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

c-Src is a proto-oncogene, belonging to the nonreceptor protein kinases family, which plays a prominent role in carcinogenesis. In this study, we tested the hypothesis that c-Src could promote breast cancer metastasis acting on several cell types and that pharmacological disruption of its kinase activity could be beneficial for the treatment of metastases. Female BALB/c-nu/nu mice were subjected to intracardiac injection of the human breast cancer cells MDA-MB-231 (MDA-231), which induced prominent bone and visceral metastases. These were pharmacologically reduced by treatment with the c-Src inhibitor [7-{4-[2-(2-methoxy-ethylamino-ethoxy]-phenyl}-5-(3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine] CGP76030 (100 mg/kg/day p.o.), resulting in decreased morbidity and lethality. Metastases were more severe in mice injected with MDA-231 cells stably transfected with wild-type c-Src (MDA-231-SrcWT), whereas transfection in injected cells of a c-Src kinase-dead dominant-negative construct (MDA-231-SrcDN) resulted in reduced morbidity, lethality, and incidence of metastases similar to the mice treated with the inhibitor. An analogous beneficial effect of c-Src inhibition was observed in subcutaneous and intratibial implanted tumors. In vitro, c-Src suppression reduced MDA-231 cell aggressiveness. It also impaired osteoclast bone resorption both directly and by reducing expression by osteoblasts of the osteoclastogenic cytokines interleukin-1beta and interleukin-6, whereas parathyroid hormone-related peptide was not implicated. c-Src was also modestly but consistently involved in the enhancement of endothelial cell proliferation in vitro and angiogenesis in vivo. In conclusion, we propose that c-Src disruption affects the metastatic process and thus is a therapeutic target for the treatment of breast cancer.
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PMID:Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. 1662 50

The current therapy of uveal melanoma (UM) metastases remains inefficient, which warrants the development of new treatment modalities. For the first time we investigated the effects of retinoic acid (RA) on a panel of UM cell lines and found that RA induces morphological changes compatible with differentiation, suppresses proliferation and causes apoptosis in these cells. RA treatment resulted in an increase of p21, p27 and p53 protein levels and G1 arrest in UM cells, which correlated with significant down-modulation of surface Her2/neu proto-oncogene expression. In addition, RA-treated UM cells exhibited increased sensitivity to both MHC class I-restricted killing by cytotoxic T lymphocytes and NK cell-mediated lysis that were accompanied by more efficient conjugate formation between UM cells and killer lymphocytes. Taken together, our results implicate UM as a new target for treatment with retinoids and suggest that retinoids and T- or NK-cell based immunotherapy can have mutually enhancing effects in UM patients.
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PMID:Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells. 1675 55

Endothelin (ET) is a peptide released by vascular endothelial cells. Except for the potent vasoconstrictor function it plays an important physiological role in tissue differentiation and development, cell proliferation and hormone production. Investigation of the role of ET axis in a variety of tumors such as prostatic, cervical, breast carcinoma has provided evidences of its importance in cancer, recently. Data suggest that multiple functions of the ET axis have associations with mitogenesis, apoptosis inhibition, angiogenesis, and activation of proto-oncogene. The ET axis relates to invasiveness, osteoblast function, and metastatic cancer pain in advanced prostate cancer.
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PMID:[Roles of endothelin and its receptors in prostate cancer]. 1675 81

Metastasis follows the inappropriate activation of a genetic programme termed invasive growth, which is a physiological process that occurs during embryonic development and post-natal organ regeneration. Burgeoning evidence indicates that invasive growth is also executed by stem and progenitor cells, and is usurped by cancer stem cells. The MET proto-oncogene, which is expressed in both stem and cancer cells, is a key regulator of invasive growth. Recent findings indicate that the MET tyrosine-kinase receptor is a sensor of adverse microenvironmental conditions (such as hypoxia) and drives cell invasion and metastasis through the transcriptional activation of a set of genes that control blood coagulation.
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PMID:Invasive growth: a MET-driven genetic programme for cancer and stem cells. 1686 93

