectors and discuss the therapeutic potential of developed targeted agents. Existing data show occasional overexpression of Ras, BCL2 oncoproteins, absence of active EGFR/c-KIT/PDGFR signalling, uncommon presence of tumour-suppressor gene mutations and highly active angiogenesis in CUP. High-throughput multi-gene, multi-protein platforms offer promise for unravelling the complex molecular pathophysiology of CUP, for identification of targets suitable for modulation and ultimately hope for abrogation of its aggressive natural history.
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PMID:Perspectives for targeted therapies in cancer of unknown primary site. 1704 64

The factors regulating the bone tropism of disseminated prostate cancer cells are still vaguely defined. We report that prostate cancer cells that metastasize to the skeleton respond to human bone marrow with a robust stimulation of the phosphatidylinositol 3-kinase/Akt pathway, whereas prostate cells that lack bone-metastatic potential respond negligibly. The majority of this Akt activation is dependent on alpha-platelet-derived growth factor receptor (alpha-PDGFR) signaling, which was shown using the small-molecule inhibitor of PDGFR signaling AG1296. Low concentrations of PDGF-AA and PDGF-BB found in bone marrow aspirates, which were detected by ELISA, do not account for the high levels of alpha-PDGFR signaling. Additionally, neutralizing PDGF binding using a alpha-PDGFR-specific antibody (IMC-3G3) failed to produce a significant inhibition of bone marrow-induced Akt activation. However, the inhibitory effect of IMC-3G3 rivaled that of AG1296 when incubation was done under conditions that stimulated alpha-PDGFR internalization. We conclude that alpha-PDGFR is activated by multiple soluble factors contained within human bone marrow, in addition to its natural ligands, and this transactivation is dependent on receptor localization to the plasma membrane. Therefore, alpha-PDGFR expression may provide select prostate phenotypes with a growth advantage within the bone microenvironment.
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PMID:Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the alpha-platelet-derived growth factor receptor. 1723 63

Gastrointestinal stromal tumors have until recently had a uniformly poor prognosis with lack of effective drug therapies. These tumors usually have activating mutations in either KIT or PDGFR-alpha tyrosine kinase receptors. Over the past decade, imatinib (Gleevec), a selective tyrosine kinase inhibitor has become the standard of care for the first-line treatment of patients with unresectable and metastatic disease. For patients with imatinib-resistant disease or intolerant to the side effects of imatinib, sunitinib (Sutent), a multitargeted tyrosine kinase inhibitor was recently approved. For earlier-stage disease, status post-complete surgical excision, preliminary data seem encouraging for the role of adjuvant imatinib in prolonging patients' disease-free interval. The impact of neoadjuvant drug therapy needs to be further classified and explored. With additional evaluation of other tyrosine kinase inhibitors and novel therapies against other molecular markers, the treatment paradigm for this malignancy should continue to evolve.
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PMID:New therapeutic options in gastrointestinal stromal tumors. 1840 63

NSCLC cells with a mesenchymal phenotype have shown a marked reduction in sensitivity to EGFR inhibitors, though the molecular rationale has remained obscure. Here we find that in mesenchymal-like tumor cells both tyrosine phosphorylation of EGFR, ErbB2, and ErbB3 signaling networks and expression of EGFR family ligands were decreased. While chronic activation of EGFR can promote an EMT-like transition, once having occurred EGFR family signaling was attenuated. We investigated the mechanisms by which mesenchymal-like cells bypass EGFR signaling and acquire alternative routes of proliferative and survival signaling. Mesenchymal-like NSCLC cells exhibit aberrant PDGFR and FGFR expression and autocrine signaling through these receptors can activate the MEK-ERK and PI3K pathways. Selective pharmacological inhibition of PDGFR or FGFR receptor tyrosine kinases reduced cell proliferation in mesenchymal-like but not epithelial NSCLC cell lines. A metastable, reversible EMT-like transition in the NSCLC line H358 was achieved by exogenous TGFbeta, which served as a model EMT system. The H358/TGFbeta cells showed many of the attributes of established mesenchymal-like NSCLC cells including a loss of cell-cell junctions, a loss of EGF-family ligand expression, a loss of ErbB3 expression, increased EGFR-independent Mek-Erk pathway activation and reduced sensitivity to EGFR inhibition. Notably an EMT-dependent acquisition of PDGFR, FGFR and TGFbeta receptors in H358/TGFbeta cells was also observed. In H358/TGFbeta cells both PDGFR and FGFR showed functional ligand stimulation of their intrinsic tyrosine kinase activities. The findings of kinase switching and acquired PDGFR and FGFR signaling suggest investigation of new inhibitor combinations to target NSCLC metastases.
Clin Exp Metastasis 2008
PMID:Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. 1869 32


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