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)

Metastasis is the leading cause of treatment failure in medulloblastoma. Understanding the genetic regulation of metastasis may aid in the development of novel treatments. We therefore performed in silico analysis of the mRNA expression of 83 medulloblastomas compiled from two independent microarray studies by focusing on 135 genes most frequently linked to metastasis in other tumors. We then asked whether expression of these genes correlated with metastasis in the medulloblastoma array data sets. We found the platelet-derived growth factor receptor alpha, early growth response protein 1 and insulin-like growth factor 2 genes as well as several genes associated with MYCC and ERBB2 overexpressed by at least 2-fold in metastatic tumors in both array data sets. We conclude that these genes may interact to promote prometastatic signaling in medulloblastoma.
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PMID:The use of gene expression analysis to gain insights into signaling mechanisms of metastatic medulloblastoma. 1284 96

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

Lymph node metastasis from gastrointestinal stromal tumor (GIST) is quite rare. We report two cases of gastric GIST with nodal metastases and results of their mutation analyses. In the first case (78-year-old male), a mass 4.0 cm in size was located at the gastric cardia. Proximal gastrectomy was performed. In the other case (40-year-old female), the gastric tumor was 2.5 cm in size. Computed tomography scan revealed a hepatic metastasis. Imatinib mesylate was administered as primary treatment, at the patient's preference, but the tumors exhibited no response. Wedge resection of the stomach and partial hepatectomy were performed. In both cases, histological examination revealed that the tumors consisted of spindle cells. In the former case, there was an isolated lymph node metastasis at the right cardia. In the latter, three of 5 sampled nodes adjacent to the tumor were positive. In both cases, immunohistochemical analyses showed that primary and metastatic tumors were diffusely positive for CD117 and CD34 and negative for desmin and S100-protein. In the former case, there was a deletion mutation in CD117 exon 11, the most common genotype in GIST. In the latter, there were no detectable mutations in CD117 or platelet-derived growth factor receptor alpha.
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PMID:Two cases of gastrointestinal stromal tumor of the stomach with lymph node metastasis. 1762 38

Synovial sarcoma (SS) is the most frequent nonrhabdomyosarcomatous soft tissue sarcoma encountered in adolescents and young adults, and despite advances in the treatment of local disease, metastases remain the main cause of death. The aim of this study was to characterize a single-center series of pediatric SS molecularly to seek any biomarkers or pathways that might make suitable targets for new agents. Seventeen cases of pediatric SS showing the SYT-SSX fusion transcript were screened immunohistochemically, biochemically, molecularly, and cytogenetically (depending on the available material) to investigate any expression/activation of epidermal growth factor receptor, platelet-derived growth factor receptor alpha (PDGFRalpha), PDGFRbeta, Akt, and deregulated Wnt pathway. The most relevant outcome was the finding of activated epidermal growth factor receptor, PDGFRalpha, and PDGFRbeta, which activated Akt in both the monophasic and biphasic histologic subtypes. Consistently, Akt activation was completely abolished in an SS cell line assay when stimulated by PDGF-AA and treated with the phosphatidylinositol 3-kinase inhibitor LY294002. Our results also showed the nuclear localization of beta-catenin and cyclin D1 gene products in monophasic SS and the movement of beta-catenin into the cytoplasm in the glandular component of the biphasic subtype. Although they need to be confirmed in larger series, these preliminary data suggest that therapeutic strategies including specific inhibitors of the phosphatidylinositol 3-kinase/Akt pathway might be exploited in SS.
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PMID:Molecular characterization of synovial sarcoma in children and adolescents: evidence of akt activation. 1863 59

We report the case of a woman with 3 different types of gastrointestinal tumors--stromal, fibrous, and fatty--and a germline defect of the platelet-derived growth factor receptor alpha (PDGFRA) gene (V561D). The patient, now 52 years old, presented in 1977 at age 22 years with a gastric tumor and a duodenal lipoma. Subsequently, she developed obstructing small intestinal fibrous tumors that required 3 laparotomies and intestinal resections. Most recently (in 2002), more than 100 fibrous tumors were resected and also multiple small intestinal lipomas and multiple gastric KIT, PDGFRalpha, and CD34-positive stromal tumors. The nosology of the fibrous tumors was not clear. The lesions were hypocellular and featured poorly outlined spindle, stellate, and polygonal CD34 positive, and KIT- and PDGFRalpha-negative cells. They extended through the muscularis propria, expanded the subserosa, and occasionally extended into the mesentery but did not metastasize. The patient is currently asymptomatic; radiologic study in June 2007 revealed postoperative changes only. None of the patient's primary relatives have had similar tumors.
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PMID:Stromal, fibrous, and fatty gastrointestinal tumors in a patient with a PDGFRA gene mutation. 1867 Mar 46

