Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mammary phyllodes tumors are uncommon stromal neoplasms, and are divided into benign, borderline and malignant groups basing on histologic criteria. While benign phyllodes tumors may recur, borderline phyllodes tumors show higher propensity to recur locally and rarely metastasize, and malignant phyllodes tumors show even higher chances of local recurrences or distant metastases. c-kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117) and is a marker for gastrointestinal stromal tumors (GIST). With the advent of therapeutic agent targeted at this receptor for GIST, we investigated 179 phyllodes tumors (101 benign, 50 borderline, 28 malignant) for c-kit expression using immunohistochemistry. The staining was compared to the degree of malignancy, and to the degree of stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. The overall positive rate for c-kit was 29% (52/179) and 17% (17/101), 24% (12/50) and 46% (13/28), respectively, for benign, borderline malignant and frank malignant phyllodes and the differences between all categories were significant (chi2=13.844, P=0.001). In mammary phyllodes tumors, there was increasing c-kit expression with increasing degree of malignancy, up to 46% in malignant cases. This provides strong evidence that c-kit receptor mediated tyrosine kinase involvement in the pathogenesis of phyllodes tumors, and the therapeutic agent, STI571, Glivec, may be a potentially useful drug for its management.
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PMID:Increased c-kit (CD117) expression in malignant mammary phyllodes tumors. 1504 24

CD1d-restricted Valpha24-Jalpha18-invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. However, little is known about their localization to tumors. We analyzed 98 untreated primary neuroblastomas from patients with metastatic disease (stage 4) for tumor-infiltrating iNKTs using TaqMan((R)) reverse transcription polymerase chain reaction and immunofluorescent microscopy. 52 tumors (53%) contained iNKTs, and oligonucleotide microarray analysis of the iNKT(+) and iNKT(-) tumors revealed that the former expressed higher levels of CCL2/MCP-1, CXCL12/SDF-1, CCL5/RANTES, and CCL21/SLC. Eight tested neuroblastoma cell lines secreted a range of CCL2 (0-21.6 ng/ml), little CXCL12 (</=0.1 ng/ml), and no detectable CCL5 or CCL21. CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001). Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody. CCL2 expression by tumors was found to inversely correlate with MYCN proto-oncogene amplification and expression (r = 0.5, P < 0.001), and MYCN-high/CCL2-low expression accurately predicted the absence of iNKTs (P < 0.001). In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2.
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PMID:Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. 1512 43

The aggressive behavior of breast cancer cells can at times be modulated by hormonal mechanisms. Exposure to glucocorticoids (GC) has been shown to stimulate the invasiveness, motility and adhesiveness of breast cancer cells containing the glucocorticoid receptor. This is largely explained by GC-associated overexpression of the c-fms proto-oncogene, which encodes the receptor for the colony stimulating factor-1 (CSF-1). Our objective is to investigate additional GC-associated genetic alterations that could modulate c-fms related malignant behavior in breast cancer cells. A microarray technique using an oligonucleotide array representing 16,700 known expressed human genes was used to analyze the gene expression profile of breast cancer cells exposed to dexamethasone (Dex) or vehicle. Results were confirmed by western blot analysis. Six genes were found to be consistently differentially overexpressed in the Dex-exposed cells compared to control. We focused on serum-glucose kinase 1 (SGK1), a serine-threonine kinase known to be involved in intracellular signal transduction pathways and induced by GC and serum. An adhesion assay was performed on extracellular matrix after exposing the breast cancer cells to Dex, CSF-1 or to Dex or CSF-1 plus LY294002, a functional inhibitor of SGK1 action. Exposure to LY294002 significantly decreased both CSF-1 and Dex-induced adhesiveness to the level of control cells. SGK1 may act as a downstream intracellular regulator of c-fms, particularly of c-fms-induced adhesiveness of breast cancer cells after exposure to GC or CSF-1. This finding may have implications for potential therapeutic interventions aimed at decreasing the aggressiveness of breast cancer cells.
Clin Exp Metastasis 2004
PMID:SGK1, a potential regulator of c-fms related breast cancer aggressiveness. 1567 45

