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  1. Inhibition of Phosphatidylinositol 3-Kinase/Akt Signaling Suppresses Tumor Cell Proliferation and Neuroendocrine Marker Expression in GI Carcinoid Tumors

    PubMed Central

    Pitt, Susan C.; Chen, Herbert; Kunnimalaiyaan, Muthusamy

    2010-01-01

    Background Over-activation of PI3K/Akt signaling facilitates tumor proliferation in several cancers. We have shown that various signal transduction pathways promote tumorigenesis in carcinoid tumors, which exhibit endogenously high levels of active, phosphorylated Akt. Therefore, we hypothesized that inhibition of the PI3K/Akt pathway would suppress carcinoid tumor cell growth and neuroendocrine (NE) marker production. Methods Human carcinoid BON cells were treated in vitro with LY294002, a PI3 kinase inhibitor, or transfected with Akt1 siRNA. Tumor cell proliferation was measured by MTT for six days. The effect of LY294002 or Akt1 siRNA treatment was assessed by western analysis. We examined the levels of phosphorylated Akt, total Akt, Akt1, and the NE markers human achaete-scute homolog1 (ASCL1) and chromogranin A (CgA). Results Treatment of BON cells with LY294002 reduced tumor cell proliferation (76%) in a dose-dependent manner. Growth also decreased in Akt1 siRNA transfected cells (29%). Levels of active, phosphorylated Akt and the NE tumor markers, ASCL1 and CgA, were diminished with both LY294002 and Akt1 siRNA treatments proportional to the degree of Akt inhibition. Total Akt, Akt2, and Akt3 levels were unaffected by these experiments. Conclusions These data indicate that PI3K/Akt signaling performs a critical role in human carcinoid tumor cell survival and NE hormone generation. Furthermore, the development of novel therapeutics targeting Akt1 or components of the PI3K/Akt pathway may enhance the management of carcinoid disease. Synopsis Carcinoid tumor cells were treated with a PI3K inhibitor, LY294002, and Akt1 siRNA to delineate the role of PI3K/Akt signaling in carcinoids. The effects of treatment on cellular proliferation and neuroendocrine marker expression were observed. PMID:19588205

  2. The CCK(2) receptor antagonist, YF476, inhibits Mastomys ECL cell hyperplasia and gastric carcinoid tumor development.

    PubMed

    Kidd, M; Siddique, Z-L; Drozdov, I; Gustafsson, B I; Camp, R L; Black, J W; Boyce, M; Modlin, I M

    2010-06-08

    YF476 is a potent and highly selective cholecystokin 2 (CCK(2)) receptor antagonist of the benzodiazepine class. It inhibits gastric neuroendocrine enterochromaffin-like (ECL) cell secretion, proliferation and spontaneous formation of gastric neuroendocrine tumors (carcinoids) in cotton rats. The Mastomys rodent species exhibits a genetic predisposition to gastric ECL neuroendocrine tumor formation which can be accelerated by acid suppression and induction of hypergastrinemia. In this respect, it mimics the human condition of atrophic gastritis, hypergastrinemia and gastric carcinoid development. We investigated whether YF476 could inhibit acid suppression-induced ECL cell hyperplasia and neoplasia in this model. In addition, we examined whether YF476 could reverse established ECL cell hyperplasia and neoplasia. Targeting the CCK(2) receptor during Loxtidine-induced hypergastrinemia resulted in a reduction in ECL cell secretion (plasma and mucosal histamine, and histidine decarboxylase (HDC) transcripts, p<0.05) and proliferation (numbers of HDC-positive cells, connective tissue growth factor (CTGF) and cyclin D1 transcription). This was associated with a decrease in ECL cell hyperplasia and a 60% reduction in gastric ECL cell microcarcinoid (tumors <0.3mm in size) formation. YF476 inhibited ECL cell neoplasia (gastric carcinoid) in animals with hyperplasia, inhibited the formation of ECL cell tumors when co-administered with Loxtidine and reversed the growth and developement of gastric ECL cell carcinoids in long-term acid suppressed Mastomys. Variable importance analysis using a logistic multinomial regression model indicated the effects of YF476 were specific to the ECL cell and alterations in ECL cell function reflected inhibition of transcripts for HDC, Chromogranin A (CgA), CCK(2) and the autocrine growth factor, CTGF. We conclude that specifically targeting the CCK(2) receptor inhibits gastrin-mediated ECL cell secretion and ECL cell proliferation and tumor

  3. Combined classical carcinoid and goblet cell carcinoid tumor: a new morphologic variant of carcinoid tumor of the appendix.

    PubMed

    Chetty, Runjan; Klimstra, David S; Henson, Donald E; Albores-Saavedra, Jorge

    2010-08-01

    Carcinoid tumors are the most common neoplasms of the appendix. Histologically they have been categorized as classical, tubular, or goblet cell types. Goblet cell carcinoid has been regarded as a distinctive tumor type, not related to classic carcinoids, and to our knowledge combinations of these 2 tumor types have not been described in detail. In this report, we describe 5 cases of combined classical carcinoid and goblet cell carcinoid (GCC) tumors of the appendix. Four men and 1 woman, (mean age 53.4 y) presented with acute appendicitis (4 cases), whereas 1 presented with a pelvic mass owing to widespread pelvic disseminated disease. The tumors (0.6 to 6.0 cm) were located in the mid-portion and the tip of the appendix. Four patients were treated with right hemicolectomies (the patient with disseminated pelvic and ovarian metastases also had a pelvic exenteration), and 1 was treated with an appendectomy only. Four patients are alive and asymptomatic, whereas the patient with disseminated pelvic disease died 6 months after surgery. All 5 appendiceal tumors had microscopic features of both classical carcinoid and GCC, either intimately admixed or separate but closely apposed. The extent of the 2 components varied, with classical carcinoid representing 60% to 90% of the tumor. Both components stained for the general neuroendocrine markers, however, staining in the classic component was greater. The Mib-1 proliferation index varied from 1-15%, again with higher Mib-1 indices seen in the GCC component of all 5 cases. The pelvic soft tissue and ovarian metastases in case 4 consisted predominantly of a signet ring cell carcinoma with a minor component of goblet cells and was interpreted as an adenocarcinoma ex-GCC. In view of the fact that these combined carcinoid tumors appear to behave more as goblet cell carcinoids, detailed microscopic examination of classical carcinoid tumors of the appendix is suggested and larger series with longer follow-up is required to

  4. VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis

    PubMed Central

    Silva, Scott R.; Bowen, Kanika A.; Rychahou, Piotr G.; Jackson, Lindsey N.; Weiss, Heidi L.; Lee, Eun Y.; Townsend, Courtney M.; Evers, B. Mark

    2014-01-01

    Carcinoid tumors are slow growing and highly vascular neuroendocrine neoplasms that are increasing in incidence. Previously, we showed that carcinoid tumors express vascular endothelial growth factor receptor 2 (VEGFR-2) in the epithelial compartment of carcinoid tumor sections; yet, its role is not completely understood. The purpose of our study was to: (i) assess the expression of VEGFR-2 in the novel human carcinoid cell line BON, (ii) to determine the role of PI3K/Akt signaling on VEGFR-2 expression and (iii) to assess the effect of VEGFR-2 on BON cell invasion, migration and proliferation. We found that, although VEGFR-2 is expressed in BON cells, reduction in VEGFR-2 expression actually enhanced proliferation, invasion, and migration of the BON cell line. Also, expression of VEGFR-2 was inversely related to PI3K signaling. Carcinoid liver metastases in mice demonstrated decreased VEGFR-2 expression. Furthermore, the expression of a truncated, soluble form of VEGFR-2 (sVEGFR-2), a protein demonstrated to inhibit cell growth, was detected in BON cells. The presence of VEGFR-2 in the epithelial component of carcinoid tumors and in the BON cell line suggests an alternate role for VEGFR-2, in addition to its well-defined role in angiogenesis. The expression of sVEGFR-2 may explain the inverse relationship between VEGFR-2 expression and PI3K/Akt signaling and the inhibitory effect VEGFR-2 has on BON cell proliferation, migration and invasion. PMID:20473929

  5. Carcinoid heart disease.

    PubMed

    Hassan, Saamir A; Banchs, Jose; Iliescu, Cezar; Dasari, Arvind; Lopez-Mattei, Juan; Yusuf, Syed Wamique

    2017-10-01

    Rare neuroendocrine tumours (NETs) that most commonly arise in the gastrointestinal tract can lead to carcinoid syndrome and carcinoid heart disease. Patients with carcinoid syndrome present with vasomotor changes, hypermotility of the gastrointestinal system, hypotension and bronchospasm. Medical therapy for carcinoid syndrome, typically with somatostatin analogues, can help control symptoms, inhibit tumour progression and prolong survival. Carcinoid heart disease occurs in more than 50% of these patients and is the initial presentation of carcinoid syndrome in up to 20% of patients. Carcinoid heart disease has characteristic findings of plaque-like deposits composed of smooth muscle cells, myofibroblasts, extracellular matrix and an overlying endothelial layer which can lead to valve dysfunction. Valvular dysfunction can lead to oedema, ascites and right-sided heart failure. Medical therapy of carcinoid heart disease is limited to symptom control and palliation. Valve surgery for carcinoid heart disease should be considered for symptomatic patients with controlled metastatic carcinoid syndrome. A multidisciplinary approach is needed to guide optimal management. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. New cancer or carcinoid progression to small cell lung cancer?

    PubMed

    Ie, Susanti; Boyd, Michael

    2015-04-01

    Carcinoids and small cell lung cancer share neuroendocrine cellular origins. Surgery is the definitive treatment in typical carcinoid with few recurrences. For patients considered to be poor surgical candidates, ablative and cryotherapies have been utilized with good results. The long-term consequences of these alternatives approaches are unclear. We report a case of typical carcinoid treated with various alternative approaches over a period of 6 years with either transformation to small cell lung cancer or the development of a new primary in the same location.

  7. Generation and sequencing of pulmonary carcinoid tumor cell lines.

    PubMed

    Asiedu, Michael K; Thomas, Charles F; Tomaszek, Sandra C; Peikert, Tobias; Sanyal, Bharati; Sutor, Shari L; Aubry, Marie-Christine; Li, Peter; Wigle, Dennis A

    2014-12-01

    Pulmonary carcinoid tumors account for approximately 5% of all lung malignancies in adults, and comprise 30% of all carcinoid tumors. There are limited reagents available to study these rare tumors, and consequently no major advances have been made for patient treatment. We report the generation and characterization of human pulmonary carcinoid tumor cell lines to study underlying biology, and to provide models for testing novel chemotherapeutic agents. Tissue was harvested from three patients with primary pulmonary typical carcinoid tumors undergoing surgical resection. The tumor was dissociated and plated onto dishes in culture media. The established cell lines were characterized by immunohistochemistry, Western blotting, and cell proliferation assays. Tumorigenicity was confirmed by soft agar growth and the ability to form tumors in a mouse xenograft model. Exome and RNA sequencing of patient tumor samples and cell lines was performed using standard protocols. Three typical carcinoid tumor lines grew as adherent monolayers in vitro, expressed neuroendocrine markers consistent with the primary tumor, and formed colonies in soft agar. A single cell line produced lung tumors in nude mice after intravenous injection. Exome and RNA sequencing of this cell line showed lineage relationship with the primary tumor, and demonstrated mutations in a number of genes related to neuronal differentiation. Three human pulmonary typical carcinoid tumor cell lines have been generated and characterized as a tool for studying the biology and novel treatment approaches for these rare tumors.

  8. FAIM2, as a novel diagnostic maker and a potential therapeutic target for small-cell lung cancer and atypical carcinoid

    PubMed Central

    Kang, Hio Chung; Kim, Jong In; Chang, Hee Kyung; Woodard, Gavitt; Choi, Young Sik; Ku, Ja-Lok; Jablons, David M.; Kim, Il-Jin

    2016-01-01

    Lung neuroendocrine (NE) tumors are a heterogeneous group of tumors arising from neuroendocrine cells that includes typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell NE cancer. The subtyping of NE tumors is based on the number of mitoses per high powered field and the presences of necrosis. However, the best diagnostic criteria to differentiate various subtypes of lung NE tumors remains controversial and few diagnostic markers distinguish typical and atypical carcinoid. In this study, we show that FAIM2, an inhibitory molecule in the Fas-apoptosis pathway, is significantly overexpressed in SCLC compared to non-small cell lung cancer. In addition, FAIM2 expression is significantly higher in atypical carcinoid than typical carcinoid. As atypical carcinoid has been shown to have worse clinical outcomes than typical carcinoid, our data suggests that FAIM2 may be a useful diagnostic marker for atypical carcinoid. Knockdown of FAIM2 expression increases Fas-induced apoptotic cell death in SCLC cells. Etoposide treatment combined with FAIM2 inhibition also shows modest but significant reduction of viable SCLC cells. Taken together, our results suggest that FAIM2 is a potential NE tumor marker with higher expression in atypical carcinoid and SCLC, and could be a new therapeutic target for SCLC. PMID:27677402

  9. The PARP inhibitor ABT-888 potentiates darbazine-induced cell death in carcinoids

    PubMed Central

    Somnay, Yash; Lubner, Sam; Gill, Harpreet; Matsumura, Jon Blake; Chen, Herbert

    2016-01-01

    Monoagent DNA-alkylating chemotherapies like dacarbazine are among a paucity of medical treatments for advanced carcinoid tumors, but are limited by host toxicity and intrinsic chemoresistance through the base excision repair (BER) pathway via poly (ADP-ribose) polymerase (PARP). Hence, inhibitors of PARP may potentiate DNA-damaging agents by blocking BER and DNA restoration. We show that the PARP inhibitor ABT-888 (Veliparib) enhances the cytotoxic effects of dacarbazine in carcinoids. Two human carcinoid cell lines (BON and H727) treated with a combination of ABT-888 and dacarbazine resulted in synergistic growth inhibition signified by combination indices <1 on the Chou-Talalay scale. ABT-888 administered prior to varying dacarbazine doses promoted the suppression of neuroendocrine biomarkers of malignancy ASCL1 and CgA, shown by Western analysis. ATM phosphorylation and p21Waf1/Cip1 activation, indicative of DNA damage, were increased by ABT-888 when combined with dacarbazine treatment, suggesting BER pathway attenuation by ABT-888. PE Annexin V/7-AAD staining and sorting revealed a profound induction of apoptosis following combination treatment, which was further confirmed by increased PARP cleavage. These results demonstrate that ABT-888 synergizes dacarbazine treatment in carcinoids. Therefore, ABT-888 may help treat carcinoids unresponsive or refractory to mainstay therapies. PMID:27632933

  10. Clear cell carcinoid tumor of the distal common bile duct

    PubMed Central

    Todoroki, Takeshi; Sano, Takaaki; Yamada, Shuji; Hirahara, Nobutsune; Toda, Naotaka; Tsukada, Katsuhiko; Motojima, Ryuji; Motojima, Teiji

    2007-01-01

    Background Carcinoid tumors rarely arise in the extrahepatic bile duct and can be difficult to distinguish from carcinoma. There are no reports of clear cell carcinoid (CCC) tumors in the distal bile duct (DBD) to the best of our knowledge. Herein, we report a CCC tumor in the DBD and review the literature concerning extrahepatic bile duct carcinoid tumors. Case presentation A 73-old man presented with fever and occult obstructive jaundice. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreaticography (MRCP) demonstrated a nodular tumor projection in the DBD without regional lymph node swelling. Under suspicion of carcinoma, we resected the head of the pancreas along with 2nd portion duodenectomy and a lymph node dissection. The surgical specimen showed a golden yellow polypoid tumor in the DBD (0.8 × 0.6 × 0.5 cm in size). The lesion was composed of clear polygonal cells arranged in nests and a trabecular pattern. The tumor invaded through the wall into the fibromuscular layer. Immunohistochemical stains showed that neoplastic cells were positive for neuron-specific enolase (NSE), chromogranin A, synaptophysin, and pancreatic polypeptide and negative for inhibin, keratin, CD56, serotonin, gastrin and somatostatin. The postoperative course was uneventful and he is living well without relapse 12 months after surgery. Conclusion Given the preoperative difficulty in differentiating carcinoid from carcinoma, the pancreaticoduodenectomy is an appropriate treatment choice for carcinoid tumors located within the intra-pancreatic bile duct. PMID:17227590

  11. The role of endogenous gastrin in the development of enterochromaffin-like cell carcinoid tumors in Mastomys natalensis: a study with the specific gastrin receptor antagonist AG-041R.

    PubMed

    Chiba, T; Kinoshita, Y; Sawada, M; Kishi, K; Baba, A; Hoshino, E

    1998-01-01

    We examined the effects of a newly synthesized gastrin receptor antagonist, AG-041R, on the growth of enterochromaffin-like (ECL) carcinoid tumors in Mastomys natalensis both in vitro and in vivo. AG-041R was as potent as the well known gastrin antagonist L365,260 in inhibiting not only the gastrin-induced release of histamine from but also histidine decarboxylase (HDC) gene expression in the ECL carcinoid tumor cells. AG-041R also inhibited gastrin-induced DNA synthesis and c-fos gene expression in the tumor cells. Furthermore, AG-041R significantly inhibited the growth of the transplanted Mastomys ECL carcinoid tumors in vivo. From these data, it is concluded that endogenous gastrin is involved in the growth of ECL carcinoid tumors in Mastomys natalensis. Moreover, AG-041R is shown to have a potential as an anti-neoplastic agent for ECL carcinoid tumor of the stomach.

  12. Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines

    PubMed Central

    2013-01-01

    Background Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14-25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids. Methods In vitro studies were used for the dose–response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase). Results Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0–80 μM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content. Conclusions The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids. PMID:23927827

  13. Conservation of the Notch1 signaling pathway in gastrointestinal carcinoid cells.

    PubMed

    Kunnimalaiyaan, Muthusamy; Traeger, Kelly; Chen, Herbert

    2005-10-01

    Gastrointestinal (GI) carcinoid cells secrete multiple neuroendocrine (NE) markers and hormones including 5-hydroxytryptamine and chromogranin A. We were interested in determining whether activation of the Notch1 signal transduction pathway in carcinoid cells could modulate production of NE markers and hormones. Human pancreatic carcinoid cells (BON cells) were stably transduced with an estrogen-inducible Notch1 construct, creating BON-NIER cells. In the present study, we found that Notch1 is not detectable in human GI carcinoid tumor cells. The induction of Notch1 in human BON carcinoid cells led to high levels of functional Notch1, as measured by CBF-1 binding studies, resulting in activation of the Notch1 pathway. Similar to its developmental role in the GI tract, Notch1 pathway activation led to an increase in hairy enhancer of split 1 (HES-1) protein and a concomitant silencing of human Notch1/HES-1/achaete-scute homolog 1. Furthermore, Notch1 activation led to a significant reduction in NE markers. Most interestingly, activation of the Notch1 pathway caused a significant reduction in 5-hydroxytryptamine, an important bioactive hormone in carcinoid syndrome. In addition, persistent activation of the Notch1 pathway in BON cells led to a notable reduction in cellular proliferation. These results demonstrate that the Notch1 pathway, which plays a critical role in the differentiation of enteroendocrine cells, is highly conserved in the gut. Therefore, manipulation of the Notch1 signaling pathway may be useful for expanding the targets for therapeutic and palliative treatment of patients with carcinoid tumors.

  14. Small cell carcinoma of the colon arising in a carcinoid tumor.

    PubMed

    Saif, M Wasif

    2013-04-01

    Small cell carcinomas of the gastrointestinal tract are rare and clinically aggressive tumors. A case is presented of a 70 year-old woman who presented with small bowel obstruction and was found to have a cecal mass. She underwent right hemicolectomy, and histopathology showed a small cell carcinoma arising in the background of a carcinoid tumor. Although small cell carcinomas of the colon have frequently been found in association with colonic adenomas, this appears to be the first report of a low-grade carcinoid tumor in combination with a small cell carcinoma.

  15. Goblet cells carcinoid with mucinous adenocarcinoma of the vermiform appendix: a step towards the unitary intestinal stem cell theory?

    PubMed

    Gravante, G; Yahia, S; Gopalakrishnan, K; Mathew, G

    2014-06-01

    Associations of various histotypes in appendiceal neoplasms may help elucidate the histogenesis of such uncommon tumors. We present the fourth published case of Goblet Cell Carcinoid (GCC) associated with mucinous adenocarcinoma of the appendix. This association has been described only for GCC and not for classic appendix carcinoids which are thought to originate from neuroendocrine-committed cells. The GCC-mucinous association adds more towards the theory of a pluripotent intestinal stem cell with amphicrine possibilities of differentiation.

  16. Polysialic acid of the neural cell adhesion molecule distinguishes small cell lung carcinoma from carcinoids.

    PubMed Central

    Komminoth, P.; Roth, J.; Lackie, P. M.; Bitter-Suermann, D.; Heitz, P. U.

    1991-01-01

    The neural cell adhesion molecule (NCAM) exists in various types of neuroendocrine cells and their tumors. A typical feature of NCAM is polysialic acid, of which the chain length is developmentally regulated. The authors have performed a comparative immunohistochemical study on small cell lung carcinomas and bronchial as well as gastrointestinal carcinoids with the monoclonal antibody (MAb) 735 reactive with the long-chain form of polysialic acid. The small cell lung carcinomas, irrespective of their histological type, were positive for polysialic acid. Metastatic tumor cell complexes also exhibited immunostaining. The tumor cell-surface-associated immunostaining for polysialic acid was sensitive to endoneuraminidase. The mature and atypical bronchial and gastrointestinal carcinoids were not immunoreactive for polysialic acid. Cytoplasmic staining in groups of cells of carcinoids (2 of 28 cases) was due to nonspecific antibody binding, which could be prevented by increased ion strength. These data indicate that neuroendocrine tumors of the lung can be distinguished by their content of highly sialylated NCAM. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:1651057

  17. Carcinoid Tumor

    MedlinePlus

    ... are here Home > Types of Cancer > Carcinoid Tumor Carcinoid Tumor This is Cancer.Net’s Guide to Carcinoid Tumor. Use the menu below to choose the ... social workers, and patient advocates. Cancer.Net Guide Carcinoid Tumor Introduction Statistics Medical Illustrations Risk Factors Symptoms ...

  18. Composite renal cell carcinoma with clear cell renal cell carcinomatous and carcinoid tumoral elements: a first case report.

    PubMed

    Bressenot, A; Delaunay, C; Gauchotte, G; Oliver, A; Boudrant, G; Montagne, K

    2010-02-01

    Renal endocrine tumours are extremely rare, and carcinoid tumoral elements in renal cell carcinoma have never been reported. This is the first report of a composite renal cell carcinoma containing a clear cell renal cell carcinoma associated with carcinoid tumoral elements, in a patient with synchronous metastatic disease. In the absence of specific radiological and clinical manifestations, typical morphological features as well as an immunostaining profile of neuroendocrine differentiation were identified by microscopy. Secondary nodal and liver localisations were characterised by carcinoid elements only. Despite antiangiogenic therapy, liver metastasis progressed, suggesting that adjuvant therapy cannot be based on the presence of the clear cell renal cell carcinoma component. In this context, extensive tissue sampling is recommended to reveal the endocrine component that is the most aggressive element of such a composite carcinoma.

  19. Giant cell arteritis and polymyalgia rheumatica as first manifestation of typical pulmonary carcinoid tumor.

    PubMed

    Aguiar, T; Vincent, M B

    2015-12-23

    Giant cell arteritis (GCA), a systemic vasculitis of unknown origin, may appear rarely as a paraneoplastic syndrome. Cases secondary to pulmonary neuroendocrine tumors have not been reported. A 75-year-old female developed prednisone-responsive GCA/polymyalgia rheumatica (PMR) shortly followed by syndrome of inappropriate antidiuretic hormone secretion. An 8 mm carcinoid lung tumor with positron emission tomography normal uptake was found. After a thoracoscopic tumor resection the patient experienced complete clinical and laboratory remission. This is the first report of GCA with PMR in the context of carcinoid lung tumor. It emphasizes the role of paraneoplastic vasculitis as a possible cause of GCA.

  20. The role of endogenous gastrin in the development of enterochromaffin-like cell carcinoid tumors in Mastomys natalensis: a study with the specific gastrin receptor antagonist AG-041R.

    PubMed Central

    Chiba, T.; Kinoshita, Y.; Sawada, M.; Kishi, K.; Baba, A.; Hoshino, E.

    1998-01-01

    We examined the effects of a newly synthesized gastrin receptor antagonist, AG-041R, on the growth of enterochromaffin-like (ECL) carcinoid tumors in Mastomys natalensis both in vitro and in vivo. AG-041R was as potent as the well known gastrin antagonist L365,260 in inhibiting not only the gastrin-induced release of histamine from but also histidine decarboxylase (HDC) gene expression in the ECL carcinoid tumor cells. AG-041R also inhibited gastrin-induced DNA synthesis and c-fos gene expression in the tumor cells. Furthermore, AG-041R significantly inhibited the growth of the transplanted Mastomys ECL carcinoid tumors in vivo. From these data, it is concluded that endogenous gastrin is involved in the growth of ECL carcinoid tumors in Mastomys natalensis. Moreover, AG-041R is shown to have a potential as an anti-neoplastic agent for ECL carcinoid tumor of the stomach. Images Figure 1 Figure 5 Figure 6 PMID:10461356

  1. [Carcinoid papillomatosis].

    PubMed

    Cardama, J E; Gatti, J C; Cabrera, H N; Bianchi, O; Garófalo, M

    1976-01-01

    Papilomatosis Carcinoides, presents clinical and histological characteristics that may be authentically described as a transition state between the benign papillomatous proliferations and spindle cell carcinoma. It involves a series of clinical conditions, that are described with different names that correspond to the condyloma accuminatum gigantum. [Buschke and Lowenstein) wartic carcinoma [Ackerman], Papillomatosis oral florid [Rock and Fisher], carcinomatoid [Gilbert] profuse conjuntival papillomatosis [Bazex], etc. These latter only refer to partial localizations or a special clinical form. That is why we believe the denonmination Papillomatosis Carcinoides, is preferable, which is its cutaneous, mucose or semimucose forms involves all of them. The treatments applied to the 18 cases presented have been very diverse: they vary from the elimination of the lesions by the application of topical podophylin to large surgical ablations. But most of them showed a regression or cure of their lesions by citostatics [methotrexate] not prevent the proliferative advance of the lessions. These therapeutic data can also contribute to its nosologic classification. In some cases they have an evolutive character with slow progression for years, still being curable with podophylin and in others that due to their chronic evolution with added supuration, and complications of the general health, make surgery necessary. In most cases, the antimetabolities are the therapy of choice the radiations seem inoperative. It may be noted that tumoral papillomatous lesions produced by virus, exist in veterinatian pathology (fibropapillomatosis in the bovine genitals, equine sarcoid, papilomatosis of goats, monkeys, etc.). Noteworthy are those of the oral mucosa of rabbits which are white greyish sesiles or pedunculated small nodules localized mostly on the inferior surface of tongue with a similar histology to the papilomatosis carcinoides. These observations would suggest a viral ethiology

  2. Carcinoid Tumors

    MedlinePlus

    Carcinoid tumors are rare, slow-growing cancers. They usually start in the lining of the digestive tract or in the lungs. They grow ... trouble breathing. Surgery is the main treatment for carcinoid tumors. If they haven't spread to other parts of the body, surgery can cure the cancer.

  3. Glucagon-, glicentin-, and pancreatic polypeptide-like immunoreativities in rectal carcinoids and related colorectal cells.

    PubMed Central

    Fiocca, R.; Capella, C.; Buffa, R.; Fontana, R.; Solcia, E.; Hage, E.; Chance, R. E.; Moody, A. J.

    1980-01-01

    Three nonargentaffin rectal carcinoids have been investigated immunohistochemically. In one case most tumor cells reacted with antiglucagon sera as well as with antiglicentin, antibovine pancreatic polypeptide (BPP), and antihuman pancreatic polypeptide (HPP) sera; they were identified ultrastructurally as L cells. Another case showed glucagon-, glicentin-, and BPP-immunoreactive cells but lacked HPP immunoreactivity. In the third case glucagon- and glicentin-immunoreactive cells were well represented, while PP immunoreactivities were scarce. Parallel investigations of human rectal and sigmoid mucosa showed numerous cells reacting with glucagon, glicentin, and BPP antisera, most of which lacked HPP immunoreactivity. Cells reacting with glucagon and glicentin antisera, while lacking PP immunoreactivities, were also found. Thus, both tumor and nontumor cells produce glucagonlike immunoreactive (GLI) peptides--one of which may be glicentin or a related molecule--as well as PP-related sequences, although differing histochemically and ultrastructurally from glucagon or PP cells of the human pancreas. It is concluded that nonargentaffin rectal carcinoids are histogenetically linked to nonargentaffin endocrine cells of the human rectum. Images p[92]-a Figures 1-3 Figure 4 Figure 5 PMID:7395969

  4. Multiple carcinoid tumors of the rectum: report of two cases suggesting the origin of carcinoid tumors.

    PubMed

    Sasou, Shunichi; Suto, Takeshi; Satoh, Toshihiko; Tamura, Gen; Kudara, Norihiko

    2012-10-01

    Two cases of multiple carcinoid tumors of the rectum with numerous micronests of carcinoid tumors are reported. The patients were 51- and 58-year-old males. Many carcinoid tumors and numerous carcinoid micronests were found in the resected rectum; the total number of carcinoid tumors, groups of micronests, and solitary micronests was 69 in the first case and 62 in the second case. The micronests, consisting of a few to many endocrine cells, were observed in the lamina propria, muscularis mucosa, and/or submucosa. Micronests increased in number, gathered and formed carcinoid tumors, which were up to 8 mm in diameter. It was found that a nest of the carcinoid tumors in the lamina propria showed continuity with the endocrine cells of a crypt in the different carcinoid tumors in both cases. The carcinoid tumor and micronest infiltrated the nerves and ganglions in the muscularis mucosa and submucosa. Nests of the carcinoid tumors and micronests were surrounded by S-100-positive cells. Lymph node metastases of the carcinoid tumor were found in both cases. Rectal carcinoid tumors may originate from endocrine cells of the crypts, and multiple carcinoid tumors may occur heterogeneously. © 2012 The Authors. Pathology International © 2012 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  5. A Rare Combination of Ovarian and Uterine Leiomyomas with Goblet Cell Carcinoid of the Appendix

    PubMed Central

    Al-Shaikh, Abdulrahman F.; Darwish, Abdulla; Nagaraj, Veena; Alsada, Abeer

    2015-01-01

    We present a case of the rare combination of unilateral ovarian leiomyoma, uterine leiomyoma, and goblet cell carcinoid tumor of the appendix in a premenopausal woman who presented with right iliac pain. Immunohistochemistry study for desmin (muscle marker) and chromogranin and synaptophysin (neuroendocrine markers) confirmed immunophenotyping origin. Interestingly, both tumors showed positive reaction for estrogen receptor. To our knowledge, such a combination has not been reported previously in the literature. In this paper, the pathogenesis and differential diagnosis of both types of tumors are discussed. PMID:25685587

  6. A Prospective Study of Gastric Carcinoids and Enterochromaffin-Like Cell Changes in Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome: Identification of Risk Factors

    PubMed Central

    Berna, Marc J.; Annibale, Bruno; Marignani, Massimo; Luong, Tu Vinh; Corleto, Vito; Pace, Andrea; Ito, Tetsuhide; Liewehr, David; Venzon, David J.; Delle Fave, Gianfranco; Bordi, Cesare; Jensen, Robert T.

    2008-01-01

    Context: Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. Objectives: Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. Setting and Patients: Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. Interventions and Outcome Measures: Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and α-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. Results: ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong α-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. Conclusions: Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better

  7. A Study of Appendiceal Crypt Cell Adenocarcinoma (So-Called Goblet Cell Carcinoid and Its Related Adenocarcinoma).

    PubMed

    Nonaka, Daisuke; Papaxoinis, George; Lamarca, Angela; Fulford, Paul; Valle, Juan; Chakrabarty, Bipasha

    2017-08-17

    Goblet cell carcinoids (GCCs) of the appendix are rare tumors, characterized by a carcinoid-like organoid growth pattern. Despite the term carcinoid, neuroendocrine features are inconspicuous, and its behavior is distinct from carcinoid. Its high grade counterpart is designated as adenocarcinoma ex GCC. We conducted a retrospective study of 105 tumors to find prognostic values of a variety of clinico-pathologic features. The tumors were subclassified as low grade, equivalent to classic type, and high grade, defined as loss of organoid pattern, and a proportion (%) of low and high grades were documented in each tumor. Correlations between survival and various clinico-pathologic parameters were investigated. One-third were pure low grade while the remainder contained variable high grade component ranging 5-95%. Neuroendocrine cell component ranged 0-90% (median 5) while mucus cell component ranged 5-100% (median 70). By univariate analysis, size, stage, high grade component, nuclear grade, surgery and chemotherapy correlated with cancer-related survival (CSS), and by multivariate analysis, stage (P=.001), high grade component (P=.008) and tumor size (P=.005) correlated with CSS. There was significant difference in CSS when the cases were grouped in high grade component <40%, 40-90 and ≤90% (P<.001). Our results indicate that staging and proportion of high grade histology may provide important prognostic information. Neuroendocrine component was insignificant in both low and high grade areas. In light of our findings, this tumor type is best regarded as a variant of adenocarcinoma, and the term crypt cell adenocarcinoma more appropriately reflects the nature and origin of this tumor group. Copyright © 2017. Published by Elsevier Inc.

  8. Primary renal carcinoid tumour with lung metastasis misdiagnosed as renal cell carcinoma.

    PubMed

    Daboul, Nour; Monga, Dulabh; Bunker, Mark

    2016-03-07

    A 58-year-old man with a history of metastatic renal cell carcinoma (RCC) diagnosed 10 years prior, status post right nephrectomy, presented for evaluation of pulmonary nodules. A year after the nephrectomy, he had undergone cutaneous metastasectomy in the right flank area, and a further 2 years later he had had his second cutaneous metastasectomy in the right chest wall. Both cutaneous pathologies had, at the time, shown metastatic neoplasm with histological features compatible with those of the previous renal tumour. He was treated with sorafenib. 3 years later he developed asymptomatic pulmonary nodules, which gradually doubled in size over the next 2.5 years. He underwent bronchoscopy and left lower lobe biopsy. Pathology revealed a metastatic renal carcinoid/neuroendocrine tumour. Second review of the previous renal neoplasm and the cutaneous metastatic pathology showed trabecular architecture, consistent with carcinoid, but mimicking the long parallel arrays that have been described in some cases of papillary RCC. 2016 BMJ Publishing Group Ltd.

  9. Stages of Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... cancer cells have spread within the stomach and intestines or to other parts of the body. Staging ... the NCI website . Carcinoid Tumors in the Small Intestine It is not clear what the best treatment ...

