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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated that bone marrow (BM) cells migrate to Ewing's tumors and differentiate into endothelial cells within the tumor vasculature. Recent evidence suggests that the roles of BM cells in tumors are more diverse. We investigated whether non-endothelial cell types critical for tumor vessel development are also derived from migrated BM cells. We utilized BM transplantation with GFP(+) transgenic mice as BM donors and nude mice as recipients to track the fate of migrated BM cells. After engraftment, we injected recipient mice either subcutaneously or intramuscularly with Ewing's sarcoma cells. We labeled functional tumor vessels using intravascular perfusion staining with tomato lectin. We assessed BM cell recruitment/differentiation within the tumor microenvironment using immunohistochemistry. Ewing's tumors contained BM-derived cells that had differentiated into endothelial cells lining perfused tumor vessels. A substantial fraction of recruited BM cells also resided in the vessel vicinity and expressed desmin and PDGFR-beta, indicating smooth muscle cell differentiation. In order to further characterize the role of stem/progenitor cells in Ewing's sarcoma, we sorted Tie2(-) BM cells from Tie2-GFP transgenic mice and then injected them intravenously into Ewing's tumor-bearing mice. Tie2(-) BM progenitors migrated to Ewing's tumors and differentiated into Tie2(+) cells occupying a perivascular residence and expressing alpha-smooth muscle actin, desmin and PDGFR-beta, as well as VEGFR-2. We did not observe differentiation of Tie2(-) cells into Tie2(+) perivascular cells in VEGF(165)-inhibited TC/siVEGF(7-1) tumors. The differentiation of Tie2(-) BM cells into Tie2(+) cells in parental but not VEGF(165)-inhibited tumors indicates that the tumor microenvironment may influence the differentiation pathway.
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PMID:VEGF165 expression in the tumor microenvironment influences the differentiation of bone marrow-derived pericytes that contribute to the Ewing's sarcoma vasculature. 1834 25

The aim of the present study was to evaluate the clinicopathological, immunohistochemical, and molecular genetic features of gastrointestinal stromal tumors in Brazil and compare them with cases from other countries. Five hundred and thirteen cases were retrospectively analyzed. HE-stained sections and clinical information were reviewed and the immunohistochemical expression of CD117, CD34, smooth-muscle actin, S-100 protein, desmin, CD44v3 adhesion molecule, p53 protein, epidermal growth factor receptor, and Ki-67 antigen was studied using tissue microarrays. Mutation analysis of KIT and platelet-derived growth factor receptor-alpha genes was also performed. There was a slight female predominance (50.3%) and the median age at diagnosis was 59 years. The tumors were mainly located in the stomach (38.4%). Immunohistochemistry showed that CD117 was expressed in 95.7% of cases. Epidermal growth factor receptor expression was observed in 84.4% of tumors. p53 protein expression was found only in 2.6% of cases but all belonged to the high-risk group for aggressive behavior according to the National Institutes of Health consensus approach. No CD44v3 adhesion molecule expression was detected. KIT exon 11 mutations were the most frequent (62.2%). The present data confirm that gastrointestinal stromal tumors in Brazilian patients do not differ from tumors occurring in other countries.
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PMID:Gastrointestinal stromal tumor in Brazil: clinicopathology, immunohistochemistry, and molecular genetics of 513 cases. 1847 13

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare inflammatory tumor-like lesion composed of vascular nodules and non-neoplastic stroma including spindle cells and inflammatory cells. The focus of our study was on the stromal proliferating process in SANT. Nine cases of SANT were examined. All cases showed alpha-smooth muscle actin (alpha-SMA) and vimentin on the spindle cells but not CD21, CD31, CD34, CD68, desmin, S100, human herpes virus-8, or anaplastic lymphoma kinase-1. In one case, 20-30% of the myofibroblasts in Epstein-Barr-virus (EBV)-positive spindle cells were detected using double-labeling immunohistochemistry for alpha-SMA and EBV-encoded small RNA in situ hybridization. A quantitative analysis of IgG and IgG4-positive plasma cells (pPCs) in SANT was performed. The median densities of IgG-pPCs and IgG4-pPCs in SANT were approximately four-fold and 13-fold higher than those in the normal spleens, respectively. In addition, there was a statistically significant increase of IgG4/IgG-pPCs ratio in SANT in comparison to the control specimens. In conclusion, the fibrogenesis in a subset of SANT may be associated with EBV-infected myofibroblasts in an overlapping immune reaction indicated by the presence of infiltrating IgG4-pPCs. Further investigation is needed to elucidate the association between SANT and IgG4-related sclerosing disease.
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PMID:Detection of Epstein-Barr virus-encoded small RNA-expressed myofibroblasts and IgG4-producing plasma cells in sclerosing angiomatoid nodular transformation of the spleen. 1869 8