Approximately 80% of advanced metastatic gastrointestinal stromal tumors (GISTs) respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. In general, progressing GISTs retain their typical morphology. Herein, we report 5 cases of progressing metastatic GIST with heterologous rhabdomyoblastic differentiation after TKI treatment. Histologic, immunohistochemical, and mutational analyses were performed on histologically classic GISTs and components with rhabdomyoblastic differentiation. There were 3 men and 2 women (ranging from 35 to 66 y of age). Three tumors were localized at presentation (2 stomach and 1 small bowel) and 2 presented with metastases. All localized primary tumors were high risk. Two tumors showed spindle cell morphology and 3 were epithelioid, including 1 with marked pleomorphism. After resection of the 3 localized primary tumors, intra-abdominal (2 patients) and liver (1 patient) metastases developed. All patients were treated with imatinib and showed partial clinical responses (4 patient) or stable disease (1 patient). Four patients subsequently progressed; 2 patients were treated with sunitinib after progression with minor responses. Four patients underwent surgical debulking. At last follow-up (range: 20 to 87 mo), 2 patients died of disease, 2 were alive with metastatic disease resistant to TKIs, and 1 was alive without evidence of disease. In all cases, rhabdomyoblastic differentiation was identified adjacent to areas with classic GIST morphology in at least 1 metastatic site; in 1 case, the primary tumor (after treatment with TKIs) showed heterologous differentiation. The rhabdomyoblastic components showed strong and diffuse positivity for desmin and expressed myogenin, whereas KIT was negative in the rhabdomyoblastic component in all cases. Primary KIT mutations were detected in both the conventional GIST and rhabdomyoblastic components from all patients: KIT exon 11 mutations in 4 cases and a platelet-derived growth factor receptor alpha gene exon 18 deletion in 1 case. No secondary mutations of the type associated with TKI resistance were identified in the rhabdomyoblastic areas. This is the first report of rhabdomyoblastic differentiation occurring in GISTs that progressed on TKI therapy. It is associated with loss of KIT expression, but retention of the receptor tyrosine kinase mutation of the precursor GIST. The rhabdomyoblastic differentiation can represent a diagnostic pitfall. The molecular mechanisms for this form of TKI-resistant clonal evolution remain to be determined.
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PMID:Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression. 1883 Jan 21

Gastrointestinal stromal tumors (GISTs) comprise a great majority of small intestinal mesenchymal tumors previously designated as smooth muscle tumors (SMTs), but true SMTs occur with a low-frequency encompassing both leiomyomas and leiomyosarcomas (LMSs). In this study, we analyzed 25 tumors in the spectrum of primary SMTs of the small intestine. Metastatic tumors and those with external attachment only were excluded. These tumors occurred in 15 men and 10 women of median age of 62 years (range: 18 to 80 y). There were 9 well-differentiated SMTs with no atypia and low mitotic activity [< or = 5/50 high-power fields (HPFs)] and these were considered leiomyomas. All 6 tumors examined were positive for SMA and desmin, and negative for KIT; all 3 tumors in female patients that were tested were negative for estrogen receptor. Two leiomyomas, a 5 mm, and another, 2 cm tumor, were examples of a muscularis mucosae leiomyomas. The other 7 were considered intramural leiomyomas; their median diameter was 4.5 cm (range: 0.8 to 9 cm). No patient with these tumors experienced recurrences or metastases, and 6 patients were alive with a median follow-up of 16 years (range: 9 to 28 y). Sixteen tumors had atypia and mitotic activity warranting the designation of LMS. One of these tumors, a 16 cm diverticular tumor, had mitotic activity of only 1/50 HPFs, and this tumor recurred 4 times. All other LMSs had > or =35 mitoses/50 HPFs. Four of 5 such LMSs with follow-up recurred or metastasized, and at least 3 patients died of disease; several others had a short survival but cause of death could not be determined. One patient, an 18-year-old woman, who died of LMS, was a survivor of a Wilms tumor radiated in infancy. All 6 LMSs studied for GIST-specific KIT and platelet-derived growth factor receptor alpha mutations showed wild-type sequences. This series demonstrates that primary small intestinal SMTs are rare (estimated frequency 1 SMT for 36 GISTs). A majority of these are mitotically active tumors with atypia warranting the diagnosis of LMS, and have a high malignant potential. The number of LMS cases is too small for stratification for risk assessment. True SMTs of small intestine should be separated from GISTs because of different pathogenesis and treatment.
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PMID:True smooth muscle tumors of the small intestine: a clinicopathologic, immunhistochemical, and molecular genetic study of 25 cases. 1897 81