  10. Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer

    ClinicalTrials.gov

    2017-07-10

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Endometrial Serous Adenocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Lung Carcinoid Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Metastatic Digestive System Neuroendocrine Tumor G1; Ovarian Carcinosarcoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Polypeptide Tumor; Recurrent Adult Liver Carcinoma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IIIC Uterine Corpus Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  11. Chrysin suppresses the achaete-scute complex-like1 and alters the neuroendocrine phenotype of carcinoids

    PubMed Central

    Somnay, Yash R.; Dull, Barbara Zarebczan; Eide, Jacob; Jaskula-Sztul, Renata; Chen, Herbert

    2015-01-01

    Carcinoids are neuroendocrine neoplasms that cause significant morbidity and mortality, and for which few effective therapies are available. Given the recent identification of the anti-cancer flavonoid chrysin, we sought to investigate its therapeutic potential in carcinoids. Here, we report chrysin’s ability to modulate the achaete-scute complex-like1 (ASCL1), a neuroendocrine-specific transcription factor highly implicated in the malignant phenotype of carcinoids and other neuroendocrine cancers. Moreover, we elucidate the role of ASCL1 in carcinoid growth and bioactivity. Treatment of two carcinoid cell lines (BON and H727) with varying chrysin concentrations suppressed cell proliferation, while reducing expression of ASCL1 and the neuroendocrine biomarker chromogranin A (CgA), demonstrated by Western blotting. Propidium iodide and PE AnnexinV/7-AAD staining and sorting following chrysin treatment revealed S/G2 phase arrest and apoptosis, respectively. This was corroborated by chrysin-induced cleavage of caspase-3 and PARP and activation of p21Waf1/Cip1. Furthermore, direct ASCL1 knockdown with an ASCL1-specific small interfering RNA inhibited CgA and synaptophysin expression as well as carcinoid proliferation, while also reducing cyclin B1 and D1, and increasing p21Waf1/Cip1 and p27Kip1 expression, suggesting an arrest of the cell-cycle. Collectively, these findings warrant the deliberation of targeted ASCL1 suppression by chrysin or other agents as a therapeutic approach for carcinoid management. PMID:26403073

  12. Goblet cell carcinoids of the appendix: Tumor biology, mutations and management strategies

    PubMed Central

    Shenoy, Santosh

    2016-01-01

    Malignant neoplasms of the appendix are rare and represent less than 1% of gastrointestinal cancers. Goblet cell carcinoids (GCC) tumors are a distinctive group of heterogeneous appendiceal neoplasm that exhibit unique clinical and pathologic features. This review focuses on the current diagnostic procedures, pathogenesis, possible signaling mechanisms and treatment options for GCC. Perspectives for future research are discussed. The tumor likely arises from pluripotent intestinal epithelial crypt base stem cells. Previous findings of Notch signaling as a tumor suppressor in Neuroendocrine tumors may have a similar role in this tumor too. Loss of Notch signaling may be the driver mutation with other successive downstream mutations likely favors them into progressing and behavior similar to poorly differentiated adenocarcinoma with minimal neuroendocrine differentiation. A multidisciplinary approach is suggested for optimal outcomes. Surgery remains the main treatment modality. Simple appendectomy may be sufficient in early stages while right hemicolectomy is recommended for advanced tumors. Cytoreductive surgery with heated intraperitoneal chemotherapy may improve survival in a select few with metastatic peritoneal disease. These tumors have an unpredictable behavior even in early stages and local recurrence and delayed metastases may be seen. Lifelong surveillance is warranted. PMID:27830037

  13. Carcinoid tumor with bilateral renal involvement in a child.

    PubMed

    Warrier, Raj P; Varma, Aditi Vian; Chauhan, Aman; Ward, Ken; Craver, Randal

    2011-12-01

    Carcinoid tumors are uncommon in children. Kidneys are rarely involved as they do not possess neuro-endocrine cells. Work up of painless hematuria after abdominal trauma in a 10-year-old boy revealed primary carcinoid tumors with metastasis to both kidneys. We were unable to find any previous reports of renal involvement by carcinoid tumor in children.

  14. The novel somatostatin receptor 2/dopamine type 2 receptor chimeric compound BIM-23A758 decreases the viability of human GOT1 midgut carcinoid cells.

    PubMed

    Zitzmann, Kathrin; Andersen, Sandra; Vlotides, George; Spöttl, Gerald; Zhang, Shengwen; Datta, Rakesh; Culler, Michael; Göke, Burkhard; Auernhammer, Christoph J

    2013-01-01

    The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system coexpress somatostatin receptors (SSTRs) and dopamine type 2 receptors (D2R), thus providing a rationale for the use of novel SSTR2/D2R chimeric compounds in NET disease. Here we investigate the antitumor potential of the SSTR2/D2R chimeric compounds BIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonist BIM-23023 and the selective D2R agonist BIM-53097 on human NET cell lines of heterogeneous origin. While having only minor effects on human pancreatic and bronchus carcinoid cells (BON1 and NCI-H727), BIM-23A758 induced significant antitumor effects in human midgut carcinoid cells (GOT1). These effects involved apoptosis induction as well as inhibition of mitogen-activated protein kinase and Akt signaling. Consistent with their antitumor response to BIM-23A758, GOT1 cells showed relatively high expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cells highly express the short transcript variant of D2R. In contrast to BIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as the individual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097 induced no or only minor antitumor responses in the examined NET cell lines. Taken together, our findings suggest that the novel SSTR2/D2R chimeric compound BIM-23A758 might be a promising substance for the treatment of NETs highly expressing SSTR2 and D2R. In particular, a sufficient expression of the short transcript variant of DR2 might play a pivotal role for effective treatment.

  15. What Are Lung Carcinoid Tumors?

    MedlinePlus

    ... Carcinoid Tumor About Lung Carcinoid Tumors What Are Lung Carcinoid Tumors? Lung carcinoid tumors (also known as ... lungs, as well as the neuroendocrine system. The lungs The lungs are 2 sponge-like organs in ...

  16. Concurrent primary carcinoid tumor arising within mature teratoma and clear cell renal cell carcinoma in the horseshoe kidney: report of a rare case and review of the literature.

    PubMed

    Sun, Ke; You, Qihan; Zhao, Ming; Yao, Hongtian; Xiang, Hua; Wang, Lijun

    2013-01-01

    Primary carcinoid tumor arising in a mature teratoma of the horseshoe kidney is exceptionally rare and only 4 such cases have been reported in the world literature to date. The simultaneous occurrence of different subtypes of renal cell carcinoma (RCC) or RCC coexistence with non-RCC neoplasms from the same kidney is unusual and infrequently reported. Herein we report a case of primary carcinoid tumor arising within mature teratoma, concurrent with a clear cell RCC in the horseshoe kidney of a 37-year-old man. Histologically, both the carcinoid tumor and clear cell RCC demonstrated the characteristic morphology in their classic forms. In addition to the carcinoid tumor, the mature teratoma consisted of variably sized, large cystic spaces lined by cytologically bland mucinous columnar epithelium, pseudostratified columnar epithelium, ciliated epithelium and mature smooth muscle fibers were also identified within the cystic wall. Furthermore, foci of round, small nodules composed of mature prostatic acinus were noted in the teratoma which was confirmed by exhibiting strong immunoreactivity for prostate specific antigen. The present case serves to expand the histologic component that may be encountered in the mature terotoma of the kidney and further broadens the spectrum of primary tumors occurring in the horseshoe kidney.

  17. Concurrent primary carcinoid tumor arising within mature teratoma and clear cell renal cell carcinoma in the horseshoe kidney: report of a rare case and review of the literature

    PubMed Central

    Sun, Ke; You, Qihan; Zhao, Ming; Yao, Hongtian; Xiang, Hua; Wang, Lijun

    2013-01-01

    Primary carcinoid tumor arising in a mature teratoma of the horseshoe kidney is exceptionally rare and only 4 such cases have been reported in the world literature to date. The simultaneous occurrence of different subtypes of renal cell carcinoma (RCC) or RCC coexistence with non-RCC neoplasms from the same kidney is unusual and infrequently reported. Herein we report a case of primary carcinoid tumor arising within mature teratoma, concurrent with a clear cell RCC in the horseshoe kidney of a 37-year-old man. Histologically, both the carcinoid tumor and clear cell RCC demonstrated the characteristic morphology in their classic forms. In addition to the carcinoid tumor, the mature teratoma consisted of variably sized, large cystic spaces lined by cytologically bland mucinous columnar epithelium, pseudostratified columnar epithelium, ciliated epithelium and mature smooth muscle fibers were also identified within the cystic wall. Furthermore, foci of round, small nodules composed of mature prostatic acinus were noted in the teratoma which was confirmed by exhibiting strong immunoreactivity for prostate specific antigen. The present case serves to expand the histologic component that may be encountered in the mature terotoma of the kidney and further broadens the spectrum of primary tumors occurring in the horseshoe kidney. PMID:24228123

  18. Atypical carcinoid and large cell neuroendocrine carcinoma of the lung: a proteomic dataset from formalin-fixed archival samples

    PubMed Central

    Tanca, Alessandro; Addis, Maria Filippa; Pisanu, Salvatore; Abbondio, Marcello; Pagnozzi, Daniela; Eccher, Albino; Rindi, Guido; Cossu-Rocca, Paolo; Uzzau, Sergio; Fanciulli, Giuseppe

    2016-01-01

    Here we present a dataset generated using formalin-fixed paraffin-embedded archival samples from two rare lung neuroendocrine tumor subtypes (namely, two atypical carcinoids, ACs, and two large-cell neuroendocrine carcinomas, LCNECs). Samples were subjected to a shotgun proteomics pipeline, comprising full-length protein extraction, SDS removal through spin columns, in solution trypsin digestion, long gradient liquid chromatography peptide separation and LTQ-Orbitrap mass spectrometry analysis. A total of 1260 and 2436 proteins were identified in the AC and LCNEC samples, respectively, with FDR <1%. MS data are available in the PeptideAtlas repository at http://www.peptideatlas.org/PASS/PASS00375. PMID:27054153

  19. Carcinoid Cancer Foundation

    MedlinePlus

    ... size). The Latest News Project Zebra Report: Real-World Insights from the Carcinoid and NET Patient Community ... release the first ever Project Zebra Report: Real-World Insights from the Carcinoid and Neuroendocrine Tumor Patient ...

  20. Primary renal carcinoid tumor.

    PubMed

    Kanodia, K V; Vanikar, A V; Patel, R D; Suthar, K S; Kute, V B; Modi, P R; Trivedi, H L

    2013-09-01

    Primary renal carcinoid tumor is extremely rare and, therefore, its pathogenesis and prognosis is not well known. We report a primary renal carcinoid in a 26-year-old man treated by radical nephrectomy.

  1. Erroneous diagnosis of small cell lung cancer based on small biopsies with far-reaching consequences: case report of a typical carcinoid tumor

    PubMed Central

    Krebs, Bettina; Kampe, Sandra; Theegarten, Dirk; Aigner, Clemens

    2017-01-01

    Although neuroendocrine tumors (NETs) of the lung are frequently discussed together, carcinoids are very different from high-grade small cell lung carcinoma (SCLC). SCLC is found in heavy-smoking, older patients, whereas smoking is not strongly associated with carcinoid tumors. We present the case of a 46-year-old never smoking woman who was misdiagnosed with SCLC. The patient was not responsive to radio-chemotherapy plus prophylactic cranial irradiation (PCI); she had a typical carcinoid (TC) tumor according to the final pathology report. We aim to demonstrate that diagnosis of SCLC based on cytology or small biopsy specimens must be scrutinized when the clinical constellation is unusual, or when the follow-up assessment shows no response to systemic treatment. PMID:28275490

  2. Activation of Type 1 CRH receptor isoforms induces serotonin release from human carcinoid BON-1N cells: an enterochromaffin cell model.

    PubMed

    Wu, S Vincent; Yuan, Pu-Qing; Lai, Jim; Wong, Kelvin; Chen, Monica C; Ohning, Gordon V; Taché, Yvette

    2011-01-01

    CRH and 5-hydroxytryptamine (5-HT) are expressed in human colonic enterochromaffin (EC) cells, but their interactions at the cellular level remain largely unknown. The mechanistic and functional relationship between CRH and 5-HT systems in EC cells was investigated in a human carcinoid cloned BON cell line (BON-1N), widely used as an in vitro model of EC cell function. First, we identified multiple CRH(1) splice variants, including CRH(1a), CRH(1c), CRH(1f), and a novel form lacking exon 4, designated here as CRH(1i), in the BON-1N cells. The expression of CRH(1i) was also confirmed in human brain cortex, pituitary gland, and ileum. Immunocytochemistry and immunoblot analysis confirmed that BON-1N cells were CRH(1) and 5-HT positive. CRH, urocortin (Ucn)-1, and cortagine, a selective CRH(1) agonist, all increased intracellular cAMP, and this concentration-dependent response was inhibited by CRH(1)-selective antagonist NBI-35965. CRH and Ucn-1, but not Ucn-2, stimulated significant ERK1/2 phosphorylation. In transfected human embryonic kidney-293 cells, CRH(1i) isoforms produced a significant increase in pERK1/2 in response to CRH(1) agonists that was sensitive to NBI-35965. CRH and Ucn-1 stimulated 5-HT release that reached a maximal increase of 3.3- and 4-fold at 10(-8) m over the basal level, respectively. In addition, exposure to CRH for 24-h up-regulated tryptophan hydroxylase-1 mRNA levels in the BON-1N cells. These findings define the expression of EC cell-specific CRH(1) isoforms and activation of CRH(1)-dependent pathways leading to 5-HT release and synthesis; thus, providing functional evidence of a link exists between CRH and 5-HT systems, which have implications in stress-induced CRH(1) and 5-HT-mediated stimulation of lower intestinal function.

  3. Evaluation of the natural killer cell-interferon system in patients with mid-gut carcinoid tumours treated with leucocyte interferon.

    PubMed Central

    Funa, K; Alm, G V; Rönnblom, L; Oberg, K

    1983-01-01

    Nine patients with mid-gut carcinoid tumours received leucocyte interferon (IFN) i.m. daily for 90 days. Six patients clearly ameliorated in symptoms typical of the carcinoid syndrome (flushing, diarrhoea, asthma) which correlated with reduced serum levels of tumour related polypeptides and urinary output of 5-hydroxyindole acetic acid (5-HIAA). Before IFN treatment, peripheral blood mononuclear leucocytes (PBLs) from carcinoid patients showed markedly deficient production of pH 2 labile IFN-alpha in response to Staphylococcus aureus Cowan I (SACoI) in vitro. In contrast, IFN-alpha responses to the inducers Sendai virus and beta-haemolytic streptococcus group G and IFN-gamma responses to Lens culinaris lectin and concanavalin A were normal. Also, basal and in vitro IFN enhanced natural killer (NK) cell activity and T cell mitogen-induced cell proliferation were similar in patients and controls. During 90 days of IFN therapy, SACoI-induced IFN responses became entirely undetectable. There were transient declines at 1 and 30 days in IFN responses to the other IFN inducers, of mitogen-induced lymphocyte proliferation and of basal NK activities. The increments of NK cell activities after in vitro IFN exposure were clearly decreased in IFN treated patients, suggesting in vivo activation of these cells. Thus, the results demonstrate one remarkable abnormality in carcinoid patients: a deficient IFN response to SACoI and a clear influence of IFN therapy on several parameters of the IFN-NK system. PMID:6616963

  4. Synergistic effects of erlotinib and everolimus on bronchial carcinoids and large-cell neuroendocrine carcinomas with activated EGFR/AKT/mTOR pathway.

    PubMed

    Bago-Horvath, Zsuzsanna; Sieghart, Wolfgang; Grusch, Michael; Lackner, Andreas; Hayden, Hubert; Pirker, Christine; Komina, Oxana; Węsierska-Gądek, Józefa; Haitel, Andrea; Filipits, Martin; Berger, Walter; Schmid, Katharina

    2012-01-01

    Epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) are crucial targets in cancer therapy. Combined inhibition of both targets yielded synergistic effects in vitro and in vivo in several cancer entities. However, the impact of EGFR and mTOR expression and combined inhibition in neuroendocrine lung tumors other than small-cell lung cancer remains unclear. Expression and activation of EGFR/AKT/mTOR pathway constituents were investigated in typical and atypical bronchial carcinoid (AC) tumors and large-cell neuroendocrine lung carcinomas (LCNEC) by immunohistochemistry in 110 tumor samples, and correlated with clinicopathological parameters and patient survival. Cytotoxicity of mTOR inhibitor everolimus and EGFR inhibitor erlotinib alone and in combination was assessed using growth inhibition assay in NCI-H720 AC and SHP-77 LCNEC cells. Cell cycle phase distribution was determined by FACS. Apoptosis-associated activation of caspase-3/7 was measured by Caspase-Glo® assay. Activity status of EGFR and mTOR pathway components was analyzed by immunoblotting. Activation of the EGFR/AKT/mTOR axis could be demonstrated in all entities and was significantly increased in higher grade tumors. Neoadjuvant chemotherapy correlated significantly with p-AKT expression and p-ERK loss. Erlotinib combined with everolimus exerted synergistic combination effects in AC and LCNEC cells by induction of apoptosis, while cell cycle phase distribution remained unaffected. These effects could be explained by synergistic downregulation of phospho-mTOR, phospho-p70S6 kinase and phospho-AKT expression by everolimus and erlotinib. Our study indicates that EGFR and mTOR are clinically important targets in bronchial neuroendocrine tumors, and further in vivo and clinical exploration of combined inhibition is warranted. Copyright © 2012 S. Karger AG, Basel.

  5. Treatment Option Overview (Gastrointestinal Carcinoid Tumors)

    MedlinePlus

    ... cancer cells have spread within the stomach and intestines or to other parts of the body. Staging ... the NCI website . Carcinoid Tumors in the Small Intestine It is not clear what the best treatment ...

  6. General Information about Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... cancer cells have spread within the stomach and intestines or to other parts of the body. Staging ... the NCI website . Carcinoid Tumors in the Small Intestine It is not clear what the best treatment ...

  7. Treatment Options for Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... cancer cells have spread within the stomach and intestines or to other parts of the body. Staging ... the NCI website . Carcinoid Tumors in the Small Intestine It is not clear what the best treatment ...

  8. L1 cell adhesion molecule as a predictor for recurrence in pulmonary carcinoids and large-cell neuroendocrine tumors.

    PubMed

    Kim, Hyo Song; Yi, Seong Yoon; Jun, Hyun Jung; Ahn, Jin Seok; Ahn, Myung-Ju; Lee, Jeeyun; Kim, Youngwook; Cui, Zheng Yun; Hong, Hyo Jeong; Kim, Jin-Man; Li, Shengjin; Hwang, In Gyu; Park, Keunchil

    2009-02-01

    Pulmonary neuroendocrine tumors are a distinct subset of neoplasms with indolent to aggressive behavior. This study was conducted to evaluate the prognostic role of L1 cell adhesion molecule (L1CAM) in pulmonary neuroendocrine tumors. We retrospectively analyzed L1 expression in 55 cases of completely resected carcinoids and large-cell neuroendocrine carcinomas, by the immunohistochemistry with monoclonal antibody A10-A3 against human L1. L1 immunoreactivity was detected in 34 (61.8%) of 55 specimens. There was a significant correlation between L1 expression and the World Health Organization classification of this tumor (Spearman rank correlation, rho=0.60, p<0.001). With median follow-up of 52.0 months, the 5-year survival rate for patients with low expression of L1 (<20% of tumor cells stained) was significantly better compared with those with high expression of L1 (82.6% vs. 43.7%, p=0.005). L1 was also a significant independent predictor of disease-free survival, and patients with high L1 expression have a higher risk for recurrence compared with those with low L1 expression (hazard ratio, 3.0; 95% confidence interval, 1.2-8.3; p=0.034). L1 expression is significantly associated with aggressiveness and further studies with larger samples are needed to validate potential prognostic value for pulmonary neuroendocrine tumors.

  9. Effects of the single and combined treatment with dopamine agonist, somatostatin analog and mTOR inhibitors in a human lung carcinoid cell line: an in vitro study.

    PubMed

    Pivonello, Claudia; Rousaki, Panagoula; Negri, Mariarosaria; Sarnataro, Maddalena; Napolitano, Maria; Marino, Federica Zito; Patalano, Roberta; De Martino, Maria Cristina; Sciammarella, Concetta; Faggiano, Antongiulio; Rocco, Gaetano; Franco, Renato; Kaltsas, Gregory A; Colao, Annamaria; Pivonello, Rosario

    2016-09-29

    Somatostatin analogues and mTOR inhibitors have been used as medical therapy in lung carcinoids with variable results. No data are available on dopamine agonists as treatment for lung carcinoids. The main aim of the current study was to evaluate the effect of the combined treatment of somatostatin analogue octreotide and the dopamine agonist cabergoline with mTOR inhibitors in an in vitro model of typical lung carcinoids: the NCI-H727 cell line. In NCI-H727 cell line, reverse transcriptase-quantitative polymerase chain reaction and immunofluorescence were assessed to characterize the expression of the somatostatin receptor 2 and 5, dopamine receptor 2 and mTOR pathway components. Fifteen typical lung carcinoids tissue samples have been used for somatostatin receptor 2, dopamine receptor 2, and the main mTOR pathway component p70S6K expression and localization by immunohistochemistry. Cell viability, fluorescence-activated cell sorting analysis and western blot have been assessed to test the pharmacological effects of octreotide, cabergoline and mTOR inhibitors, and to evaluate the activation of specific cell signaling pathways in NCI-H727 cell line. NCI-H727 cell line expressed somatostatin receptor 2, somatostatin receptor 5 and dopamine receptor 2 and all mTOR pathway components at messenger and protein levels. Somatostatin receptor 2, dopamine receptor 2, and p70S6K (non phosphorylated and phosphorylated) proteins were expressed in most typical lung carcinoids tissue samples. Octreotide and cabergoline did not reduce cell viability as single agents but, when combined with mTOR inhibitors, they potentiate mTOR inhibitors effect after long-term exposure, reducing Akt and ERK phosphorylation, mTOR escape mechanisms, and increasing the expression DNA-damage-inducible transcript 4, an mTOR suppressor. In conclusion, the single use of octreotide and cabergoline is not sufficient to block cell viability but the combined approach of these agents with mTOR inhibitors

  10. Fine needle aspiration cytology of thymic carcinoid tumor.

    PubMed

    Wang, D Y; Kuo, S H; Chang, D B; Yang, P C; Lee, Y C; Hsu, H C; Luh, K T

    1995-01-01

    Carcinoid tumors of the thymus are very rare, and their cytologic findings have not been reported previously in English. Retrospective study of fine needle aspiration (FNA) cytologic features in four histopathologically verified thymic carcinoid tumors are described here in detail. The FNA cytology of thymic carcinoids is characterized by predominantly single and some loose clusters of small, round to oval cells with scanty cytoplasm, interspersed with some larger cells with moderate to abundant, granular cytoplasm. The differential diagnosis of the cytologic features between carcinoid tumor and other mediastinal tumors is also discussed.

  11. Metastatic carcinoid tumor--atypical presentation.

    PubMed

    Pleşa, Alina; Sarca, Emanuela; Maxim, Roxana

    2014-01-01

    Carcinoid tumor is a slow-growing type of neuroendocrine tumor, originating in the enterochromaffin cells and secreting mainly serotonin. Neuroendocrine tumors (NETs) are found throughout the intestinal tract, the appendix and terminal ileum being the most common locations, and are classified by site of origin and by degree of differentiation, with well-differentiated lesions representing those tumors formerly referred to as carcinoid tumors. The clinical symptoms are characterized by flushing, diarrhea, abdominal pain, and/or bronchial constriction and occur almost exclusively in patients with liver metastases due to the release of bioactive peptides and amines directly into the systemic circulation. We report the clinical, serological and histological diagnosis of a 67-years-old male patient with congestive heart failure secondary to carcinoid heart disease in the context of liver metastases of an ileum carcinoid tumor.

  12. [Case of primary renal carcinoid tumor with hemorrhage].

    PubMed

    Kubota, Yasuaki; Seike, Kensaku; Maeda, Shinichi; Tashiro, Kazuhiro

    2010-04-01

    Carcinoid tumors are low-grade malignant tumors that arise from neuroendocrine cells. Primary renal carcinoid tumors are extremely uncommon. A 63-year-old woman presented with a right abdominal mass and fever. Abdominal computed tomography demonstrated a mass in the right kidney; the mass measured 120 mm in diameter and showed hemorrhage. The patient underwent an uneventful right radical nephrectomy, and histological appearance was typical of carcinoid tumor. Immunohistochemistry demonstrated strong cytoplasmic labeling for neuron-specific enolase and synaptophysin. Additional examinations of the gastrointestinal tract did not show any evidence of carcinoid tumors. The patient remains free from disease recurrence at 8 months after the operation. The prognosis for primary renal carcinoid tumor is relatively optimistic. Complete surgical excision is the only recommended treatment for localized renal carcinoid tumor.

  13. Peptide YY producing strumal carcinoid tumor of the ovary.

    PubMed

    Matsunami, K; Takagi, H; Ichigo, S; Murase, T; Ikeda, T; Imai, A

    2011-01-01

    Primary ovarian carcinoid tumor is uncommon and represents less than 0.1% of ovarian malignancies. The strumal carcinoid may be complicated by carcinoid syndrome induced by peptide YY (PYY). We describe a 45-year-old woman with a bilateral ovarian tumor diagnosed through periodical gynecological examination. She presented with severe constipation. Right ovarian cyst laparoscopically resected was diagnosed as a strumal carcinoid tumor; the left one was mature cystic teratoma. No metastatic findings were seen macroscopically on the ovarian surface and pelvic peritoneum. Constipation was drastically improved by resecting the tumor. The carcinoid tumor cells were positive for tumor-producing PYY by mRNA analysis. It is important to be aware of this entity in the pathological diagnosis of ovarian tumors, in the presence of any clinical indicator of carcinoid tumor/syndrome, as it carries a markedly better prognosis and clinical outcome in comparison with most other malignant ovarian tumors.

  14. [Metastatic bronchial carcinoid tumors].

    PubMed

    Bouledrak, K; Walter, T; Souquet, P J; Lombard-Bohas, C

    2016-02-01

    Bronchial carcinoids are uncommon pulmonary neoplasms and represent 1 to 2 % of all lung tumors. In early stage of disease, the mainstay and only curative treatment is surgery. Bronchial carcinoids are generally regarded as low-grade carcinomas and metastatic dissemination is unusual. The management of the metastatic stage is not currently standardized due to a lack of relevant studies. As bronchial carcinoids and in particular their metastatic forms are rare, we apply treatment strategies that have been evaluated in gastrointestinal and pancreatic neuroendocrine tumors. However, bronchial carcinoids have their own characteristic. A specific therapeutic feature of these metastatic tumors is that they require a dual approach: both anti-secretory for the carcinoid syndrome, and anti-tumoral.

  15. [A case of peritonitis carcinomatosa from goblet cell carcinoid of the appendix treated by intraperitoneal paclitaxel and systemic S-1 chemotherapy].

    PubMed

    Nakamura, Shingen; Kimura, Shigeaki; Kashima, Masahiro; Shichijo, Kana; Yoshida, Sumiko; Harada, Eiji; Matsushita, Takaya; Oshima, Yasushi; Tamaki, Yasutami; Horiuchi, Noriaki; Takeichi, Toshiaki; Fujimoto, Hiroshi; Masuda, Kazuhiko; Iwasaka, Naohito; Shinomiya, Sadao

    2008-12-01

    Goblet cell carcinoid of the appendix is a rare neoplasm and clinically tends to take a malignant course. Most cases are young and early stage, and the surgical strategy is available. But appropriate chemotherapy for inoperable cases with peritoneal dissemination is not established. A 77-year-old woman with a past history of appendectomy was admitted to our hospital complaining of abdominal fullness. Abdominal computed tomography showed massive ascites and slight contrast enhancement of appendix. A tumor was found by colonoscopic examination at the orifice of vermiform and was diagnosed pathologically as goblet cell carcinoid of the appendix. Laparoscopy showed multiple peritoneal dissemination. We performed intraperitoneal paclitaxel(PTX)administration at 70 mg/m(2) week without any resection of the tumor. Ascites were reduced immediately, but drug-induced interstitial pneumonia occurred due to PTX. After steroid therapy, we switched to systemic S-1 therapy. For about one year, her tumor was controlled but became worse thirteen months after diagnosis and died. It is thought that intraabdominal paclitaxel administration and systemic S-1 therapy can be one of appropriate forms of chemotherapy for inoperable peritoneal carcinomatosis from goblet cell carcinoid of appendix.

  16. How Are Lung Carcinoid Tumors Staged?

    MedlinePlus

    ... Tumor Early Detection, Diagnosis, and Staging How Are Lung Carcinoid Tumors Staged? The stage of a cancer ... Your Doctor About Lung Carcinoid Tumors? More In Lung Carcinoid Tumors About Lung Carcinoid Tumors Causes, Risk ...

  17. How Are Lung Carcinoid Tumors Diagnosed?

    MedlinePlus

    ... Tumor Early Detection, Diagnosis, and Staging How Are Lung Carcinoid Tumors Diagnosed? Certain signs and symptoms might ... Your Doctor About Lung Carcinoid Tumors? More In Lung Carcinoid Tumors About Lung Carcinoid Tumors Causes, Risk ...

  18. Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

    ClinicalTrials.gov

    2017-10-09

    Atypical Carcinoid Tumor; Foregut Carcinoid Tumor; Hindgut Carcinoid Tumor; Lung Carcinoid Tumor; Metastatic Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Midgut Carcinoid Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Regional Digestive System Neuroendocrine Tumor G1

  19. The predictive value of mean platelet volume, plateletcrit and red cell distribution width in the differentiation of autoimmune gastritis patients with and without type I gastric carcinoid tumors.

    PubMed

    Tüzün, Ali; Keskin, Onur; Yakut, Mustafa; Kalkan, Cagdas; Soykan, Irfan

    2014-01-01

    Autoimmune gastritis is an autoimmune and inflammatory condition that may predispose to gastric carcinoid tumors or adenocarcinomas. The early diagnosis of these tumors is important in order to decrease morbidity and mortality. Platelet indices such as mean platelet volume and plateletcrit levels increase in inflammatory, infectious and malign conditions. The primary aim of this study was to explore wheter platelet indices and red cell distribution width have any predictive role in the discrimination of autoimmune gastritis patients with and without gastric carcinoid tumors. Also secondary aim of this study was to investigate whether any changes exist betwenn autoimmune gastritis and functional dyspepsia patients by means of platelet indices. Plateletcrit (0.22 ± 0.06 vs. 0.20 ± 0.03%, p < 0.001) and red cell distribution width (16.11 ± 3.04 vs. 13.41 ± 0.95%, p < 0.001) were significantly higher in autoimmune gastritis patients compared to control group. Receiver operating curve analysis suggested that optimum plateletcrit cut-off point was 0.20% (AUC: 0.646), and 13.95% as the cut off value for red cell distribution width (AUC: 0.860). Although plateletcrit (0.22 ± 0.06 vs. 0.21 ± 0.04%, p = 0.220) and mean platelet volume (8.94 ± 1.44 vs. 8.68 ± 0.89 fl, p = 0.265) were higher in autoimmune gastritis patients without carcinoid tumor compared to patients with carcinoid tumors, these parameters were not statistically significant. Changes in plateletcrit and red cell distribution width values may be used as a marker in the discrimination of autoimmune gastritis and fucntional dyspepsia patients but not useful in patients with gastric carcinoid tumor type I.

  20. Diagnosis and management of typical and atypical lung carcinoids.

    PubMed

    Pusceddu, Sara; Lo Russo, Giuseppe; Macerelli, Marianna; Proto, Claudia; Vitali, Milena; Signorelli, Diego; Ganzinelli, Monica; Scanagatta, Paolo; Duranti, Leonardo; Trama, Annalisa; Buzzoni, Roberto; Pelosi, Giuseppe; Pastorino, Ugo; de Braud, Filippo; Garassino, Marina Chiara

    2016-04-01

    An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1-5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades. Surgery is the treatment of choice for loco-regional disease but for advanced lung carcinoids there is no recognized standard of care and successful management requires a multidisciplinary approach. The aim of this review is to provide a useful guide for the clinical management of lung carcinoids.

  1. Primary hepatic carcinoid tumor.

    PubMed

    Gao, Jinbo; Hu, Zhijian; Wu, Junwei; Bai, Lishan; Chai, Xinqun

    2011-11-19

    Primary hepatic carcinoid tumor is rare and poses a challenge for diagnosis and management. We presented a case of primary hepatic carcinoid tumor in a 53-year-old female with a complaint of right upper abdominal pain. Computer tomography scans revealed a hypervascular mass in segment 4 of the liver. An ultrasonography-guided biopsy showed a carcinoid tumor. No other lesions were found by the radiological investigations. Surgery resection was performed and histopathological examination revealed a primary hepatic carcinoid tumor. Three years later, recurrence was found and transcatheter arterial chemoembolization was performed. After transcatheter arterial chemoembolization, the patient has been free of symptom and had no radiological disease progression for over 6 months. Surgical resection combination with transcatheter arterial chemoembolization is effective to offer excellent palliation.

  2. A Case of Primary Combined Squamous Cell Carcinoma with Neuroendocrine (Atypical Carcinoid) Tumor in the Floor of the Mouth

    PubMed Central

    Terada, Kazuhiro; Uchida, Fumihiko; Kanno, Naomi; Yanagawa, Toru; Bukawa, Hiroki

    2016-01-01

    The combined squamous cell carcinoma (SCC) with neuroendocrine (atypical carcinoid (AC)) tumor is extremely rare in the head and neck. We present here the first case of SCC with AC arising in the floor of the mouth of 65-year-old man. The tumor is comprised of two components of SCC and AC in the biopsy specimen. Neuroendocrine tumor component was classified as AC from the punctate necrosis and 2–10>/10 HPF. Immunohistochemical staining was HMW-CK/34B (+) and P63 (+) in SCC and synaptophysin (+) and CD56 (+) in AC. The pathological diagnosis of SCC with AC was made from both the morphological and immunological exam. Concurrent chemoradiotherapy was performed with radiotherapy 70.2 Gy and chemotherapy of CDDP and VP-16. Although the treatment effect was complete response both of primary tumor and of neck metastases, the recurrence of the primary tumor was after 6 months. Bilateral modified radical neck dissection and tumor resection of the floor of the mouth with reconstructive surgery of anterior lateral thigh free flap were performed. Although the primary and neck tumor did not recur, the multiple lung metastases and mediastinum lymph node metastases occurred at 6 months after surgery. PMID:28116178

  3. Atypical carcinoid presenting as dumb-bell-shaped tumour in the normal kidney.

    PubMed

    Verma, Ritu; Gupta, Pallav

    2013-09-24

    Carcinoid tumours are low-grade malignant neoplasms with neuroendocrine differentiation and occur frequently in the gastrointestinal and respiratory tracts. Primary carcinoid tumours of the kidney are rare and a majority of these tumours occur in anomalous kidney and exhibit typical renal carcinoid morphology. We reported a middle-aged man with primary atypical carcinoid tumour occurring in a normal kidney. The patient was diagnosed as having renal cell carcinoma owing to a lack of neuroendocrinal clinical features. Immunohistochemical staining of the nephrectomy specimen helped in the diagnosis of atypical renal carcinoid.

  4. PHACES syndrome associated with carcinoid endobronchial tumor.

    PubMed

    Mama, Nadia; H'mida, Dorra; Lahmar, Imen; Yacoubi, Mohamed Tahar; Tlili-Graiess, Kalthoum

    2014-05-01

    PHACES syndrome consists of the constellation of manifestations including posterior fossa anomalies of the brain (most commonly Dandy-Walker malformations), hemangiomas of the face and scalp, arterial abnormalities, cardiac defects, eye anomalies and sternal defects. We present a case with a possible PHACES syndrome including sternal cleft and supraumbilical raphé, precordial skin tag, persistent left superior vena cava and subtle narrowing of the aorta with an endobronchial carcinoid tumor. All these anomalies were discovered on chest multi-detector CT. This is a unique case of PHACES syndrome associated with carcinoid tumor. Review of the literature revealed 3 cases of PHACES syndrome with glial tumor. The authors tried to find the relationship between PHACES syndrome and carcinoid tumors or gliomas, which all derive from the neural crest cells.

  5. Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases.

