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)

Although gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal neoplasm of the gastrointestinal tract, until recently it has been an obscure disease. Now, there is widespread scientific and clinical interest in GIST because its principal pathogenetic defect has been identified and a specific molecular inhibitor of GIST has been developed. Most GISTs contain a gain-of-function mutation in the c-kit proto-oncogene. Mutation results in constitutive activation of the Kit receptor tyrosine kinase, which induces cellular proliferation. STI571 is an oral agent that selectively inhibits Kit. It is a landmark development in cancer treatment and marks a new era of targeted molecular therapy. Its efficacy proves that a specific inhibitor can counteract the effects of a genetic defect responsible for neoplasia. Although STI571 was first applied to GIST only 2 years ago, it has already revolutionized the treatment of patients with metastatic disease and is also currently being tested as an adjuvant therapy after the resection of primary GIST.
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PMID:The GIST of targeted cancer therapy: a tumor (gastrointestinal stromal tumor), a mutated gene (c-kit), and a molecular inhibitor (STI571). 1241 3

Neuroblastoma is the most frequent solid extracranial neoplasm of childhood, with a median age of presentation of under 2 years. This tumour is highly malignant in patients older than 12 months of age with metastatic disease. Clinical studies have confirmed that amplification of the MYCN proto-oncogene is one of the best prognostic indicators of poor outcome. Approximately 30% of neuroblastoma tumours present MYCN amplification at diagnosis. Far less is known about the incidence and consequences of overrepresentation of the gene due to duplication or rearrangement of the chromosome arm in which the gene is situated. This study has analysed 110 neuroblastomas by FISH and has detected a gain of 1-3 copies per cell of MYCN in 8% of MYCN-non-amplified tumours. In these primary tumours, cells gained small numbers of additional MYCN genes by two mechanisms: formation of an isochromosome 2p, or an unbalanced translocation involving the short arm of chromosome 2 (with MYCN) and various partner chromosomes. Quantitative RT-PCR showed three- to seven-fold elevated MYCN expression in three tumours. Although the follow-up time to date is still short, clinical outcome suggests that low-level overexpression of the MYCN gene does not enhance tumour aggressiveness and rapidity of disease progression, as is often seen in neuroblastoma with MYCN amplification. It is hypothesized that the small elevation in MYCN expression could alter the regulation of apoptosis, as has been shown in experimental models.
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PMID:MYCN gene overrepresentation detected in primary neuroblastoma tumour cells without amplification. 1243 19

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The concept of GIST and the definition of GIST pathology have evolved greatly over the past 5 years. GIST has been shown to share immunohistochemical, ultrastructural and histogenic similarities with the interstitial cells of Cajal. Both GIST and the interstitial cells of Cajal express KIT, the receptor tyrosine kinase that is the protein product of the c-kit proto-oncogene. KIT is universally phosphorylated in GISTs. Sequencing of c-kit complementary DNA from human GIST cells has demonstrated a high frequency of mutations that lead to constitutive activation of the KIT tyrosine kinase in the absence of stimulation by its physiologic ligand (stem cell factor). This, in turn, causes uncontrolled stimulation of downstream signaling cascades with aberrant cellular proliferation and resistance to apoptosis. Historically, malignant GIST has been highly refractory to conventional cytotoxic therapy. Signal transduction inhibition as cancer therapy was first tested successfully with imatinib mesylate (formerly known as STI571), a selective small-molecule tyrosine kinase inhibitor, with the initial target being blockade of Bcr-Abl, the oncogene with tyrosine kinase activity responsible for the pathogenesis of chronic myelogenous leukemia (CML). Imatinib was subsequently shown to block activity of the KIT tyrosine kinase as well, and in laboratory studies this led to apoptotic death of GIST cells. The first GIST patient to receive imatinib exhibited dramatic benefit despite far-advanced metastatic disease that was previously refractory to all chemotherapy. Subsequently, multicenter clinical trials have been performed to assess the safety, efficacy and biologic activity of imatinib in patients with advanced GIST. The results from these studies have established imatinib as an effective new therapeutic alternative for the majority of patients with advanced GIST, a solid tumor for which no prior chemotherapy has ever shown antitumor efficacy. This work provides proof of concept to the hypothesis that selective inhibition of aberrant signal transduction can provide important anticancer activity, if the proper signaling pathways are identified and blocked.
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PMID:Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571). 1252 73

The clinical significance of microscopic papillary thyroid carcinoma (PTCa) is controversial. Many authors think that microscopic PTCa (<1 cm) have the same pathogenetic origin as clinically sized papillary carcinomas (>1 cm). Despite the fact that all clinical risk prognostication schemes have the size of the tumor as a primary category, small tumors do have malignant potential and can metastasize. There is growing evidence that small PTCa have the molecular translocations between the proto-oncogene RET and various activating partner genes that are characteristic of clinically sized PTCa. This study used a microdissection and genotyping assay to study the patterns of loss of heterozygosity of tumor suppressor genes in microscopic and clinically sized PTCa. Our results indicate that all PTCa harbor mutations with similar frequencies and distribution patterns, regardless of the size of the tumor. These data are further evidence that microscopic and clinically sized PTCa are pathogenetically related.
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PMID:Microscopic papillary thyroid carcinoma compared with clinical carcinomas by loss of heterozygosity mutational profile. 1254 61