The author reports a rare case of primary large cystic extragastrointestinal stromal tumor (eGIST) of the transverse mesocolon with genetic analyses of the c-kit and platelet-derived growth factor receptor-alpha (PDGFRA) genes. A 78-year-old man was found to have a large cystic tumor in the abdomen, and the tumor was resected. Grossly, the tumor was located in the transverse mesocolon, and cystic. Microscopically, the tumor consisted of epithelioid cells with atypia. Mitotic figures were noted in five of 50 high power fields. Immunohistochemically, the tumor cells were positive for KIT, CD34, PDGFRA, and vimentin, but negative for cytokeratins, neuron specific enolase, desmin, S100 protein, alpha-smooth muscle actin, p53 protein, HMB45, CD68, CEA, factor VIII-related antigen, chromogranin, and synaptophysin. Ki67 labeling was 5%. Genetically, the tumor showed a point mutation (GAC --> GTC) at codon 842 of exon 18 of the PDGFRA gene. Exon 12 of the PDGFRA gene and exons 9, 11, 13, and 17 of the c-kit gene showed no mutations. No recurrence is noted 3 years after the operation. This case shows that eGIST may occur in the transverse mesocolon.
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PMID:Primary extragastrointestinal stromal tumor of the transverse mesocolon without c-kit mutations but with PDGFRA mutations. 1877 14

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

Spindle cell lesions of the urinary bladder are uncommon, but when encountered in clinical practice, pose a difficult diagnostic challenge as the differential diagnostic considerations are vast. Pseudosarcomatous processes significantly overlap with malignant tumors (sarcomatoid urothelial carcinoma and leiomyosarcoma) in their morphology and published immunohistochemical profile [pancytokeratin pan (CK), smooth muscle actin (SMA), and desmin]. p63 has been studied rarely and CK 5/6 and CK 34betaE12 have not been analyzed in the bladder in this diagnostic context. In the current study, 45 typical examples of spindle cell lesions [10 pseudosarcomatous myofibroblastic proliferations (PMP), 22 sarcomatoid urothelial carcinomas, and 13 smooth muscle tumors] of the urinary bladder were immunostained with a panel containing broad spectrum anticytokeratin antibodies (OSCAR or AE1/AE3), as well as antibodies to CK 34betaE12, CK 5/6, p63, SMA, and anaplastic lymphoma kinase (ALK). The immunoreactivity was as follows: PMP-CK (OSCAR) 7/10 (70%), CK (AE1/AE3) 7/9 (78%), CK 34betaE12 0/10 (0%), CK 5/6 0/9 (0%), p63 0/9 (0%), SMA 10/10 (100%), ALK 2/10 (20%); sarcomatoid urothelial carcinoma-CK (OSCAR) 15/22 (68%), CK (AE1/AE3) 14/20 (70%), CK 34betaE12 5/20 (25%), CK5/6 6/22 (27%), p63 11/22 (50%), SMA 16/22 (73%), ALK 0/22 (0%); and smooth muscle tumors-CK (OSCAR) 7/13 (54%), CK (AE1/AE3) 7/12 (58%), CK 34betaE12 0/12 (0%), CK 5/6 0/12 (0%), p63 3/13 (23%), SMA 11/13 (85%), ALK 0/13 (0%). Positivity for keratin was typically focal to moderate in smooth muscle tumors and more commonly moderate to diffuse in sarcomatoid carcinomas and PMP. Our data indicate that there is significant immunohistochemical overlap between the different spindle cell lesions, each of which has unique clinicopathologic, prognostic, and therapeutic ramifications. Within the context of morphology, an immunohistochemical panel composed of broad-spectrum antibodies to cytokeratin as well as antibodies to SMA, ALK, p63, and CK 5/6 will be a useful diagnostic adjunct: a combination of pankeratin, SMA, and ALK positivity favors PMP; expression of several cytokeratin and especially CK 34betaE12 and CK 5/6 with p63 favors sarcomatoid carcinoma and SMA positivity with overall absence of other markers favors leiomyosarcoma.
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PMID:Utility of a comprehensive immunohistochemical panel in the differential diagnosis of spindle cell lesions of the urinary bladder. 1894 4