    PubMed

    Reid, Michelle D; Basturk, Olca; Shaib, Walid L; Xue, Yue; Balci, Serdar; Choi, Hye-Jeong; Akkas, Gizem; Memis, Bahar; Robinson, Brian S; El-Rayes, Bassel F; Staley, Charles A; Staley, Christopher A; Winer, Joshua H; Russell, Maria C; Knight, Jessica H; Goodman, Michael; Krasinskas, Alyssa M; Adsay, Volkan

    2016-10-01

    High-grade versions of appendiceal goblet cell carcinoids ('adenocarcinoma ex-goblet cell carcinoids') are poorly characterized. We herein document 77 examples. Tumors occurred predominantly in females (74%), mean age 55 years (29-84), most with disseminated abdominal (77% peritoneal, 58% gynecologic tract involvement) and stage IV (65%) disease. Many presented to gynecologic oncologists, and nine had a working diagnosis of ovarian carcinoma. Metastases to liver (n=3) and lung (n=1) were uncommon and none arose in adenomatous lesions. Tumors had various histologic patterns, in variable combinations, most of which were fairly specific, making them recognizable as appendiceal in origin, even at metastatic sites: I: Ordinary goblet cell carcinoid/crypt pattern (rounded, non-luminal acini with well-oriented goblet cells), in variable amounts in all cases. II: Poorly cohesive goblet cell pattern (diffusely infiltrative cords/single files of signet ring-like/goblet cells). III: Poorly cohesive non-mucinous cell (diffuse-infiltrative growth of non-mucinous cells). IV: Microglandular (rosette-like glandular) pattern without goblet cells. V: Mixed 'other' carcinoma foci (including ordinary intestinal/mucinous). VI: goblet cell carcinoid pattern with high-grade morphology (marked nuclear atypia). VII: Solid sheet-like pattern punctuated by goblet cells/microglandular units. Ordinary nested/trabecular ('carcinoid pattern') was very uncommon. In total, 33(52%) died of disease, with median overall survival 38 months and 5-year survival 32%. On multivariate analysis perineural invasion and younger age (<55) were independently associated with worse outcome while lymph-vascular invasion, stage, and nodal status trended toward, but failed to reach, statistical significance. Worse behavior in younger patients combined with female predilection and ovarian-affinity raise the possibility of hormone-assisted tumor progression. In conclusion, 'adenocarcinoma ex-goblet cell carcinoid' is

  6. Endobronchial Carcinoid and Concurrent Carcinoid Syndrome in an Adolescent Female

    PubMed Central

    Swanson, Jonathan; Ong, Thida

    2016-01-01

    Endobronchial carcinoid tumors are the most common intrabronchial tumors in children and adolescents. Common signs and symptoms include persistent cough and wheezing not responsive to bronchodilators, hemoptysis, and recurrent fever. Diagnosis is frequently made by imaging and direct visualization with flexible bronchoscopy; surgery remains the gold standard treatment, and lung-sparing resections should be performed whenever possible. Though carcinoid syndrome—characterized by flushing, palpitations, wheezing, shortness of breath, and diarrhea—has been found in association with adult bronchial carcinoid tumors, to our knowledge only one previous study has reported the presence of carcinoid syndrome in a pediatric patient with an endobronchial carcinoid. Here, we report a case of a 14-year-old girl with chronic cough found to have an endobronchial carcinoid tumor and signs and symptoms consistent with carcinoid syndrome. PMID:27895950

  7. Squamous cell carcinoma of the cecum developing in a patient with long-standing ulcerative colitis and a coexistent carcinoid tumor in the appendix: A case report.

    PubMed

    Ahmad, Saqib; Watson, Nicholas; Shamim, Kiran; Menon, Achyuth; Abdullah, Khorrum

    2015-09-01

    Squamous cell carcinoma (SCC) of the colon is a rare tumor that accounts for 0.1%-0.2% of colonic malignancies. However, pure SCC of the cecum is extremely rare. Although SCC of the colon is a rare complication of idiopathic inflammatory bowel disease (IBD), SCC of the cecum in the context of IBD has not been previously reported in the English literature. We report a case of the coexistence of SCC of the cecum and a carcinoid tumor in a 46-year-old female with long-standing pan-ulcerative colitis.

  8. ECL-cell carcinoids and carcinoma in patients homozygous for an inactivating mutation in the gastric H(+) K(+) ATPase alpha subunit.

    PubMed

    Fossmark, Reidar; Calvete, Oriol; Mjønes, Patricia; Benitez, Javier; Waldum, Helge L

    2016-07-01

    A family with a missense variant of the ATP4A gene encoding the alpha subunit of the gastric proton pump (H(+) K(+) ATPase) has recently been described. Homozygous siblings were hypergastrinemic (median gastrin 486 pM) and had gastric tumours diagnosed at a median age of 33 years. In the current histopathological study, we further characterized the tumours found in the gastric corpus. The tumours had the histological appearance of carcinoids (NET G1 or G2) and were immunoreactive for the general neuroendocrine markers chromogranin A (CgA) and synaptophysin as well as the ECL-cell markers vesicular monoamine transporter 2 (VMAT2) and histidine decarbozylase (HDC). One of the tumours consisted of a NET G2 component, but also had a component with glandular growth, which morphologically was classified as an intestinal type adenocarcinoma. Many glands of the adenocarcinoma contained a large proportion of cells positive for neuroendocrine markers, especially the small vesicle marker synaptophysin and the cytoplasmic enzyme HDC. In conclusion, patients homozygous for an inactivating ATP4A mutation develop gastric ECL-cell carcinoids in their 3rd or 4th decade. The adenocarcinoma may be classified as neuroendocrine with ECL-cell differentiation.

  9. What Are the Key Statistics for Lung Carcinoid Tumors?

    MedlinePlus

    ... Carcinoid Tumors What Are the Key Statistics About Lung Carcinoid Tumors? About 1% to 2% of all ... Lung Carcinoid Tumor Research and Treatment? More In Lung Carcinoid Tumors About Lung Carcinoid Tumors Causes, Risk ...

  10. Treatment of Lung Carcinoid by Type and Extent of Disease

    MedlinePlus

    ... Carcinoid Tumor Treating Lung Carcinoid Tumors Treatment of Lung Carcinoid, by Type and Extent of Disease The ... those that can’t be removed completely Resectable lung carcinoid tumors Resectable carcinoid tumors haven’t spread ...

  11. What's New in Lung Carcinoid Tumor Research and Treatment?

    MedlinePlus

    ... Tumor About Lung Carcinoid Tumors What’s New in Lung Carcinoid Tumor Research and Treatment? Many medical centers ... Lung Carcinoid Tumor Research and Treatment? More In Lung Carcinoid Tumors About Lung Carcinoid Tumors Causes, Risk ...

  12. What Happens after Treatment for Lung Carcinoid Tumors?

    MedlinePlus

    ... Tumor After Treatment What Happens After Treatment for Lung Carcinoid Tumors? For many people with carcinoid tumors, ... Lung Carcinoid Tumor Treatment Stops Working More In Lung Carcinoid Tumors About Lung Carcinoid Tumors Causes, Risk ...

  13. [Somatostatin receptor scintigraphy in pediatric bronchial carcinoid tumor].

    PubMed

    Hervás Benito, I; Bello Arques, P; Loaiza, J L; Vercher, J L; Velasco, R P; Rivas Sánchez, A; Ruiz Llorca, C; Martí Vidal, J F; Mateo Navarro, A

    2010-01-01

    Carcinoid tumor is a rare neuroendocrine neoplasm with different locations, the most frequent ones during the pediatric age being the appendix and lung. Scintigraphy with (111)In-DTPA-d-Phe(1)-octreotide has led to an importance advance in the diagnosis of extension in carcinoid tumor patients. We present three pediatric patients with bronchial carcinoid studied with somatostatin analogue scintigraphy (SSRS). The first patient (9 years) was studied using the SSRS after surgery due to carcinoid tumor in the right lower lobe in which tumor remains was observed (this being clearer in the tomography study). The second patient (10 years) presented due to endobronchial tumor in the left lower lobe together with atelectasis of the LUL and emphysema of the LLL. Radiology imaging techniques suggested the differential diagnosis between the endobronchial carcinoid tumor or plasma cells or foreign body gramuloma. The SSRS showed an abnormal deposit of activity in the left hemithorax consisted with carcinoid tumor. No other areas suggesting metastasis were observed. After the surgery (endobronchial resection), new controls with SSRS showed absence of disease. The third patient (12 years) came after a lobectomy (RUL) due to bronchial carcinoid. The SSRS did not show any abnormal areas of activity. In the subsequent control (3 months), a deposit of activity was observed in the middle third of the right hemithorax, after which a lobectomy was performed (RLL and ML) that showed small remains of neuroendocrine carcinoid. Subsequent controls were negative. The SSRS has demonstrated great utility in the diagnosis, follow-up and staging of pediatric patients, carriers of neuroendocrine carcinoid tumors. Copyright 2008 Elsevier España, S.L. y SEMNIM. All rights reserved.

  14. Pre-surgical bronchoscopic treatment for typical endobronchial carcinoids.

    PubMed

    Guarino, Carmine; Mazzarella, Gennaro; De Rosa, Nicolina; Cesaro, Cristiano; La Cerra, Giuseppe; Grella, Edoardo; Perrotta, Fabio; Curcio, Carlo; Guerra, Germano; Bianco, Andrea

    2016-09-01

    Carcinoids are tumors that originate from diffuse neuroendocrine system cells (APUD cells) and represent 1-2% of all pulmonary tumors. Although surgical resection remains the mainstay of treatment, bronchoscopic radical resection of typical carcinoids in selected cases exhibiting endoluminal growth and small implant base has also been explored. Bronchoscopic removal of endobronchial lesions may also reduce the risk of post-obstructive infections and improve pulmonary function, allowing the patient to undergo surgery in better clinical and respiratory state. In this paper we have evaluated the impact on surgical planning and outcome of preoperative bronchoscopic resection in treatment of endobronchial typical carcinoids. Our observations further support the role of bronchoscopic treatment before surgery in endobronchial typical carcinoids.

  15. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids.

    PubMed

    Fernandez-Cuesta, Lynnette; Peifer, Martin; Lu, Xin; Sun, Ruping; Ozretić, Luka; Seidal, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin M; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael Pa; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine; Cappuzzo, Federico; Travis, William D; Wolf, Jürgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A; Buettner, Reinhard; Thomas, Roman K

    2014-03-27

    Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.

  16. Gastrointestinal carcinoid tumours. Histogenetic, histochemical, immunohistochemical, clinical and therapeutic aspects.

    PubMed

    Wilander, E; Lundqvist, M; Oberg, K

    1989-01-01

    The increased knowledge of the pathobiology of gastrointestinal carcinoid (neuroendocrine) tumours and the improved therapeutic possibilities have brought a demand for more precise diagnosis. Although the carcinoid tumours can often be tentatively recognized in routinely processed microscopic slides, their more accurate identification requires additional diagnostic procedures. General neuroendocrine markers such as the argyrophil reaction of Grimelius and immunohistochemistry with application of antibodies against chromogranin A and of neuron-specific enolase are discriminatory staining methods which are used to reveal the neuroendocrine origin of almost all highly differentiated carcinoid tumours of the gastrointestinal tract. Mid-gut carcinoids, which predominate among these tumours almost unexceptionally contain serotonin. This biogenic amine can be demonstrated by the argentaffin reaction of Masson, serotonin immunoreactively or by formalin-induced fluorescence. The characteristic staining pattern of mid-gut carcinoids is almost invariably preserved in the metastatic deposits and consequently the staining methods for identifying serotonin can also be used on metastases to reveal a primary mid-gut carcinoid. The enterochromaffin-like (ECL) cell carcinoids of the body and fundic area of the stomach often seen in association with pernicious anaemia are argyrophil with the Sevier-Munger silver stain. Other neuroendocrine tumours, viz. antral, duodenal and rectal carcinoids should be studied by a battery of relevant peptide hormone antisera for adequate diagnosis. During the last decade new peptide hormones have been found in circulation in patients with carcinoid tumours, but serotonin and urinary 5-HIAA are still the most important markers for carcinoids of the mid-gut origin. Other clinically useful tumour markers are chromogranin A + B, pancreatic polypeptide, human chorionic gonadotropin alpha and beta subunits. For localizing procedures, angiography is the

  17. Chromogranin-reactive endocrine cells in argyrophilic carcinomas ("carcinoids") and normal tissue of the breast.

    PubMed Central

    Bussolati, G.; Gugliotta, P.; Sapino, A.; Eusebi, V.; Lloyd, R. V.

    1985-01-01

    Breast carcinomas, either positive or negative with the Grimelius' silver procedure, benign fibroadenomas, duct papillomas, and areas of histologically normal breast tissue were tested immunocytochemically with the mouse monoclonal antibody LK2H10 directed against human chromogranin. This is regarded as a general stain for polypeptide-hormone-producing cells and tumors. In 3 of the 9 cases of argyrophilic carcinoma, but in none of 12 ductal infiltrating carcinomas, chromogranin-positive cells were found: the number of reactive cells was very low in 1 case, while in the other 2 carcinomas about 50% of the argyrophilic cells appeared stained. In areas of histologically normal breast tissue, rare argyrophilic chromogranin-positive cells were detected. This study is the first reported evidence concerning the presence of endocrinelike cells probably belonging to the diffuse neuroendocrine system in the normal mammary parenchyma. Our data are consistent with the endocrine nature of at least some of the breast argyrophilic carcinomas. Images Figure 1 Figure 2 Figures 3 and 4 Figure 5 Figure 6 PMID:4025508

  18. Development of a gastric carcinoid tumor following allogeneic hematopoietic stem cell transplantation for early T-cell precursor acute lymphoblastic leukemia.

    PubMed

    Chang, Tsung-Yen; Lai, Jin-Yao; Wang, Chao-Jan; Chen, Shih-Yen; Jaing, Tang-Her; Hsueh, Chuen; Shih, Lee-Yung; Chen, Shih-Hsiang

    2017-06-01

    Gastric carcinoid tumor is rarely diagnosed in children. We report a case of gastric carcinoid tumor that occurred after allogeneic HSCT. A 13-year-old girl with ETP acute lymphoblastic leukemia underwent allogeneic HSCT from a 7/8 HLA-matched unrelated donor. She presented with rashes, abdominal pain, and diarrhea, which were suggestive of GVHD, 7 months after HSCT. Immunosuppressive agents failed to resolve these symptoms well. After a series of evaluations, carcinoid syndrome caused by a gastric carcinoid tumor was diagnosed. The tumor was located in the antral region and resulted in partial gastric outlet obstruction. She received subtotal gastrectomy with regional lymph node dissection. However, she had a flare-up of GVHD 1 month after surgery, and immunosuppressive therapy was intensified accordingly. Although her GVHD was getting better, she developed respiratory syncytial viral pneumonia with rapid progression to respiratory failure. She died of multiple organ failure 2 months postoperatively. This is the first pediatric case of a gastric carcinoid tumor following allogeneic HSCT. Our case also highlights the necessity for pediatric transplant physicians to be aware of carcinoid syndrome caused by this rare tumor in the setting of GVHD with poor response to immunosuppressive agents. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. I-131 MIBG imaging of carcinoid tumors

    SciTech Connect

    Blinder, R.A.; Feldman, J.M.; Coleman, R.E.

    1985-05-01

    The potential of I-131 MIBG to image carcinoid tumors was evaluated in nine patients with pathologically proven carcinoid. Three patients with foregut carcinoid tumors (2 bronchial and one pancreatic), had abnormal urinary 5-HIAA, and one had the carcinoid syndrome. Six patients had midgut carcinoid tumors (5 ileal and 1 cecal), 5 had abnormal urinary 5-HIAA, and 4 had the carcinoid syndrome. All of the patients with midgut carcinoids had metestatic disease to the liver and/or mesentery. Two hundred microcuries of I-131 MIBG were injected intravenously and the patients were studied at 24 and 48 hours. In all patients except those with bronchial carcinoids Tc-99m sulfur colloid liver exams with computer subtraction were performed during the study. The patients with bronchial carcinoids showed no uptake in the tumors. The patient with a pancreatic carcinoid who had carcinoid syndrome demonstrated tumor uptake in hepatic metastases. Of the six patients with midgut carcinoids, 4 demonstrated MIBG uptake in tumors. One patient with mesenteric disease did not have definitive tumor uptake. A second patient with liver involvement at surgery was negative on the MIBG study. Hepatic CT and scintigraphy were negative and the patient's 5-HIAA was normal. The 4 patients with carcinoid syndrome had abnormal MIBG scans. I-131 MIBG demonstrated tumor in 4 of six patients with midgut carcinoids. MIBG was not concentrated in two carcinoids of bronchial origin. The five patients with carcinoid syndrome had positive scans. MIBG has potential as a diagnostic agent in carcinoid tumors.

  20. Multiple rectal carcinoid tumors in monozygotic twins.

    PubMed

    Doi, Momoko; Ikawa, Osamu; Taniguchi, Hiroki; Kawamura, Takuji; Katsura, Kanade

    2016-08-01

    We report multiple rectal carcinoid tumors in monozygotic twins who, respectively, had 42 and 36 carcinoid tumors in the lower rectum. This is the first report about carcinoid tumors in monozygotic twins. Both twins developed a similar number of rectal carcinoids with a similar distribution. Investigation of their genetic background may provide information about the origin of these tumors.

  1. Disseminated typical bronchial carcinoid tumor.

    PubMed

    Novković, Dobrivoje; Skuletić, Vesna; Vuković, Jelena; Cerović, Snezana; Tomić, Ilija; Karlicić, Vukojica; Stojisavljević, Marko

    2013-05-01

    Bronchial carcinoids belong to a rare type of lung tumors. If they do not expose outstanding neuroendocrine activity, they develop without clearly visible symptoms. They are often detected during a routine examination. According to their clinical pathological features, they are divided into typical and atypical tumors. Typical bronchial carcinoids metastasize to distant organs very rarely. Localized forms are effectively treated by surgery. The methods of conservative treatment should be applied in other cases. We presented a 65-year-old patient with carcinoid lung tumor detected by a routine examination. Additional analysis (chest X-ray, computed tomography of the chest, ultrasound of the abdomen, skeletal scintigraphy, bronhoscopy, histopathological analysis of the bioptate of bronchial tumor, as well as bronchial brushing cytology and immunohistochemical staining performed with markers specific for neuroendocrine tumor) proved a morphologically typical lung carcinoid with dissemination to the liver and skeletal system, which is very rarely found in typical carcinoids. The presented case with carcinoid used to be showed morphological and pathohistological characteristics of typical bronchial carcinoid. With its metastasis to the liver and skeletal system it demonstrated unusual clinical course that used to be considered as rare phenomenon. Due to its frequent asymptomatic course and varied manifestation, bronchial carcinoid could be considered as a diagnostic challenge requiring a multidisciplinary approach.

  2. A case of carotid body tumor concomitant with carcinoid tumor.

    PubMed

    Mun, Mi Jin; Lee, Jin Choon; Lee, Byung Joo

    2015-02-01

    Neuroendocrine tumors typically fall into two broad categories: those of epithelial origin and those of neural derivation. The former group includes carcinoid tumors and the latter includes paraganglioma. Although paraganglioma and carcinoid tumor have different biologic behaviors, their overlapping histological appearance can pose diagnostic challenges. Carcinoid tumors are rare, slow-growing neuroendocrine tumors arising from the enterochromaffin cells disseminated throughout the gastrointestinal and bronchopulmonary systems. Carotid body tumor is the most common type of extra-adrenal paraganglioma. Paraganglioma tends to grow slowly but can compress adjacent vessel and nerve. A 63-year-old woman showed huge mass extending from carotid body to skull base, encircling internal and external carotid arteries on magnetic resonance image. Surgical removal of carotid body tumor was done after embolization procedure. Postoperative histopathologic examination and immunohistochemical analysis were consistent with paraganglioma concomitant with carcinoid tumor in carotid body. Primary cervical carcinoid tumor is extremely rare, and to the best of our knowledge, this is the first case of concomitant existence of paraganglioma and carcinoid tumor in carotid body.

  3. Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases

    PubMed Central

    Reid, Michelle D; Basturk, Olca; Shaib, Walid L; Xue, Yue; Balci, Serdar; Choi, Hye-Jeong; Akkas, Gizem; Memis, Bahar; Robinson, Brian S; El-Rayes, Bassel F; Staley, Charles A; Staley, Christopher A; Winer, Joshua H; Russell, Maria C; Knight, Jessica H; Goodman, Michael; Krasinskas, Alyssa M; Adsay, Volkan

    2016-01-01

    High-grade versions of appendiceal goblet cell carcinoids (‘adenocarcinoma ex-goblet cell carcinoids’) are poorly characterized. We herein document 77 examples. Tumors occurred predominantly in females (74%), mean age 55 years (29–84), most with disseminated abdominal (77% peritoneal, 58% gynecologic tract involvement) and stage IV (65%) disease. Many presented to gynecologic oncologists, and nine had a working diagnosis of ovarian carcinoma. Metastases to liver (n =3) and lung (n =1) were uncommon and none arose in adenomatous lesions. Tumors had various histologic patterns, in variable combinations, most of which were fairly specific, making them recognizable as appendiceal in origin, even at metastatic sites: I: Ordinary goblet cell carcinoid/crypt pattern (rounded, non-luminal acini with well-oriented goblet cells), in variable amounts in all cases. II: Poorly cohesive goblet cell pattern (diffusely infiltrative cords/single files of signet ring-like/goblet cells). III: Poorly cohesive non-mucinous cell (diffuse-infiltrative growth of non-mucinous cells). IV: Microglandular (rosette-like glandular) pattern without goblet cells. V: Mixed ‘other’ carcinoma foci (including ordinary intestinal/mucinous). VI: goblet cell carcinoid pattern with high-grade morphology (marked nuclear atypia). VII: Solid sheet-like pattern punctuated by goblet cells/microglandular units. Ordinary nested/trabecular (‘carcinoid pattern’) was very uncommon. In total, 33(52%) died of disease, with median overall survival 38 months and 5-year survival 32%. On multivariate analysis perineural invasion and younger age (<55) were independently associated with worse outcome while lymph-vascular invasion, stage, and nodal status trended toward, but failed to reach, statistical significance. Worse behavior in younger patients combined with female predilection and ovarian-affinity raise the possibility of hormone-assisted tumor progression. In conclusion, ‘adenocarcinoma ex

  4. What Are the Key Statistics about Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... About Gastrointestinal Carcinoid Tumors What Are the Key Statistics About Gastrointestinal Carcinoid Tumors? Although the exact number ... a Gastrointestinal Carcinoid Tumor? What Are the Key Statistics About Gastrointestinal Carcinoid Tumors? What’s New in Gastrointestinal ...

  5. What Are the Risk Factors for Lung Carcinoid Tumors?

    MedlinePlus

    ... and Prevention What Are the Risk Factors for Lung Carcinoid Tumors? A risk factor is anything that ... Can Lung Carcinoid Tumors Be Prevented? More In Lung Carcinoid Tumors About Lung Carcinoid Tumors Causes, Risk ...

  6. What Should You Ask Your Doctor about Lung Carcinoid Tumors?

    MedlinePlus

    ... Staging What Should You Ask Your Doctor About Lung Carcinoid Tumors? It is important to have honest, ... Your Doctor About Lung Carcinoid Tumors? More In Lung Carcinoid Tumors About Lung Carcinoid Tumors Causes, Risk ...

  7. What Should You Ask Your Doctor about Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... What Should You Ask Your Doctor About Gastrointestinal Carcinoid Tumors? It is important to have honest, open ... Doctor About Gastrointestinal Carcinoid Tumors? More In Gastrointestinal Carcinoid Tumors About Gastrointestinal Carcinoid Tumors Causes, Risk Factors, ...

  8. Primary Hepatic Carcinoid Tumor with Poor Outcome.

    PubMed

    Parkash, Om; Ayub, Adil; Naeem, Buria; Najam, Sehrish; Ahmed, Zubair; Jafri, Wasim; Hamid, Saeed

    2016-03-01

    Primary Hepatic Carcinoid Tumor (PHCT) represents an extremely rare clinical entity with only a few cases reported to date. These tumors are rarely associated with metastasis and surgical resection is usually curative. Herein, we report two cases of PHCT associated with poor outcomes due to late diagnosis. Both cases presented late with non-specific symptoms. One patient presented after a 2-week history of symptoms and the second case had a longstanding two years symptomatic interval during which he remained undiagnosed and not properly worked up. Both these cases were diagnosed with hepatic carcinoid tumor, which originates from neuroendocrine cells. Case 1 opted for palliative care and expired in one month’s time. Surgical resection was advised to the second case, but he left against medical advice.

  9. Carcinoid heart disease.

    PubMed

    Flaherty, Anne Marie C

    2014-11-01

    The patient, C.P., is a 59-year-old woman who was diagnosed with metastatic carcinoid of the terminal ileum in May 2003. In June 2003, she underwent an extensive resection including hemicolectomy, cholecystectomy, distal pancreatectomy, and splenectomy with metastatic disease in her pancreas, mesentery, and liver. She had been treated with octreotide, everolimus, oxaliplatin, and multiple hepatic artery embolizations in the past eight years and, most recently, capecitabine and bevacizumab with monthly octreotide. She has had intermittent pleural effusions not requiring intervention and a trace pericardial effusion. Her tumor is functional, meaning it demonstrates hormonal hypersecretion which causes flushing, diarrhea, bronchospasm, and abdominal pain.

  10. FDG-PET imaging in patients with pulmonary carcinoid tumor.

    PubMed

    Moore, William; Freiberg, Evan; Bishawi, Muath; Halbreiner, Micheal S; Matthews, Robert; Baram, Daniel; Bilfinger, Thomas V

    2013-07-01

    This study aimed to assess the imaging findings in patients with pathologically proven carcinoid tumors and determine if SUV can help to differentiate typical from atypical (more aggressive) pulmonary carcinoid tumors. A retrospective review of patients with a biopsy-proven diagnosis of a pulmonary carcinoid tumor at our institution from 2002 to 2010 that had a preoperative PET scan was performed after institutional review board approval was obtained. PET results, including SUV uptake and location, were recorded as well as all data from pathology reports. Carcinoids were considered to be more aggressive if they showed pathological diagnosis consistent with atypical carcinoid, lymph node invasion, poor histological grade (poorly differentiated), or evidence of systemic metastases. Atypical carcinoid pathology consisted of focal necrosis or a higher mitotic index (2-10 per square millimeter) with features of nests, trabeculae, pleomorphic cells, or dense hyperchromasia. SUV uptake was then evaluated and compared between the typical and atypical carcinoid groups using nonparametric statistical methods. We identified 29 patients from 2002 to 2010 at our institution with a pathological diagnosis of pulmonary carcinoid. Twenty-three were histopathologically typical, and the other 6 showed atypia. Mean (SD) nodule size was 2.4 (1.3) cm in the typical group versus 5.0 (3.2) cm in the atypical group (P = 0.065). Mean (SD) SUV uptake in the typical carcinoid group was 2.7 (1.6) and in the atypical group the SUV was 8.1 (4.1) (P < 0.01). A cutoff SUV of 6 or greater is predictive of malignancy (odds ratio, 23.6; P < 0.01), as well as a nodule size of 3.5 cm or greater (odds ratio, 5.1; P = 0.024). Preoperative PET imaging result is frequently positive in carcinoid tumors, and the biological behavior correlates well with SUV; however, size is not as strong of a predictor of malignancy. Size of 3.5 cm or greater and SUV of 6 or greater have a predictive value of greater than 95

  11. Carcinoid Tumors of Digestive Organs: a Clinicopathologic Study of 13 Cases

    PubMed Central

    Terada, Tadashi

    2009-01-01

    The author investigated clinicopathologic features of 13 cases of carcinoid tumor in the digestive organs. The 13 cases of carcinoid were identified from 18,267 pathological specimens of digestive organs in the last 10 years in our pathology laboratory. The tumor locations were rectum in 9 cases, duodenum in 2 cases, liver in 1 case, and stomach in 1 case. The age of the patients ranged from 52 to 82 years with a mean of 63 years. Male to female ratio was 7 : 6. The presenting symptoms were abnormal pain in 3 cases and asymptomatic in 10 cases. None of the cases showed carcinoid syndrome. The diameter ranged from 5 mm to 25 mm in gastrointestinal carcinoids, and 60 mm in the hepatic carcinoid. The treatment was endoscopic mucosal resection in 10 cases and surgical resection in 3 cases. The outcome is good except for hepatic atypical carcinoid which showed metastases and died of systemic metastasis. Histologically, 12 carcinoid tumors were typical carcinoids, and one (liver) was atypical carcinoid. Organoid pattern was present in 12 cases. Trabecular arrangement, ribbon arrangement, rosette formation, and pseudoglandular arrangement were recognized in 12 cases, in 8 cases, in 7 cases, and in 5 cases, respectively. Immunohistochemically, tumor cells were positive for at least one of pan-neuroendocrine markers including chromogranin, synaptophysin, neuron-specific enolase, CD56, and glucagon. Of these, synaptophysin was positive in 11/13 (85%), neuron-specific enolase 10/13 (80%), chromogranin 8/13 (62%), CD56 6/13 (46%), and glucagon 4/13 (31%). In summary, the author reported the incidence of digestive organ carcinoid tumors, and the clinicopathologic features of the 13 cases with carcinoid. PMID:27956948

  12. Esophageal carcinoid tumor treated by endoscopic resection.

    PubMed

    Yagi, Makoto; Abe, Yasuhiko; Sasaki, Yu; Nomura, Eiki; Sato, Takeshi; Iwano, Daisuke; Yoshizawa, Kazuya; Sakuta, Kazuhiro; Kanno, Nana; Nishise, Syouichi; Ueno, Yoshiyuki

    2015-05-01

    The present report describes a rare case of esophageal carcinoid tumor that was treated by endoscopic resection. A 43-year-old woman underwent esophagogastroduodenoscopy at her family clinic for screening of the upper digestive tract and a small lesion resembling a submucosal tumor was detected in the lower esophagus. A biopsy sample from the lesion was diagnosed as esophageal carcinoid tumor and the patient visited our hospital for detailed examination. The tumor was approximately 3 mm in diameter and its surface appeared to be covered with normal squamous epithelium. The tumor had a shiny reddish surface without ulceration or erosion. Magnifying endoscopy with narrow-band imaging showed structures resembling reticular vessels under the epithelium. Endoscopic ultrasonography depicted the tumor as a low-echoic mass within the lamina propria. Computed tomography did not detect the tumor and no metastatic lesions were evident in other organs. With the patient's informed consent, the tumor was resected using endoscopic submucosal dissection, with a sufficient free margin in both the vertical and horizontal directions. Magnifying endoscopic examination showed the resected tumor to have abundant reticular vessels. Finally, the tumor was diagnosed immunopathologically as an esophageal carcinoid tumor (neuroendocrine cell tumor, grade 1), without lymphatic or vascular invasion.

  13. Carcinoid Heart Disease in a Primary Ovarian Carcinoid

    PubMed Central

    T., Kolouch; H., Linkova; O., Lang; V., Ciprova; L., Brunerova

    2016-01-01

    Ovarian carcinoids are very rare, and only their insular form is associated with carcinoid syndrome. We herein describe a case report of an elderly woman who presented with typical carcinoid syndrome, which is routinely characterized by right-sided heart failure, diarrhoea, flushes, and other common manifestations. Further examination and biochemical testing of the patient confirmed suspected carcinoid tumor. However, the tumor was surprisingly localized in the left ovary. The presence of the patient’s severe combined tricuspid valve disease would create impossible surgical management conditions, so we decided to first perform cardio-surgery with tricuspid valve replacement. After tumor removal, levels of hydroxyindolacetic acid did not normalize and although the patient was asymptomatic, a small lesion was detected by tectrotyd scan paravertebrally. Treatment with lanreotide led to complete remission with negative biochemical and imaging signs of tumor. Thus, to summarize, carcinoid tumor even in an atypical localization (ovary) should be considered in elderly female patients with severe combined tricuspid valve disease due to carcinoid syndrome. PMID:27122940

  14. Carcinoid Tumor: Frequently Asked Questions

    MedlinePlus

    ... the middle ages in Europe. Centuries of anecdotal observation and more recent experience in carcinoid patients under ... Dr. Kjell Oberg (as well as myself through observation) reports greater than 60% effectiveness from CHRONIC treatment ...

  15. Laser excision of a typical carcinoid tumor of the larynx: a case report.

    PubMed

    Cevizci, Raşit; Karakullukçu, Barış; van den Brekel, Michiel W M; Balm, Alfons J

    2010-01-01

    Neuroendocrine carcinomas of the larynx include a range of rare tumors which have variable biologic behavior, affecting treatment and prognosis. Among these, typical carcinoid tumors are the least common type. Prognosis of typical carcinoid tumor is better than atypical carcinoid tumor and small cell carcinoma of the larynx. Conservation surgery is the preferred treatment modality. Transoral CO2 laser surgery can be a good alternative for appropriate cases because of the functional results and less morbidity. In this article, a 71-year-old female presented with complaints of feeling a mass during swallowing. Fiberoptic examination of the larynx revealed a mass located on the right aryepiglottic fold and biopsy revealed the tumor as a typical carcinoid tumor. We describe CO2 laser excision of a typical carcinoid tumor of the larynx in this case report.

  16. Intramedullary spinal metastasis of a carcinoid tumor.

    PubMed

    Kumar, Jay I; Yanamadala, Vijay; Shin, John H

    2015-12-01

    We report an intramedullary spinal cord metastasis from a bronchial carcinoid, and discuss its mechanisms and management. Intramedullary spinal cord metastases from any cancer are rare, and bronchial carcinoids account for only a small fraction of lung cancers. To our knowledge, an intramedullary spinal cord metastasis from a bronchial carcinoid has been described only once previously.

  17. Carcinoid tumor of the duodenum and accessory papilla associated with polycythemia vera

    PubMed Central

    Wang, Horng-Yuan; Chen, Ming-Jen; Yang, Tsen-Long; Chang, Ming-Chih; Chan, Yu-Jan

    2005-01-01

    Carcinoid tumors have been reported in a wide range of organs but most frequently involve the gastrointestinal tract; however, duodenal carcinoid tumors are rare. We report a 50-year-old male patient complaining of multiple melenas for 3 wk. The panendoscopy and endoscopic retrograde cholangiopancreaticography revealed swelling accessory papilla with an ulcer. The biopsy taken showed a carcinoid tumor. The lesion was removed by wide resection. Patient was found to have an abnormal blood cell count during the follow-up period with elevated levels of hemoglobin and hematocrit of 21.2 g/dL and 63.5%, respectively, thrombocytosis of 501000/µL, and leukocytosis of 20410/µL. He was diagnosed as a polycythemia vera by a hematologist after further evaluation. He received periodic phlebotomy and hydroxyurea treatment. The response was good and his hematocrit was stabilized by periodic phlebotomy in the range of 44-49% during the last 2 years. The possible origin of UGI bleeding by a duodenal carcinoid tumor, although rare, should be considered. There has been one case report of a duodenal carcinoid tumor that involved accessory papilla of the pancreas divisum and one case report of metastatic carcinoid tumor associated with polycythemia vera. It is different in our patient as compared with the latter report, which mentioned a polycythemia vera patient who was found to have a metastatic carcinoid in the 17 years follow-up period. Chemotherapy had been given before the carcinoid tumor was revealed. Our patient had no previous chemotherapy for polycythemia vera before he was found to have duodenal carcinoid tumor; this excludes the possibility of chemotherapy induced carcinoid tumor, although it had been suspected in the previous report. In our patient, the existence of both diseases may be by predisposition of each other since both diseases have an increased incidence of other neoplasm, or they may be coexistent incidentally. PMID:15968742

  18. Carcinoid tumours of the bronchus: a 33 year experience.

    PubMed Central

    Hurt, R; Bates, M

    1984-01-01

    The term adenoma of the bronchus is discussed, and 79 cases of bronchial carcinoid seen from 1951 to 1983 are reviewed. The symptoms, radiological findings, and bronchoscopic appearances are described. There was no case of the carcinoid syndrome. In no case did haemorrhage cause any serious problem after biopsy at rigid bronchoscopy. In three patients the tumour was reported to be an oat cell carcinoma-in two on the basis of material obtained at fibreoptic bronchoscopy. Resection was by pneumonectomy in 10 cases, lobectomy in 52, segmentectomy in six, a bronchoplastic procedure without resection of lung in seven cases, enucleation in two, and a wedge resection in one case. There was one case of atypical carcinoid which was found at operation to be unresectable. A 5-30 year follow up in 57 cases revealed a recurrence of tumour in two cases, nine and 16 years after lung resection. No recurrence occurred in the nine cases treated by conservative bronchial resection with conservation of lung tissue. An actuarially assessed life table analysis shows survival rates of 94% after 10 years, 80% after 15 years, and 64% after 25 years without recurrence. The similarity of carcinoid to oat cell carcinoma is noted and the serious clinical implications of this are analysed, especially in view of the increasing use of fibreoptic bronchoscopy. The malignant potential of carcinoid and the extent of pulmonary resection is discussed. It is concluded that a carcinoid tumour of the lung has only slight malignant potential and that it may be treated by bronchotomy or sleeve resection of the bronchus in suitable cases. If serious infective changes have occurred in the lung distal to the tumour or if the tumour has extended into the lung parenchyma (88% of cases in this series) lung resection will be necessary. The follow up period should be for at least 25 years, in view of the incidence of late recurrence. PMID:6089366

  19. The effect of preceding biopsy on complete endoscopic resection in rectal carcinoid tumor.

    PubMed

    Lee, Sang Pyo; Sung, In-Kyung; Kim, Jeong Hwan; Lee, Sun-Young; Park, Hyung Seok; Shim, Chan Sup

    2014-04-01

    Biopsy of rectal carcinoid tumor is commonly taken before endoscopic resection. However the preceding biopsy can inhibit complete resection by causing blurred tumor border and fibrosis of the tissue. The objective of the study was to investigate the effect of preceding biopsy on complete endoscopic resection in rectal carcinoid tumor. It was also determined if rectal carcinoid tumors can be macroscopically distinguished by endoscopy. We reviewed retrospectively the records of patients with rectal carcinoid tumor who had undergone an endoscopic treatment at our hospital, during a 7-yr period. The resection margin was clear in 57 of 98 cases. The preceding biopsy was taken in 57 cases and the biopsy was significantly associated with the risk of incomplete tumor resection (OR, 3.696; 95% CI, 1.528-8.938, P = 0.004). In 95.9% of the cases, it was possible to suspect a carcinoid tumor by macroscopic appearance during initial endoscopy. The preceding biopsy may disturb complete resection of rectal carcinoid tumor. In most cases, the carcinoid tumor could be suspected by macroscopic appearance. Therefore the preceding biopsy is not essential, and it may be avoided for the complete resection.

