Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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Several studies have suggested that biochemical or molecular markers examined in non-small cell lung cancer carry prognostic or treatment response information. Non-small cell lung cancer patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of HER2 (c-erbB-2), a membrane-bound receptor with tyrosine kinase activity, has been associated with shortened survival. The Cancer and Leukemia Group B (CALGB) performed a study of patients with stage IIIA (N2 nodes positive) non-small cell lung cancer in which patients received initial chemotherapy followed by surgery, then post-operative therapy consisting of sequential chemotherapy and radiation therapy. Since all patients underwent mediastinoscopy, this provided an opportunity to compare pre- and post-chemotherapy tumor specimens to test the hypothesis that these proteins would predict treatment response. In particular, we hypothesized that the post-chemotherapy specimens would be enriched for NE marker negative cells because of the increased sensitivity of NE positive cells to chemotherapy. We performed immunohistochemical analysis for a panel of NE markers [neuron-specific enolase (NSE), Leu-7, chromogranin A (ChrA), synaptophysin (Syn)], HER2 and CEA to determine if there was an effect of therapy on the percentage of cells expressing these markers. Secondary endpoints were a correlation with chemotherapy response and survival. Slides were scored for intensity (0-4) and percentage of cells positive (0-4). Of 61 eligible patients, there were 38 with both pre- and post-chemotherapy specimens. When both intensity of staining and percentage of positive cells were considered, post-chemotherapy specimens had a higher percentage of positive NE markers compared with pre-chemotherapy. In addition, there was no correlation between NE marker, HER2 or CEA expression (prior to or post treatment) and response to chemotherapy or survival. These data do not support the hypothesis that NE positive tumor cells are preferentially killed by chemotherapy in patients with stage IIIA non-small cell lung cancer.
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PMID:Analysis of neuroendocrine markers, HER2 and CEA before and after chemotherapy in patients with stage IIIA non-small cell lung cancer: a Cancer and Leukemia Group B study. 985 98

Several studies have suggested that non-small cell lung cancer (NSCLC) patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of p53 and HER2 may confer relative chemotherapy resistance and shortened survival. The Cancer and Leukemia Group B performed a series of studies involving sequential chemotherapy followed by radiation for patients with unresectable stage III NSCLC. The objectives of this study were to analyze pathological specimens using immunohistochemistry for NE markers, p53 and HER2 to determine if there was a correlation between marker expression and response or survival. Of 160 eligible patients, 28 (18%) were not evaluable because of inadequate material. The percentage of specimens positive for markers was as follows: neuron-specific enolase 38%, Leu-7 2%, chromogranin A 0%, synaptophysin 5%, > or =2+NE markers 3%, p53 61%, and HER2 65%. There was no statistically significant correlation between any individual marker and response to induction chemotherapy or response to combined chemotherapy/radiation except for synaptophysin. Six of 6 (100%) synaptophysin positive tumors responded by the completion of all therapy compared with 69/125 (55%) synaptophysin negative tumors (P=0.04). None of the individual markers had a significant effect on survival in univariate analysis. Neuron-specific enolase was marginally significant in multivariate analysis (P=0.08). In conclusion, this study did not demonstrate that expression of NE markers, p53 and HER2 were predictive of response to chemotherapy, combined chemotherapy/radiation or for survival in this group of patients with stage III NSCLC. Future studies must employ either different markers or be performed on more adequate surgical specimens.
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PMID:Use of neuroendocrine markers, p53, and HER2 to predict response to chemotherapy in patients with stage III non-small cell lung cancer: a Cancer and Leukemia Group B study. 1155 6

Since the development of the first immunoassay for circulating chromogranin A in 1984, a lot of studies have evaluated its clinical impact in neuroendocrine tumors. Initially studied in pheochromocytoma patients, the clinical impact of chromogranin A has rapidly extended to most neuroendocrine tumours, sometimes in combination with other eutopic or ectopic secretions. In our experience, CgA demonstrates a variable sensitivity between NET primary and a high specificity. Our results suggest that CgA should be routinely screened in foregut-derived NET and abandoned in the routine screening of medullary thyroid carcinoma. In addition, in phaeochromocytoma and ileum-NET patients, CgA demonstrates a comparable sensitivity with urinary reference markers and its impact on the follow-up will form a key point when recommending routine screening. Both tumor burden and secretory activity should be taken into account when interpreting CgA results.
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PMID:Impact of chromogranin A measurement in the work-up of neuroendocrine tumors. 1176 57