Colorectal mesenchymal tumors are rare. Therefore, distinguishing between gastrointestinal stromal (GIST) and smooth muscle tumors is important. This study aimed to delineate the immunophenotype and prognostic factors of 75 colorectal mesenchymal tumors. Fifty-three GIST and 22 smooth muscle tumor specimens were included from 1986 to 2007. Forty of 53 GIST were initially diagnosed as smooth muscle tumors and re-diagnosed as CD117 (+) GIST. Immunohistochemical studies were performed with antibodies of CD117, CD34, smooth muscle actin (SMA), desmin, S-100, Ki-67 and PCNA for clinicopathologic and prognostic correlation. In comparison, colorectal GIST exhibited a larger tumor size (P<0.001), higher mitotic count (P<0.001), higher cellularity (P<0.001), less spindle cell type (P=0.004), higher nuclear pleomorphism (P=0.004), and a higher NIH risk (P<0.001) than that of smooth muscle tumors. Positive immunoreactivities of GIST to a panel of antibodies were 88.6% to CD34, 28.3% to SMA, 1.8% to S-100 and 15.1% to desmin. For 75 mesenchymal tumors, survival analyses revealed that older patients (P=0.006), with a large tumor size (P<0.001), high mitotic count (P<0.001), increased NIH risk (P<0.001), non-spindle cell type (P<0.001), high cellularity (P=0.015), high cell pleomorphism (P<0.001), positive Ki-67 (P<0.001), high PCNA (P<0.001) and GIST (P=0.001) had a shorter disease-free survival than that of comparative groups. When the analyses concentrated on 53 GIST, the cell type and cellularity were no longer viable prognostic factors. The tumor mitotic count was the only independent prognostic factor for either mesenchymal tumors or GIST. In conclusion, GIST exhibited heterogeneous characteristics and was significantly larger, more mitotic and a poorer prognostic factor than smooth muscle tumor. The mitotic count is still the most valuable prognostic factor for colorectal mesenchymal tumors after KIT.
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PMID:Colorectal mesenchymal tumors - from smooth muscle tumors to stromal tumors. 1894 16

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

The author reports a very rare case of a gastrointestinal stromal tumor in the uterus. A 74-year-old woman was admitted to our hospital because of pelvic pain. Imaging modalities showed a large tumor of the posterior aspect of the uterus, and enucleation was performed. The tumor was attached to the posterior uterus, similar to subserosal leiomyoma. No attachment to the gastrointestinal organs was recognized. The tumor was soft, tan, and measured 13 x 15 x 12 cm. The tumor consisted of cellular spindle cells with focal necrotic areas. Mitotic figures were noted in 3 of 50 high-power fields. The tumor cells were positive for KIT, CD34, platelet-derived growth factor receptor alpha, and vimentin, but negative for alpha-smooth muscle actin, S100 protein, p53 protein, HMB45, and desmin. Ki-67 labeling was 3%. Five normal uteruses used as controls showed KIT-positive Cajal-like mesenchymal cell scattering in the myometrium. Genetic analyses of the c-kit gene (exons 9, 11, 13, and 17) and platelet-derived growth factor receptor alpha gene (exons 12 and 18) revealed a point mutation at codon 559 (GTT-->GAT) of exon 11 of the c-kit gene. Other exons showed no abnormalities. This case shows that gastrointestinal stromal tumor may occur in the uterus.
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PMID:Gastrointestinal stromal tumor of the uterus: a case report with genetic analyses of c-kit and PDGFRA genes. 1904 11

The author reports a very rare case of sporadic primary multiple extragastrointestinal stromal tumors (EGISTs) of the omentum associated with different mutations of the exon 11 of the c-kit gene in a 75-year-old man with gastric cancer. During an operation for the cancer, two solid tumors (10 mm and 8 mm) were found in the omentum. Both tumors consisted of cellular spindle cells. Mitotic figures were two and three per 50 high power fields. The tumor cells were positive for KIT, CD34 and vimentin, but negative for desmin, S100 protein, alpha-smooth muscle actin and p53 protein. Ki67 labeling was 2% and 3%. The larger EGIST showed a deletion of codons 552-558 of exon 11 of the c-kit gene, while the smaller EGIST had a point mutation at codon 559 (GTT-->GAT) in exon 11 of the c-kit gene. Exons 9, 13, and 17 of the c-kit gene, and exons 12 and 18 of the platelet derived growth factor receptor alpha genes showed no mutations. The case shows that sporadic multiple EGISTs can occur in the omentum.
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PMID:Primary multiple extragastrointestinal stromal tumors of the omentum with different mutations of c-kit gene. 1908 44


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