The proto-oncogene c-kit is a transmembrane-tyrosine-kinase receptor that is structurally related to the platelet-derived growth-factor receptor (PDGFR) and is involved in cell differentiation. C-kit has been found to be expressed in certain solid tumors and may play a role in their tumorigenesis. Recently, a tyrosine-kinase inhibitor specific for the PDGFR family, bcr-abl, and c-kit (STI571) has been reported to have therapeutic effects in tumors expressing the aberrant forms or high quantities of target proteins. Expression of c-kit has not been well evaluated in endometrial adenocarcinomas. In this study, c-kit immunoreactivity was evaluated on paraffin sections of 72 endometrial adenocarcinomas (57 endometrioid, 10 serous, and 5 clear cell) with a polyclonal antibody. Immunoreactivity of c-kit was analyzed semiquantitatively and correlated with various clinicopathologic factors. Cytoplasmic c-kit immunoreactivity was detected in 42 (58%) tumors. Thirty-four (60%) endometrioid, 8 (80%) serous, and 0 of the 5 clear-cell adenocarcinomas were c-kit positive. There was a significant correlation between c-kit positivity and the depth of myometrial invasion. Patients with c-kit-positive endometrial adenocarcinomas more frequently had metastases and shorter disease-free survival. Expression of c-kit may be a potentially adverse prognostic feature in endometrial adenocarcinoma. Patients with c-kit-positive advanced endometrial adenocarcinoma might benefit from tyrosine-kinase-inhibitor therapy.
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PMID:C-kit immunoreactivity in endometrial adenocarcinomas and its clinicopathologic significance. 1264 69

Uterine malignant stromal tumors are rare neoplasms characterized by fatal prognosis. At the moment no effective systemic treatment is available for metastases or recurrent disease. The drugs employed in advanced neoplasms are iposfamide, doxorubicin or epidoxorubicin, but the clinical response to chemotherapy is poor. Recent studies have shown that cells in gastrointestinal stromal tumors express a growth factor receptor with tyrosine kinase activity termed c-kit. Lately reports of efficacy of a specific anticancer drug with imatinib (ST1571) based on specific molecular abnormalities of proto-oncogene c-kit present in gastrointestinal stromal tumors induced us to identify the c-kit phenotype also in uterine leiomyosarcomas. These data may be useful for treating metastatic uterine leiomyosarcomas with increased c-kit kinase activity.
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PMID:C-kit expression in uterine leiomyosarcomas: an immunocytochemical study of 29 cases of malignant smooth muscle tumors of the uterus. 1267 20

A metastatic renal cell carcinoma (RCC) tumor model xenograft that expresses the targetable, membrane-bound tumor-associated antigen carbonic anhydrase type 9 (CA IX) is described. The xenograft, established from a high-grade type-2 chromophil RCC (cRCC), has been serially transplanted in immune compromised mice, in which it grows orthotopically under the renal capsule, doubling its size every 9 weeks and sending metastases to the lung and liver at approximately 20 weeks. Tumors were capable of being imaged using a micro-PET (micro-positron emission tomograph) with an 18-fluorodeoxyglucose (18-FDG) tracer. Subsequent xenograft generations have conserved immunohistochemical and ultrastructural properties typical for malignant renal epithelium-derived neoplasia (vimentin+, CK-19+, CA IX+ with hypoxia-inducible factor (HIF)-1 alpha constitutive expression) and have demonstrated extensive proliferation, lack of apoptosis, severe genetic alterations, and molecular expression alterations; transforming growth factor beta 1 (TGF-beta 1), hepatocyte growth factor (HGF), proto-oncogene (c-met), matrix metalloproteinase (MMP)-1, and vascular endothelial growth factor (VEGF) C and D were overexpressed, whereas human epidermal growth factor receptor (HER)-2, MMP-2 and MMP-9, VEGF-R3, p53, and p27 were severely down-regulated, suggesting a proangiogenic environment, local invasiveness, and facilitated lymphatic metastasis. Altogether, LABAZ1 provides a relevant and flexible model to study the biology of cRCC, the role of CA IX in RCC tumorigenesis, progression, and metastasis, and a platform for testing new targeted therapeutic strategies.
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PMID:LABAZ1: A metastatic tumor model for renal cell carcinoma expressing the carbonic anhydrase type 9 tumor antigen. 1294 20