Metastasized neuroendocrine tumors of the gastrointestinal tract and of unknown origin show a highly variable clinical course. Within this group, low-grade and high-grade malignant tumors can be recognized based on the revised classification of neuroendocrine tumors of the lung, pancreas, and gut published by Capella et al in 1995. The present study investigated whether fine-tuning the prediction of prognosis was possible by dividing the group of low-grade malignant tumors of the midgut and of unknown origin into typical and atypical carcinoids by grading them according to the World Health Organization (WHO) classification criteria for neuroendocrine tumors of the lung. Moreover, the prognostic value of immunohistochemical stainings and clinical parameters was evaluated. The study group comprised patients diagnosed between 1983 and 1999 with liver metastases of a neuroendocrine tumor of the midgut n = 40) or of unknown origin (n = 16). As a control for the consistency of grading, 10 patients with metastasized neuroendocrine tumors of the lung also were evaluated. Immunohistochemical stainings for chromogranin A, synaptophysin, Leu 7/CD57, neural cell adhesion molecule/CD56, cytokeratin 8, bcl-2, p53, ki67, and HER2/neu were performed. The clinical parameters age, gender, urinary 5-HIAA level, and presence or absence of the carcinoid syndrome were evaluated. Tumors of the midgut and of unknown origin were evaluated together, because they were clinically similar. In this group of 56 patients, both the Capella and the WHO classification systems recognized the high-grade malignant tumors with a bad prognosis. When the low-grade malignant tumors (Capella) were divided into typical and atypical carcinoids (WHO), no difference in survival was observed, but when the dichotomy into typical and atypical was based on mitotic count alone, the difference became borderline significant (P =.072). Of the immunohistochemical stainings used, synaptophysin, cytokeratin 8, and ki67 had limited prognostic value. Age above 60 was the only clinical parameter of unfavorable prognostic significance. We conclude that high-grade malignant neuroendocrine tumors of the midgut and of unknown origin are recognized by both the Capella classification and the WHO classification of neuroendocrine tumors of the lung. Further subdividing low-grade malignant tumors at this location appears to be of less value than in the lung, but assessing the mitotic activity of these tumors might be of prognostic value.
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PMID:Classification of low-grade neuroendocrine tumors of midgut and unknown origin. 1245 18

Mammary small cell carcinoma (SmCC) is a very rare neoplasm with a poor prognosis compared with other invasive carcinomas. We studied the histological and immunohistochemical profiles of two cases of mammary SmCC, and compared them with those of five cases of carcinoma with endocrine features (CEF) and five cases of invasive ductal carcinoma (IDC), to elucidate the correct diagnosis of mammary SmCC. Immunohistochemical analysis was performed with antibodies against cytokeratins (CKAE1/AE3, CK34betaE12, CKCAM5.2, CK7, CK8, CK19, CK20), epithelial membrane antigen (EMA), vimentin, CD10, neural cell adhesion molecule (NCAM; CD56), neuron-specific enolase (NSE), chromogranin A, S-100 protein, carcino-embryonic antigen (CEA), E-cadherin, N-cadherin, thyroid transcription factor-1 (TTF-1), p53, estrogen (ER), progesterone (PR), HER2/neu, bcl-2, synaptophysin, calcitonin and Leu7. SmCCs were diffusely and strongly positive for NCAM in comparison with CEFs and IDCs. SmCCs were negative for vimentin, whereas CEFs and IDCs were positive. Neuro-endocrine carcinomas, including SmCCs and CEFs, were diffusely and strongly positive for NSE, compared with IDCs. Moreover, neuroendocrine carcinomas were negative for CK34betaE12, CK20 and CD10, whereas IDCs were positive. Our study suggests that NCAM and vimentin are useful markers for the diagnosis of mammary SmCC. CK34betaE12, NSE, CD10, CK20 and chromogranin A appear to be useful for differentiating neuroendocrine carcinoma from IDCs.
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PMID:Comparative study of primary mammary small cell carcinoma, carcinoma with endocrine features and invasive ductal carcinoma. 1501 Aug 80