  20. [Ovarian carcinoid tumor responsible of permanent facial erythrosis and flushings during sexual intercourse].

    PubMed

    Talvande, B; Dorange, A; Lecouflet, M; Le Nezet, M; Kianifard, B; Maillard, H; Duquenne, M

    2016-11-01

    Ovarian neuroendocrine tumors are extremely rare. In the ovary, the term of neuroendocrine tumor is usually related to carcinoid tumors although it may be sometimes applied to neuroendocrine carcinomas of non-small cells or small cells cancers usually occurring in the lungs. These carcinoid tumors may develop de novo or from other tumors including teratomas. We report a patient who presented with an ovarian carcinoid tumor developed, near or from a dermoid cyst, which was original by its mode of discovery in the dermatology department. Indeed, the patient consulted because of permanent facial erythrosis, with flushes but also facial telangiectasias. During medical examination, classic symptoms of carcinoid syndrome including heart disease were obvious. The occurrence of flushes during coitus should evoke pelvic tumor location. A carcinoid syndrome is naturally evoked in the presence of flushes but it must also be part of the differential diagnosis in a patient with facial erythrosis or telangiectasias, especially if they are associated with diarrhea or right heart failure. The prognosis of carcinoid heart disease is considerably better in case of ovarian location than when it is a primitive carcinoid tumor of lung or from gastrointestinal tract. Copyright © 2016 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  1. Cytohistology of papillary carcinoid and emerging concept of pulmonary neuroendocrine neoplasms.

    PubMed

    Yang, Grace C H

    2016-01-01

    This timely review starts by reporting the clinical, cytologic and histologic features of a morphologic variant of pulmonary carcinoid tumor forming exclusively of papillae. This growth pattern is so rare that it was not included in 2014 WHO classification of pulmonary neuroendocrine neoplasms. The current concept is reviewed, and example of spindle cell carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma are illustrated with fine needle aspiration cytology, surgical and clinical follow-up. Finally, the new findings in cell biology and molecular biology that led to the emerging concept that carcinoids and high-grade neuroendocrine lung carcinomas are separate biological entities are reviewed and summarized in a tumorigenic module.

  2. A Rare Primary Neuroendocrine Tumor (Typical Carcinoid) of the Sublingual Gland

    PubMed Central

    Ohki, Kousuke; Uchida, Fumihiko; Kanno, Naomi; Hasegawa, Shogo; Yanagawa, Toru; Bukawa, Hiroki

    2016-01-01

    A typical carcinoid is extremely rare in the oral cavity. We here present a case of a typical carcinoid arising in the sublingual gland of a 62-year-old woman. The tumor was removed by primary excision with 10 mm surgical margins and submandibular dissection. Examination of the tumor showed medium-sized tumor cells that were positive for CD56 and chromogranin A, with no necrosis, and with a mitotic count less than 1/10 HPF. A pathological diagnosis of typical carcinoid was made from both morphological and immunological examinations. One year after excision surgery, there was no tumor recurrence or neck metastasis. PMID:27840746

  3. Calcitonin-producing well-differentiated neuroendocrine carcinoma (carcinoid tumor) of the urinary bladder: case report

    PubMed Central

    Mascolo, Massimo; Altieri, Vincenzo; Mignogna, Chiara; Napodano, Giorgio; De Rosa, Gaetano; Insabato, Luigi

    2005-01-01

    Background The occurrence of calcitonin-secreting primary carcinoid tumor of the urinary bladder is extremely rare. Case presentation The case of a 68-year-old male with carcinoid tumor arising in the urinary bladder is presented. Transurethral resection of a polypoid small tumor 0.4 cm in diameter was performed. Immunohistochemical study using neuroendocrine markers allowed a straightforward diagnosis of a low-grade neuroendocrine carcinoma (carcinoid tumor) of the urinary bladder. Immunohistochemistry demonstrated calcitonin immunoreactivity in the most of the tumor cells. Conclusion This tumor shows specific clinical, macroscopical and histological features and must be considered in the differential diagnosis of bladder neoplasms. PMID:16048646

  4. Primary ovarian carcinoid tumor showing unusual histology and nuclear accumulation of β-catenin.

    PubMed

    Kim, Hyun-Soo; Yoon, Gun; Jang, Hye-In; Song, Sang Yong; Kim, Byoung-Gie

    2015-01-01

    Carcinoid tumor of the ovary is uncommon. We herein report a very rare case of primary ovarian carcinoid tumor with aggressive histology and an unusual immunophenotype. A 21-year-old woman presented with a palpable abdominal mass. Computed tomographic scan revealed a large, extensively necrotic solid mass in the left ovary. The patient underwent a left salpingo-oophorectomy. Grossly, the left adnexa showed a large, vaguely lobulated ovarian tumor measuring 22×15×13 cm. Histologically, the tumor had a readily identifiable neuroendocrine growth pattern, but some areas showed solid growth pattern associated with mild nuclear pleomorphism and multiple foci of punctate necrosis. Furthermore, mitotic figures were recognized in 8 per 10 high-power fields, and a few foci of large coagulative tumor necrosis were also noted. In addition, the tumor tissue exhibited uniform, strong nuclear β-catenin immunoreactivity, indicating the nuclear accumulation of β-catenin in the individual tumor cells. In summary, we described the first case of primary ovarian carcinoid tumor with loss of neuroendocrine growth pattern, increased mitotic activity and large areas of coagulative tumor necrosis. According to the WHO classification of pulmonary carcinoid tumor, this case may be classified as "atypical" carcinoid. However, currently, no primary ovarian atypical carcinoid exists in the classification system. Due to its rarity, there are no established diagnostic criteria and clinical data on patient outcomes for ovarian carcinoid tumors with aggressive histology. Additional reports are clearly necessary. We also showed for the first time the nuclear accumulation of β-catenin in carcinoid tumor cells, suggestive of a role for β-catenin in the tumorigenesis of ovarian atypical carcinoid tumor or its aggressive histology.

  5. Primary ovarian carcinoid tumor showing unusual histology and nuclear accumulation of β-catenin

    PubMed Central

    Kim, Hyun-Soo; Yoon, Gun; Jang, Hye-In; Song, Sang Yong; Kim, Byoung-Gie

    2015-01-01

    Carcinoid tumor of the ovary is uncommon. We herein report a very rare case of primary ovarian carcinoid tumor with aggressive histology and an unusual immunophenotype. A 21-year-old woman presented with a palpable abdominal mass. Computed tomographic scan revealed a large, extensively necrotic solid mass in the left ovary. The patient underwent a left salpingo-oophorectomy. Grossly, the left adnexa showed a large, vaguely lobulated ovarian tumor measuring 22×15×13 cm. Histologically, the tumor had a readily identifiable neuroendocrine growth pattern, but some areas showed solid growth pattern associated with mild nuclear pleomorphism and multiple foci of punctate necrosis. Furthermore, mitotic figures were recognized in 8 per 10 high-power fields, and a few foci of large coagulative tumor necrosis were also noted. In addition, the tumor tissue exhibited uniform, strong nuclear β-catenin immunoreactivity, indicating the nuclear accumulation of β-catenin in the individual tumor cells. In summary, we described the first case of primary ovarian carcinoid tumor with loss of neuroendocrine growth pattern, increased mitotic activity and large areas of coagulative tumor necrosis. According to the WHO classification of pulmonary carcinoid tumor, this case may be classified as “atypical” carcinoid. However, currently, no primary ovarian atypical carcinoid exists in the classification system. Due to its rarity, there are no established diagnostic criteria and clinical data on patient outcomes for ovarian carcinoid tumors with aggressive histology. Additional reports are clearly necessary. We also showed for the first time the nuclear accumulation of β-catenin in carcinoid tumor cells, suggestive of a role for β-catenin in the tumorigenesis of ovarian atypical carcinoid tumor or its aggressive histology. PMID:26191292

  6. Minute ampullary carcinoid tumor with lymph node metastases: a case report and review of literature

    PubMed Central

    Senda, Eri; Fujimoto, Koji; Ohnishi, Katsuhiro; Higashida, Akihiro; Ashida, Cho; Okutani, Toshio; Sakano, Shigeru; Yamamoto, Masayuki; Ito, Rieko; Yamada, Hajime

    2009-01-01

    Background Carcinoid tumors are usually considered to have a low degree of malignancy and show slow progression. One of the factors indicating the malignancy of these tumors is their size, and small ampullary carcinoid tumors have been sometimes treated by endoscopic resection. Case presentation We report a case of a 63-year-old woman with a minute ampullary carcinoid tumor that was 7 mm in diameter, but was associated with 2 peripancreatic lymph node metastases. Mild elevation of liver enzymes was found at her regular medical check-up. Computed tomography (CT) revealed a markedly dilated common bile duct (CBD) and two enlarged peripancreatic lymph nodes. Endoscopy showed that the ampulla was slightly enlarged by a submucosal tumor. The biopsy specimen revealed tumor cells that showed monotonous proliferation suggestive of a carcinoid tumor. She underwent a pylorus-preserving whipple resection with lymph node dissection. The resected lesion was a small submucosal tumor (7 mm in diameter) at the ampulla, with metastasis to 2 peripancreatic lymph nodes, and it was diagnosed as a malignant carcinoid tumor. Conclusion Recently there have been some reports of endoscopic ampullectomy for small carcinoid tumors. However, this case suggests that attention should be paid to the possibility of lymph node metastases as well as that of regional infiltration of the tumor even for minute ampullary carcinoid tumors to provide the best chance for cure. PMID:19159493

  7. Primary carcinoid tumor of the urinary bladder with prominent subnuclear eosinophilic granules.

    PubMed

    Zozumi, Masataka; Nakai, Mayumi; Matsuda, Ikuo; Hao, Hiroyuki; Ueda, Yasuo; Nojima, Michio; Yamamoto, Shingo; Hirota, Seiichi

    2012-02-15

    Primary carcinoid tumor of the urinary bladder is a very rare neoplasm. We report here a case of primary carcinoid tumor of the urinary bladder with an unusual cytological feature in a 72-year-old Japanese man. A bladder polypoid mass was incidentally found by ultrasonography during the follow-up of a benign prostate hyperplasia. Histological examination of the transurethrally resected tissue revealed that the upper part of the mass was a tumor showing tubuloglandular anastomosing structures. Most of the tumor cells had peculiar subnuclear eosinophilic granules. The features of the granules were reminiscent of those observed in neuroendocrine cells of the intestine. The tumor cells were immunohistochemically positive for chromogranin A and synaptophysin. The tumor was diagnosed as carcinoid tumor of pure form of the urinary bladder. The lower part of the mass showed the findings of glandular cystitis, as its coexistence with carcinoid tumors of the bladder has often been described in previous reports.

  8. What Happens after Treatment for Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... for Gastrointestinal Carcinoid Tumors? For some people with gastrointestinal (GI) carcinoid tumor, treatment may remove or destroy the cancer. Completing treatment can be both stressful and exciting. ...

  9. [Renal carcinoid tumor presenting as bladder tamponade: a case report and review of the Japanese cases].

    PubMed

    Kajita, Yoichiro; Megumi, Yuzuru; Okabe, Tatsushiro

    2005-07-01

    A 65-year-old man presented with sudden onset of gross hematuria and urinary retention. Computed tomographic scan (CT) showed a cystic multilocular enhancing lesion (9 cm in diameter) at the left renal hilum causing thinning and lateral displacement of the left renal parenchyma. Left hydronephrosis and a renal calculi were observed. We performed radical nephrectomy suspecting a cystic renal cell carcinoma. Microscopic examination and immunohistochemical studies confirmed the diagnosis of the carcinoid tumor. The tumor cells were fully positive for neuron-specific enolase and keratin, and partially positive for chromogranin-A. One of the resected lymph nodes was positive for metastasis. Additional gastrointestinal tract examinations for carcinoid tumor were negative. However, he was concurrently diagnosed with poorly differentiated prostate cancer and hormonal therapy was started. He is free of recurrent carcinoid tumor nine months postoperatively. This case is the 31st report of renal carcinoid tumors in Japan.

  10. Duodenal carcinoid tumor - a case report.

    PubMed

    Debnath, C R; Debnath, M R; Haque, M A; Das, S N; Moshwan, M M; Karim, R; Uddoula, M S

    2014-01-01

    Carcinoid tumors are well differentiated neuroendochrine tumors which most frequently involve the gastrointestinal tract; however duodenal carcinoid tumors are rare. They can present with various clinical symptoms and are difficult to diagnose. A 52 years old lady presented with the symptoms of recurrent upper abdominal pain, burning sensation of whole body and passage of loose stool. On endoscopy of upper GIT, there was a duodenal polyp. Polyp was removed by endoscopic resection and tissue was taken for biopsy. Histological findings of biopsy specimen shows carcinoid tumor. As duodenal carcinoid tumor is a rare presentation so we are going to present this case in this article.

  11. [Bronchial carcinoid tumor: study of 60 patients].

    PubMed

    Madrid-Carbajal, Claudia; García-Clemente, Marta; Pando-Sandoval, Ana; Cubillas Martín, Hugo; González-Budiño, Teresa; Casan-Clarà, Pere

    2013-07-21

    To describe the casuistry of bronchial carcinoid tumor in the last 20 years in our hospital and determine survival after surgical treatment. We retrospectively reviewed the medical records from January 1992 to June 2012 of patients diagnosed with carcinoid tumor by the pulmonary service. Fifty-two patients (87%) had typical carcinoid and 8 (13%) atypical carcinoid. The mean age at diagnosis was 60 years (SD: 14.4). There was no relationship between consumption of tobacco and carcinoid tumor. Twenty-two per cent were asymptomatic radiographic finding (incidental finding) Three patients showed carcinoid syndrome and one patient had Cushing syndrome. There was a right dominance and the mean lesion size was between 2.1 and 5 cm. Nine per cent had lymph node involvement, predominantly in atypical carcinoid. Overall survival at 3.5 and 10 years was 94%, 86% and 82%. Survival at 5 years was 90% for typical and 86% for atypical and survival at 10 years was 85% for typical and 57% for atypical carcinoids. Carcinoid tumors are malignant tumors by their ability to metastasize. In our study, both histological type and staging were predictors of survival. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  12. [Intestinal carcinoid tumour: Case report].

    PubMed

    Mussan-Chelminsky, Gil; Vidal-González, Pablo; Núñez-García, Edgar; Valencia-García, Luis César; Márquez-Ugalde, Miguel Ángel

    2015-01-01

    Carcinoid of the small intestine, is a well-differentiated neuroendocrine tumor that rarely presents with clinical signs. This tumour can be associated with other conditions, such as inflammatory bowel disease, presenting a wide range of symptoms. In some cases they have an aggressive and highly symptomatic behaviour; thus, clinical suspicion must be high to make an early diagnosis. A 60 year-old male patient with Crohn's disease and gastrointestinal symptoms attributed to this disease within the last year. He presented with intestinal obstruction initially treated with conservative management with no improvement. Exploratory laparotomy was performed finding a mesenteric tumour that caused the bowel obstruction. Bowel resection with primary anastomosis was performed. The pathology report showed an intestinal carcinoid tumour with lymph node metastases. The patient recovered well, and was discharged without complications to continue medical treatment and follow-up by the Oncology department. In almost 42% of the cases, the most common site of carcinoid tumours is the small intestine, and of these, 41% are presented as locoregional disease. Patients with Crohn's disease present a higher incidence. In these cases, the most common presentation is an acute intestinal obstruction (90%). Surgery is usually curative, and follow up is important as the symptoms of Crohn's disease can hide any recurrence. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  13. Scintigraphic imaging of carcinoid tumors

    SciTech Connect

    Fischer, M.; Kamanabroo, D.

    1985-05-01

    131-1-metaiodobenzylguanidine (131-1-MIBG) is used for scintigraphic localization and treatment of pheochromocytoma and neuroblastoma. Several other tumors, deriving from neuroectoderm (APUD tumors) may also produce catecholamines. 4 patients with surgically proven carcinoid tumors were studied by 131-1-MIBG scintigraphy. Scintigraphic images were performed with a computer assisted gamma camera 2.24, 48 and 72 hours after IV injection of 26 MBq 131-I-MIBG. In one patient single photon emission computed tomography (SPECT) with 185 Mgq 123-I-MIBG was performed additionally. Catecholamines were determined in 24-hours-urinary samples by HPLC. Serotonine was determined in plasma. Catecholamine excretion was normal in all patients, whereas serotonine was elevated in all of them. In 2 of 4 patients slight tracer uptake was observed in some of liver metastases, whereas other metastases in the liver and the primary tumor did not show 131-1-MIBG uptake. In one patient with a carcinoid tumor of the pancreas 131-1-MIBG scintigraphy and SPECT with 123-1-MIBG was positive. In one patient scintigraphy was false negative. MIBG scintigraphy is not only suitable for imaging pheochromocytoma and neuroblastoma, but may also localize carcinoid tumors and their metastases.

  14. Skeletal metastasis of carcinoid tumors: Two case reports and review of the literature.

    PubMed

    Hori, Takeshi; Yasuda, Taketoshi; Suzuki, Kayo; Kanamori, Masahiko; Kimura, Tomoatsu

    2012-05-01

    Carcinoid tumors are neuroendocrine neoplasms derived from enterochromaffin cells. Skeletal metastases from carcinoid tumors are considered to be extremely rare. In this study, we present two cases of carcinoid tumors that metastasized to the bone. Furthermore, we review 50 published case reports and reveal the features of skeletal metastasis of carcinoid tumors. The first case involved a 59-year-old man with a history of multiple metastases of a lung carcinoid tumor. The patient complained of back pain and numbness in the lower limbs. Magnetic resonance imaging revealed metastases in the thoracic spine. A spinal decompression was performed and the symptoms were resolved. The second case involved a 74-year-old man had been diagnosed with a lung carcinoid tumor 15 years previously and complained of left thigh pain. A radiograph showed osteolytic lesions in the shaft of the left femur. We repaired the femur using an intramedullary nail following curettage of the tumor. A radiograph of the femur revealed a callus on the pathological fracture. The patient was able to walk using a crutch 3 months after surgery. We reviewed 50 cases that described skeletal metastasis from carcinoid tumors. The average age of the patients was 54.9 years and 33 patients (66%) were male. The most common site of skeletal metastasis was the spine. We also investigated the survival rate of patients who developed skeletal metastasis from carcinoid tumors. The findings showed that survival of patients who developed osteolytic skeletal metastasis was worse than that of patients who developed osteosclerotic skeletal metastasis.

  15. Pulmonary carcinoid tumor associated with nephrotic syndrome.

    PubMed

    DePace, N L; Elquezabal, A; Hardenburg, H C

    1980-04-01

    A patient with carcinoid tumor of the lung associated with nephrotic syndrome was treated. Excision of the tumor resulted in remission of marked proteinuria, hypoalbuminemia, and edema. A review of the literature disclosed many neoplasms associated with the nephrotic syndrome; however, no association of the nephrotic syndrome and a carcinoid tumor of the lung has previously been reported, to our knowledge.

  16. Liver metastasis secondary to primary mesenteric carcinoid.

    PubMed

    Juanmartiñena Fernández, José Francisco; Fernández Urién, Ignacio; Amat Villegas, Irene; Prieto Martínez, Carlos

    2017-03-01

    Carcinoid tumors are rare, slow-growing neoplasms that display neuroendocrine properties. The term carcinoid is generally applied to well-differentiated neoplasms, while neuroendocrine carcinoma is reserved only for poorly differentiated lesions. They can be found throughout the different regions of the gastrointestinal system, although they have predilection for the ileum.

  17. Aprepitant for the management of refractory emesis in a patient with a small bowel carcinoid tumor.

    PubMed

    Kyeremateng, Sam; Boland, Jason W

    2014-06-01

    Nausea and vomiting are common distressing symptoms with multiple etiologies. Serotonin and substance P can induce nausea and vomiting by binding to specific receptors (5-hydroxytryptamine3 [5HT3] and neurokinin-1 [NK-1] receptors respectively). Carcinoid tumors, which originate from enterochromaffin cells of the neuroendocrine system, secrete several biologically active amines and peptides, including serotonin and substance P, that are responsible for the distant effects of this tumor. The authors present an 88-year-old lady with metastatic carcinoid tumor, with evidence of carcinoid syndrome. She had nausea and vomiting that became unresponsive to 5HT3 receptor antagonists and other antiemetics. As substance P is released from carcinoid tumors and has a role in the pathogenesis of emesis, the NK-1 receptor antagonist aprepitant was trialed. This provided complete and sustained improvement of the nausea and vomiting until her death 2 months later. This case demonstrates the potential role and rationale of NK-1 receptor antagonists in the management of resistant emesis in patients with carcinoid tumors. Clinical trials are needed to evaluate the efficacy and toxicity of these drugs in the management of emesis in patients with carcinoid syndrome.

  18. Primary hepatic carcinoid tumor: case report and literature review

    PubMed Central

    Camargo, Éden Sartor; Viveiros, Marcelo de Melo; Corrêa, Isaac José Felippe; Robles, Laercio; Rezende, Marcelo Bruno

    2014-01-01

    Primary hepatic carcinoid tumors are extremely rare neoplasms derived from hormone-producing neuroendocrine cells. It is difficult to make their diagnosis before biopsy, surgical resection or necropsy. A recent publication described only 94 cases of these tumors. There is no sex predilection and apparently it has no association with cirrhosis or preexisting hepatic disease. The most effective treatment is hepatectomy, and resection is determined by size and location of the lesions. PMID:25628206

  19. [Localised bronchiectasis revealing carcinoid tumor].

    PubMed

    Janah, Hind; Jabri, Hasna; Bopaka, Régis Gothard; Khattabi, Wiam El; Afif, Hicham

    2016-01-01

    We here report the case of a 32-year old female patient with a 5-year history of recurrent purulent bronchial syndrome. Radiological assessment showed a left basithoracic finely ringed bright areas related to cylindrical bronchiectasis located in the left lower lobe. Flexible bronchoscopy showed smooth surface, reddish tumor obstructing the entrance of the left basal pyramid. The patient underwent left lower lobectomy associated with mediastinal lymph node dissection. Histological examination of the surgical specimen was in favor of typical carcinoid tumor. Postoperative outcome was uncomplicated and clinical and radiological evolution was good.

  20. Primary carcinoid tumor of the gallbladder: a case report and brief review of the literature.

    PubMed

    Zou, Yi-Ping; Li, Wei-Min; Liu, Hao-Run; Li, Ning

    2010-02-23

    Primary carcinoid tumor of the gallbladder is rare and comprises less than 1% of all carcinoid tumors. Preoperative diagnosis of carcinoid tumor of the gallbladder is difficult. The imageology findings are similar to those in other gallbladder cancers. A 46-year-old woman was hospitalized with a preoperative diagnosis of gallbladder carcinoma, The patient was referred for surgical opinion and laparotomy was subsequently performed. A 4 x 5 cm mass was found within the gallbladder, located on the free surface of the body and fundus of the gallbladder. Neither metastases nor direct invasion to the liver was found. The entire mass and gallbladder were excised and intact. Histologically, the tumor consisted of small oval cells with round-to-oval neclei and tumor cells formed small nodular, trabeculare and acinar structures. The tumor showed moderate pleomorphism with scattered mitotic figures, but no definite evidence of vascular permeation, perineural invasion or lymphatic permeation was seen. The tumor cells invaded the mucosa extensively, and some penetrated the muscular layer but not through the serosa of the gallbladder into the liver. Immunohistochemical studies revealed strong positive reaction for chromogranin A and NSE. This lesion was proved to be a primary carcinoid tumor of the gallbladder. A brief review of literature, clinical feature, pathology and treatment of this rare disease was discussed. Primary carcinoid tumor of the gallbladder is uncommon. The definite diagnosis is often made on histopathological results after surgery.

  1. Two different types of carcinoid tumors of the lung: immunohistochemical and ultrastructural investigation and their histogenetic consideration.

    PubMed

    Min, Kyung-Whan

    2013-02-01

    Carcinoid tumors have been an interesting clinical and pathological entity for pathologists because of their unique histopathologic pattern of "Zellballen" (cell ball) and the hormones they produce demonstrable by histochemical and biochemical methods, including immunohistochemistry, and the presence of cytoplasmic dense-core particles demonstrable by electron microscopy. Since carcinoid tumors were established as an entity more than a century ago by Oberndorfer, who was credited with coining the term "carcinoid," meaning carcinoma-like tumors, tumors presenting with similar characteristics have been reported in most of parenchymal organs, including lungs. Carcinoid tumors in the lungs usually occur as bronchocentric tumors and present with typical histopathologic characteristics of carcinoid tumors, but they may present with significant variation in their cellular compositions, in contrast to the midgut carcinoid tumors. In the latter, tumor cells are quite similar to enterochromaffin granule containing crypt cells, which are regarded as their progenitor cells. Currently, a similar histogenetic explanation is applied to all carcinoid tumors occurring elsewhere. The bronchus is one of the most common anatomic sites in which the carcinoid tumors occur. However, bronchial carcinoid tumors differ from the midgut counterparts in microscopic appearance, showing more variability in cellular shape and composition from the classical form of midgut carcinoid tumors. In the lungs, neuroendocrine cells (NEC) are normally found in two different ways. Firstly, they are found as randomly scattered single cells (Kultchitsky cells) similar to enteric counterparts, and, secondly, they are found in aggregates known as "neuroepithelial bodies" (NEB) usually found in the branching point of bronchi. Interestingly, they keep a close anatomic relationship with parasympathetic nerve structures and even form synapses. NEB are usually found in the early stage of fetal development and are

  2. Small duodenal carcinoids: a case series comparing endoscopic resection and autoamputation with band ligation.

    PubMed

    Scherer, John R; Holinga, Julie; Sanders, Michael; Chennat, Jennifer; Khalid, Asif; Fasanella, Kenneth; Singhi, Aatur D; McGrath, Kevin

    2015-04-01

    We sought to compare the efficacy and safety of endoscopic ultrasound-guided endoscopic resection (ER) and endoscopic band ligation (EBL) for autoamputation of small duodenal carcinoids. The ideal management of small duodenal carcinoid tumors remains unclear. A retrospective review of duodenal carcinoids over a 10-year period (2002 to 2012) was performed at our tertiary-care teaching hospital. All patients with duodenal carcinoids ≤10 mm in size treated with either ER or EBL were included. The main outcome measurements were the efficacy and safety of endotherapy. A total of 37 patients with 39 subcentimeter duodenal carcinoids were identified. In the EBL group, the mean (SD) tumor size was 6.7±2.1 mm compared with 6.7±1.7 mm in the ER group (P=0.943). The mean Ki-67 index was ≤2% in specimens available for histologic analysis in both groups (16/23 EBL and 15/16 ER). The positive deep margin rate in the ER group was 68.8%. Residual carcinoid tumor cells were detected on follow-up biopsies in 1 patient after EBL, and 2 patients after ER. All underwent subsequent successful endotherapy. No adverse events occurred in the EBL group compared with an 18.8% adverse event rate in the ER group (P=0.066). Endoscopic ultrasound-guided EBL is a safe, effective method for removal of small superficial duodenal carcinoids and seems to be a lower risk alternative to conventional ER with cautery.

  3. A carcinoid tumor arising from a mature cystic teratoma in a 25-year-old patient: a case study.

    PubMed

    Kim, Joo-Yeon

    2016-04-21

    Mature cystic teratomas (MCTs) are common benign tumors occurring in the ovaries. Malignant transformation of teratomas (TMT) occurs in 1-3% of all MCTs, usually in postmenopausal women. Squamous cell carcinoma is the most common tumor type. Primary carcinoid tumors of the ovary are uncommon, representing only 0.3% of all carcinoid tumors and less than 0.1% of all ovarian cancers. A carcinoid tumor of the trabecular type arising from a MCT is presented in a 25-year-old woman. TMT was detected incidentally. Histologically, uniform, polygonal cells were arranged in a cord and trabecular pattern. Immunohistochemical staining showed positivity for neuro-specific enolase, synaptophysin, and CD56. This case represents a very rare example of carcinoid tumor occurring in a woman younger than 30 years of age. Our findings suggest that sufficient tumor sampling is necessary to avoid overlooking small lesions, which, in our case, were not detected on either radiologic or gross examination.

  4. High-grade neuroendocrine carcinomas of the lung highly express enhancer of zeste homolog 2, but carcinoids do not.

    PubMed

    Findeis-Hosey, Jennifer J; Huang, Jiaoti; Li, Faqian; Yang, Qi; McMahon, Loralee A; Xu, Haodong

    2011-06-01

    Enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, is a histone methyltransferase and plays an important role in cell proliferation and cell cycle regulation. It has been shown to be overexpressed in a number of malignant neoplasms. This study aimed to determine the expression pattern of enhancer of zeste homolog 2 in neuroendocrine tumors of the lung and the potential of enhancer of zeste homolog 2 to serve as a biomarker to segregate carcinoids from high-grade neuroendocrine carcinomas. Fifty-four cases, including 25 typical carcinoids, 7 atypical carcinoids, 9 large-cell neuroendocrine carcinomas, and 13 small-cell lung carcinomas, were immunohistochemically studied using a monoclonal antibody against enhancer of zeste homolog 2. All 13 small-cell lung carcinomas demonstrated moderate to strong nuclear staining with 12 exhibiting more than 90% of tumor cells staining. All 9 large-cell neuroendocrine carcinomas were moderately to strongly positive for enhancer of zeste homolog 2, with 6 cases having staining in more than 80% of tumor cells. In contrast, all 25 typical carcinoids and 6 atypical carcinoids showed only rare scattered enhancer of zeste homolog 2-positive tumor cells, with 1 case of atypical carcinoid exhibiting moderate staining in 40% of tumor cells. A subsequent validation study of the 14 specimens of lung or mediastinal lymph node biopsy and fine-needle aspiration, including 6 small-cell lung carcinomas, 2 large-cell neuroendocrine carcinomas, 5 typical carcinoids, and 1 atypical carcinoid, was performed. Enhancer of zeste homolog 2 was diffusely and strongly positive in all small-cell lung carcinomas and large-cell neuroendocrine carcinomas, even with severe crush artifact, whereas it was only positive in rare tumor cells in carcinoids. These findings support the formulation that enhancer of zeste homolog 2 may play an important role in the regulation of biologic behavior of high-grade neuroendocrine carcinomas

  5. Primary carcinoid tumor of the cavernous sinus.

    PubMed

    Hood, Brian; Bray, Eric; Bregy, Amade; Norenberg, Michael; Weed, Donald; Morcos, Jacques J

    2014-01-01

    Intracranial carcinoid tumors belong to the class of neuroendocrine tumors and their incidence is extremely rare. The pathogenesis and clinical manifestations of carcinoid tumors of the skull base are outlined in this case report. A 61-year-old multimorbid woman presented with transient memory loss. Computed tomographic and magnetic resonance imaging scan of the brain demonstrated a left cavernous sinus mass extending into the infratemporal fossa. The lesion was biopsied using the Caldwell-Luc approach, and histology showed a low-grade neuroendocrine tumor. The tumor was subtotally resected with a neurosurgery/head and neck combined preauricular infratemporal and subtemporal extradural approaches to the cavernous sinus. Further histologic evaluation revealed that the tumor was of carcinoid differentiation with no other primary or metastatic sites detectable. Primary intracranial carcinoid tumors, though rare, should be included in the differential diagnosis of extradural and dural-based lesions. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Bioprosthetic tricuspid valve replacement in carcinoid heart disease from primary ovarian carcinoid tumor.

    PubMed

    Tsugu, Toshimitsu; Iwanaga, Shiro; Murata, Mitsushige; Fukuda, Keiichi

    2015-07-01

    Carcinoid heart disease (CHD) commonly occurs in association with primary gastrointestinal tract carcinoid tumors with hepatic metastases. Unlike primary gastrointestinal tract carcinoid tumors, primary ovarian carcinoid tumors may cause CHD without hepatic metastases, accounting for only 0.3 % of all carcinoid tumors. Only 37 cases of CHD from primary ovarian carcinoid tumors have been reported. We present a case of CHD in which tricuspid valve thickening and shortening led to reduced valve mobility with the resulting severe tricuspid regurgitation. Considering these characteristics of an abnormal tricuspid valve, we suspected CHD, but prosthetic valve replacement was performed without sufficient systemic examination before surgery. Two years after valve replacement, the patient underwent excision of a mass in the lower abdomen, which was diagnosed as an ovarian carcinoid tumor by histopathological examination. The patient has been observed for more than 3 years after tricuspid valve replacement. She has not experienced bioprosthetic valve leaflet degeneration or dysfunction, although it has been reported that bioprosthetic valves may degenerate in patients with carcinoid tumors. Sufficient systemic examinations should be performed to explore the cause of disease.

  7. Primary pulmonary carcinoid tumor: a long-term single institution experience/Primary pulmonary carcinoid tumor

    PubMed Central

    Herde, Ryan F.; Kokeny, Kristine E.; Reddy, Chakravarthy B.; Akerley, Wallace L.; Hu, Nan; Boltax, Jonathan P.; Hitchcock, Ying J.

    2015-01-01

    Objectives Primary carcinoid tumors of the lung are rare tumors which comprise approximately 0.5 to 5% of all lung malignancies in adults and roughly 20 to 30% of all carcinoid tumors. The purpose of this retrospective, descriptive study was to describe the incidence, characteristics, and outcomes of patients treated for primary pulmonary carcinoid tumor at a single institution. Methods All patients with a diagnosis of primary pulmonary carcinoid tumor treated from 1989 to 2009 were reviewed. Data collected included demographics, pathology, tobacco use, clinical presentation, tumor location, tumor spread, treatment and survival. Results There were 59 cases of pulmonary carcinoid tumors: 47 typical (80%) and 12 atypical (20%). All but 4 patients underwent surgery, including 54 (92%) lung-sparing resections and 1 pneumonectomy. Five out of 55 patients received concurrent adjuvant chemoradiation therapy; 4 patients with atypical and 1 with typical histology. Three additional patients with atypical carcinoid were treated only with adjuvant radiotherapy, palliative radiotherapy, or palliative chemotherapy, respectively. The Kaplan-Meier 5- and 10-year overall survivals were both 80% within the entire population. In the 88% of patients who achieved complete remission, disease-free survival was 98%. A review of a large series from the literature is also presented. Conclusions Surgical resection was primary and adequate therapy for most typical carcinoid tumors with high overall survival and disease-free survival. Adjuvant chemotherapy or radiotherapy might be considered for patients with atypical carcinoid tumors who present with adverse pathological findings. PMID:26270444

  8. A case of very well-differentiated adenocarcinoma with carcinoid tumor in the ascending colon.

    PubMed

    Yamauchi, Hayato; Sakurai, Shinji; Tsukagoshi, Ritsuko; Suzuki, Masaki; Tabe, Yuichi; Fukasawa, Takaharu; Kiriyama, Shinsuke; Fukuchi, Minoru; Naitoh, Hiroshi; Kuwano, Hiroyuki

    2014-01-01

    Malignant tumors with mixed glandular and neuroendocrine characteristics with at least 30% of each component are classified as mixed adenoneuroendocrine carcinoma (MANEC) by the World Health Organization 2010 classification. We report here a case of very well-differentiated adenocarcinoma accompanied by carcinoid tumor, categorized as MANEC. A 41-year-old Japanese man was clinically diagnosed with ascending colon cancer and underwent right hemicolectomy. Using an immunohistologic technique, the pathologic diagnosis was very well-differentiated adenocarcinoma accompanied by carcinoid tumor and marked eosinophil infiltration, which was categorized as MANEC. By immunohistochemical analysis, tumor cells of the carcinoid component exhibited very low proliferation activity. Our case was thought to be MANEC without high malignant potential. MANEC as per the World Health Organization 2010 classification seems to include tumors with diverse grades of malignancy, and it might need to have subclassifications according to the malignancy potential of the tumor cells.