Gastrointestinal stromal tumours (GIST) are rare neoplasms originating from connective tissue in the digestive tract with an incidence of less than 1% and account for most non-epithelial primitive digestive tumours. Metastasis diagnosed at the time of disease discovery confirms GIST malignancy. Kit protein, a trans-membrane tyrosine kinase receptor of staminal cells, is characteristically expressed by GIST. Most GIST have a mutation in the kit proto-oncogene. Resistance to conventional chemotherapy is commonly shown by malignant GIST. Most patients with advanced malignant GIST achieve clinical benefit with imatinib mesilate, an orally administered selective inhibitor of the tyrosine kinase receptor. We treated a 43-year-old male patient suffering from a gastric GIST diagnosed during a surgical emergency operation for peritonitis caused by gastric perforation. At the time of the first operation the patient had lost 10 kg body weight over the previous months and was seriously cachectic. During the emergency operation the perforation was sutured. The biopsy results showed the presence of CD1 17 (c-kit) and CD34 markers. A total body CT scan documented the substantial size of the gastric wall lesion, an increased volume of abdominal lymph nodes and compression of the splenic vein with alternative collateral circulation. The liver presented no less than 5 large metastases distributed in both the left and right lobes. There was also a pulmonary metastasis. Because of frequent spontaneous bleeding and starvation the patient was seriously anaemic. Considering the action mechanism of imatinib and the extent of the lesion we decided to perform a total gastrectomy procedure. At the time of the operation the stomach seemed to have a modified volume and shape: it appeared to be divided into two sacs, the larger and deeper of which was the original gastric cavity, while the superficial, smaller one seemed to be a protrusion of the organ. The stomach was indistinguishable from the spleen, the transverse colon and the distal pancreatic tract. The neoplasm was directly linked to the left liver and to the inferior diaphragmatic surface. We performed total gastrectomy and resection of the tail of the pancreas, the spleen, and the transverse colon all in one and the same session. The patient was discharged on postoperative day 8 and commenced imatinib therapy 30 days after the operation with 4 tablets per day. In the following months the patient repeated the CT scan to monitor the progressive volume reduction of the liver and lung lesions and a PET scan confirmed that the lesions were not active; the patient experienced a 13 kg body weight increase. One year after the operation the outcome appears to be lasting and the patient has tolerated the drug treatment well.
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PMID:[New orientations in the management of advanced, metastatic gastrointestinal stromal tumors (GIST): combination of surgery and systemic therapy with imatinib in a case of primary gastric location]. 1583 50

The cellular proto-oncogene c-src is thought to be involved in formation, progression, and metastasis of a variety of tumor cell types, although its exact role during tumor cell genesis is not well defined. v-src, the viral oncogene counterpart of c-src, causes metastatic sarcomas, hemorrhagic disease, and hemangiosarcomas in chicken embryos and, thus, can be used as a constitutively activated form of src for experimentally-induced tumorigenesis. Here, we used retroviral vectors to express wild-type v-src or SH2 or SH3 domain-deleted forms (DeltaSH2 or DeltaSH3) to determine if different pathogenic effects resulted. Vectors were injected into early chick embryo midbrain ventricles and embryos were sacrificed at various ages up to embryonic day (E) 18. Retroviral expression of all forms of v-src resulted in transformation of pial connective tissue cells into large, rounded abnormal-appearing cells. Surprisingly, all forms of v-src were lethal. The v-src retrovirus was lethal and killed most embryos by E15 with the development of hemangiosarcomas over the injection site between E10-E12. The DeltaSH3 retrovirus was the most deadly, killing most embryos by E12, however, it never resulted in hemangiosarcoma formation. The DeltaSH2 retrovirus injected embryos survived longer than v-src or DeltaSH3 embryos, and some of these embryos also developed large hemangiosarcomas over the injection site between E13 and E18. These results demonstrate that the src SH2 domain is required to be fully lethal, whereas the presence of the SH3 domain attenuated lethality. Furthermore, the formation of hemangiosarcomas absolutely required the presence of the src SH3 domain and to some extent required the SH2 domain. This implicates distinct and opposite roles for SH2 and SH3 domains of src and their cellular binding partners in tumorigenesis and hemorrhagic disease.
Clin Exp Metastasis 2005
PMID:Distinct and opposite roles for SH2 and SH3 domains of v-src in embryo survival and hemangiosarcoma formation. 1608 37

Bone sialoprotein (BSP), a major protein in the extracellular matrix of bone, is expressed almost exclusively by bone cells and by cancer cells that have a propensity to metastasize to bone. Previous studies have shown that v-src stimulates basal transcription of bsp in osteosarcoma (ROS 17/2.8) cells by targeting the inverted CCAAT element (ICE) in the proximal promoter. To identify possible downstream effectors of Src we studied the effects of the proto-oncogene c-jun, which functions downstream of Src, on basal transcription of bsp using transient transfection assays. Increased expression of endogenous c-Jun induced by the tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate and ectopic expression of c-Jun increased basal transcription of chimeric reporter constructs encompassing the proximal promoter by 1.5-3-fold in ROS 17/2.8 osteosarcoma cells, with more modest effects in a normal bone cell line, RBMC-D8. The effects of c-Jun were abrogated by mutations in the ICE box and by co-expression of dominant negative nuclear factor Y, subunit A (NF-YA). The increase in bsp transcription did not require phosphorylation of c-Jun and was not altered by trichostatin treatment or by ectopic expression of p300/CREB-binding protein (CBP) or mutated forms lacking histone acetyltransferase (HAT) activity. Similarly, ectopic expression of p300/CBP-associated factor (P/CAF), which transduces p300/CBP effects, or of HAT-defective P/CAF did not influence the c-jun effects. Surprisingly, E1A, which competes with P/CAF binding to p300/CBP, also stimulated BSP transcription through NF-Y independently of c-jun, p300/CBP, and P/CAF. Collectively, these studies show that c-Jun and E1A regulate basal transcription of bsp in osteosarcoma cells by recruiting the NF-Y transcriptional complex to the ICE box in a mechanism that is independent of p300/CBP and P/CAF HAT activities.
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PMID:Recruitment of nuclear factor Y to the inverted CCAAT element (ICE) by c-Jun and E1A stimulates basal transcription of the bone sialoprotein gene in osteosarcoma cells. 1608 80