The peptide hormone gastrin is the key regulator of gastric acid secretion. Gastrin exerts its effects as acid secretagogue through functional activation of gastric enterochromaffin-like (ECL) cells, which control acid secretion through biosynthesis and release of histamine. In ECL cells, concerted activation of histidine decarboxylase (HDC), vesicular monoamine transporter 2 (VMAT2), and chromogranin A (CgA) genes by gastrin is a prerequisite for proper acid control. To elucidate the molecular pathways underlying gastrin-dependent control of ECL cell genes, we recently analyzed the signaling cascades, regulatory promoter elements, and transcription factors mediating the transcriptional effects of gastrin. Our studies identified the Raf>MEK1>ERK 1/-2 kinase module as the common signaling pathway mediating gastrin-dependent ECL cell gene transcription. In contrast to this uniform signaling cascade, pronounced heterogeneity was detected between cis- and trans-activating regulatory factors conferring gastrin responsiveness. The molecular diversity of transcription factors and regulatory enhancer elements transmitting gastrin-triggered gene transcription offers the molecular basis for synergistic, but differential, regulation of HDC, VMAT2, and CgA genes during a secretory challenge of ECL cells by gastrin and possibly other acid secretagogues.
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PMID:Molecular mechanisms of gastrin-dependent gene regulation. 1515 24

IFN-alpha controls hormone secretion and symptoms in human gastroenteropancreatic neuroendocrine tumors (GEP-NET) but it rarely induces a measurable tumor size reduction. The effect of other type I IFNs, e.g., IFN-beta, has not been evaluated. We compared the antitumor effects of IFN-alpha and IFN-beta in BON cells, a functioning human GEP-NET cell line. As determined by quantitative reverse transcription-PCR analysis and immunocytochemistry, BON cells expressed the active type I IFN receptor mRNA and protein (IFNAR-1 and IFNAR-2c subunits). After 3 and 6 days of treatment, IFN-beta significantly inhibited BON cell growth in a time- and dose-dependent manner. IC50 and maximal inhibitory effect on day 6 were 8 IU/mL and 98%, respectively. In contrast, the effect of IFN-alpha resulted significantly in a less potent effect (IC50: 44 IU/mL, maximal inhibition: 26%). IFN-alpha induced only cell cycle arrest, with an accumulation of the cells in S phase. IFN-beta, apart from a more potent delay in S-G2-M phase transit of the cell cycle, also induced a strong stimulation of apoptosis, evaluated by flow cytometry (Annexin V and 7-AAD) and measurement of the DNA fragmentation. Besides, only IFN-beta severely suppressed chromogranin A levels in the medium from BON cells after 6 days of treatment. In conclusion, IFN-beta is much more potent, compared with IFN-alpha, in its inhibitory effect on GEP-NET cell proliferation in vitro through the induction of apoptosis and cell cycle arrest. Further studies are required to establish whether IFN-beta has comparable potent tumor growth inhibitory effects in vivo.
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PMID:IFN-beta is a highly potent inhibitor of gastroenteropancreatic neuroendocrine tumor cell growth in vitro. 1639 72