  9. CDX2 may be a useful marker to distinguish primary ovarian carcinoid from gastrointestinal metastatic carcinoids to the ovary.

    PubMed

    Desouki, Mohamed Mokhtar; Lioyd, Joshua; Xu, Haodong; Cao, Dengfeng; Barner, Ross; Zhao, Chengquan

    2013-11-01

    Primary ovarian carcinoids and metastatic tumors share similar morphologic features. Metastatic carcinoids must be excluded from primary ones for prognostic and therapeutic reasons. Gastrointestinal neuroendocrine (carcinoid) tumors are much more common with the majority arising from small intestine and appendix. The aim of this study is to evaluate the role of immunohistochemistry for CDX2 in differentiating primary ovarian from metastatic carcinoids of primary gastrointestinal origin. Thirty primary pure ovarian carcinoids, 16 primary ovarian carcinoids arising in association with benign teratomas, 10 ovarian carcinoids metastatic from primary gastrointestinal tract and 70 gastrointestinal neuroendocrine tumors were studied for the expression of CDX2 by immunohistochemistry. CDX2 expression revealed that 40 (57.1%) of 70 cases of gastrointestinal carcinoids and 9 (90%) of 10 ovarian metastatic carcinoids showed positive nuclear staining (diffuse or focal). On the other hand, 3 (18.8%) of 16 primary carcinoids with teratomatous elements showed weak positivity. Among the 70 gastrointestinal carcinoids, CDX2 was positive in 38 (90.5%) of 42 cases in the duodenum, small intestine, appendix, and only in 2 (11.8%) of 17 cases of colorectal carcinoids and none of the 11 cases in the stomach. It is concluded that CDX2 may be a useful marker to distinguish primary ovarian carcinoid from metastasis from small intestinal and appendiceal neuroendocrine tumors.

  10. Do We Know What Causes Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... and Prevention Do We Know What Causes Gastrointestinal Carcinoid Tumors? Researchers have made great progress in understanding ... than having been inherited. The mutations that cause carcinoid tumors often affect the MEN1 gene, the same ...

  11. Large presacral tailgut cyst with a carcinoid tumor in a male: report of a case.

    PubMed

    Charalampakis, Vasileios; Stamatiou, Dimitrios; Christodoulakis, Manousos; Kafousi, Maria; Chryssou, Evangelia; de Bree, Eelco; Melissas, John

    2014-05-01

    Tailgut cysts are developmental hamartomas found in the presacral space. They are usually detected incidentally during physical examinations or imaging studies. However, they may cause symptoms due to compression of nearby organs. Due to their potential malignant transformation, surgical resection is warranted, while routine biopsy is considered controversial because of the concern about infection of the tailgut cyst and needle-track implantation of malignant cells. The co-existence of a carcinoid in a tailgut cyst is extremely rare. Only 16 cases have been reported previously, the vast majority of which were found in females. We herein present the case of a carcinoid in a tailgut cyst found in a male patient, discuss the potential pathogenesis of tailgut carcinoids, and underline the fact that their previous consideration of the condition as a female-restricted entity should be rejected.

  12. An Unusual Case of Rectal and Ileal Carcinoid Tumors

    PubMed Central

    Abdulsamad, Molham; Abbas, Naeem; Balar, Bhavna

    2016-01-01

    Carcinoid tumor is the most common neuroendocrine tumor affecting the gastrointestinal tract. The coexistence of multifocal carcinoid lesions is a well-established phenomenon. Although intubation of the terminal ileum is not routinely attempted during colonoscopy, it can occasionally reveal the presence of some incidental findings. We present a patient with known rectal carcinoid, who was found to have another carcinoid lesion in the terminal ileum during surveillance colonoscopy. The patient underwent right hemicolectomy, and no chemotherapy was required as the patient was found to have stage 1 carcinoid tumor. PMID:28203126

  13. Incidental Primary Intradural Carcinoid Tumor in a Patient with Lumbar Radiculopathy.

    PubMed

    Koustais, Stavros; O'Halloran, Philip J; Hassan, Alfrazdaq; Brett, Francesca; Young, Steven

    2017-09-01

    Carcinoid tumors are neuroendocrine neoplasms derived from enterochromaffin cells. Central nervous system involvement is rare. The reported cases include metastases to brain or spinal cord, and primary skeletal or extradural disease resulting in compressive myeloradiculopathy. There are 2 previously reported cases of primary intradural extramedullary carcinoid tumor, presenting with compressive symptoms. We report the first case of primary incidental intradural extramedullary carcinoid tumor. A 68-year-old man was complaining of a 2-month history of left-sided back pain and sciatica; however, he presented with acutely worse symptoms of severe left sciatica. There was no sphincter dysfunction nor power deficit on examination. A magnetic resonance imaging (MRI) scan of the lumbar spine revealed an L4-5 central disk protrusion causing left L5 nerve root compression, and a heterogeneous enhancing intradural mass at the L2-3 level displacing the cauda equina. An L4-5 microdiscectomy followed by an L2-3 laminectomy and resection of the intradural mass was performed. There was a postoperative left S1 paresthesia that was managed medically; however, the postoperative period was unremarkable. A postoperative MRI of the lumbar spine showed complete resection of the mass. A staging scan revealed an incidental thyroid nodule; however, there was no other disease burden. Histopathology of the resected specimen revealed a primary spinal carcinoid tumor. To our knowledge, this is the first reported case of incidental primary intradural spinal carcinoid tumor. Even though intradural spinal carcinoid tumors are exceedingly rare, they should be included in the differential diagnosis of enhancing intradural lesions. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Metastatic carcinoid tumor obstructing left ventricular outflow.

    PubMed

    Chrysant, George S; Horstmanshof, Douglas A; Guniganti, Uma M

    2011-01-01

    Cardiac tumors are rare and usually indicate metastatic disease. Characterizing a tumor and reaching an exact diagnosis can be difficult. Diagnosis has been aided greatly by advances in imaging, such as cardiovascular magnetic resonance with the use of gadolinium-pentetic acid. Carcinoid tumors are neuroendocrine neoplasms that are found most often in the intestinal tract, although they can also develop in the lung, stomach, or heart. Herein, we report the case of a 72-year-old woman with a history of intestinal carcinoid disease and presenting symptoms of dizziness, fatigue, and chest pain. We used cardiovascular magnetic resonance with gadolinium enhancement to identify a large mass obstructing left ventricular outflow. The histopathologic results of an endomyocardial biopsy confirmed that the mass was a left-sided metastatic carcinoid cardiac tumor. To our knowledge, we are reporting the 1st combined use of clinical evaluation, cardiovascular magnetic resonance, and histopathologic studies to reach such a diagnosis.

  15. Primary renal carcinoid tumor: A radiologic review

    PubMed Central

    Lamb, Leslie; Shaban, Wael

    2015-01-01

    Carcinoid tumor is the classic famous anonym of neuroendocrine neoplasms. Primary renal carcinoid tumors are extremely rare, first described by Resnick and colleagues in 1966, with fewer than a total of 100 cases reported in the literature. Thus, given the paucity of cases, the clinical and histological behavior is not well understood, impairing the ability to predict prognosis. Computed tomography and (occasionally) octreotide studies are used in the diagnosis and followup of these rare entites. A review of 85 cases in the literature shows that no distinctive imaging features differentiate them from other primary renal masses. The lesions tend to demonstrate a hypodense appearance and do not usually enhance in the arterial phases, but can occasionally calcify. Octreotide scans do not seem to help in the diagnosis; however, they are more commonly used in the postoperative followup. In addition, we report a new case of primary renal carcinoid in a horseshoe kidney. PMID:27186242

  16. Metastatic Carcinoid Tumor Obstructing Left Ventricular Outflow

    PubMed Central

    Chrysant, George S.; Horstmanshof, Douglas A.; Guniganti, Uma M.

    2011-01-01

    Cardiac tumors are rare and usually indicate metastatic disease. Characterizing a tumor and reaching an exact diagnosis can be difficult. Diagnosis has been aided greatly by advances in imaging, such as cardiovascular magnetic resonance with the use of gadolinium-pentetic acid. Carcinoid tumors are neuroendocrine neoplasms that are found most often in the intestinal tract, although they can also develop in the lung, stomach, or heart. Herein, we report the case of a 72-year-old woman with a history of intestinal carcinoid disease and presenting symptoms of dizziness, fatigue, and chest pain. We used cardiovascular magnetic resonance with gadolinium enhancement to identify a large mass obstructing left ventricular outflow. The histopathologic results of an endomyocardial biopsy confirmed that the mass was a left-sided metastatic carcinoid cardiac tumor. To our knowledge, we are reporting the 1st combined use of clinical evaluation, cardiovascular magnetic resonance, and histopathologic studies to reach such a diagnosis. PMID:21720473

  17. Serum alpha-fetoprotein-positive gastric carcinoid with liver metastasis.

    PubMed

    Mori, H; Onji, M; Yoshida, A; Fukunishi, R

    1980-01-01

    The patient was a 60-year-old Japanese male. He complained of epigastralgia and right chest pain of 4 month's duration, and general malaise, nausea and vomiting of 2 month's duration. Physical examination revealed on the right third rib a tender mass with a diameter of 2 cm and hepatomegaly with a multi-nodular surface and red palms. There were no signs of carcinoid syndrome, such as cutaneous flushing. Laboratory examinations disclosed certain biochemical alterations; alkaline phosphatase 810 IU/l, gamma-glutamyl transpeptidase (gamma-GTP) 2090 IU/l, carcinoembryonic antigen (CEA) 23.5 ng/ml and alpha-fetoprotein (AFP) 6,800 ng/ml. Both HBs-Ag and HBs-Ab were negative. The patient died in a uremic state, with rapid increases of jaundice and ascites. Autopsy revealed gastric carcinoid with extensive metastases to the liver and the bone marrow. Tumor cells showed argyrophilia but not argentaffinity. Immunofluorescence specific for AFP was positive in the hepatocytes, particularly those adjacent to the metastatic tumor cells but not in the tumor cells, either primary or secondary. 79 cases reported in Japan of serum AFP-positive malignant tumor other than hepatocellular carcinoma and certain other malignancies of germ cell origin are reviewed and discussed.

  18. Overexpression of wild-type PKD2 leads to increased proliferation and invasion of BON endocrine cells

    SciTech Connect

    Jackson, Lindsey N.; Li Jing; Chen, L. Andy; Townsend, Courtney M.; Evers, B. Mark . E-mail: mevers@utmb.edu

    2006-09-29

    Carcinoid tumors are rare neuroendocrine tumors with a predilection for the gastrointestinal tract. Protein kinase D (PKD), a novel serine/threonine protein kinase, has been implicated in the regulation of transport processes in certain cell types. We have reported an important role for PKD in stimulated peptide secretion from a human (BON) carcinoid cell line; however, the role of PKD isoforms, including PKD2, in the proliferation and invasion of carcinoid tumors remains unclear. In the present study, we found that overexpression of PKD2 by stable transfection of BON cells with PKD2-wild type (PKD2{sub WT}) significantly increased proliferation and invasion compared to cells transfected with PKD2-kinase dead (PKD2{sub KD}) or pcDNA3 (control). Similarly, inhibition of PKD2 activity with small interfering RNA (siRNA) significantly decreased proliferation and invasion compared to cells transfected with non-targeting control (NTC) siRNA. These data support an important role for PKD2 in carcinoid tumor progression. Targeted inhibition of the PKD family may prove to be a novel treatment option for patients with carcinoid tumors.

  19. Carcinoid Heart Disease without Liver Involvement Caused by a Primary Ovarian Carcinoid Tumour.

    PubMed

    Agarwal, Chirag; Goel, Sunny; Stern, Eric; Warner, Richard; Castillo, Javier; Croft, Lori; Lavine, Ronald; Zacks, Jerome

    2015-07-01

    Carcinoid heart disease, caused by primary ovarian carcinoid tumour, is a rare form of valvular heart disease. This form of heart disease usually presents with symptoms of right-sided valvular dysfunction, ultimately leading to right-sided heart failure. This entity is unique as it develops in the absence of liver metastasis. We report a case of 75 year-old woman with primary ovarian carcinoid tumour who presented with symptoms of severe right-sided heart failure and successfully underwent pulmonic and tricuspid valve replacement along with a right ventricular (RV) outflow patch enlargement. This patient later underwent uneventful resection of the primary ovarian carcinoid tumour, with complete resolution of her symptoms.

  20. Intranuclear Pseudo-inclusions and Grooves in Fine Needle Aspiration Cytology of Pulmonary Carcinoid Tumor.

    PubMed

    Mokhtari, Maral; Kumar, Perikala Vijayananda

    2016-02-01

    Cytologic findings of pulmonary carcinoid have been well described. We report new cytological findings in a case of carcinoid tumor. The patient is a 36-year-old man presenting with hemoptysis of about six months in duration. Chest CT scans showed a well-defined round polypoid lesion measuring 1 × 1 cm within the right upper lobe of the bronchus with hyperinflation of the right upper lobe. Trans-bronchial fine needle aspiration and biopsy were done. Cytologic smears showed isolated and loose clusters of uniform round to spindle shape cells with round centrally located nuclei, fine granular (salt and pepper) chromatin and pale cytoplasm. Intranuclear pseudo-inclusions and grooves were seen in some tumor cells. No mitotic figures or necrosis were evident. A cytological diagnosis of carcinoid tumor was made and histopathologic examination and subsequent immunohistochemical study confirmed the diagnosis. Carcinoid tumor may be reliably diagnosed on fine needle aspiration cytology smears. Intranuclear pseudo-inclusions and grooves may be evident in tumor cells.

  1. Oncocytic carcinoid tumor of the lung with intense F-18 fluorodeoxyglucose (FDG) uptake in positron emission tomography-computed tomography (PET/CT).

    PubMed

    Tanabe, Yuki; Sugawara, Yoshifumi; Nishimura, Rieko; Hosokawa, Kohei; Kajihara, Makoto; Shimizu, Teruhiko; Takahashi, Tadaaki; Sakai, Shinya; Sawada, Shigeki; Yamashita, Motohiro; Ohtani, Haruhiko

    2013-10-01

    The present report describes a case of typical carcinoid tumor with intense fluorodeoxyglucose (FDG) uptake. The most of tumor cells were characterized by eosinophilic cytoplasm resulting from accumulation of mitochondria, which was called an oncocytic carcinoid tumor. Glucose transporter type 1 (GLUT-1) was expressed in a membranous pattern in the oncocytic component. Oncocytic carcinoid tumors could show intense FDG uptake due to the numerous intracellular mitochondria and the membranous overexpression of GLUT-1. Thus, it could be a potential pitfall of interpreting FDG-PET/CT image.

  2. Carcinoid Syndrome and Carcinoid Heart Disease as Manifestations of Non-Metastatic Ovarian Neuroendocrine Tumour.

    PubMed

    Simões-Pereira, Joana; Wang, Lai Mun; Kardos, Attila; Grossman, Ashley

    2017-05-31

    The carcinoid syndrome is rare but it is associated with carcinoid heart disease in more than a half of the cases. Carcinoid heart disease is typically characterised by morphological and functional modifications of right-sided valves. Its aetiology is probable multifactorial but serotonin appears to play a key role in the development of this valvular disease. Unlike gastrointestinal neuroendocrine tumours, ovarian neuroendocrine tumours can present with carcinoid syndrome and carcinoid heart disease in the absence of liver metastases; such ovarian neuroendocrine tumours are a unique clinical entity. The additional burden of cardiac impairment in these patients represents a significant reduction in survival. Early recognition and surgical valve replacement before advanced heart failure is established may improve the clinical outcome. We report the case of a woman with an ovarian neuroendocrine tumour and highly symptomatic carcinoid heart disease who was submitted to tumour resection followed by valvuloplasty. She demonstrated an outstanding clinical improvement and has remained free of tumour and symptomatology.

  3. Therapeutic options for gastrointestinal carcinoids.

    PubMed

    Modlin, Irvin M; Latich, Igor; Kidd, Mark; Zikusoka, Michelle; Eick, Geeta

    2006-05-01

    Although wide surgical resection is the optimal curative therapy for carcinoid tumors, in most patients the presence of metastatic disease at diagnosis usually renders excision a palliative procedure. This nevertheless decreases tumor burden, facilitates symptom control, and prevents complications caused by bleeding, perforation, or bowel obstruction resulting from fibrosis. In the stomach (types I and II) and rectum endoscopic excision may be adequate provided the lesion(s) are local. Long-term therapy is focused on symptom alleviation and improvement of quality of life using somatostatin analogues, particularly in a subcutaneous depot formulation. In some instances interferons may have a role but their usage often is associated with substantial adverse events. Conventional chemotherapy and external radiotherapy either alone or in a variety of permutations are of minimal efficacy and should be balanced against the decrease in quality of life often engendered by such agents. Hepatic metastases may be amenable to surgery, radiofrequency ablation, or embolization either alone or in combination with chemotherapeutic agents or isotopically loaded microspheres. Rarely hepatic transplantation may be of benefit although controversy exists as to its actual use. Peptide-receptor-targeted radiotherapy for advanced disease using radiolabeled octapeptide analogs (111In/90Yt/177Lu-octreotide) appear promising but data are limited and its status remains investigational. A variety of antiangiogenesis and growth factor-targeted agents have been evaluated, but as yet have shown little promise. The keystone of current therapy remains the long-acting somatostatin analogues that alleviate symptomatology and substantially improve quality of life with minimal adverse effects.

  4. Primary cervical spine carcinoid tumor in a woman with arm paresthesias and weakness: a case report

    PubMed Central

    2013-01-01

    Introduction Carcinoid tumors are neuroendocrine neoplasms derived from the enterochromaffin cells. Central nervous system involvement is rare and has been reported either as metastases to the brain and spine or primary tumors involving the sacrococcygeal spine. We report the first case of a primary carcinoid tumor of the cervical spine. Case presentation A 50-year-old African-American woman presented with a 4-month history of numbness, paresthesias, and mild left-hand weakness. Magnetic resonance imaging of her cervical spine revealed a homogenously enhancing extradural mass, indenting the cervical cord and expanding the left neural foramen at C7–T1. A C7 corpectomy, en bloc resection of the tumor, and anterior C6–T1 fusion were performed to decompress the spinal cord and nerves and provide stability. Postoperative histopathologic examination and immunohistochemical analysis were consistent with carcinoid tumor. There has been no recurrence at the 6-year follow-up visit. Conclusions Primary cervical carcinoid tumor is extremely rare, but should be included in the differential diagnosis of enhancing expansile extradural masses compressing the spinal cord and nerves. Surgical resection may provide a definitive cure. PMID:23972315

  5. The First Reported Case of Recurrent Carcinoid Tumor in the External Auditory Canal.

    PubMed

    McCrary, Hilary C; Faucett, Erynne A; Reghunathan, Saranya; Aly, F Zahra; Khan, Rihan; Carmody, Raymond F; Jacob, Abraham

    2017-01-01

    Cutaneous neuroendocrine lesions of the external auditory canal (EAC) are exceptionally rare, with only five cases reported in the literature. In this case report, we present a patient with a recurrent carcinoid tumor in the EAC, which has yet to be described. A 38-year-old woman presenting with otalgia, aural fullness, and decreased hearing was found to have a recurrent EAC carcinoid tumor, 8-years after initial resection at an outside facility. The recurrent tumor involved much of the proximal, anterior bony ear canal and was trans-tympanic, extending to the middle ear and epitympanum; therefore, a lateral temporal bone resection was performed to ensure complete resection. Surgical pathology confirmed the presence a recurrent carcinoid tumor in the EAC, with immunohistochemistry positive for pancytokeratin (MAK6), CD56, and synaptophysin, with chromogranin showing rare cells positive for cytoplasmic granules. There was no evidence of metastasis. Lateral temporal bone resection was successful and the patient is being followed with annual imaging. The patient is considering future hearing rehabilitation with a bone anchored hearing device. This case report highlights the first known case of recurrent carcinoid tumor in the EAC, treated with lateral temporal bone resection. Clinical presentation, imaging, treatment, and pathology are reviewed along with a review of the literature.

  6. Limitation of liver function tests in metastatic carcinoid tumors

    SciTech Connect

    Moinuddin, M.; Dean, P.; Vander Zwaag, R.; Dragutsky, M.

    1987-04-01

    To evaluate the utility of liver function tests (LFT) as indicators of metastatic carcinoid tumors, a retrospective study was performed. The LFT results of 17 patients with carcinoid tumors metastatic to the liver were compared with 17 patients with other malignant tumors. In the noncarcinoid group, 82.4% of the patients had elevated alkaline phosphatase (AP) or gamma glutamyl transpeptidase (GGTP), whereas only 28.6% of carcinoid patients had abnormal enzymes. The medians of all LFT values were significantly higher in noncarcinoid patients than in the carcinoid group, except for glutamic pyruvic transaminase (SGPT). Our data indicate that LFT are helpful in screening for liver metastases in patients with noncarcinoid tumors, but are unreliable in carcinoid tumors. Imaging tests should be used to rule out liver metastases in carcinoid tumors, irrespective of LFT results.

  7. Ultrastructural cytochemistry of platelets and megakaryocytes in the carcinoid syndrome.

    PubMed

    Lewis, J C; Maldonado, J E; Mann, K G; Moertel, C G

    1976-09-01

    Platelets and megakaryocytes from 11 patients with the carcinoid syndrome have been studied by transmission electron microscopy. Cells fixed in phosphate-buffered glutaraldehyde are oval to discoid, with pseudopods, a dilated open-channel system, and a prominent dense tubular system as defined by peroxidase activity and alkaline bismuth stain. Atypical with hexagonal lattices and treaded substructures and large (diameter greater than 0.5 mum), phosphatase-positive, debris-containing vacuoles are four times more numerous than in normal platelets. Incubation of platelets in a 0.05% suspension of latex results in particle incorporation into phagosomes and the debris-containing vacuoles. Molybdate-dichromate stain reveals two classes of dense bodies, one of which (with a reticular core) is 20 times more numerous than in normal platelets. Bone marrow megakaryocytes lack both dense bodies and debris vacuoles analogous to those found in circulating platelets. These results suggest autophagy or endocytosis abnormalities and provide evidence for multiple types of dense bodies in carcinoid platelets.

  8. Carcinoid tumor and intravenous octreotide infusion during labor and delivery.

    PubMed

    Le, B T; Bharadwaj, S; Malinow, A M

    2009-04-01

    There are limited numbers of reports concerning the management of pregnancy complicated by carcinoid tumors. Octreotide, the synthetic analogue of somatostatin, has been found to be beneficial in preventing the perioperative exacerbation of carcinoid syndrome. We present a case of the successful use of neuraxial analgesia/anesthesia for labor and vaginal delivery in a symptomatic parturient afflicted with carcinoid syndrome, who received an intravenous infusion of octreotide throughout labor and vaginal delivery.

  9. Epidemiology of carcinoid neoplasms in Vaud, Switzerland, 1974–97

    PubMed Central

    Levi, F; Te, V-C; Randimbison, L; Rindi, G; La Vecchia, C

    2000-01-01

    In Vaud, Switzerland, the incidence of carcinoids based on 218 malignant and 215 benign cases rose from 19.6/106in 1974–85 to 28.2/106in 1986–97, more so among males and malignant neoplasms. Lung was the commonest site for malignant and large intestine for benign carcinoids. Sixty-eight (16%) carcinoids had another neoplasm. © 2000 Cancer Research Campaign PMID:10970700

  10. Valvular Disorders in Carcinoid Heart Disease

    PubMed Central

    Yuan, Shi-Min

    2016-01-01

    Carcinoid heart disease is a rare but important cause of intrinsic right heart valve disorders leading to right heart failure. Occasionally, left-sided heart valves may also be involved. The characteristic cardiac pathological findings of carcinoid heart disease are endocardial thickening as a result of fibrous deposits on the endocardium. Echocardiographic examination and right heart catheterization are very useful for the diagnosis of the lesion. If more cardiac valves are affected, multiple valve replacement should be considered. The management of the pulmonary valve lesion depends on the extent of the diseased valve, either by valvulotomy, valvectomy, or valve replacement. Percutaneous valve implantations in the pulmonary and in the inferior vena cava positions have been advocated for high-risk patients. PMID:27982350

  11. Metastatic carcinoid tumour with spinal cord compression.

    PubMed

    Scott, Si; Antwi-Yeboah, Y; Bucur, Sd

    2012-07-01

    Carcinoid tumours are rare with an incidence of 5.25/100,000. They predominantly originate in the gastrointestinal tract (50-60%) or bronchopulmonary system (25-30%). Common sites of metastasis are lymph nodes, liver, lungs and bone. Spinal metastasis are rare, but has been reported in patients with symptoms of spinal cord compression including neurological deficits. We report a rare case of carcinoid metastasis with spinal cord compression, in a 63-year-old man, presenting with a one-year history of back pain without any neurological symptoms. The patient underwent a two-level decompressive laminectomy of T10 and T11 as well as piecemeal tumour resection. Post-operatively the patient made a good recovery without complications.

  12. Metastatic carcinoid tumour with spinal cord compression

    PubMed Central

    Scott, SI; Antwi-Yeboah, Y; Bucur, SD

    2012-01-01

    Carcinoid tumours are rare with an incidence of 5.25/100,000. They predominantly originate in the gastrointestinal tract (50-60%) or bronchopulmonary system (25-30%). Common sites of metastasis are lymph nodes, liver, lungs and bone. Spinal metastasis are rare, but has been reported in patients with symptoms of spinal cord compression including neurological deficits. We report a rare case of carcinoid metastasis with spinal cord compression, in a 63-year-old man, presenting with a one-year history of back pain without any neurological symptoms. The patient underwent a two-level decompressive laminectomy of T10 and T11 as well as piecemeal tumour resection. Post-operatively the patient made a good recovery without complications. PMID:24960730

  13. Carcinoid Tumor in Accidental, Asymptomatic Meckel's Diverticulum.

    PubMed

    Baranyai, Zsolt; Jósa, Valeria; Merkel, Keresztely; Zolnai, Zsofia

    2013-01-01

    Although Meckel's diverticulum is the most common congenital gastrointestinal disorder, it is controversial whether asymptomatic diverticula in adults should be respected. The authors report the case of a patient who was operated due to ileus caused by adhesions and a Meckel's diverticulum without any sign of inflammation was accidentally noted and removed. As a surprise, the pathological examination of the diverticulum proved carcinoid tumor, a neuroendocrine malignant tumor. The case raises the importance of the removal of asymptomatic Meckel's diverticulum.

  14. Carcinoid Tumor in Accidental, Asymptomatic Meckel's Diverticulum

    PubMed Central

    Baranyai, Zsolt; Jósa, Valeria; Merkel, Keresztely; Zolnai, Zsofia

    2013-01-01

    Although Meckel's diverticulum is the most common congenital gastrointestinal disorder, it is controversial whether asymptomatic diverticula in adults should be respected. The authors report the case of a patient who was operated due to ileus caused by adhesions and a Meckel's diverticulum without any sign of inflammation was accidentally noted and removed. As a surprise, the pathological examination of the diverticulum proved carcinoid tumor, a neuroendocrine malignant tumor. The case raises the importance of the removal of asymptomatic Meckel's diverticulum. PMID:24470856

  15. Surgical management of carcinoid heart valve disease.

    PubMed

    Castillo, Javier G; Milla, Federico; Adams, David H

    2012-01-01

    Carcinoid tumors are neuroendocrine tumors with an unpredictable clinical behavior. In the setting of hepatic metastases, the release of bioactive amines from the tumor into the systemic circulation results in carcinoid syndrome: a constellation of clinical symptoms, among which cutaneous flushing, gastrointestinal hypermotility, and cardiac involvement are the most frequent. Cardiac manifestations, also known as carcinoid heart disease, are secondary to a severe endocardial fibrotic reaction that leads to progressive valve thickening and retraction. Imaging studies commonly reveal severe right-sided valve disease, with fixed leaflets or cusps in a semiopen position. The replacement of the right-sided valves, including the patch enlargement of the right ventricular outflow tract, is currently the only definitive treatment to potentially improve quality of life and provide survival benefit. Although cardiac surgery has been traditionally reserved for those patients with symptomatic right ventricular failure, a significant trend toward improved surgical outcomes has triggered a more liberal referral for valve replacement during the past decade. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Lanreotide Depot: An Antineoplastic Treatment of Carcinoid or Neuroendocrine Tumors.

    PubMed

    Wolin, Edward M; Manon, Amandine; Chassaing, Christophe; Lewis, Andy; Bertocchi, Laurent; Richard, Joel; Phan, Alexandria T

    2016-12-01

    Peptide drugs for antineoplastic therapies usually have low oral bioavailability and short in vivo half-lives, requiring less preferred delivery methods. Lanreotide depot is a sustained-release somatostatin analog (SSA) formulation produced via an innovative peptide self-assembly method. Lanreotide is approved in the USA and Europe to improve progression-free survival (PFS) in patients with unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and also approved in Europe for symptom control in carcinoid syndrome associated with GEP-NETs. This review discusses how the distinct molecule and formulation of lanreotide depot provide advantages to patients and health care providers, as well as the most recent clinical evidence demonstrating the safety and efficacy of lanreotide depot in inhibiting tumor growth and controlling hormonal symptoms in GEP-NETs. The lanreotide depot formulation confers a remarkable pharmacokinetic profile with no excipients, comprised only of lanreotide acetate and water. Of note, lanreotide depot constitutes an example for peptide self-assembly based formulations, providing insights that could help future development of sustained-release formulations of other antineoplastic peptides. Most patients with GEP-NETs will present with inoperable or incurable disease; thus, medical management for symptoms and tumor control plays a crucial role. Recent long-term clinical studies have demonstrated that lanreotide depot is well tolerated, prolongs PFS in GEP-NET patients, and significantly reduces symptoms related to carcinoid syndrome. The unique depot formulation and delivery method of lanreotide confer advantages in the treatment of metastatic GEP-NETs, contributing to improvements in NET-related symptoms and PFS without reducing quality of life in this patient population.

  17. Limited additive value of the Ki-67 proliferative index on patient survival in World Health Organization-classified pulmonary carcinoids.

    PubMed

    Swarts, Dorian R A; Rudelius, Martina; Claessen, Sandra M H; Cleutjens, Jack P; Seidl, Stefan; Volante, Marco; Ramaekers, Frans C S; Speel, Ernst J M

    2017-02-01

    Currently pulmonary carcinoids are separated into typical and atypical based on mitotic count and presence of necrosis, according to the World Health Organization. At variance with gastroenteropancreatic neuroendocrine tumours, which are graded based on mitotic count and Ki-67 proliferative index, the use of Ki-67 for grading pulmonary carcinoids is still under debate. In this study we evaluated the prognostic impact of Ki-67 assessment in a multicentre cohort of 201 carcinoids [147 typical carcinoids (TCs) and 54 atypical carcinoids (ACs)] using manual analysis (2000 cells counted) and digital image analysis (in-house Leica Qwin program; ≥4500 cells counted). The Ki-67 proliferative index was correlated with overall survival by means of univariate analysis and in comparison to clinical data by means of multivariable analysis. The Ki-67 index was significantly higher in ACs than in TCs for both counting methods (P ≤ 2.7e(-5) ). In addition, using cut-offs of 2.5% and 4% (manual counting) or 1% and 5% (digital analysis), the highest differences in overall survival were observed (P ≤ 0.0067). Nevertheless, histopathological classification into TCs and ACs showed an equally strong association with disease outcome, although Ki-67 had some additive value within TCs. Ki-67 index was not an independent predictor of survival in multivariable analysis. Our study demonstrates that, although Ki-67 is a strong prognostic factor for pulmonary carcinoids, its usefulness in addition to histopathology in prediction of prognosis is limited. None the less, it may have additional value, especially in cases that are difficult to classify, in combination with histopathology and other molecular markers. © 2016 John Wiley & Sons Ltd.

  18. Primary pulmonary carcinoid tumor with metastasis to endometrial polyp

    PubMed Central

    Momeni, Mazdak; Kolev, Valentin; Costin, Dan; Mizrachi, Howard H.; Chuang, Linus; Warner, Richard R.P.; Gretz, Herbert F.

    2012-01-01

    INTRODUCTION A carcinoid tumor occurring in the endometrium has been documented in the literature, but there is no report in regard to carcinoid tumor metastasis to endometrium. PRESENTATION OF CASE We report a case of a malignant carcinoid metastasis to an endometrial polyp. Patient underwent hysteroscopy, and polypectomy. The pathology demonstrated an endometrial polyp containing a 4 mm x 5 mm nodule of metastatic carcinoid tumor, consistent with metastasis from patient's known pulmonary carcinoid. The tumor was morphologically similar to the tumors of the right lung, with similar immune-profile. DISCUSSION This patient presented with a suspicious pelvic ultrasound. Due to her age, the first priority was to exclude uterine cancer. The endometrial polyp, which was found, had a small focus of metastatic carcinoid tumor. To the best of our knowledge, this finding has not been previously recorded in the literature. Our patient also had a history of metastatic carcinoid tumor to breast. This finding is also very uncommon. CONCLUSION This is the first case in the literature described a malignant carcinoid metastasis to an endometrial polyp. PMID:23127865

  19. In vitro chemoresistance testing in well differentiated carcinoid tumors.

    USDA-ARS?s Scientific Manuscript database

    Well-differentiated, “typical” carcinoid tumors traditionally have a very poor response to chemotherapy. We hypothesized that tumor specimens from well differentiated carcinoid tumors would be highly resistant to the effects of chemotherapy when tested against a variety of antineoplastic agents in v...

  20. Review of renal carcinoid tumor with focus on clinical and pathobiological aspects.

    PubMed

    Kuroda, N; Tanaka, A; Ohe, C; Mikami, S; Nagashima, Y; Inoue, K; Shuin, T; Taguchi, T; Tominaga, A; Alvarado-Cabrero, I; Petersson, F; Brunelli, M; Martignoni, G; Michal, M; Hes, O

    2013-01-01

    Renal carcinoid tumor is a rare neoplasm. In this article, we review this neoplasm with a focus on clinical and pathobiological aspects. The majority of patients present in the fourth to seventh decades, but there is no gender predilection. Clinically, patients with renal carcinoid tumor frequently present with abdominal, back or flank pain. This tumor is occassionally associated with horseshoe kidney and/or mature cystic teratoma located in the kidney. Macroscopically, these tumors are well demarcated with a lobulated appearance and yellow or tan-brown color cut surface. Microscopically, these tumors are composed of monomorphic round to polygonal cells with granular amphophilic to eosinophilic cytoplasm. Tumor cells are arranged in trabecular, ribbon-like, gyriform, insular, glandular and solid patterns. The nuclei are round to oval and with evenly distributed nuclear chromatin, frequently with a "salt and pepper"-pattern. Immunohistochemically, tumor cells demonstrate immuno-labeling for chromogranin A and synaptophysin. Ultrastructurally, the neoplastic cells contain abundant dense core neurosecretory granules. In previous genetic studies, abnormalities of chromosomes 3 or 13 have been reported. The clinical behavior of renal carcinoid tumors is variable, but is more indolent than most renal cell carcinomas. Further investigations are warranted in order to elucidate the critical genetic abnormalities responsible for the pathogenesis of this rare entity in renal neoplastic pathology.

  1. Primary carcinoid tumor of the frontal sinus: A case report.

    PubMed

    Chu, Michael W; Karakla, Daniel W; Silverberg, Marc; Han, Joseph K

    2010-10-01

    Carcinoid tumors are rare, indolent, neuroendocrine tumors that are most commonly found in the gastrointestinal tract and lungs. They occasionally develop in the head and neck, either as a primary tumor or, more commonly, as a metastasis. The most common sites of head and neck carcinoids are the larynx and middle ear. Only a few cases of carcinoid in the nasal cavity and paranasal sinuses have been reported. We describe a case of primary typical carcinoid of the frontal sinus in a 61-year-old man, and we review the clinical, imaging, surgical, and histochemical findings in this case. The patient was treated with endoscopic resection. A subsequent workup for metastatic and occult primary disease was negative, confirming that the frontal sinus was the primary source. At follow-up 12 months postoperatively, the patient remained without disease. To the best of our knowledge, this is the first report of a primary typical carcinoid tumor originating in the frontal sinus.

  2. [Carcinoid tumours of the lung and definition of the medico-legal term "lung cancer" used in the list of occupational disease in Germany--results of the German Mesothelioma Register].