Mutational activation of the K-Ras proto-oncogene is frequently observed during the very early stages of colorectal cancer (CRC) development. The mutant alleles are preserved during the progression from pre-malignant lesions to invasive carcinomas and distant metastases. Activated K-Ras may therefore not only promote tumor initiation, but also tumor progression and metastasis formation. Metastasis formation is a very complex and inefficient process: Tumor cells have to disseminate from the primary tumor, invade the local stroma to gain access to the vasculature (intravasation), survive in the hostile environment of the circulation and the distant microvascular beds, gain access to the distant parenchyma (extravasation) and survive and grow out in this new environment. In this review, we discuss the potential influence of mutant K-Ras on each of these phases. Furthermore, we have evaluated the clinical evidence that suggests a role for K-Ras in the formation of colorectal metastases.
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PMID:Control of colorectal metastasis formation by K-Ras. 1609 78

Although proto-oncogene expression has been shown to correlate with clinical outcome in breast carcinoma, an experimental model has not been proposed to study this phenomenon in vivo. In addition, the ability to modulate this proto-oncogene in vivo to correlate with phenotypic behavior has not been determined. Utilizing an intraperitoneal model for metastatic spread with BT20 human breast carcinoma cells, clonally expanded cells expressing five fold higher c-fms protein were compared with parent BT20 cells as well as an underexpressing clone using intrasplenic injection following left flank cut-down in female nude and Severe combined immunodeficient (SCID) mice. Athymic BALB/c nude and SCID animals were observed for clinical evidence of tumorigenicity with necropsy performed at either 50 or 80 days unless compromised earlier. Immunohistochemistry (IHC) of the harvested tumors was performed to correlate c-fms expression from its original in vitro culture to the in vivo model. At day 50, differences in primary tumor take and spread to the pelvis were already evident favoring the c-fms over-expression group with IHC of these tumors revealing significantly higher intensity of staining for c-fms, (mean H score of 205 vs. 43 in the over-expression and parent groups, respectively). At day 80, tumor take and spread was comparable; however, tumor size in the over-expression group was significantly larger than the parent and under-expressing group in both the BALB/c and SCID experiments. Modulation of c-fms proto-oncogene expression was also achieved using the anti-glucocorticoid, RU-486, via oral administration to SCID mice with subsequent correlation to IHC staining. This model thus provides tumors of significant size and organ diversity which retain their phenotype early in tumorigenesis allowing an early endpoint to assess efficacy of novel treatments.
Clin Exp Metastasis 2005
PMID:Correlation of tumor phenotype with c-fms proto-oncogene expression in an in vivo intraperitoneal model for experimental human breast cancer metastasis. 1613 73

Src, a proto-oncogene, has been strongly implicated in the growth, progression and metastasis of a number of human cancers. Its role in lung cancer is, however, still unknown. In the present study, we assessed the expression of Src in three different human lung adenocarcinoma cell lines (PC-9, PC14PE6, A549), and explored the effect of a novel Src kinase inhibitor, M475271, on the behavior of the cell lines. The three cell lines expressed various levels of auto-phosphorylated Src. While M475271 reduced Src-phosphorylation and invasiveness of all three cell lines, it inhibited the proliferation of PC-9 and A549 cells with highly phosphorylated Src, but not PC14PE6 cells. We further examined the effect of M475271 on subcutaneous tumors and lung metastasis caused by PC-9 and/or A549 cells in NK-cell depleted SCID mice. Daily oral treatment with M475271 inhibited the growth of subcutaneous tumors with PC-9 and A549 cells via inhibition of tumor cells proliferation, VEGF production and/or vascularization in the mice in a dose-dependent manner. In the metastasis model with A549 cells, the lung weight in the M475271 (50 mg/kg)-treated group was less than that of the control group, despite no difference in the number of metastatic nodules. Our results suggest that inhibition of tyrosine kinase Src by M475271 could reduce the growth, invasion and VEGF-mediated neovascularization of lung adenocarcinoma cells, resulting in inhibition of growth of subcutaneous tumors and lung metastasis. Therefore, a novel Src tyrosine kinase inhibitor, M475271, might be helpful for controlling the progression of human lung adenocarcinoma.
Clin Exp Metastasis 2005
PMID:SRC tyrosine kinase inhibitor, m475271, suppresses subcutaneous growth and production of lung metastasis via inhibition of proliferation, invasion, and vascularization of human lung adenocarcinoma cells. 1615 47

Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.
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PMID:Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor. 1636 33


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