Papillary renal cell carcinoma is a rare type of renal malignancy. Cytogenetic findings characteristic for this tumor have been described as well as mutations of the proto-oncogene c-met. Secondary malignancies occurring together with papillary renal cell carcinomas are rare, and are often of genitourinary tract origin. We describe two cases of papillary renal cell carcinoma occurring in association with two other visceral malignancies, gastrointestinal stromal tumor and colon adenocarcinoma.Two cases of papillary renal cell carcinoma diagnosed by fine-needle aspiration (FNA), occurring in association with gastrointestinal malignancies were reviewed. Both aspirates showed cytologic features characteristic for papillary renal cell carcinoma, namely papillary structures, foamy histiocytes, intracytoplasmic hemosiderin, and nuclear grooves. Subsequent histology and immunohistochemical stains supported the cytologic diagnosis. The histologic diagnosis of gastrointestinal stromal tumor and colon adenocarcinoma were confirmed. Papillary renal cell carcinoma is a type of renal carcinoma that can be often accurately diagnosed by FNA. The occurrence of associated visceral malignancies has never been reported. The possible role of the protooncogene c-met in the development of these tumors was explored.
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PMID:Fine-needle aspiration cytology of papillary renal cell carcinoma: the association with concomitant secondary malignancies. 1711 41

We have previously demonstrated the use of pyrosequencing to investigate NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] mutations in melanoma biopsies. Here, we expanded the analysis to include BRAF (V-raf murine sarcoma viral oncogene homolog B1), another member of the Ras-Raf-mitogen-activated protein kinase (MAPK) signalling pathway, and analysed a total of 294 melanoma tumours from 219 patients. Mutations in BRAF exons 11 and 15 were identified in 156 (53%) tumours and NRAS exon 2 mutations in 86 (29%) tumours. Overall, mutations in NRAS or BRAF were found in 242 of 294 tumours (82%) and were found to be mutually exclusive in all but two cases (0.7%). Multiple metastases were analysed in 57 of the cases and mutations were identical in all except three, indicating that BRAF and NRAS mutations occur before metastasis. Association with preexisting nevi was significantly higher in BRAF mutated tumours (P=0.014). In addition, tumours with BRAF mutations showed a significantly more frequent moderate to pronounced infiltration of lymphocytes (P=0.013). NRAS mutations were associated with a significantly higher Clark level of invasion (P=0.022) than BRAF mutations. Age at diagnosis was significantly higher in tumours with NRAS mutations than in those with BRAF mutations (P=0.019). NRAS and BRAF mutations, however, did not influence the overall survival from time of diagnosis (P=0.7). In conclusion, the separate genotypes were associated with differences in several key clinical and pathological parameters, indicating differences in the biology of melanoma tumours with different proto-oncogene mutations.
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PMID:NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. 1711 47

The ability of the thyroid to accumulate iodide provides the basis for radioiodine ablation of differentiated thyroid cancers and their metastases. Most thyroid tumours exhibit reduced iodide uptake, although the mechanisms accounting for this remain poorly understood. Pituitary tumour transforming gene (PTTG) is a proto-oncogene implicated in the pathogenesis of thyroid tumours. We now show that PTTG and its binding factor PBF repress expression of sodium iodide symporter (NIS) messenger RNA (mRNA), and inhibit iodide uptake. This process is mediated at least in part through fibroblast growth factor-2. In detailed studies of the NIS promoter in rat FRTL-5 cells, PTTG and PBF demonstrated specific inhibition of promoter activity via the human upstream enhancer element (hNUE). Within this approximately 1 kb element, a complex PAX8-upstream stimulating factor 1 (USF1) response element proved critical both to basal promoter activity and to PTTG and PBF repression of NIS. In particular, repression by PTTG was contingent upon the USF1, but not the PAX8, site. Finally, in human primary thyroid cells, PTTG and PBF similarly repressed the NIS promoter via hNUE. Taken together, our data suggest that the reported overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the efficacy of radioiodine treatment.
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PMID:PTTG and PBF repress the human sodium iodide symporter. 1729 75

Metastasis, the cardinal feature of malignant tumors, is an important clinical variable in patient prognosis. To understand the basis for metastasis, we systematically selected for highly invasive cells from breast cancer cell lines, MCF7 and MDA-MB-453, with moderate to low invasive ability using Boyden chamber invasion assay. The four-cycle selected invasive lines, named MCF7-I4 and MDA-MB-453-I4, respectively, displayed epithelial-mesenchymal transition (EMT) and dramatically enhanced invasive ability. EMT changes were corroborated with decreased level of E-cadherin and increased vimentin, fibronectin, and beta(1) integrin. Twist, a basic helix-loop-helix transcription factor, and AKT2, a known proto-oncogene, were found to be elevated in the invasive cells compared with the parental. Ectopic expression and knockdown of Twist by short interference RNA resulted in significant increase and reduction, respectively, of AKT2 protein and mRNA expression. Twist bound to E-box elements on AKT2 promoter and enhanced its transcriptional activity. Moreover, silencing AKT2 decreased Twist-promoted migration, invasion, and paclitaxel resistance. Reintroducing AKT2 largely rescued the phenotype resulted from knockdown of Twist in I4 cells, suggesting that AKT2 is a downstream target and functional mediator of Twist. Finally, we observed a 68.8% correlation of elevated Twist and AKT2 expression in late-stage breast cancers as oppose to 13% in early-stage breast cancers. Our study identifies Twist as a positive transcriptional regulator of AKT2 expression, and Twist-AKT2 signaling is involved in promoting invasive ability and survival of breast cancer cells.
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PMID:Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. 1733 25