    PubMed

    Neumann, V; Fischer, M; Tannapfel, A

    2008-09-01

    Carcinoid tumours are considered to be malignant epithelial tumours according to the recent WHO classification. This study is based on the examinations of tissue from 108 patients with carcinoid tumours. Our data agree with those of other studies: carcinoid tumours developed mainly in the right lung (40 %) and the lower lobe (30 %), mean age was 56 years, typical carcinoid tumours (74 %) predominated, comparatively high proportion of females (32 %), the mean latency period after asbestos exposure - assuming asbestos as one causal factor - was 35 years. A higher incidence of carcinoid tumours (1.3 %) in the collective of the mesothelioma register compared to the incidence in the collective of all lung carcinomas (1 - 2 %) was not observed. The increased pulmonary asbestos burden analysed in 26 % of patients is explained by the exposure-dependent selection of patients in the register. So far, no association between smoking habits or exposure to other, i. e., occupational pollutions and the development of carcinoid tumours could be established. In the list of occupational diseases (No. 4104) the term "lung cancer" is used without further specification. Thus the following question remains open for discussion: does the term "lung cancer" include carcinoid tumours such as malignant epithelial lung tumours, or is it restricted to the common subtypes such as small cell carcinoma, squamous cell carcinoma, adenocarcinoma, large cell carcinoma with regard to occupational disease and compensation?

  3. 5-HIAA excretion is not associated with bone metabolism in carcinoid syndrome patients.

    PubMed

    van Dijk, S C; de Herder, W W; Kwekkeboom, D J; Zillikens, M C; Feelders, R A; van Schaik, R H N; van Driel, M; van Leeuwen, J P T M

    2012-06-01

    In patients with a carcinoid syndrome and neuroendocrine tumors of the digestive tract (carcinoids), elevated circulating serotonin (5-hydroxytryptamine, 5-HT) levels can be demonstrated. It can be hypothesized that bone metabolism will be affected in these patients, since serotonin receptors are expressed on bone cells and serotonin effects on bone have been demonstrated. However, to date, no data are available on bone metabolism parameters in patients with neuroendocrine tumors of the digestive tract (carcinoids). In the current retrospective study we have measured serum bone formation markers P1CP (pro-collagen type I C-terminal), and osteocalcin, and the bone resorption marker NTx (collagen breakdown product N-terminal), in a group of 61 carcinoid patients with increased circulating serotonin levels as demonstrated by increased excretion of the serotonin breakdown product, 5-hydroxy indole acetic acid (5-HIAA), in the urine (>50 μmol/24 h, so-called "hyper-secretors") and a control group of 23 carcinoid patients, without increased 5-HIAA excretion (so-called non-secretors). The 24-h urinary excretion of 5-HIAA reflects the 24-h production of serotonin. Measurements of markers of bone metabolism were performed in serum samples obtained before the start of medical treatment. The hypersecretor group had on average a 10-fold higher urinary 5-HIAA excretion than the control (non-secretor) group. No significant differences in bone metabolism parameters could be demonstrated between hyper-secretors and controls (non-secretors). Correlation and regression analyses could not demonstrate significant age- and sex-adjusted correlations between urinary 5-HIAA excretion and any of the markers for bone turnover. A limitation is that the exposure time to elevated levels of serotonin is unknown, which might have been too short to induce effects on bone metabolism. Treatment of human pre-osteoblasts SV-HFO with serotonin didn't change alkaline phosphatase activity throughout

  4. Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids.

    PubMed

    Zatelli, Maria Chiara; Minoia, Mariella; Martini, Chiara; Tagliati, Federico; Ambrosio, Maria Rosaria; Schiavon, Marco; Buratto, Mattia; Calabrese, Fiorella; Gentilin, Erica; Cavallesco, Giorgio; Berdondini, Lisa; Rea, Federico; degli Uberti, Ettore C

    2010-09-01

    Bronchial carcinoids (BCs) are rare tumors originating from endocrine cells dispersed in the respiratory epithelium. It has been previously demonstrated that everolimus, or RAD001, an mTOR inhibitor, has potent antiproliferative effects in human endocrine tumors. Our aim was to evaluate the possible antiproliferative effects of everolimus in human BCs in primary culture. We collected 24 BCs that were dispersed in primary cultures, treated without or with 1 nM-1 muM everolimus, 10 nM SOM230 (pasireotide, a somatostatin receptor multiligand), and/or 50 nM IGF1. Cell viability was evaluated after 48 h, and chromogranin A (CgA) as well as vascular endothelial growth factor (VEGF) secretion was assessed after 8 h incubation. Somatostatin receptors, mTOR, and AKT expression were investigated by quantitative PCR. We found that in 15 cultures (67.5%), everolimus significantly reduced cell viability (by approximately 30%; P<0.05 versus control), inhibited p70S6K activity (-30%), and blocked IGF1 proliferative effects. Everolimus also significantly reduced CgA (by approximately 20%) and VEGF (by approximately 15%) secretion. Cotreatment with SOM230 did not exert additive effects on cell viability and secretory activity. AKT expression was similar in responder and nonresponder tissues, while mTOR expression was significantly higher in the responder group, which was characterized by higher CgA plasma levels and bigger tumors with higher mitotic index and angiogenesis. Our data demonstrate that everolimus reduces VEGF secretion and cell viability in BCs with a mechanism likely involving IGF1 signaling, suggesting that it might represent a possible medical treatment for BCs.

  5. Carcinoid tumor of the middle ear: a case report and review of literature.

    PubMed

    Liu, Guo; Chen, Fei; Li, Jin-Nan; Liu, Shi-Xi

    2014-01-01

    Carcinoid tumors of the middle ear are very rare. Here we describe a 37-year-old man with multiple recurrent carcinoid tumor of the right middle ear. The CT demonstrated the recurrent mass that filled the tympanum and mastoid with osteolytic invasion, and the tumor was removed by surgery. The pathological findings showed the tumor cells, without necrosis and mitotic activity, had round, oval, or slightly irregular nuclei and finely-dispersed chromatin, arranged in cords, nests, and glandular structures. They were strongly positive for synaptophysin and CD56, but were negative for S-100 and chromogranin A. Ki-67 proliferation activity was low (<2%). With a review of the literature, the clinical, pathological characteristics and treatment modalities of this rare tumor are discussed.

  6. Carcinoid tumor of the middle ear: a case report and review of literature

    PubMed Central

    Liu, Guo; Chen, Fei; Li, Jin-Nan; Liu, Shi-Xi

    2014-01-01

    Carcinoid tumors of the middle ear are very rare. Here we describe a 37-year-old man with multiple recurrent carcinoid tumor of the right middle ear. The CT demonstrated the recurrent mass that filled the tympanum and mastoid with osteolytic invasion, and the tumor was removed by surgery. The pathological findings showed the tumor cells, without necrosis and mitotic activity, had round, oval, or slightly irregular nuclei and finely-dispersed chromatin, arranged in cords, nests, and glandular structures. They were strongly positive for synaptophysin and CD56, but were negative for S-100 and chromogranin A. Ki-67 proliferation activity was low (<2%). With a review of the literature, the clinical, pathological characteristics and treatment modalities of this rare tumor are discussed. PMID:25400805

  7. Antagonists of alcohol inhibition of cell adhesion

    PubMed Central

    Wilkemeyer, Michael F.; Sebastian, Anita B.; Smith, Sherri A.; Charness, Michael E.

    2000-01-01

    Increasing evidence suggests that alcohols act within specific binding pockets of selective neural proteins; however, antagonists at these sites have not been identified. 1-Alcohols from methanol through 1-butanol inhibit with increasing potency the cell–cell adhesion mediated by the immunoglobulin cell adhesion molecule L1. An abrupt cutoff exists after 1-butanol, with 1-pentanol and higher 1-alcohols showing no effect. Here, we demonstrate surprisingly strict structural requirements for alcohol inhibition of cell–cell adhesion in L1-transfected NIH 3T3 fibroblasts and in NG108–15 neuroblastoma × glioma hybrid cells treated with BMP-7, an inducer of L1 and neural cell adhesion molecule. The target site discriminates the tertiary structure of straight-chain and branched-chain alcohols and appears to comprise both a hydrophobic binding site and an adjacent hydrophilic allosteric site. Modifications to the 2- and 3-carbon positions of 1-butanol increased potency, whereas modifications that restrict movement about the 4-carbon abolished activity. The effects of ethanol and 1-butanol on cell–cell adhesion were antagonized by 1-pentanol (IC50 = 715 μM) and 1-octanol (IC50 = 3.6 μM). Antagonism by 1-octanol was complete, reversible, and noncompetitive. 1-Octanol also antagonized ethanol inhibition of BMP-7 morphogenesis in NG108–15 cells. 1-Octanol and related compounds may prove useful in dissecting the role of altered cell adhesion in ethanol-induced injury of the nervous system. PMID:10725368

  8. Computed tomography of abdominal carcinoid tumors

    SciTech Connect

    Picus, D.; Glazer, H.S.; Levitt, R.G.; Husband, J.E.

    1984-09-01

    Computed tomographic (CT) scans were obtained in 20 patients with primary and/or metastatic abdominal carcinoid tumors. The primary tumors were seen rarely on CT. Mesenteric involvement was seen in eight of the 20 patients, usually as a soft-tissue mass surrounded by fat and radiating soft-tissue strands. Enlarged retroperitoneal lymph nodes were seen in seven patients, but rarely were they the only manifestation of intraabdominal disease. The most common finding was liver metastases (13 of 20 patients). CT is helpful in evaluating the extent of tumor before surgical exploration an in following the progression of disease once the diagnosis has been established.

  9. Synchronous Adenocarcinoma of the Colon and Rectal Carcinoid

    PubMed Central

    Vootla, Vamshidhar; Ahmed, Rafeeq; Niazi, Masooma; Balar, Bhavna; Nayudu, Suresh

    2016-01-01

    Primary colonic adenocarcinoma and synchronous rectal carcinoids are rare tumors. Whenever a synchronous tumor with a nonmetastatic carcinoid component is encountered, its prognosis is determined by the associate malignancy. The discovery of an asymptomatic gastrointestinal carcinoid during the operative treatment of another malignancy will usually only require resection without additional treatment and will have little effect on the prognosis of the individual. This article reports a synchronous rectal carcinoid in a patient with hepatic flexure adenocarcinoma. We present a case of a 46-year-old Hispanic woman with a history of hypothyroidism, uterine fibroids and hypercholesterolemia presenting with a 2-week history of intermittent abdominal pain, mainly in the right upper quadrant. She had no family history of cancers. Physical examination was significant for pallor. Laboratory findings showed microcytic anemia with a hemoglobin of 6.6 g/dl. CT abdomen showed circumferential wall thickening in the ascending colon near the hepatic flexure and pulmonary nodules. Colonoscopy showed hepatic flexure mass and rectal nodule which were biopsied. Pathology showed a moderately differentiated invasive adenocarcinoma of the colon (hepatic flexure mass) and a low-grade neuroendocrine neoplasm (carcinoid of rectum). The patient underwent laparoscopic right hemicolectomy and chemotherapy. In patients diagnosed with adenocarcinoma of the colon and rectum, carcinoids could be missed due to their submucosal location, multicentricity and indolent growth pattern. Studies suggest a closer surveillance of the GI tract for noncarcinoid synchronous malignancy when a carcinoid tumor is detected and vice versa. PMID:27920648

  10. Carcinoid tumour of the thymus with systemic manifestations: a radiological and pathological study

    PubMed Central

    Lowenthal, R. M.; Gumpel, J. M.; Kreel, L.; McLaughlin, J. E.; Skeggs, D. B. L.

    1974-01-01

    Lowenthal, R. M., Gumpel, J. M., Kreel, L., McLaughlin, J. E., and Skeggs. D. B. L. (1974).Thorax, 29, 553-558. Carcinoid tumour of the thymus with systemic manifestations: a radiological and pathological study. Following recent reports of an unusual mediastinal tumour described as `mediastinal endocrine neoplasm of probable thymic origin, related to carcinoid tumour' (Rosai and Higa, 1972), a further case, in a 72-year-old man, has been studied. Polyarthropathy was the presenting feature, and the patient also had clubbing of the fingers and clinical evidence of a probable proximal myopathy and a peripheral neuropathy. These non-metastatic systemic manifestations have not previously been described with this type of tumour. By retrograde thymic venography the tumour was conclusively shown to be arising in the thymus, as had been suspected but not proven in previously described cases. Histologically the typical picture, including areas of cells with true rosette formation and cells with argyrophil granules, was seen. In contrast to the more usual thymic tumours, this type of neoplasm responds poorly to radiotherapy, but surgical treatment may give good results. Therefore, in a situation where the possibility of carcinoid tumour of the thymus exists, it is imperative that tissue be obtained for histological diagnosis before any therapeutic decision is made. Images PMID:4428455

  11. Imaging features of carcinoid tumors metastatic to the breast

    PubMed Central

    Jones, Katie N.; Dilaveri, Christina A.; Perry, Kyle; Reynolds, Carol

    2011-01-01

    Abstract The objective of this study was to describe the imaging findings of carcinoid tumors metastatic to the breast, with pathologic and clinical correlations. We searched our surgical database for cases of pathologically proven carcinoid tumors metastatic to the breast from October 1, 2000, to May 31, 2010. Of the approximate 10,000 breast biopsies identified, 7000 had malignant findings. Ten cases of metastatic carcinoid (0.1% of all malignancies), all with imaging studies available for review, were included in the study. All patients were women and had their primary carcinoid in the gastrointestinal tract (n=9) or lung (n = 1). One patient presented with a palpable breast mass and no history of carcinoid tumor; an ileal carcinoid was discovered after the pathologic diagnosis of metastatic carcinoid was established. In the breast, tumors presented as solitary lesions in half the cases. Metastases to the breast typically presented as circumscribed masses mammographically and as hypoechoic circumscribed masses ultrasonographically; some showed increased through-transmission and increased vascularity with color Doppler evaluation. Five patients had octreotide scans; of these, 4 had increased focal activity in the region of metastasis within the breast. Six patients underwent computed tomography. Without contrast, nodular masses were observed; with contrast, the masses showed rapid enhancement during arterial phase imaging. Magnetic resonance imaging (n = 4) also showed rapid enhancement and washout kinetics after contrast administration. Recognition of carcinoid metastases to the breast in patients with known or occult primary carcinoid tumors is important to avoid unnecessary treatment for primary breast cancer. PMID:21771708

  12. Apigenin inhibits renal cell carcinoma cell proliferation.

    PubMed

    Meng, Shuai; Zhu, Yi; Li, Jiang-Feng; Wang, Xiao; Liang, Zhen; Li, Shi-Qi; Xu, Xin; Chen, Hong; Liu, Ben; Zheng, Xiang-Yi; Xie, Li-Ping

    2017-03-21

    Apigenin, a natural flavonoid found in vegetables and fruits, has antitumor activity in several cancer types. The present study evaluated the effects and mechanism of action of apigenin in renal cell carcinoma (RCC) cells. We found that apigenin suppressed ACHN, 786-0, and Caki-1 RCC cell proliferation in a dose- and time-dependent manner. A comet assay suggested that apigenin caused DNA damage in ACHN cells, especially at higher doses, and induced G2/M phase cell cycle arrest through ATM signal modulation. Small interfering RNA (siRNA)-mediated p53 knockdown showed that apigenin-induced apoptosis was likely p53 dependent. Apigenin anti-proliferative effects were confirmed in an ACHN cell xenograft mouse model. Apigenin treatment reduced tumor growth and volume in vivo, and immunohistochemical staining revealed lower Ki-67 indices in tumors derived from apigenin-treated mice. These findings suggest that apigenin exposure induces DNA damage, G2/M phase cell cycle arrest, p53 accumulation and apoptosis, which collectively suppress ACHN RCC cell proliferation in vitro and in vivo. Given its antitumor effects and low in vivo toxicity, apigenin is a highly promising agent for treatment of RCC.

  13. [Retrospective evaluation of carcinoid tumors of the appendix in children].

    PubMed

    San Vicente, B; Bardají, C; Rigol, S; Obiols, P; Melo, M; Bella, R

    2009-04-01

    Carcinoids of the appendix are rare in children. Usually diagnosed incidentally on histologic investigation following appendectomy for acute apendicitis. To investigate the significance of the diagnosis of appendiceal carcinoid tumors in children, we conducted a retrospective study in our institution. Between 1990 and 2007 a total of 1158 appendectomy were done. In four patients the diagnosis was appendiceal carcinoid. We studied treatment, follow-up and prognosis of this patients. Indicacion for appendectomy was acute pain in lower right quadrant. The median tumor diameter was lower than 1 cm and the appropriate treatment was appendectomy. The prognosis was excellent in all the patients.

  14. Inhibition of cell-cell binding by lipid assemblies

    DOEpatents

    Nagy, Jon O.; Bargatze, Robert F.

    2001-05-22

    This invention relates generally to the field of therapeutic compounds designed to interfere between the binding of ligands and their receptors on cell surface. More specifically, it provides products and methods for inhibiting cell migration and activation using lipid assemblies with surface recognition elements that are specific for the receptors involved in cell migration and activation.

  15. Acute inflammatory bowel disease complicating chronic alcoholism and mimicking carcinoid syndrome.

    PubMed

    Ballo, Piercarlo; Dattolo, Pietro; Mangialavori, Giuseppe; Ferro, Giuseppe; Fusco, Francesca; Consalvo, Matteo; Chiodi, Leandro; Pizzarelli, Francesco; Zuppiroli, Alfredo

    2012-05-01

    We report the case of a woman with a history of chronic alcohol abuse who was hospitalized with diarrhea, severe hypokalemia refractory to potassium infusion, nausea, vomiting, abdominal pain, alternations of high blood pressure with phases of hypotension, irritability and increased urinary 5-hydroxyindoleacetic acid and cortisol. Although carcinoid syndrome was hypothesized, abdominal computed tomography and colonoscopy showed non-specific inflammatory bowel disease with severe colic wall thickening, and multiple colic biopsies confirmed non-specific inflammation with no evidence of carcinoid cells. During the following days diarrhea slowly decreased and the patient's condition progressively improved. One year after stopping alcohol consumption, the patient was asymptomatic and serum potassium was normal. Chronic alcohol exposure is known to have several deleterious effects on the intestinal mucosa and can favor and sustain local inflammation. Chronic alcohol intake may also be associated with high blood pressure, behavior disorders, abnormalities in blood pressure regulation with episodes of hypotension during hospitalization due to impaired baroreflex sensitivity in the context of an alcohol withdrawal syndrome, increased urinary 5-hydroxyindoleacetic acid as a result of malabsorption syndrome, and increased urinary cortisol as a result of hypothalamic-pituitary-adrenal axis dysregulation. These considerations, together with the regression of symptoms and normalization of potassium levels after stopping alcohol consumption, suggest the intriguing possibility of a alcohol-related acute inflammatory bowel disease mimicking carcinoid syndrome.

  16. Acute Inflammatory Bowel Disease Complicating Chronic Alcoholism and Mimicking Carcinoid Syndrome

    PubMed Central

    Ballo, Piercarlo; Dattolo, Pietro; Mangialavori, Giuseppe; Ferro, Giuseppe; Fusco, Francesca; Consalvo, Matteo; Chiodi, Leandro; Pizzarelli, Francesco; Zuppiroli, Alfredo

    2012-01-01

    We report the case of a woman with a history of chronic alcohol abuse who was hospitalized with diarrhea, severe hypokalemia refractory to potassium infusion, nausea, vomiting, abdominal pain, alternations of high blood pressure with phases of hypotension, irritability and increased urinary 5-hydroxyindoleacetic acid and cortisol. Although carcinoid syndrome was hypothesized, abdominal computed tomography and colonoscopy showed non-specific inflammatory bowel disease with severe colic wall thickening, and multiple colic biopsies confirmed non-specific inflammation with no evidence of carcinoid cells. During the following days diarrhea slowly decreased and the patient's condition progressively improved. One year after stopping alcohol consumption, the patient was asymptomatic and serum potassium was normal. Chronic alcohol exposure is known to have several deleterious effects on the intestinal mucosa and can favor and sustain local inflammation. Chronic alcohol intake may also be associated with high blood pressure, behavior disorders, abnormalities in blood pressure regulation with episodes of hypotension during hospitalization due to impaired baroreflex sensitivity in the context of an alcohol withdrawal syndrome, increased urinary 5-hydroxyindoleacetic acid as a result of malabsorption syndrome, and increased urinary cortisol as a result of hypothalamic-pituitary-adrenal axis dysregulation. These considerations, together with the regression of symptoms and normalization of potassium levels after stopping alcohol consumption, suggest the intriguing possibility of a alcohol-related acute inflammatory bowel disease mimicking carcinoid syndrome. PMID:22949895

  17. Sphingolipids inhibit vimentin-dependent cell migration.

    PubMed

    Hyder, Claire L; Kemppainen, Kati; Isoniemi, Kimmo O; Imanishi, Susumu Y; Goto, Hidemasa; Inagaki, Masaki; Fazeli, Elnaz; Eriksson, John E; Törnquist, Kid

    2015-06-01

    The sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), can induce or inhibit cellular migration. The intermediate filament protein vimentin is an inducer of migration and a marker for epithelial-mesenchymal transition. Given that keratin intermediate filaments are regulated by SPC, with consequences for cell motility, we wanted to determine whether vimentin is also regulated by sphingolipid signalling and whether it is a determinant for sphingolipid-mediated functions. In cancer cells where S1P and SPC inhibited migration, we observed that S1P and SPC induced phosphorylation of vimentin on S71, leading to a corresponding reorganization of vimentin filaments. These effects were sphingolipid-signalling-dependent, because inhibition of either the S1P2 receptor (also known as S1PR2) or its downstream effector Rho-associated kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) nullified the sphingolipid-induced effects on vimentin organization and S71 phosphorylation. Furthermore, the anti-migratory effect of S1P and SPC could be prevented by expressing S71-phosphorylation-deficient vimentin. In addition, we demonstrated, by using wild-type and vimentin-knockout mouse embryonic fibroblasts, that the sphingolipid-mediated inhibition of migration is dependent on vimentin. These results imply that this newly discovered sphingolipid-vimentin signalling axis exerts brake-and-throttle functions in the regulation of cell migration.

  18. Metastatic carcinoid tumor to the breast: report of two cases and review of the literature.

    PubMed

    Lee, Shimwoo; Levine, Pascale; Heller, Samantha L; Hernandez, Osvaldo; Mercado, Cecilia L; Chhor, Chloe M

    The breast is an unusual site for carcinoid metastasis. Due to increasing survival rates for carcinoid tumors, however, awareness of their rare complications is important. Carcinoid metastasis to the breast typically presents as a palpable breast mass or a mass on screening mammogram. Because imaging findings are nonspecific, the diagnosis is established through histological findings of neuroendocrine features corresponding with the known primary carcinoid pathology. Correctly distinguishing metastatic carcinoid from primary breast carcinoma is crucial to avoid more invasive procedures required for the latter. Two cases of metastatic carcinoid to the breast are presented with review of the literature. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. The rare malignancy of the hepatobiliary system: ampullary carcinoid tumor.

    PubMed

    Ozsoy, Mustafa; Ozsoy, Yucel; Canda, Aras Emre; Nalbant, Olcay Ak; Haskaraca, Fatih

    2011-01-01

    Introduction. Carcinoid tumors are low-grade tumors originating from endoderm and mostly involving the gastrointestinal system. However; they may be seen in any site within the gastrointestinal system. Case Presentation. A 69-year-old female patient. The results of blood tests were observed to be consistent with obstructive jaundice. A mass appearance was not encountered on tomographic examination. Papilla that was tumor-like macroscopically was seen in the second part of the duodenum in diagnostic endoscopy. Pylorus-preserving pancreaticoduodenectomy surgical procedure was applied. On pathological examination of the mass, a tumoral mass was detected in ampulla vateri localization, 1.5 × 1 × 0.8 cm in size, which, in immunohistochemical staining, was evaluated as a neuroendocrine tumor. Also, Metastasis was observed. Conclusion. The rarest type of carcinoid tumor is ampullary located carcinoid tumor, and tumor size is not a reliable indicator for tumor aggressivity in ampullary carcinoid tumors.

  20. What Are the Risk Factors for Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... Testing: What You Need to Know . Race and gender Carcinoid tumors are more common among African Americans ... would like to unsubscribe/opt out from our communications, please follow this link: http://www.cancer.org/ ...

  1. Invasive atypical thymic carcinoid: three case reports and literature review

    PubMed Central

    Zhu, Shan; Wang, Zhong-Tang; Liu, Wen-Zhi; Zong, Shi-Xiang; Li, Bao-Sheng

    2016-01-01

    Atypical thymic carcinoid is an extremely rare thymic neuroendocrine tumor derived from the neuroendocrine system. The aims of this paper were to investigate the clinical features of atypical thymic carcinoid and collate information and experience to improve the diagnosis and treatment of this disease. We describe three cases of atypical carcinoid of the thymus; clinical features, pathological data, treatment modalities, and short-term patient outcomes were summarized and analyzed. The initial clinical symptoms and signs of all three patients were nonspecific and an anterior mediastinal mass was found in each patient on chest computed tomography scan. All three patients underwent surgical resection (total thymectomy and complete excision of the tumor), followed by postoperative radiotherapy, with or without chemotherapy. The diagnoses of three patients were confirmed by pathological and immunohistochemical evaluation. We also present a review of the literature to collate as much information as possible and provide a reference for proper diagnosis and treatment of atypical thyroid carcinoid. PMID:27785065

  2. Demonstration of TGF-β and XIIIα in Endocardial Biopsies of Carcinoid Heart Disease Patients: an Immunofluorescence Study

    PubMed Central

    Diepholz, Dorgrit; Wilke, Andreas; Maisch, Bernhard; Steverding, Dietmar

    2011-01-01

    Background Serotonin and other vasoactive substances play a critical role in the development of carcinoid heart disease, but the exact etiology of the illness is still unknown. Methods By using immunofluorescence microscopy, we investigated the expression of transforming growth factor-β (TGF-β) and the presence of fibrin-stabilizing factor (XIIIα) in endomyocardial biopsy specimens of patients with carcinoid heart disease. In addition, the tissue integrity of the specimens was studied by staining for laminin. Results Both TGF-β and XIIIα co-localized in the endocardium beneath carcinoid plaques: while TGF-β was found within myocytes, XIIIα was detected on the surface of cells in fibrotic lesions stretching out into the tissue. Laminin staining revealed that the integrity of the endocardium was dissolved and that the tissue consisted of hypertrophic and hypotrophic myocytes. Conclusions The results suggest that the presence of TGF-β and XIIIα in carcinoid heart lesions indicates that endocardial damage induced by serotonin and other vasoactive substances gives rise to an overshooting wound healing process.

  3. Long-standing malignant pancreatic carcinoid treated with octreotide.

    PubMed

    Varas-Lorenzo, M J

    2010-11-01

    A male presented with a metastatic, plasma serotonin-secreting (high 5-HIAA in urine), malignant pancreatic carcinoid with a carcinoid-like syndrome, and was assessed using ultrasounds (US), computerized tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) and Octreoscan; he sequentially received chemotherapy, interferon and octreotide, with long-term, 12-year survival after diagnosis. Given this unusual case, the second reported in our country, the overall literature is reviewed.

  4. Carcinoid tumor of the lung with massive ossification: report of a case showing the evidence of osteomimicry and review of the literature.

    PubMed

    Tsubochi, Hiroyoshi; Endo, Shunsuke; Oda, Yoshinao; Dobashi, Yoh

    2013-01-01

    Carcinoid tumor is one of the commonly encountered primary pulmonary neoplasms. Although it has been known to be accompanied by calcification and/or ossification, presentation with a large ossified mass is rare. We describe here the case of a 29-year-old female with the radiological finding of a single bony nodular lesion. Pathological examination of the surgically resected specimen led to the diagnosis of carcinoid tumor of the lung with massive ossification. Although histological features showed the tumor of low grade malignancy, subcarinal and right hilar lymph nodes were found to be positive for metastasis. Further immunohistochemical analysis revealed that the tumor cells expressed the osteogenic inducer protein, bone morphogenic protrein-2 [BMP-2] and osteoblastic marker protein, osteocalcin. We interpreted this to mean that the carcinoid tumor cells had acquired an osteoblastic phenotype and had subsequently developed marked intratumoral ossification. The relevant literature is reviewed and possible mechanisms of tumor-related osteogenesis are discussed.

  5. Long-term follow up of patients affected by pulmonary carcinoid at the Istituto Nazionale Tumori of Milan: a retrospective analysis

    PubMed Central

    Pusceddu, S; Catena, L; Valente, M; Buzzoni, R; Formisano, B; Del Vecchio, M; Ducceschi, M; Tavecchio, L; Fabbri, A; Bajetta, E

    2010-01-01

    Neuroendocrine tumors of the lung involve an heterogeneous group of tumors representing a wide range of histological variants, from well-differentiated typical carcinoid (TC) tumors to poorly differentiated small cell carcinomas. The epidemiology, clinical outcome, and management of these neoplasms differ significantly from other lung malignancies. The main aim of this report consists in describing the single Center experience of the Istituto Nazionale Tumori of Milan on neuroendocrine lung tumors, with an emphasis on bronchopulmonary carcinoid subtypes. From 1986 to 2009, 91 cases of carcinoid tumors were diagnosed; these were divided in two series, according to typical (66 patients) or atypical [25] histotypes. These two groups were compared in relation to various features, including pathologic classification, clinical behavior, treatment modalities and long-term survival. At the moment of diagnosis 11 patients had locally advanced/metastatic disease, while 80 patients showed non metastatic disease. The comparative analysis between typical and atypical series disclosed significant differences in terms of long-term survival; in fact, 5-year and 10-year survival rates were 98 % and 94 % for the first carcinoid series versus 76 % and 18 % for the atypical series, respectively (p<0.001). The median overall survival (OS) was 76 months (range 3-182) for atypical carcinoids and has not yet been reached for TCs patients. PMID:22263011

  6. Long-term follow up of patients affected by pulmonary carcinoid at the Istituto Nazionale Tumori of Milan: a retrospective analysis.

    PubMed

    Pusceddu, S; Catena, L; Valente, M; Buzzoni, R; Formisano, B; Del Vecchio, M; Ducceschi, M; Tavecchio, L; Fabbri, A; Bajetta, E

    2010-03-01

    Neuroendocrine tumors of the lung involve an heterogeneous group of tumors representing a wide range of histological variants, from well-differentiated typical carcinoid (TC) tumors to poorly differentiated small cell carcinomas. The epidemiology, clinical outcome, and management of these neoplasms differ significantly from other lung malignancies. The main aim of this report consists in describing the single Center experience of the Istituto Nazionale Tumori of Milan on neuroendocrine lung tumors, with an emphasis on bronchopulmonary carcinoid subtypes. From 1986 to 2009, 91 cases of carcinoid tumors were diagnosed; these were divided in two series, according to typical (66 patients) or atypical [25] histotypes. These two groups were compared in relation to various features, including pathologic classification, clinical behavior, treatment modalities and long-term survival. At the moment of diagnosis 11 patients had locally advanced/metastatic disease, while 80 patients showed non metastatic disease. The comparative analysis between typical and atypical series disclosed significant differences in terms of long-term survival; in fact, 5-year and 10-year survival rates were 98 % and 94 % for the first carcinoid series versus 76 % and 18 % for the atypical series, respectively (p<0.001). The median overall survival (OS) was 76 months (range 3-182) for atypical carcinoids and has not yet been reached for TCs patients.

  7. Carcinoid tumor of the ileoanal pouch in a patient with ulcerative colitis.

    PubMed

    Resnick, Murray; Pricolo, Victor; Chen, Sonja

    2013-01-04

    Carcinoid tumors have been reported to occur in various locations, particularly in the gastrointestinal tract. The relationship between the development of carcinoids and ulcerative colitis has been an unclear and controversial one. The association of ulcerative colitis and the development of ileal-pouch carcinoids has not, however, been well documented. We report a case of carcinoid tumor arising in an ileoanal pouch and discuss its unique diagnostic and therapeutic considerations.

  8. Platelets Inhibit Migration of Canine Osteosarcoma Cells.

    PubMed

    Bulla, S C; Badial, P R; Silva, R C; Lunsford, K; Bulla, C

    2017-01-01

    The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition. Copyright © 2016. Published by Elsevier Ltd.

  9. FNC efficiently inhibits mantle cell lymphoma growth.

    PubMed

    Zhang, Yan; Zhang, Rong; Ding, Xixi; Peng, Bangan; Wang, Ning; Ma, Fang; Peng, Youmei; Wang, Qingduan; Chang, Junbiao

    2017-01-01

    FNC, 2'-deoxy-2'-β-fluoro-4'-azidocytidine, is a novel cytidine analogue, that has shown strong antiproliferative activity in human lymphoma, lung adenocarcinoma and acute myeloid leukemia. In this study, we investigated the effects of FNC on mantle cell lymphoma (MCL) and the underlying mechanisms. In in vitro experiments, cell viability was detected by the CCK8 assay, and cell cycle progression and apoptosis were assessed by flow cytometry, and the expression of relative apoptosis proteins were detected by Western Blot. The in vivo antitumor effect of FNC was investigated in a SCID xenograft model. Finally, the mechanisms of action of FNC were assessed using a whole human genome expression profile chip. The data showed that FNC inhibited cell growth in a dose- and time-dependent manner, and FNC could induce apoptosis by the death recepter pathways in JeKo-1 cells and arrest the cell cycle in the G1/S or G2/M phase. Notably, FNC showed in vivo efficacy in mice bearing JeKo-1 xenograft tumors. Gene expression profile analysis revealed that the differentially expressed genes were mainly focused on the immune system process, cellular process and death. These findings implied that FNC may be a valuable therapeutic in mantle cell lymphoma and provided an experimental basis for the early clinical application of FNC.

  10. FNC efficiently inhibits mantle cell lymphoma growth

    PubMed Central

    Ding, Xixi; Peng, Bangan; Wang, Ning; Ma, Fang; Peng, Youmei; Wang, Qingduan; Chang, Junbiao

    2017-01-01

    FNC, 2'-deoxy-2'-β-fluoro-4'-azidocytidine, is a novel cytidine analogue, that has shown strong antiproliferative activity in human lymphoma, lung adenocarcinoma and acute myeloid leukemia. In this study, we investigated the effects of FNC on mantle cell lymphoma (MCL) and the underlying mechanisms. In in vitro experiments, cell viability was detected by the CCK8 assay, and cell cycle progression and apoptosis were assessed by flow cytometry, and the expression of relative apoptosis proteins were detected by Western Blot. The in vivo antitumor effect of FNC was investigated in a SCID xenograft model. Finally, the mechanisms of action of FNC were assessed using a whole human genome expression profile chip. The data showed that FNC inhibited cell growth in a dose- and time-dependent manner, and FNC could induce apoptosis by the death recepter pathways in JeKo-1 cells and arrest the cell cycle in the G1/S or G2/M phase. Notably, FNC showed in vivo efficacy in mice bearing JeKo-1 xenograft tumors. Gene expression profile analysis revealed that the differentially expressed genes were mainly focused on the immune system process, cellular process and death. These findings implied that FNC may be a valuable therapeutic in mantle cell lymphoma and provided an experimental basis for the early clinical application of FNC. PMID:28333959

  11. Increased incidence of second primary malignancy in patients with carcinoid tumors: case report and literature review.

    PubMed Central

    Rivadeneira, D. E.; Tuckson, W. B.; Naab, T.

    1996-01-01

    There is an increased incidence of second noncarcinoid neoplasms in patients with carcinoid tumors. This article reports a case of a synchronous malignant ileal carcinoid tumor in a patient with an adenocarcinoma of the sigmoid colon. This report illustrates the increased association of carcinoid tumors with other gastrointestinal malignancies. Images Figure 1 Figure 2 Figure 3 PMID:8667441

  12. Resveratrol Inhibits Protein Translation in Hepatic Cells

    PubMed Central

    Villa-Cuesta, Eugenia; Boylan, Joan M.; Tatar, Marc; Gruppuso, Philip A.