We describe a case of primary neuroendocrine carcinoma arising from the anterior vaginal wall of a 67-year-old woman. Primary neuroendocrine carcinoma of the vagina is a rare entity with only 25 previously reported cases in the literature. In previous reports, these tumors have not been distinguished from primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). The tumor was composed of cells that showed neuroendocrine-type nuclear features with hyperchromasia, nuclear molding, occasional small nucleoli, and a chromatin pattern that was finely granular. The tumor cells were positive for cytokeratin 20 (CK20), neuron specific enolase, pancytokeratin, epithelial membrane antigen, and chromogranin A expression. Ki-67, a marker of proliferation, was also positive in>90% of cells. The tumor cells showed intense expression of Bcl-2 oncoprotein and mild to moderate expression of c-KIT. Synaptophysin, neurofilament, CD45, CD56, CD10, S-100, HMB-45, cytokeratin 7, and thyroid transcription factor 1 were negative. This pattern of staining is consistent with a Merkel cell carcinoma. This is the first report of a primary neuroendocrine carcinoma of the vagina with a Merkel cell phenotype. Previous studies have not distinguished primary neuroendocrine carcinoma of the vagina from Merkel cell carcinoma of the skin. Positive expression of CK20 in primary small cell carcinoma of the vagina might represent a Merkel cell carcinoma subtype of this tumor.
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PMID:Primary neuroendocrine carcinoma of the vagina with Merkel cell carcinoma phenotype. 1653 63

A new method that allows fast and quantitative recovery of hydrophobic or amphipathic peptides, or both, after their intimate incorporation into lipid membranes, is proposed. It relies on the use of small Sep-Pak cartridges and simple chromatographic handling. Peptides selected for this study are the 35 amino acid transmembrane domain of the Neu/erbB-2 protein and its point mutated (V664E) analogue expressed in some cancers, the 25 amino acid BH4 domain from the Bcl-2 antiapoptotic protein and the 15 amino acid Catestatin segment from chromogranin A found to have antimicrobial capabilities. Incorporation of peptides into membranes is accomplished using organic solvent cosolubilization and several cycles of freeze-drying/hydration from aqueous solution. For the hydrophobic peptides, separation from the membrane is performed on Sep-Pak C2 columns in two steps: (i) water/methanol elution of lipids and (ii) peptide elution using aprotic solvents (acetonitrile, 2-propanol). For amphipathic peptides, separation is performed on Sep-Pak C(18) columns using selective elution in one single step: water/methanol elution to recover first the peptide and then the lipids. Peptide and lipid recovery after all purification steps range from 60 to 80%, with peptide purity above 96%. This new method is simple, inexpensive, and very fast: a 10-mg membranous mixture containing 10% (w/w) peptide may be separated in 20-30 min.
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PMID:Fast and quantitative recovery of hydrophobic and amphipathic peptides after incorporation into phospholipid membranes. 1687 68

Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations in the RET proto-oncogene, resulting in constitutive activation of the RET tyrosine kinase. A substantial proportion of sporadic MTCs also have RET mutations, making the RET tyrosine kinase a potential therapeutic target in MTC. We have established a transplantable MTC in nude mice from a sporadic human MTC carrying a RET C634R mutation. Transplanted tumors had an exponential growth rate with an approximate doubling time of about 3 weeks, and expressed a neuroendocrine phenotype characteristic of MTC, e.g., expression of calcitonin, chromogranin A (CgA), synaptophysin, synaptic vesicle protein 2 (SV2), vesicular monoamine transporter-1 and -2, carcinoembryonic antigen, cytokeratin 8/18, epithelial cadherin, and neural cell adhesion molecule. Plasma calcitonin and CgA levels were elevated in tumor-bearing mice and correlated with tumor size. Cytogenetic analysis, including spectral karyotyping, confirmed the human origin of the xenografted tumors and demonstrated an abnormal, near triploid karyotype. Treatment of tumor-bearing nude mice with the tyrosine kinase inhibitor ZD6474, which specifically inhibits RET, epidermal growth factor receptor (EGFR), and vascular endothelium growth factor receptor (VEGFR) tyrosine kinases, resulted in a dose-dependent inhibition of tumor growth. Oral ZD6474 given once daily (250 mg/kg, 5 days/week) reduced tumor volume to 11% when compared with controls after 4 weeks. Our results show that this transplantable MTC, designated GOT2, represents a novel and useful model for studies of MTC and RET tyrosine kinase-dependent tumor growth.
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PMID:A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis. 1763 56


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