The proto-oncogene, c-src, has been implicated in the tumorigenesis in breast cancer. However, the relationship of c-src with distant metastasis is unclear. Moreover, the role of c-src in organ-preferential metastasis of breast cancer is unknown. Because breast cancer has a strong predilection for metastasizing to bone, we examined the role of c-src in bone metastases using an animal model in which inoculation of the MDA-231 human breast cancer cells into the left cardiac ventricle preferentially developed osteolytic bone metastases in female nude mice. A clone of the MDA-231 with the increased capacity of bone metastasis exhibited elevated c-src tyrosine kinase (TK) activity compared with parental cells. MDAsrc527 cells caused significantly increased size of the osteolytic bone metastases with increased number of osteoclasts and mitotic cancer cells compared with MDA-231EV or MDAsrcWT. In contrast, MDAsrc295 cells caused impaired metastases to bone. Of note, mice inoculated with MDAsrc295 cells via tail vein developed reduced lung metastases and prolonged survival compared with mice with MDA-231EV cells, suggesting that c-src TK is unlikely to play a specific role in bone metastases. The growth in vitro and in vivo and production of parathyroid hormone-related protein, a key cytokine in the pathogenesis of osteolytic bone metastases in breast cancer, were promoted in MDAsrc527 and diminished in MDAsrc295. These results suggest that c-src TK is associated with the capacity of breast cancer to metastasize to bone through regulating cell growth and parathyroid hormone-related protein production. Our results together with the fact that c-src is an essential molecule for bone resorption by osteoclasts, which are central players in osteolytic bone metastases, support the notion that c-src TK is a potential target molecule for designing novel therapeutic interventions, especially for bone metastases in breast cancer.
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PMID:C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. 1294 30

To evaluate the relationship between the c-kit proto-oncogene product and malignant transformation of human breast tissue, we examined the immunohistochemical expression of the c-kit proto-oncogene product in both malignant and non-malignant breast tissues. The immunohistochemical expression of the c-kit proto-oncogene product in 40 primary breast cancer tissues (22 axillary lymph nodes negative, 18 lymph nodes positive), in 18 corresponding axillary lymph nodes, and in 10 distant metastastic tissues were studied using an anti-c-kit proto-oncogene product antibody in comparison with 20 normal and 20 benign breast tissues. The mean values of immunoreactive score (IRS) were compared. The IRS of the c-kit proto-oncogene product in normal mammary epithelia was 5.90 +/- 1.37 (mean +/- s.d.). In benign tissues, the c-kit proto-oncogene product was detected heterogeneously with a reduced IRS (4.05 +/- 1.82). In primary breast cancer tissues, the expression of the c-kit proto-oncogene product was often deleted and the average IRS (0.90 +/- 1.73) was significantly reduced compared to those of the normal breast tissues or benign breast disease tissues, but no significant difference was shown between the breast cancer groups. The c-kit proto-oncogene product may correlate with growth control or the differentiation of normal breast epithelium. This result suggests that the loss of expression of this protein might correlate with malignant breast cancer progression, but it is most likely involved at an early stage of human breast cancer development.
Clin Exp Metastasis 2003
PMID:The meaning of the c-kit proto-oncogene product in malignant transformation in human mammary epithelium. 1466 90

Colorectal tumorigenesis has been associated with the progressive acquisition of a variety of genetic alterations. These include mutations of the Ki-ras proto-oncogene in codons 12 and 13, which account for 85% of genetic changes in colorectal cancer. In murine in vitro models of oncogenic transformation, an association between ras-mediated transformation and downregulation of different components of the MHC class I antigen processing machinery (APM) has been described. In order to investigate whether this association also exists in human tumors, 10 cases of high-grade intraepithelial neoplasia (HIN), as well as primary tumors and autologous lymph node metastases from 42 patients with colorectal carcinoma, were monitored by allele-specific restriction analysis for Ki-ras mutations. In parallel, APM component expression and tumor cell proliferation were analyzed by immunohistochemistry. In comparison to autologous colorectal mucosa, TAP1, LMP2 and tapasin loss was found in 68%, 67% and 80% of HIN, respectively. In contrast, impaired TAP1, LMP2 and tapasin expression was found in 42%, 42% and 63% of primary adenocarcinomas of stage III disease and in 63%, 47% and 79% of the matched lymph node metastases, respectively. More than 60% of colorectal tumor lesions with TAP1, LMP2 and/or tapasin defects displayed Ki-ras mutations. The frequency of TAP1, LMP2 and tapasin loss varied between 33% of primary adenocarcinomas, 40% of HIN to approximately 67% of metastases. These data suggest that i) APM component deficiencies occur more frequently in Ki-ras-mutated colorectal carcinoma lesions and ii) APM abnormalities in conjunction with Ki-ras mutations appear to be associated with disease stage. These findings support the hypothesis that Ki-ras mutations may contribute to immune escape mechanisms of tumors by downregulating the MHC class I APM component expression.
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PMID:MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma. 1475 Jan 79


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