    2011-01-01

    Resveratrol is a plant-derived polyphenol that extends lifespan and healthspan in model organism. Despite extensive investigation, the biological processes mediating resveratrol's effects have yet to be elucidated. Because repression of translation shares many of resveratrol's beneficial effects, we hypothesized that resveratrol was a modulator of protein synthesis. We studied the effect of the drug on the H4-II-E rat hepatoma cell line. Initial studies showed that resveratrol inhibited global protein synthesis. Given the role of the mammalian Target of Rapamycin (mTOR) in regulating protein synthesis, we examined the effect of resveratrol on mTOR signaling. Resveratrol inhibited mTOR self-phosphorylation and the phosphorylation of mTOR targets S6K1 and eIF4E-BP1. It attenuated the formation of the translation initiation complex eIF4F and increased the phosphorylation of eIF2α. The latter event, also a mechanism for translation inhibition, was not recapitulated by mTOR inhibitors. The effects on mTOR signaling were independent of effects on AMP-activated kinase or AKT. We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling. PMID:22242130

  13. SIRT1 controls cell proliferation by regulating contact inhibition.

    PubMed

    Cho, Elizabeth H; Dai, Yan

    2016-09-16

    Contact inhibition keeps cell proliferation in check and serves as a built-in protection against cancer development by arresting cell division upon cell-cell contact. Yet the complete mechanism behind this anti-cancer process remains largely unclear. Here we present SIRT1 as a novel regulator of contact inhibition. SIRT1 performs a wide variety of functions in biological processes, but its involvement in contact inhibition has not been explored to date. We used NIH3T3 cells, which are sensitive to contact inhibition, and H460 and DU145 cancer cells, which lack contact inhibition, to investigate the relationship between SIRT1 and contact inhibition. We show that SIRT1 overexpression in NIH3T3 cells overcomes contact inhibition while SIRT1 knockdown in cancer cells restores their lost contact inhibition. Moreover, we demonstrate that p27 protein expression is controlled by SIRT1 in contact inhibition. Overall, our findings underline the critical role of SIRT1 in contact inhibition and suggest SIRT1 inhibition as a potential strategy to suppress cancer cell growth by restoring contact inhibition. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Bronchial carcinoid tumors: clinical and radiological correlation.

    PubMed

    Squerzanti, Antonella; Basteri, Vittoria; Antinolfi, Gabriele; D'agostino, Fulvio; Scutellari, Pier Nuccio; Ravenna, Franco; Ghirardi, Redenta; Cavallesco, Giorgio

    2002-10-01

    To evaluate the incidence of bronchial carcinoid tumor (BCT) in population affected by various lung tumors, retrospectively reviewed between 1986-2001, and to emphasize the radiographic patterns if they are characteristic. In the above mentioned period, chest x-ray and CT were performed in 1110 patients, both male and female, affected by lung neoplasms. 20 patients were affected by BCT (16 males, and 13 females), aged between 26 and 75 years (mean age 57.5), with histopathologic diagnosis of typical (9 cases, 31%) and atypical (20 cases, 69%) bronchial carcinoid tumors. Localized right lung lesion were as follows: 7 cases in superior, 9 in middle and 4 in inferior lobes; in the left lung, 5 cases in superior, and 4 in inferior lobes. Size of the lesions was as average 2.4 cm in diameter (with a range of 0.5-12 cm). On x-ray and CT images, BCT appeared as a well marginated nodule, of which 9 were peripheral and 20 central. BCT are classified as neuroendocrine carcinomas,and are divided in typical and atypical forms, with variable grade of malignancy. Central neoplasms are symptomatic due to bronchial obstruction (i.e., pneumonia, atelectasis, bronchiectasis, emphysema and/or lung abscess); if airway obstruction is partial, then cough, wheezing and recurrent pulmonary infections occur. Peripheral tumors are generally asymptomatic and they are discovered occasionally, when chest x-ray is made for other reasons. Radiographic features are similar in typical and atypical BCT. In central tumors a rounded well circumscribed hilar mass is noted, with lobulated or bumpy margins. Central cavitation is not referred to. Peripheral BCT appear as a solitary nodule, inferioer then 3 cm in size, marginated, surrounded by normal pulmonary tissue. Signs and symptoms of BCT are evasive and vague. No current clinical or laboratory procedures are useful in confirming the diagnosis; particularly, no imaging modalities are able to differentiate between BCT and other pulmonary tumors. For

  15. [Primary Carcinoid Tumor of the Urinary Bladder: A Case Report and Questionnaire Survey on the Reported Cases in Japan].

    PubMed

    Ueda, Norichika; Arai, Hiroki; Honda, Masahito; Yoshida, Kyotaro

    2015-11-01

    An 83-year-old man presented with asymptomatic macroscopic hematuria while being treated for prostate cancer with hormonal therapy in January 2009. Cystoscopy revealed a 5 mm surface-smooth non pedunculated tumor lateral to the left ureteral orifice. Transurethral resection was carried out to examine the histology of the tumor. Histopathologic examination revealed the tumor arranged in a pseudoglandular pattern covered with erosive urothelial cells. The tumor had inconspicuous nucleoli, and abundant eosinophilic cytoplasm. An immunohistochemical study showed the tumor cells were positively stained for chromogranin A, synaptophysin, CD56, and NSE. Ki67 index of the tumor was below 2 %, indicating that the tumor was a carcinoid tumor. He showed no carcinoid syndrome, and neither recurrence nor metastasis has been detected for 66 months.

  16. A Case of Multicentric Carcinoid in a Patient with Psoriatic Spondyloarthropathy

    PubMed Central

    George, Nabil; Depala, Archana; Al Sweedan, Laith; Chakravarty, Kuntal

    2015-01-01

    We describe the first case of a patient presenting with multicentric carcinoid occurring in the lung and subsequently in the rectum, with chronic psoriatic arthritis. Although reports have been published regarding carcinoid syndrome occurring alongside rheumatoid arthritis, no reports have been made on such a case. Initial presentation of carcinoid syndrome in this patient was insidious and atypical with few symptoms, including shortness of breath and long standing abdominal bloating. Several years later a sudden change in bowel habit prompted a colonoscopy with biopsy that revealed a carcinoid rectal polyp. The case we report describes a rare presentation of carcinoid syndrome in chronic psoriatic arthropathy. PMID:25802789

  17. A case of multicentric carcinoid in a patient with psoriatic spondyloarthropathy.

    PubMed

    George, Nabil; Depala, Archana; Al Sweedan, Laith; Chakravarty, Kuntal

    2015-01-01

    We describe the first case of a patient presenting with multicentric carcinoid occurring in the lung and subsequently in the rectum, with chronic psoriatic arthritis. Although reports have been published regarding carcinoid syndrome occurring alongside rheumatoid arthritis, no reports have been made on such a case. Initial presentation of carcinoid syndrome in this patient was insidious and atypical with few symptoms, including shortness of breath and long standing abdominal bloating. Several years later a sudden change in bowel habit prompted a colonoscopy with biopsy that revealed a carcinoid rectal polyp. The case we report describes a rare presentation of carcinoid syndrome in chronic psoriatic arthropathy.

  18. Activating Cell Death Ligand Signaling Through Proteasome Inhibition

    DTIC Science & Technology

    2009-05-01

    Activating Cell Death Ligand Signaling Through Proteasome Inhibition PRINCIPAL INVESTIGATOR: Steven R Schwarze...SUBTITLE Activating Cell Death Ligand Signaling Through 5a. CONTRACT NUMBER Proteasome Inhibition 5b. GRANT NUMBER W81XWH-08-1-0392 5c...proteasome inhibition can act as an anti-neoplastic agent in vivo by sensitizing cancer cells to cell death ligands in the tumor microenvironment

  19. Appendiceal carcinoid tumor in children: implications for less radical surgery?

    PubMed

    Malkan, A D; Wahid, F N; Fernandez-Pineda, I; Sandoval, J A

    2015-03-01

    The discovery of an appendiceal carcinoid tumor found incidentally or during the course of diagnostic or therapeutic procedures is a burden to both the patient and clinician. The role of the correct surgical operation is paramount for lesions suspected to be malignant. In the pediatric population, appendiceal carcinoids continue to challenge the clinician in choosing the optimal treatment when lesions are larger than 2 cm or involve the appendical base. While the criteria used to define these distinct lesions are available in most cases, the management and treatment are still debated and controversial when considering more radical surgical intervention. The purpose of this article is to give an overview regarding the history, diagnosis, histopathology, management, and controversies associated with appendiceal carcinoid in the pediatric population.

  20. Atypical intermediate-grade mediastinal carcinoid. Case presentation.

    PubMed

    Carrillo-Muñoz, Araceli; Onofre-Borja, Melissa; Borrego-Borrego, Rafael; Chávez-Mercado, Leonora; Navarro-Reynoso, Francisco Pascual; Ibarra-Pérez, Carlos

    2011-01-01

    Approximately 25% of carcinoid tumors develop in the respiratory system. Neuroendocrine carcinoids represent ~5% of all mediastinal tumors and 1-5% of all intrathoracic neoplasms. They contain numerous neurosecretory granules that synthesize, store and release neurohumoral substances that can induce the carcinoid syndrome. A 21-year-old male presented with a rapidly progressive paraneoplastic syndrome unleashed by an acute urethritis. Two left mediastinal masses were identified and resected. Postoperative evolution has been uneventful during the first year. We emphasize the importance of early detection of primary and satellite lesions of these tumors including neurohumoral markers and PET/CT scans as in this case, as well as the participation of a multidisciplinary team.

  1. An Analysis of Trends and Growth Factor Receptor Expression of GI Carcinoid Tumors

    PubMed Central

    Bowen, Kanika A.; Silva, Scott R.; Johnson, Jessica N.; Doan, Hung Q.; Jackson, Lindsey N.; Gulhati, Pat; Qiu, Suimin; Riall, Taylor S.; Evers, B. Mark

    2009-01-01

    The purpose of our study was twofold: 1) to determine the incidence, patient and tumor characteristics, and outcome of patients with GI carcinoid tumors using the Surveillance, Epidemiology and End Results (SEER) database, and 2) to delineate the expression pattern of growth factor receptors (GFRs) in carcinoid tumors. The SEER database search provided information on patients diagnosed with carcinoid tumors from 1990–2002. Carcinoid tumor sections (n = 46) were stained for the GFRs: epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), vascular endothelial growth factor receptor (VEGFR), and HER-2/neu. Over the 12 year analysis period, 18,180 patients were identified with carcinoid tumors of the foregut, midgut, and hindgut; the incidence of carcinoid tumors increased ~2-fold during this time period. Of the patients with carcinoid tumors, there was a trend of increased expression of VEGF-R and IGF-R, particularly in the foregut and midgut carcinoids. Analysis of the SEER database confirms that the incidence of carcinoid tumors is increasing with an approximate doubling in the number of carcinoid cases from 1990–2002. Furthermore, an increase in VEGF-R and IGF-R expression suggests that GFR inhibitors may be effective adjuvant therapy for carcinoid cancer. PMID:19582519

  2. Association of autoimmune thyroid diseases, chronic atrophic gastritis and gastric carcinoid: experience from a single institution.

    PubMed

    Castoro, C; Le Moli, R; Arpi, M L; Tavarelli, M; Sapuppo, G; Frittitta, L; Squatrito, S; Pellegriti, G

    2016-07-01

    Autoimmune polyendocrine syndromes (APS) type III are characterized by the association of autoimmune thyroid disease (ATD) with other autoimmune diseases such as diabetes, alopecia, pernicious anemia, vitiligo and chronic atrophic gastritis. A strong association between ATD and atrophic gastritis (AG) has been demonstrated. Moreover 10 % of patients affected by AG have a predisposition to develop gastric carcinoid and adenocarcinoma as a result of chronic hypergastrinemia caused by achlorhydria and subsequent ELC cells neoplastic transformation. The aim of the study is to evaluate, in a consecutive series of patients followed for ATD in our outpatients clinic, the prevalence of AG. In the period 2004-2014, 242 patients with ATD underwent a screening performing APCA, Vitamin B12, ferritin, iron, and hemoglobin and red cells count measurements with subsequent gastroscopy in case of APCA positivity. We found 57/242 (23.5 %) patients with APCA positivity. Of these patients 33/57 (57.8 %), 31 F and 2 M, were affected by Graves disease; 24/57 (42.1 %) 21 F and 3 M by Hashimoto thyroiditis; 10/57 (17.5 %) presented with anemia, 14/57 (24.5 %) with vitamin B12 deficiency, 9/57 (15.7 %) with iron deficiency. In 2/57 a gastric carcinoid was found. Our data confirm the high association rate of AG in ATD which frequently is not an isolated disease but configure the picture of APS type III and need to be followed accordingly. An early diagnosis may be useful for diagnosis of gastric carcinoids and to explain and treat a gastric related L-thyroxine malabsorption and presence of chronic unexplained anemia.

  3. MET Inhibition in Clear Cell Renal Cell Carcinoma

    PubMed Central

    Xie, Zuoquan; Lee, Young H.; Boeke, Marta; Jilaveanu, Lucia B.; Liu, Zongzhi; Bottaro, Donald P.; Kluger, Harriet M.; Shuch, Brian

    2016-01-01

    Background: Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms such as activation of the MET pathway have been described. Dual MET/VEGFR2 inhibitors have recently shown clinical benefit but limited preclinical data evaluates their effects in ccRCC. Methods: An interrogation of the Cancer Genome Atlas (TCGA) dataset was performed to evaluate oncogenic alterations in the MET/VEGFR2 pathway. We evaluated the in vitro effects of Cabozantinib, a dual MET/VEGFR2 inhibitor, using a panel of ccRCC cell lines. Drug effects of cell viability and proliferation, migration, cell scatter, anchorage independent growth, and downstream MET/VEGFR2 signaling pathways were assessed. Results: Twelve percent of TCGA cases had possible MET/HGF oncogenic alterations with co-occurrence noted (p<0.001). MET/HGF altered cases had worse overall survival (p=0.044). Cabozantinib was a potent inhibitor of MET and VEGFR2 in vitro in our cell line panel. PI3K, MAPK and mTOR pathways were also suppressed by cabozantinib, however the effects on cell viability in vitro were modest. At nanomolar concentrations of cabozantinib, HGF-stimulated migration, invasion, cellular scattering and soft agar colony formation were inhibited. Conclusions: We provide further preclinical rationale for dual MET/VEGFR2 inhibition in ccRCC. While the MET pathway is implicated in VEGFR resistance, dual inhibitors may have direct anti-tumor effects in a patient subset with evidence of MET pathway involvement. Cabozantinib is a potent dual MET/VEGFR2 inhibitor, significantly inhibits cell migration and invasion in vitro and likely has anti-angiogenic effects similar to other VEGFR tyrosine kinase inhibitors. Future work involving in vivo models will be useful to better define mechanisms of potential anti-tumor activity. PMID:27390595

  4. An incidental finding of carcinoid tumor of the cystic duct.

    PubMed

    Lim, Hoang U; Chan, Cyrus C; Knotts, F Barry

    2013-04-04

    Cystic duct carcinoids are extremely rare tumors. We present a 58-year-old female with carcinoid tumor found within the cystic duct margin following laparoscopic cholecystectomy. She subsequently underwent surgical resection with a Roux-en-Y hepaticojejunostomy. No standard guidelines currently exist regarding surgical excision of these rare tumors. Therefore, we conducted a thorough review of the literature to recommend complete oncologic surgical resection with re-establishment of biliary continuity as the mainstay of definitive treatment; adjuvant therapy currently remains investigational. Long-term prognosis is good with this approach.

  5. An incidental finding of carcinoid tumor of the cystic duct

    PubMed Central

    Lim, Hoang U.; Chan, Cyrus C.; Knotts, F. Barry

    2013-01-01

    Cystic duct carcinoids are extremely rare tumors. We present a 58-year-old female with carcinoid tumor found within the cystic duct margin following laparoscopic cholecystectomy. She subsequently underwent surgical resection with a Roux-en-Y hepaticojejunostomy. No standard guidelines currently exist regarding surgical excision of these rare tumors. Therefore, we conducted a thorough review of the literature to recommend complete oncologic surgical resection with re-establishment of biliary continuity as the mainstay of definitive treatment; adjuvant therapy currently remains investigational. Long-term prognosis is good with this approach. PMID:24964431

  6. A Case of Carcinoid Tumor-Associated Hypercalcemia

    PubMed Central

    Siyam, Fadi; Abdullah, Obai; Gardner, Michael; Brietzke, Stephen; Sowers, James

    2012-01-01

    Hypercalcemia as a complication of carcinoid tumors is extremely rare. Accordingly, we report the case of a 55-year-old male with metastatic carcinoid tumor and hypercalcemia, which corrected when the patient was treated with octreotide for symptomatic relief of watery diarrhea. The etiology of the hypercalcemia is presumed to be a neoplastic expression of fibroblast growth factor-23, which was found to be inappropriately high-to-normal when other factors such as parathyroid hormone, calcitonin and vitamin D were appropriately low or low-to-normal. PMID:22493603

  7. [Carcinoid tumor of gastrointestinal tract: about two clinical cases].

    PubMed

    Blasco, María Del Carmen; Boselli O, F Giuliano; Blasco, Carmelo

    2016-01-01

    Carcinoid tumors belong to the families of neuroendocrine tumors. The major sites are the gastrointestinal tract 65% and lungs 25%. The small intestine, specifically the ileum, is the most common. These tumors although rare, are more common in tumors of neuroendocrine origin gastro-entero-pancreatic. In both cases we observe the different clinical presentations that may have carcinoid tumor; in case 1 ulceration of the tumor mass causing the elimination of melena, and severe diarrhea caused by neuroendocrine secretion. Case 2 typical course, totally asymptomatic incidental finding.

  8. Lung parenchymal invasion in pulmonary carcinoid tumor: an important histologic feature suggesting the diagnosis of atypical carcinoid and poor prognosis.

    PubMed

    Ha, Sang Yun; Lee, Jae Jun; Cho, Junhun; Hyeon, Jiyeon; Han, Joungho; Kim, Hong Kwan

    2013-05-01

    The majority of previous studies on pulmonary carcinoid tumor have usually focused on clinical behavior or outcome, seldom considering histopathologic features. We retrospectively collected 63 cases of resected pulmonary carcinoid tumors from 1995 to 2011 at Samsung Medical Center, Seoul, Korea. The clinical and pathological features were correlated and survival analyses were performed. Forty cases (63.5%) were classified as typical carcinoid (TC) and 23 cases (36.5%) were classified as atypical carcinoid (AC) according to WHO classification criteria. AC patients showed a higher frequency of current smoking status and a higher stage of the tumor by the American Joint Committee on Cancer than TC patients. The disease was associated with death and recurrence in five and seven patients, respectively, with almost all of the associations found in AC patients. The five-year survival rate of TC and AC were 100% and 83.5%, respectively, with AC showing poorer prognosis than TC in overall survival (OS) and disease free survival (DFS) (p=0.005 and p=0.002). Lung parenchymal invasion was observed more commonly in AC than in TC (39.1% vs 12.5%, p=0.01) and was a poor prognostic factor in OS and DFS. Rosette-like arrangements were found only in six cases of AC, while abundant basophilic cytoplasm mimicking paraganglioma and ossification were found only in TC. Through the comprehensive study of pulmonary carcinoid tumor in Korea, we suggest that lung parenchymal invasion could be a useful histologic feature to suspect the diagnosis of AC in daily practice as well as to predict the prognosis of carcinoid tumor.

  9. Bestatin inhibits cell growth, cell division, and spore cell differentiation in Dictyostelium discoideum.

    PubMed

    Poloz, Yekaterina; Catalano, Andrew; O'Day, Danton H

    2012-04-01

    Bestatin methyl ester (BME) is an inhibitor of Zn(2+)-binding aminopeptidases that inhibits cell proliferation and induces apoptosis in normal and cancer cells. We have used Dictyostelium as a model organism to study the effects of BME. Only two Zn(2+)-binding aminopeptidases have been identified in Dictyostelium to date, puromycin-sensitive aminopeptidase A and B (PsaA and PsaB). PSA from other organisms is known to regulate cell division and differentiation. Here we show that PsaA is differentially expressed throughout growth and development of Dictyostelium, and its expression is regulated by developmental morphogens. We present evidence that BME specifically interacts with PsaA and inhibits its aminopeptidase activity. Treatment of cells with BME inhibited the rate of cell growth and the frequency of cell division in growing cells and inhibited spore cell differentiation during late development. Overexpression of PsaA-GFP (where GFP is green fluorescent protein) also inhibited spore cell differentiation but did not affect growth. Using chimeras, we have identified that nuclear versus cytoplasmic localization of PsaA affects the choice between stalk or spore cell differentiation pathway. Cells that overexpressed PsaA-GFP (primarily nuclear) differentiated into stalk cells, while cells that overexpressed PsaAΔNLS2-GFP (cytoplasmic) differentiated into spores. In conclusion, we have identified that BME inhibits cell growth, division, and differentiation in Dictyostelium likely through inhibition of PsaA.

  10. Ghrelin-producing well-differentiated neuroendocrine tumor (carcinoid) of tailgut cyst. Morphological, immunohistochemical, ultrastructural, and RT-PCR study of a case and review of the literature.

    PubMed

    La Rosa, Stefano; Boni, Luigi; Finzi, Giovanna; Vigetti, Davide; Papanikolaou, Nikolaos; Tenconi, Silvia Maria; Dionigi, Gianlorenzo; Clerici, Moira; Garancini, Silvana; Capella, Carlo

    2010-09-01

    Well-differentiated neuroendocrine tumors (carcinoids) arising in the presacral space are rare neoplasms that can arise in association with either sacrococcygeal teratomas or tailgut cysts. Although tumors arising in tailgut cysts are more frequent than those associated with teratomas, they are still very rare, and only 13 cases have been reported in the literature. We describe the first case of a carcinoid composed of ghrelin-producing cells arising in a tailgut cyst. Ghrelin production was demonstrated using immunohistochemistry, electron microscopy, and reverse transcription-polymerase chain reaction methods. A 73-year-old woman with back and pelvic pain was found to have a presacral mass histologically diagnosed, on needle biopsy, as a well-differentiated neuroendocrine tumor. Workup did not show another primary tumor or metastatic disease. The patient underwent laparoscopic resection of the mass, and the pathological diagnosis of the surgical specimen was of a tailgut cyst-associated carcinoid composed of ghrelin-producing cells. In addition, we have accurately reviewed the literature on presacral carcinoids, associated or unassociated with tailgut cysts, to give the reader a comprehensive overview of these very rare tumor types.

  11. Hypergastrinemia and recurrent type 1 gastric carcinoid in a young Indian male: necessity for antrectomy?

    PubMed

    Senadhi, Viplove; Jani, Niraj

    2011-09-21

    Carcinoid tumors are the most common neuroendocrine tumors. Gastric carcinoids represent 2% of all carcinoids and 1% of all gastric masses. Due to the widespread use of Esophagogastroduodenoscopy for evaluating a variety of upper gastrointestinal symptoms, the detection of early gastric carcinoids has increased. We highlight an alternative management of a young patient with recurrent type 1 gastric carcinoids with greater than 5 lesions, as well as lesions intermittently greater than 1 cm. Gastric carcinoids have a variable presentation and clinical course that is highly dependent on type. Type 1 gastric carcinoids are usually indolent and have a metastasis rate of less than 2%, even with tumors larger than 2 cm. There are a number of experts as well as organizations that recommend endoscopic resection for all type 1 gastric carcinoid lesions less than 1 cm, with a follow-up every 6-12 mo. They also recommend antrectomy for type 1 gastric carcinoids with greater than 5 lesions, lesions 1 cm or greater, or refractory anemia. However, the American Society of Gastrointestinal Endoscopy guidelines state that type 1 gastric carcinoid surveillance is controversial based on the evidence and could not make an evidence-based position statement on the best treatment modality. Our report illustrates a rare cause of iron deficiency anemia in a young male (without any medical history) due to multiple recurrent gastric carcinoid type 1 lesions in the setting of atrophic gastritis causing hypergastrinemia, and in the absence of a vitamin B12 deficiency. Gastric carcinoid type 1 can present in young males without an autoimmune history, despite the known predilection for women aged 50 to 70 years. Type 1 gastric carcinoids can be managed by endoscopic resection in patients with greater than 5 lesions, even with lesions larger than 1 cm. This course of treatment enabled the avoidance of early antrectomy in our patient, who expressed a preference against more invasive measures at his

  12. A thymic carcinoid in a Bengal tiger (Panthera tigris).

    PubMed

    Powe, Joshua; Castleman, William; Fiorello, Christine

    2005-09-01

    An 18-yr-old Bengal tiger (Panthera tigris) presented with acute onset hind limb paresis. Radiographic and ultrasonographic imaging revealed a caudal abdominal aortic thrombus and a cranial mediastinal mass. Necropsy confirmed aortic thrombosis. Necrotizing enteritis and multifocal renal thrombosis were also noted. The cranial mediastinum contained a bilobed mass that histologically and ultrastructurally was consistent with a carcinoid.

  13. Association of carcinoid tumor and low grade glioma

    PubMed Central

    2012-01-01

    Background Lung carcinoid tumor and low grade glioma are two uncommon malignancies. Patients and methods We report the case of 24-year-old man who presented with respiratory disease. Imaging investigations showed a right lung tumor and histological analysis confirmed a typical carcinoid tumor. As part of initial staging, brain MRI revealed an asymptomatic right frontal lesion. First, a right pulmonary lobectomy was performed without adjuvant treatment. In second time, brain tumorectomy was performed. Histological examination confirmed the diagnosis of low grade glioma (LGG). The patient remained in complete remission 2.5 years after the initial diagnosis. Results This is the first case reporting the association between LGG and lung carcinoid tumor, while no association between LGG and a systemic tumor have been published to date. Association of lung carcinoid tumor with other malignant diseases has been reported but remained uncommon. Only minimal data support a potential molecular common origin. Conclusion This exceptional association may be fortuitous. However, their concomitant diagnoses suggest a potential association between both rare diseases. A genetic susceptibility remains possible. PMID:23137305

  14. Association of carcinoid tumor and low grade glioma.

    PubMed

    Tabouret, Emeline; Barrié, Maryline; Vicier, Cecile; Gonçalves, Anthony; Chinot, Olivier; Viens, Patrice; Madroszyk, Anne

    2012-11-08

    Lung carcinoid tumor and low grade glioma are two uncommon malignancies. We report the case of 24-year-old man who presented with respiratory disease. Imaging investigations showed a right lung tumor and histological analysis confirmed a typical carcinoid tumor. As part of initial staging, brain MRI revealed an asymptomatic right frontal lesion. First, a right pulmonary lobectomy was performed without adjuvant treatment. In second time, brain tumorectomy was performed. Histological examination confirmed the diagnosis of low grade glioma (LGG). The patient remained in complete remission 2.5 years after the initial diagnosis. This is the first case reporting the association between LGG and lung carcinoid tumor, while no association between LGG and a systemic tumor have been published to date. Association of lung carcinoid tumor with other malignant diseases has been reported but remained uncommon. Only minimal data support a potential molecular common origin. This exceptional association may be fortuitous. However, their concomitant diagnoses suggest a potential association between both rare diseases. A genetic susceptibility remains possible.

  15. Imaging of carcinoid tumors with iodine-123 metaiodobenzylguanidine

    SciTech Connect

    Bomanji, J.; Levison, D.A.; Zuzarte, J.; Britton, K.E.

    1987-12-01

    Scintigraphy with /sup 123/I-radiolabeled metaiodobenzylguanidine (MIBG) was performed successfully in two patients with metastatic carcinoid tumor. The scintigraphic findings show diversity of the tumor deposits in the uptake of (/sup 123/I)MIBG in the same patient and between patients.

  16. Unusual presentation of carcinoid tumor as acute cholecystitis

    SciTech Connect

    Saxton, C.R.

    1983-07-01

    The patient described had signs, symptoms, and laboratory data consistent with acute cholecystitis. A sonogram also suggested cholecystitis, and the gallbladder was not displayed by nuclear imaging. Cholecystectomy revealed the absence of stones but showed carcinoid tumor metastatic to the gallbladder.

  17. Conditioned medium from neural stem cells inhibits glioma cell growth.

    PubMed

    Li, Z; Zhong, Q; Liu, H; Liu, P; Wu, J; Ma, D; Chen, X; Yang, X

    2016-10-31

    Malignant glioma is one of the most common brain tumors in the central nervous system. Although the significant progress has been made in recent years, the mortality is still high and 5-year survival rate is still very low. One of the leading causes to the high mortality for glioma patients is metastasis and invasion. An efficient method to control the tumor metastasis is a promising way to treat the glioma. Previous reports indicated that neural stem cells (NSCs) were served as a delivery vector to the anti-glioma therapy. Here, we used the conditioned medium from rat NSCs (NSC-CM) to culture the human glioblastoma cell lines. We found that NSC-CM could inhibit the glioma cell growth, invasion and migration in vitro and attenuate the tumor growth in vivo. Furthermore, this anti-glioma effect was mediated by the inactivation of mitogen activated protein kinase (MAPK) pathway. Above all, this study provided the direct evidence to put forward a simple and efficient method in the inhibition of glioma cells/tumor growth, potentially advancing the anti-glioma therapy.

  18. Thymic carcinoids in multiple endocrine neoplasia type 1.

    PubMed Central

    Teh, B T; Zedenius, J; Kytölä, S; Skogseid, B; Trotter, J; Choplin, H; Twigg, S; Farnebo, F; Giraud, S; Cameron, D; Robinson, B; Calender, A; Larsson, C; Salmela, P

    1998-01-01

    OBJECTIVE: To study the clinical, pathologic, and genetic features of thymic carcinoids in the setting of multiple endocrine neoplasia type 1 (MEN1) and to study means for detection and prevention of this tumor in patients with MEN1. SUMMARY BACKGROUND DATA: Thymic carcinoid is a rare malignancy, with approximately 150 cases reported to date. It may be associated with MEN1 and carries a poor prognosis, with no effective treatment. Its underlying etiology is unknown. METHODS: Ten patients with MEN1 from eight families with anterior mediastinal tumors were included in a case series study at tertiary referring hospitals. Clinicopathologic studies were done on these patients, with a review of the literature. Mutation analysis was performed on the MEN1 gene in families with clusterings of the tumor to look for genotype-phenotype correlation. Loss of heterozygosity was studied in seven cases to look for genetic abnormalities. RESULTS: Histologic studies of all tumors were consistent with the diagnosis of thymic carcinoid. Clustering of this tumor was found in some of the families-three pairs of brothers and three families with first- or second-degree relatives who had thymic carcinoid. All patients described here were men, with a mean age at detection of 44 years (range 31 to 66). Most of the patients had chest pain or were asymptomatic; none had Cushing's or carcinoid syndrome. All tumors were detected by computed tomography (CT) or magnetic resonance imaging (MRI) of the chest. The results of octreoscans performed in three patients were all positive. Histopathologic studies were consistent with the diagnosis of thymic carcinoid and did not stain for ACTH. Mutation analysis of the families with clustering revealed mutations in different exons/introns of the MEN1 gene. Loss of heterozygosity (LOH) studies of seven tumors did not show LOH in the MEN1 region, but two tumors showed LOH in the 1p region. CONCLUSIONS: MEN1-related thymic carcinoids constitute approximately 25

  19. Integrin inhibition promotes atypical anoikis in glioma cells

    PubMed Central

    Silginer, M; Weller, M; Ziegler, U; Roth, P

    2014-01-01

    Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation and motility. They are expressed by glioma cells and may contribute to their malignant phenotype. Integrin inhibition may therefore represent a promising therapeutic strategy. GL-261 and SMA-560 glioma cells grown under standard conditions uniformly detached and formed large cell clusters after integrin gene silencing or pharmacological inhibition using EMD-121974, a synthetic Arg-Gly-Asp-motif peptide, or GLPG0187, a nonpeptidic integrin inhibitor. After 120 h, the clusters induced by integrin inhibition decayed and cells died. In contrast, when cells were cultured under stem cell (sphere) conditions, no disaggregation became apparent upon integrin inhibition, and cell death was not observed. As poly-HEMA-mediated detachment had similar effects on cell viability as integrin inhibition, we postulated that cell death may result from detachment alone, which was confirmed using various permissive and nonpermissive substrates. No surrogate markers of apoptosis were detected and electron microscopy confirmed that necrosis represents the dominant morphology of detachment-induced cell death. In addition, integrin inhibition resulted in the induction of autophagy that represents a survival signal. When integrins were inhibited in nonsphere glioma cells, the TGF-β pathway was strongly impaired, whereas no such effect was observed in glioma cells cultured under sphere conditions. Cell death induced by integrin inhibition was rescued by the addition of recombinant transforming growth factor-β (TGF-β) and accelerated by exposure to the TGF-β receptor inhibitor, SD-208. In summary, cell death following integrin inhibition is detachment mediated, represents an atypical form of anoikis involving necrosis as well as autophagy, and is modulated by TGF-β pathway activity. PMID:24457956

  20. Cutaneous and Subcutaneous Metastases From Atypical Laryngeal Carcinoids

    PubMed Central

    Wang, Kui-Rong; Jia, Yuan-Jing; Zhou, Shui-Hong; Wang, Qin-Ying; Bao, Yang-Yang; Feng, Zhi-Ying; Yao, Hong-Tian; Fan, Jun

    2016-01-01

    Abstract The incidence of cutaneous and subcutaneous metastases from atypical laryngeal carcinoids is approximately 20%. However, the pathogenesis and natural history of, and prognostic factors for, the condition remain poorly understood. We reported a 54-year-old female presented with cutaneous and subcutaneous metastases from atypical laryngeal carcinoid. Laryngoscopy revealed a 0.5 × 1.5-cm reddish mass on the laryngeal surface of the epiglottis. Under general anesthesia, a biopsy sample was obtained via suspension laryngoscopy. Routine pathology revealed atypical laryngeal carcinoid. Immunohistochemical staining of the sections of primary tumor was positive for cytokeratin, chromogranin A, synaptophysin, hypoxia-inducible factor-1α, P53, and CD56. GLUT-1, p-Akt, and PI3K were negative. The Ki-67 index was 15%. Supraglottic laryngectomy and selective right-neck dissection were performed. After 6 months, the patient complained of pain in the right wall of the chest; multiple cutaneous and subcutaneous nodules were evident at that site and in the abdomen. An abdominal nodule was biopsied and pathology revealed that the atypical metastatic carcinoid had metastasized to both cutaneous and subcutaneous areas of the abdomen. Chemotherapy was then prescribed. Currently, the intrathecal drug delivery system remains in place. No local recurrence has been detected. Furthermore, we systematically reviewed clinical manifestations of the disease, pathogenesis, prognostic factors, and treatment. The metastasis rate (cutaneous and subcutaneous) was approximately 12.2%. Thirty patients (62.5%) with cutaneous and subcutaneous metastases exhibited contemporaneous lymph node invasion. The 3-, 5-, and 10-year survival rates were 44.0%, 22.0%, and 13.0%, respectively. The prognosis of patients with atypical laryngeal carcinoids was poor. Relevant prognostic factors included the level of p53, human papilloma virus status, certain hypoxic markers, and distant metastasis. No

  1. Prognosis of patients with carcinoid heart disease after valvular surgery.

    PubMed

    Manoly, Imthiaz; McAnelly, Sarah-Louise; Sriskandarajah, Sanjeevan; McLaughlin, Kenneth Edward

    2014-08-01

    A best evidence topic in cardiac surgery was written according to a structured protocol. We addressed the following question: in patients who are diagnosed with carcinoid heart disease (CHD), do valvular surgeries improve their prognosis? Fifty percent of the patients with clinically diagnosed carcinoid syndrome had cardiac involvement which was present either as valvular dysfunction or as cardiac metastases. These patients often require surgery due to their heightened risk of cardiac disease. Altogether 217 relevant papers were identified as a result of the below-mentioned search, of which 10 papers represented the best evidence to answer the question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. Of the patients who were identified to have carcinoid heart disease in different studies, 193 patients had valve procedure, mainly replacements at tricuspid, mitral and aortic valve positions and either valvuloplasty or replacement at pulmonary valve. Tricuspid and pulmonary valves represented the majority of the excised valves among patients undergoing valvular surgery for CHD. The pathology of carcinoid valve was attributed to the presence of plaque, causing thickening and retraction. Pure regurgitation was the most common finding in all the valves except pulmonary valve which had both stenosis and insufficiency. Thirty-day mortality was 17% (range 1-63%) and long-term survivors were reported to be alive at an average of 58 months (28-80 months) after the valve surgery. The evidence demonstrates that surgical intervention can lead to improved prognosis and reduce the symptoms of heart failure. Postoperative mortality was mainly due to the carcinoid disease itself and not as a complication of the surgery. Therefore, surgery could be considered for symptomatic palliation in carefully selected individuals.