A great majority of gastric mesenchymal tumors are gastrointestinal stromal tumor (GIST). A rare group of non-GISTs include myxoid mesenchymal neoplasms. In this report, we describe 12 cases of a distinctive gastric tumor, named here as plexiform fibromyxoma. These tumors occurred in 5 men and 7 women of ages 7 to 75 years (median, 41 y). All tumors were located in the gastric antrum and 6 of them also extended into extragastric soft tissues or into the duodenal bulb. The tumors measured from 3 to 15 cm (median, 5.5 cm). Histologically typical was a plexiform intramural growth with multiple micronodules containing paucicellular to moderately cellular myxoid to collagenous and fibromyxoid neoplastic elements. A prominent, sometimes plexiform capillary pattern was typically present. Extramural components included subserosal nodules, and sometimes more cellular, solid nonplexiform spindle cell proliferation. The tumor cells varied from oval to spindled and had limited atypia and mitotic activity < 5/50 high-power fields. Frequent ulceration, mucosal invasion, and vascular invasion (4 cases) had no adverse significance in these tumors. Immunohistochemically, the tumor cells were positive for alpha smooth muscle actin, and variably for CD10, and were consistently negative for KIT, DOG1, CD34, desmin, and S100 protein. No KIT or platelet-derived growth factor receptor alpha mutations were present in the 3 examined cases. None of the 4 patients who were followed from 9 to 20 years (median, 19 y) developed recurrences or metastases. Additional 3 patients survived 14 to 25 years with unknown tumor status. Review of large numbers of mesenchymal tumors in the esophagus and intestines did not reveal similar tumors. Plexiform fibromyxoma is a distinctive benign gastric antral neoplasm that should be separated from GIST, nerve sheath tumors, and other fibromyxoid neoplasms.
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PMID:Plexiform fibromyxoma: a distinctive benign gastric antral neoplasm not to be confused with a myxoid GIST. 1967 52

Gastrointestinal stromal tumors (GISTs) present 80% of gastrointestinal tract mesenchymal tumors, with systemic chemotherapy and radiotherapy being unable to improve survival of patients with advanced disease. The identification of activating mutations in either KIT cell surface growth factor receptor or platelet-derived growth factor receptor alpha, which lead to ligand-independent signal transduction, paved the way for the development of novel agents that selectively inhibit key molecular events in disease pathogenesis. The development of imatinib mesylate in the treatment of metastatic GIST represents a therapeutic breakthrough in molecularly targeted strategies, which crucially improved patients' prognosis while its usefulness in adjuvant and neoadjuvant setting is under study. Sunitinib malate is available in the second-line setting, with ongoing studies evaluating its role in an earlier disease stage, while other targets are under intense investigation in order to enrich the therapeutical armamentarium for this disease. GIST phenotype seems to be an essential indicator of treatment response; thus, obtaining genotype information of each patient may be critical in order to tailor individualized treatment strategies and achieve maximal therapeutic results.
Cancer Metastasis Rev 2010 Mar
PMID:Targeted therapy for gastrointestinal stromal tumors: current status and future perspectives. 2011 54

Gastrointestinal stromal tumors (GISTs) are the most common nonepithelial tumors of gastrointestinal tract characterized by mutations activating c-KIT or platelet-derived growth factor receptor alpha. GISTs frequently metastasize to liver and peritoneum, but rarely to the bones. Imatinib, a tyrosine kinase inhibitor, has revolutionized the treatment of advanced and metastasized GISTs by both slowing down the disease progression and prolonging the survival. Occasionally, patients with GISTs can develop primary or secondary resistance to imatinib monotherapy. We are presenting an interesting case of metastatic GISTs with extensive bone lesions and primary resistance to imatinib. Efforts to identify bone metastases using appropriate imaging modalities are highly recommended in patients diagnosed with GISTs. Also, alternate strategies to overcome the emerging resistance with single agent imatinib chemotherapy are warranted.
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PMID:Gastrointestinal stromal tumor with primary resistance to imatinib and extensive bone metastases. 2053 17


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