Most sporadic gastrointestinal stromal tumors (GISTs) occur solitary, whereas a multicentric appearance is suspicious for a familial or syndromal setting such as with germline mutations of proto-oncogene tyrosine protein kinase Kit (KIT) or platelet derived growth factor receptor alpha (PDGFRA), or even for metastases. The aim of this study was to evaluate whether multicentric sporadic GISTs are of clonal origin. Four patients with 1 clinically apparent tumor (mean size 5.6 cm) and 1 to 3 further small incidental tumors (mean size 0.7 cm) were analysed by mutation analysis and comparative genomic hybridization for mutations of KIT and PDGFRA and chromosomal imbalances in their tumors. No clinicopathologic features have been found being indicative of one of the established familial or syndromal GIST variants. Each of the small GISTs were localized in the muscularis propria, and were visible from the serosal but not from the mucosal side. Different mutations of KIT and PDGFRA were present among individual tumors of each patient, and germline mutation of KIT and PDGFRA could be excluded. Comparative genomic hybridization revealed a mean count of 7 chromosomal imbalances in the clinically apparent tumors compared with a mean count of 0.3 in the small incidental counterparts. Sporadic GISTs can appear multicentric by coincidence. They are an important differential diagnosis to familial and syndromal GIST variants, or even to peritoneal metastases. Different mutations of KIT and PDGFRA among individual tumors in 1 patient refer to different clonal origin of multicentric sporadic GISTs. The type of mutation of KIT and PDGFRA was independent of tumor size, whereas small GISTs <1 cm rarely had genomic imbalances.
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PMID:Multicentric sporadic gastrointestinal stromal tumors (GISTs) of the stomach with distinct clonal origin: differential diagnosis to familial and syndromal GIST variants and peritoneal metastasis. 1752 83

In general, the development of CNS metastases of breast cancer depends on several prognostic factors, including younger age and a negative hormone receptor status. Also, the presence of a breast cancer 1, early onset (BRCA1) germline mutation and expression of the human epidermal growth factor receptor 2 (Her2/neu) proto-oncogene seem to contribute to an increased rate of development of CNS metastases. The choice of appropriate therapy for brain metastases also depends on prognostic factors, including the age of the patient, the Karnofsky performance score, the number of brain metastases and the presence of systemic disease. Surgery followed by whole brain radiation therapy (WBRT) is generally restricted to ambulant patients with a single brain metastasis without active extracranial disease. In patients who have two to four metastases, stereotactic focal radiotherapy (i.e. radiosurgery) with or without WBRT is usually indicated. In the remainder of patients, WBRT alone provides adequate palliation. Although breast carcinoma is sensitive to chemotherapy, the role of chemotherapy in the treatment of brain metastases is still unclear. Objective responses after cyclophosphamide-based therapies were reported in studies performed in the 1980s. Subgroup analysis of data from a randomised study indicates that survival may improve if WBRT is combined with the radiosensitiser efaproxiral. Interestingly, the Her2/neu antibody trastuzumab, which does not cross the blood-brain barrier, produces systemic responses and enhanced survival, without a clear effect on brain metastases. Breast cancer constitutes the most common solid primary tumour leading to leptomeningeal disease. Clinical symptoms such as cranial nerve dysfunction or a cauda equina syndrome can be treated with local radiotherapy. A randomised study in patients with leptomeningeal disease secondary to breast cancer has revealed that intrathecal chemotherapy is associated with substantially more adverse effects than non-intrathecal treatment, without a clear benefit in terms of response or survival. Intramedullary metastasis is rare but often presents with a rapidly progressive myelopathy. Local radiotherapy may preserve neurological function. Epidural spinal cord metastasis occurs in approximately 4% of patients and can lead to paraplegia. A randomised study has shown that surgical intervention together with local radiotherapy is superior to local radiotherapy alone.
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PMID:CNS complications of breast cancer: current and emerging treatment options. 1757 99


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