  2. Review of the pathogenesis, diagnosis, and management of type I gastric carcinoid tumor.

    PubMed

    Zhang, Linda; Ozao, Junko; Warner, Richard; Divino, Celia

    2011-08-01

    Gastric carcinoid tumors comprise 7% of all gastrointestinal carcinoids and have significantly increased in incidence over the past few decades. Seventy to 80% of gastric carcinoids are type I, which usually are clinically asymptomatic and found incidentally at endoscopic evaluation for abdominal pain or anemia. In this review, advances in understanding the pathophysiology of type I gastric carcinoid are highlighted. In addition, various current diagnostic and treatment options are discussed. Although type I carcinoids generally hold a benign course, rigorous investigation is needed to ensure accurate diagnosis and optimal treatment. This includes appropriate diagnostic procedures and imaging and accurate staging of tumor. Tumor size, depth of invasion, presence of metastasis, and the tumor's gastrin dependency dictate treatment options. Appropriate treatments can consist of endoscopic resection, antrectomy, medical management, or frequent follow-up. This article provides a systematic method of evaluating and treating type I gastric carcinoid.

  3. Synchronous Gastrointestinal Carcinoid Tumor and Colon Adenocarcinoma: Case Reports and Literature Review

    PubMed Central

    Winn, Jessica N.; Sathyamurthy, Anjana; Kneib, Jessica L.; Ibdah, Jamal A.; Tahan, Veysel

    2017-01-01

    Case series Patient: Male, 40; Male, 70 Final Diagnosis: Synchronous gastrointestinal carcinoid tumor and colon adenocarcinoma Symptoms: Weakness Medication: — Clinical Procedure: Colonoscopy Specialty: Gastroenterology and Hepatology Objective: Rare co-existance of disease or pathology Background: Coexistence of carcinoid tumor and colorectal adenocarcinoma is rare. In this report, we present two cases and review the current literature for synchronous carcinoid tumor and colorectal carcinoma occurrence. Case Reports: In both cases, the rectal carcinoid tumors and sigmoid colon adenocarcinomas were detected by colonoscopy. The colon adenocarcinomas were effectively treated with a laparoscopic sigmoidectomy and the carcinoids were successfully removed endoscopically. Our 40-year-old patient was the youngest among 17 reported patient cases. Conclusions: These two cases demonstrate that the diagnosis of gastrointestinal carcinoid requires a complete assessment of the remainder of the colon for another primary cancer to achieve a timely treatment management strategy. PMID:28579603

  4. Ligation-assisted endoscopic submucosal resection with circumferential mucosal incision for duodenal carcinoid tumor.

    PubMed

    Harada, Hideaki; Suehiro, Satoshi; Shimizu, Takanori; Katsuyama, Yasushi; Hayasaka, Kenji; Ito, Hideto

    2015-09-14

    Here we present the case of a 64-year-old female with a duodenal carcinoid tumor treated by ligation-assisted endoscopic submucosal resection (ESMR-L) with circumferential mucosal incision (CMI). Band ligation was effective in resecting the duodenal carcinoid tumor after CMI, with an uneventful post-procedural course. Histopathological examination showed clear tumor margins at deeper tissue levels. Thus, in the present case, ESMR-L with CMI was useful for the treatment of duodenal carcinoid tumor.

  5. Ligation-assisted endoscopic submucosal resection with circumferential mucosal incision for duodenal carcinoid tumor

    PubMed Central

    Harada, Hideaki; Suehiro, Satoshi; Shimizu, Takanori; Katsuyama, Yasushi; Hayasaka, Kenji; Ito, Hideto

    2015-01-01

    Here we present the case of a 64-year-old female with a duodenal carcinoid tumor treated by ligation-assisted endoscopic submucosal resection (ESMR-L) with circumferential mucosal incision (CMI). Band ligation was effective in resecting the duodenal carcinoid tumor after CMI, with an uneventful post-procedural course. Histopathological examination showed clear tumor margins at deeper tissue levels. Thus, in the present case, ESMR-L with CMI was useful for the treatment of duodenal carcinoid tumor. PMID:26379409

  6. Inhibition of caspases prevents ototoxic and ongoing hair cell death

    NASA Technical Reports Server (NTRS)

    Matsui, Jonathan I.; Ogilvie, Judith M.; Warchol, Mark E.

    2002-01-01

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  7. Inhibition of caspases prevents ototoxic and ongoing hair cell death

    NASA Technical Reports Server (NTRS)

    Matsui, Jonathan I.; Ogilvie, Judith M.; Warchol, Mark E.

    2002-01-01

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  8. Inhibition of caspases prevents ototoxic and ongoing hair cell death.

    PubMed

    Matsui, Jonathan I; Ogilvie, Judith M; Warchol, Mark E

    2002-02-15

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  9. Carcinoid heart disease from ovarian primary presenting with acute pericarditis and biventricular failure

    PubMed Central

    Vergani, D; Massironi, L; Lombardi, F; Fiorentini, C

    1998-01-01

    A case is described of a 54 year old woman who had acute pericarditis with large exudative effusion accompanied by severe right and left ventricular failure. The patient was finally diagnosed with carcinoid heart disease from an ovarian carcinoid teratoma. She was treated with octreotide—a somatostatin analogue—followed by radical surgical resection of the neoplasm. At one year follow up only mild carcinoid tricuspid regurgitation remained. Only 16 cases of carcinoid heart disease from an ovarian primary have been described in literature. Moreover clinically manifest acute, non-metastatic pericarditis and left heart failure are not considered as possible presentations of carcinoid heart disease, whatever the origin. In a recent series a small pericardial effusion was considered an infrequent and unexpected echocardiographic finding in carcinoid heart patients. One case of "carcinoid pericarditis" has previously been described as a consequence of pericardial metastasis. Left sided heart involvement is usually caused by bronchial carcinoids or patency of foramen ovale; both were excluded in the case presented.

 Keywords: carcinoid heart disease;  ovarian tumour;  acute pericarditis;  heart failure PMID:10065036

  10. Resolution of right-sided heart failure symptoms after resection of a primary ovarian carcinoid tumor.

    PubMed

    Goldman, Todd; Adamson, Kathi; Yang, Eugene

    2014-10-01

    Carcinoid tumors are rare neuroendocrine malignancies that typically originate from the gastrointestinal tract. Patients who are diagnosed with carcinoid heart disease generally have poor prognoses because of advanced metastases during staging and few therapeutic options. We present the case of a 61-year-old woman with right-sided heart failure, secondary to carcinoid heart disease caused by a primary ovarian carcinoid tumor. After undergoing surgical resection of the left ovary and fallopian tube, the patient experienced complete resolution of her heart failure symptoms. In addition to the patient's case, we discuss the diagnosis, nature, and treatment of this rare condition.

  11. An Unusual Case of Synchronous Carcinoid of Ovary and Gall Bladder

    PubMed Central

    Bassi, Rupali; Arora, Raksha; Bhasin, Sangeeta; Khurana, Nita

    2013-01-01

    Multifocal carcinoid is a known phenomenon. We present a rare combination of an ovarian carcinoid synchronous with gallbladder carcinoid. This rare combination has not been reported so far. An asymptomatic 45-years-old perimenopausal lady was diagnosed to have a metastatic ovarian cancer, but on laparotomy she was found to have a primary synchronous metastatic gall bladder as well. On histopathological evaluation she was found to have two separate primary carcinoids. Subsequently the patient received chemotherapy and is completely asymptomatic on follow up. Further research needs to be undertaken and guidelines need to be formulated for management of these cases. PMID:24371533

  12. Flavonoids from Citrus unshiu Marc. inhibit cancer cell adhesion to endothelial cells by selective inhibition of VCAM-1.

    PubMed

    Jin, Hana; Lee, Won Sup; Yun, Jeong Won; Jung, Ji Hyun; Yi, Sang Mi; Kim, Hye Jung; Choi, Yung Hyun; Kim, Gonsup; Jung, Jin-Myung; Ryu, Chung Ho; Shin, Sung Chul; Hong, Soon Chan

    2013-11-01

    Citrus fruits have been used as edible fruit and a component of traditional medicine for various diseases including cancer since ancient times. Herein, we investigated the anticancer activity of flavonoids of Citrus unshiu Marc. (FCM) focusing on anti-metastatic effects. We prepared FCM and performed experiments using MDA-MB-231 human breast cancer cells. FCM inhibited TNF-induced cancer cell adhesion to human umbilical vein endothelial cells (HUVECs) without showing any toxicity. FCM inhibited the expression of VCAM-1, but not of ICAM-1, on MDA-MB-231 cells as well as HUVECs. FCM inhibited protein kinase C (PKC) phosphorylation, but not Akt phosphorylation. FCM also inhibited cancer cell invasion in a dose-dependent manner, but not MMP-9 expression. In conclusion, this study suggested that FCM inhibits TNF-induced cancer cell adhesion to HUVECs by inhibiting VCAM-1 through inhibition of PKC, providing evidence that FCM have anti-metastatic activity by inhibiting adhesion molecules and invasion on human breast cancer cells.

  13. Decreased Contact Inhibition in Mouse Adipose Mesenchymal Stem Cells

    PubMed Central

    Jeon, Yunmi; Lee, Myung Sook; Cheon, Yong-Pil

    2012-01-01

    The proliferation of embryonic cells or adult stem cells in tissue is critically regulated during development and repair. How limited the proliferation of cells, so far, is not much explored. Cell-cell contact proliferation inhibition is known as a crucial mechanism regulating cell proliferation in vitro and in vivo. In this study we examined the characters of mouse subcutaneous adipose derived stem cells (msADSC) whether they lost or get contact inhibition during in vitro culture. The characters of msADSC growth after confluence were analyzed using confocal microscope and the expression profiles of contact inhibition related genes were analyzed according to the morphological changes using real-time PCR method. msADSC showed overlapping growth between them but not after passage 14. The cell shapes were also changed after passage 14. The expression profiles of genes which are involved in contact inhibition were modified in the msADSC after passage 14. The differentiation ability of msADSCs to adipocyte, chondrocyte and osteocyte was not changed by such changes of gene expression profiles. Based on these results, it is revealed that smADSC were characterized by getting of strong cell-cell contact inhibition after passage 14 but the proliferation and developmental ability were not blocked by the change of cell-cell contact proliferation inhibition. These finding will help to understand the growth of adipose tissue, although further studies are needed to evaluate the physiological meaning of the cell-cell contact proliferation inhibition during in vitro culture of msADSC. PMID:25949108

  14. Hyperoxia Inhibits T Cell Activation in Mice

    NASA Astrophysics Data System (ADS)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    , spleens were removed and the splenocytes were isolated and kept as individual biological samples. We have also examined transcription factors (JASPAR) and pathways of the immune system to help us understand the mechanism of regulation. Results: Our recent mouse immunology experiment aboard STS-131 suggests that the early T cell immune response was inhibited in animals that have been exposed to spaceflight, even 24 hours after return to earth. Moreover, recent experiments in hyperoxic mice show that many of the same genes involved in early T cell activation were altered. Specifically, expression of IL-2Rα, Cxcl2, TNFα, FGF2, LTA and BCL2 genes are dysregulated in mice exposed to hyperoxia. Conclusions: If these hyperoxia-induced changes of gene expression in early T cell activation are additive to the changes seen in the microgravity of spaceflight, there could be an increased infection risk to EVA astronauts, which should be addressed prior to conducting a Mars or other long-term mission.

  15. Typical laryngeal carcinoid tumor with recurrence and lymph node metastasis: a case report and review of the literature.

    PubMed

    Wang, Qinying; Chen, Haihong; Zhou, Shuihong

    2014-01-01

    Typical carcinoid tumor of the larynx is an extremely rare lesion which arises from neuroendocrine cells scanning in the laryngeal mucosa or submucosal glands. Conventionally, it is a well-differentiated neuroendocrine carcinoma, conservative surgery represents the treatment of choice, and the patient usually has a good prognosis with rarely recurrence and metastasis. In this report, we present a case of typical laryngeal carcinoid tumor with recurrence and lymph node metastasis. The patient was a 58-year-old man, complaints of intermittent burning pain in his both ears for 2 years, and for the recent one month the pain turn to continuous accompanied with a mild discomfort in the throat, he had neither hoarseness, dysphagia, nor any otorrhea and hearing loss. The patient was scheduled to undergo a tracheotomy and then a biopsy under supporting laryngoscopy. During the operation, the frozen section diagnosis from the first and the second time both indicated that the biopsy specimens originated from musculo-epithelia, it couldn't be differed from malignant to benign. So the mass was simply removed under supporting laryngoscopy. The histopathology from paraffin sections revealed typical carcinoid of the larynx and the second procedure consisted of supraglottic laryngectomy with clear margins, the otalgia resolved and the patient had no difficulty with phonation or swallowing. After 1 year follow-up, the patient was found a mass on his right neck with symptom free, B-ultrasonography indicated several enlargement lymph nodes with some merged on both sides of the neck, the patient was scheduled to undergo a "total-laryngectomy with radical neck dissection on the left side and an elective neck dissection on the right side". The specimens were positive for cytokeratin, chromogranin A and synaptophysin, a final diagnosis of typical carcinoid was made for the recurrence lesion and the metastasis of the lymph nodes. Though the post-operative recovery was uneventful, the

  16. Typical laryngeal carcinoid tumor with recurrence and lymph node metastasis: a case report and review of the literature

    PubMed Central

    Wang, Qinying; Chen, Haihong; Zhou, Shuihong

    2014-01-01

    Typical carcinoid tumor of the larynx is an extremely rare lesion which arises from neuroendocrine cells scanning in the laryngeal mucosa or submucosal glands. Conventionally, it is a well-differentiated neuroendocrine carcinoma, conservative surgery represents the treatment of choice, and the patient usually has a good prognosis with rarely recurrence and metastasis. In this report, we present a case of typical laryngeal carcinoid tumor with recurrence and lymph node metastasis. The patient was a 58-year-old man, complaints of intermittent burning pain in his both ears for 2 years, and for the recent one month the pain turn to continuous accompanied with a mild discomfort in the throat, he had neither hoarseness, dysphagia, nor any otorrhea and hearing loss. The patient was scheduled to undergo a tracheotomy and then a biopsy under supporting laryngoscopy. During the operation, the frozen section diagnosis from the first and the second time both indicated that the biopsy specimens originated from musculo-epithelia, it couldn’t be differed from malignant to benign. So the mass was simply removed under supporting laryngoscopy. The histopathology from paraffin sections revealed typical carcinoid of the larynx and the second procedure consisted of supraglottic laryngectomy with clear margins, the otalgia resolved and the patient had no difficulty with phonation or swallowing. After 1 year follow-up, the patient was found a mass on his right neck with symptom free, B-ultrasonography indicated several enlargement lymph nodes with some merged on both sides of the neck, the patient was scheduled to undergo a “total-laryngectomy with radical neck dissection on the left side and an elective neck dissection on the right side”. The specimens were positive for cytokeratin, chromogranin A and synaptophysin, a final diagnosis of typical carcinoid was made for the recurrence lesion and the metastasis of the lymph nodes. Though the post-operative recovery was uneventful, the

  17. Hili inhibits HIV replication in activated T cells.

    PubMed

    Peterlin, B Matija; Liu, Pingyang; Wang, Xiaoyun; Cary, Daniele; Shao, Wei; Leoz, Marie; Hong, Tian; Pan, Tao; Fujinaga, Koh

    2017-03-22

    Piwil proteins restrict the replication of mobile genetic elements in the germline. They are also expressed in many transformed cell lines. In this report, we discovered that the human piwil 2 (hili) can also inhibit HIV replication, especially in activated CD4+ T cells that are the preferred target cells for this virus in the infected host. Although resting cells did not express hili, it was rapidly induced following T cell activation. In these cells and transformed cell lines, depletion of hili increased levels of viral proteins and new viral particles. Further studies revealed that hili binds to tRNA. Some of them represent rare tRNA species, whose codons are over-represented in the viral genome. Targeting tRNA(Arg)(UCU) with an antisense oligonucleotide replicated effects of hili and also inhibited HIV replication. Finally, hili also inhibited the retrotransposition of the endogenous intracysternal A particle (IAP) by a similar mechanism. Thus, hili joins a list of host proteins that inhibit the replication of HIV and other mobile genetic elements.IMPORTANCE Piwil proteins inhibit the movement of mobile genetic elements in the germline. In their absence, sperm does not form and male mice are sterile. This inhibition is thought to occur via small piRNAs. However, in some species and in human somatic cells, piwil proteins bind primarily to tRNA. In this report, we demonstrate that human piwil proteins, especially hili, not only bind to select tRNA species that include rare tRNAs, but also inhibit HIV replication. Importantly, T cell activation induces the expression of hili in CD4+ T cells. Since hili also inhibited the movement of an endogenous retrovirus (IAP), our finding shed new light on this intracellular resistance to exogenous and endogenous retroviruses as well as other mobile genetic elements.

  18. Inhibition of host cell catalase by Mycoplasma pneumoniae: a possible mechanism for cell injury.

    PubMed Central

    Almagor, M; Yatziv, S; Kahane, I

    1983-01-01

    This study demonstrates that viable Mycoplasma pneumoniae cells inhibit catalase activity in several types of intact human cells as well as in solution. Human erythrocyte catalase was inhibited up to 72%, and the inhibition of catalase in human cultured skin fibroblasts, lung carcinoma epithelial cells, and ciliated epithelial cells from human nasal polyps ranged between 75 and 80%. UV light-killed mycoplasmas failed to inhibit catalase activity both in intact cells and in vitro. After M. pneumoniae infection of human cultured skin fibroblasts, the level of malonyldialdehyde, an indicator for membrane lipid peroxidation, was 3.5 times higher than in control fibroblasts. Virulent M. pneumoniae completely inhibited catalase activity in solution, whereas the nonvirulent strains had a lesser ability to inhibit catalase activity. These findings suggest that as a result of host cell catalase inhibition by M. pneumoniae, the toxicity of the hydrogen peroxide generated by the microorganism and the affected cell is enhanced, thereby inducing host cell damage. PMID:6407999

  19. Primary carcinoid tumor of the skin: a literature review.

    PubMed

    Jedrych, Jaroslaw; Pulitzer, Melissa

    2014-04-01

    Primary carcinoid tumor of the skin (PCTS) is an uncommon indolent neoplasm, with 10 cases described in the literature. The tumors affect patients in the sixth to ninth decades of life (mean = 66.3 years) with an equal gender distribution and predilection for the head and trunk. They present as slowly enlarging nodules of variable duration, ranging from 1 to 60 years (mean = 11.4 years). PCTS is characterized by architectural, cytomorphologic, ultrastructural, and immunohistochemical features typical of a low-grade neoplasm with neuroendocrine differentiation. PCTS typically follows a benign clinical course and therefore has to be distinguished from cutaneous metastases of visceral carcinoid tumors, which herald dissemination of malignancy and poor prognosis. While the distinction from other histologically similar entities can be achieved by histopathological examination, PCTS can be distinguished from a visceral metastasis only by a judicious clinicopathologic correlation. Herein we describe the clinical presentation, histological appearance, and management of these tumors.

  20. Primary renal carcinoid tumor: A rare cystic renal neoplasm

    PubMed Central

    Yoon, Jung-Hee

    2013-01-01

    We present the case of a 21-year-old man with an incidentally detected cystic renal mass. A well-defined, solid mass measuring approximately 8 cm x 6 cm with a cystic component was identified in the left kidney by abdominal multidetector computed tomography (CT) and ultrasonography. The mass was well-enhanced on the corticomedullary CT phase and washout of enhancement occurred on the nephrographic phase. The mass contained peripheral wall and septal calcifications in the cystic component. The lesion was resected and diagnosed as a primary renal carcinoid tumor. Primary carcinoid tumors of the kidney are extremely rare. This case is notable because of the rarity of this neoplasm and its unique radiologic and pathologic findings. A review of previously reported cases in the literature is also presented. PMID:24003360

  1. Postoperative radiotherapy for residual tumor of primary mediastinal carcinoid teratoma

    PubMed Central

    Tu, Lingli; Sun, Lan; Zhou, Yu; Gong, Youling; Xue, Jianxin; Gao, Jun; Lu, You

    2013-01-01

    A 36-year-old woman had presented with dry cough for 2 months. Thoracic computed tomography (CT) scan showed a 12 cm × 8 cm ×5 cm mass in the anterior mediastinum. Due to intimately involving the aortic arch, tumor was removed incompletely. Residual tumor remained approximate 2 cm × 3 cm × 4 cm. Histologic diagnosis was a mature cystic teratoma containing a carcinoid. Subsequently, radiotherapy (RT) was administrated on residual tumor for a total dose of 50 Gy at 2 Gy/d fraction in 25 fractions. At 2-year follow-up, the patient had stable disease. In conclusion, adjuvant radiotherapy with 50 Gy is an effective approach for residual tumor of mediastinal carcinoid teratoma. PMID:23585961

  2. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

    PubMed Central

    De Petrocellis, Luciano; Melck, Dominique; Palmisano, Antonella; Bisogno, Tiziana; Laezza, Chiara; Bifulco, Maurizio; Di Marzo, Vincenzo

    1998-01-01

    Anandamide was the first brain metabolite shown to act as a ligand of “central” CB1 cannabinoid receptors. Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 μM and 83–92% maximal inhibition at 5–10 μM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 μM anandamide. The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle. A stable analogue of anandamide (R)-methanandamide, another endogenous cannabinoid, 2-arachidonoylglycerol, and the synthetic cannabinoid HU-210 also inhibited EFM-19 cell proliferation, whereas arachidonic acid was much less effective. These cannabimimetic substances displaced the binding of the selective cannabinoid agonist [3H]CP 55,940 to EFM-19 membranes with an order of potency identical to that observed for the inhibition of EFM-19 cell proliferation. Moreover, anandamide cytostatic effect was inhibited by the selective CB1 receptor antagonist SR 141716A. Cell proliferation was arrested by a prolactin mAb and enhanced by exogenous human prolactin, whose mitogenic action was reverted by very low (0.1–0.5 μM) doses of anandamide. Anandamide suppressed the levels of the long form of the prolactin receptor in both EFM-19 and MCF-7 cells, as well as a typical prolactin-induced response, i.e., the expression of the breast cancer cell susceptibility gene brca1. These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor. PMID:9653194

  3. Inhibition of brain tumor cell proliferation by alternating electric fields

    SciTech Connect

    Jeong, Hyesun; Oh, Seung-ick; Hong, Sunghoi E-mail: radioyoon@korea.ac.kr; Sung, Jiwon; Jeong, Seonghoon; Yoon, Myonggeun E-mail: radioyoon@korea.ac.kr; Koh, Eui Kwan

    2014-11-17

    This study was designed to investigate the mechanism by which electric fields affect cell function, and to determine the optimal conditions for electric field inhibition of cancer cell proliferation. Low-intensity (<2 V/cm) and intermediate-frequency (100–300 kHz) alternating electric fields were applied to glioblastoma cell lines. These electric fields inhibited cell proliferation by inducing cell cycle arrest and abnormal mitosis due to the malformation of microtubules. These effects were significantly dependent on the intensity and frequency of applied electric fields.

  4. Extracellular Na+ inhibits Na+/H+ exchange: cell shrinkage reduces the inhibition.

    PubMed

    Dunham, Philip B; Kelley, Scott J; Logue, Paul J

    2004-08-01

    Na+/H+ exchangers (NHE) are ubiquitous transporters participating in regulation of cell volume and pH. Cell shrinkage, acidification, and growth factors activate NHE by increasing its sensitivity to intracellular H+ concentration. In this study, the kinetics were studied in dog red blood cells of Na+ influx through NHE as a function of external Na+ concentration ([Na+](o)). In cells in isotonic media, [Na+](o) inhibited Na+ influx >40 mM. Osmotic shrinkage activated NHE by reducing this inhibition. In cells in isotonic media + 120 mM sucrose, there was no inhibition, and influx was a hyperbolic function of [Na+](o). The kinetics of Na+-inhibited Na+ influx were analyzed at various extents of osmotic shrinkage. The curves for inhibited Na+ fluxes were sigmoid, indicating more than one Na+ inhibitory site associated with each transporter. Shrinkage significantly increased the Na+ concentration at half-maximal velocity of Na+-inhibited Na+ influx, the mechanism by which shrinkage activates NHE.

  5. Interferon-alpha and dexamethasone inhibit adhesion of T cells to endothelial cells and synovial cells

    PubMed Central

    Eguchi, K.; Kawakami, A.; Nakashima, M.; Ida, H.; Sakito, S.; Matsuoka, N.; Terada, K.; Sakai, M.; Kawabe, Y.; Fukuda, T.; Ishimaru, T.; Kurouji, K.; Fujita, N.; Aoyagi, T.; Maeda, K.; Nagataki, S.

    1992-01-01

    We investigated whether interferon-gamma (IFN-γ), interferon-alpha (IFN-α) and glucocorticoids affected the adhesion of T cells to human umbilical endothelial cells or human synovial cells. About 30% of peripheral blood T cells could bind to unstimulated endothelial cells, but only a few T cells could bind to unstimulated synovial cells. When both endothelial cells and synovial cells were cultured with recombinant IFN-γ (rIFN-γ), the percentage of T cell binding to both types of cells increased in a dose-dependent manner. rIFN-α and dexamethasone blocked the T cell binding to unstimulated endothelial cells. Furthermore, rIFN-α and dexamethasone suppressed T cell binding to both endothelial cells and synovial cells stimulated by IFN-γ, and also inhibited intercellular adhesion molecule-1 (ICAM-1) expression on both endothelial cells and synovial cells stimulated by IFN-γ. These results suggest that IFN-α and glucocorticoids may inhibit T cell binding to endothelial cells or synovial cells by modulating adhesion molecule expression on these cells. PMID:1606729

  6. Appendix carcinoid associated with the Peutz-Jeghers syndrome.

    PubMed

    Hofmann, Sabine; Barth, Thomas F E; Kornmann, Marko; Henne-Bruns, Doris

    2014-01-01

    The Peutz-Jeghers syndrome (PJS) is a rare hereditary, autosomal-dominant disorder. It is characterized by a gastrointestinal polyposis and mucocutaneous melanic spots. It has also been reported as a precondition for malignancies with a life-time-hazard for cancer up to 93%, caused by a germline mutation in the STK11 gene. A 21-year-old man presented with nausea and abdominal pain. He had a known history of PJS since the age of 13 when he was treated for intussusception due to a hamartomatous polyp. Preoperative diagnostics revealed a second intussusception and an extensive intestinal polyposis. Intraoperative findings confirmed the suspected diagnoses and desvagination was performed. Nearly 50 polyps were removed from the small intestinum over several longitudinal sections. As the appendix appeared thickened an appendectomy was performed simultaneously. Histology showed hamartomatous polyps and the incidental finding of a pT1 carcinoid of the appendix. The patient recovered well and needed no further treatment for his carcinoid tumor. The mechanism of carcinogenesis in PJS still remains debatable, although the genetic disorder underlying the syndrome is known. A predisposition for carcinoid tumors also stays questionable. To our knowledge there is no description of an association between carcinoid tumors of the appendix and PJS to date. Life-expectancy in patients with PJS is reduced. Causes are the development of malignancies and complications from the polyps such as intussusception. Since there is no treatment possible main focus must be aimed at early recognition of malignancies and the prevention of complications. Copyright © 2014. Published by Elsevier Ltd.

  7. 90Y-Edotreotide for Metastatic Carcinoid Refractory to Octreotide

    PubMed Central

    Bushnell, David L.; O'Dorisio, Thomas M.; O'Dorisio, M. Sue; Menda, Yusuf; Hicks, Rodney J.; Van Cutsem, Eric; Baulieu, Jean-Louis; Borson-Chazot, Francoise; Anthony, Lowell; Benson, Al B.; Oberg, Kjell; Grossman, Ashley B.; Connolly, Mary; Bouterfa, Hakim; Li, Yong; Kacena, Katherine A.; LaFrance, Norman; Pauwels, Stanislas A.

    2010-01-01

    Purpose Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using 90Y-edotreotide to treat symptomatic patients with carcinoid tumors. Patients and Methods Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) 90Y-edotreotide each, once every 6 weeks. Results Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. Conclusion 90Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile. PMID:20194865

  8. A new role for GABA: inhibition of tumor cell migration.

    PubMed

    Ortega, Arturo

    2003-04-01

    GABA, the main inhibitory neurotransmitter in the vertebrate brain, participates outside the CNS in diverse functions such as platelet aggregation and the acrosomal reaction in spermatozoa. A recent study now demonstrates that GABA inhibits the migration of colon carcinoma cells, paving the way to the development of specific pharmacological agents that delay or inhibit invasion and metastasis of various cancer types.

  9. Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis

    PubMed Central

    Li, Qingli; Lambrechts, Mark J; Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Yin, Rutie; Xi, Mingrong; You, Zongbing

    2013-01-01

    Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose) polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy. PMID:23983455

  10. Inhibition Of Call-Cell Binding By Kipid Assemblies

    DOEpatents

    Nagy, Jon O. , Bargatze, Robert F.

    2003-12-16

    This invention relates generally to the field of therapeutic compounds designed to interfere between the binding of ligands and their receptors on cell surface. More specifically, it provides products and methods for inhibiting cell migration and activation using lipid assemblies with surface recognition elements that are specific for the receptors involved in cell migration and activation.

  11. Sickle cell microRNAs inhibit the malaria parasite.

    PubMed

    Duraisingh, Manoj T; Lodish, Harvey F

    2012-08-16

    Sickle cell hemoglobin conveys resistance to malaria. In this issue of Cell Host & Microbe, LaMonte et al. (2012) demonstrate a surprising mechanism for this innate immunity. A microRNA enriched in sickle red blood cells is translocated into the parasite, incorporated covalently into P. falciparum mRNAs and inhibits parasite growth.

  12. Bilateral Choroidal Metastases from Endobronchial Carcinoid Treated with Somatostatin Analogues

    PubMed Central

    De Bruyn, Deborah; Lamont, Jan; Vanderstraeten, Erik; Van Belle, Simon; Platteau, Elise; De Zaeytijd, Julie; Hoornaert, Kristien P.

    2016-01-01

    Objective: To describe a patient with bilateral multifocal choroidal metastases from an endobronchial carcinoid treated with a somatostatin analogue. Method: A 60-year-old woman presenting with photopsia in the left eye underwent an extensive ophthalmic examination, including fluorescein angiography, OCT and ultrasound. Results: Fundoscopy revealed a small retinal tear in the left eye, for which she received laser treatment. In addition, choroidal masses were detected in both eyes. Her medical history of a pneumectomy for a bronchial carcinoid six years earlier together with recent elevated chromogranin A blood levels prompted a diagnosis of choroidal metastases. Subsequently, a Gallium-68 DOTANOC positron emitting tomography/computer tomography scan revealed a spinal cord metastasis and mediastinal as well as mesenterial lymph node invasion. Systemic treatment with Sandostatin®, a somatostatin analogue was started. Up until two years after the initial presentation and treatment, these choroidal lesions remained stable without any signs of growth. Conclusion: Endobronchial carcinoid tumors have an indolent nature and long-term follow-up is recommended for early detection of metastases. Although treatment with somatostatin analogues rarely induces complete tumor regression, tumor stabilization and prevention of symptoms related to hormone secretion is achieved. This well-tolerated systemic treatment provides a worthy alternative treatment for choroidal metastasis compared to classic radiotherapy without any risk of radiation or laser-related visual loss. PMID:27843513

  13. Paraneoplastic neuromyelitis optica spectrum disorder associated with stomach carcinoid tumor.

    PubMed

    Al-Harbi, Talal; Al-Sarawi, Adnan; Binfalah, Mohamed; Dermime, Said

    2014-09-01

    Neuromyelitis optica (NMO), or Devic's syndrome, is an autoimmune central nervous system demyelinating disorder primarily affecting the spinal cord and the optic nerves. It is characterized by the presence of NMO antibodies, alongside clinical and radiological findings. NMO and NMO-spectrum disorders (NMO-SD) have been reported in autoimmune disorders, and are infrequently described as a paraneoplastic syndrome with cancers of lung, breast, and carcinoid tumors of the thyroid. We report a patient who presented with severe vomiting, blurring of vision, vertigo, diplopia, left hemiparesis and hemisensory loss and ataxia. She was found to have a longitudinally-extensive demyelinating lesion extending from the medulla to the upper cervical spinal cord on MRI. Her gastric endoscopy revealed carcinoid tumor of the stomach, and classic paraneoplastic antibodies in the serum were negative. She had extremely high serum gastrin level and high titer of NMO IgG autoantibody. The patient made an excellent recovery with tumor resection and immunotherapy, with both clinical and radiological improvement. On rare instances, NMO or NMO-SD may present as a paraneoplastic neurological syndrome associated with carcinoid tumor of the stomach. Copyright © 2014 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

  14. Inhibition of Pancreatic Cancer Cell Proliferation by LRH-1 Inhibitors

    DTIC Science & Technology

    2013-09-01

    AD_________________ Award Number: W81XWH-12-1-0396 TITLE: INHIBITION OF PANCREATIC CANCER CELL...DATES COVERED 15September2012–14September2013 4. TITLE AND SUBTITLE INHIBITION OF PANCREATIC CANCER CELL PROLIFERATION BY LRH-1 INHIBITORS 5a...of pancreatic cancer is devastating, with mortality rates nearing its incidence rates. To date, there are no effective targeted anti-pancreatic

  15. Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase.

    PubMed

    Wang, Chunhuai; Xiang, Ru; Zhang, Xiangzhong; Chen, Yunxian

    2015-09-01

    Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix‑coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti‑β1‑integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)‑2 and MMP‑9 expression. Furthermore, incubation with blocking anti‑β1‑integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia.

  16. Mechanism of inhibition of cell proliferation by Vinca alkaloids.

    PubMed

    Jordan, M A; Thrower, D; Wilson, L

    1991-04-15

    We have used a structure-activity approach to investigate whether the Vinca alkaloids inhibit cell proliferation primarily by means of their effects on mitotic spindle microtubules or by another mechanism or by a combination of mechanisms. Five Vinca alkaloids were used to investigate the relationship in HeLa cells between inhibition of cell proliferation and blockage of mitosis, alteration of spindle organization, and depolymerization of microtubules. Indirect immunofluorescence staining of microtubules and 4,6-diamidino-2-phenylindole staining of chromatin were used to characterize the effects of the drugs on the distributions of cells in stages of the cell cycle and on the organization of microtubules and chromosomes in metaphase spindles. The microtubule polymer was isolated from cells and quantified using a competitive enzyme-linked immunoadsorbent assay for tubulin. We observed a nearly perfect coincidence between the concentration of each Vinca derivative that inhibited cell proliferation and the concentration that caused 50% accumulation of cells at metaphase, despite the fact that the antiproliferative potencies of the drugs varied over a broad concentration range. Inhibition of cell proliferation and blockage of cells at metaphase at the lowest effective concentrations of all Vinca derivatives occurred with little or no microtubule depolymerization or spindle disorganization. With increasing drug concentrations, the organization of microtubules and chromosomes in arrested mitotic spindles deteriorated in a manner that was common to all five congeners. These results indicate that the antiproliferative activity of the Vinca alkaloids at their lowest effective concentrations in HeLa cells is due to inhibition of mitotic spindle function. The results suggest further that the Vinca alkaloids inhibit cell proliferation by altering the dynamics of tubulin addition and loss at the ends of mitotic spindle microtubules rather than by depolymerizing the microtubules

  17. Combined MET inhibition and topoisomerase I inhibition block cell growth of small cell lung cancer.

    PubMed

    Rolle, Cleo E; Kanteti, Rajani; Surati, Mosmi; Nandi, Suvobroto; Dhanasingh, Immanuel; Yala, Soheil; Tretiakova, Maria; Arif, Qudsia; Hembrough, Todd; Brand, Toni M; Wheeler, Deric L; Husain, Aliya N; Vokes, Everett E; Bharti, Ajit; Salgia, Ravi

    2014-03-01

    Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC. ©2013 AACR.

  18. Thymoquinone Inhibits Escherichia coli ATP Synthase and Cell Growth.

    PubMed

    Ahmad, Zulfiqar; Laughlin, Thomas F; Kady, Ismail O

    2015-01-01

    We examined the thymoquinone induced inhibition of purified F1 or membrane bound F1FO E. coli ATP synthase. Both purified F1 and membrane bound F1FO were completely inhibited by thymoquinone with no residual ATPase activity. The process of inhibition was fully reversible and identical in both membrane bound F1Fo and purified F1 preparations. Moreover, thymoquinone induced inhibition of ATP synthase expressing wild-type E. coli cell growth and non-inhibition of ATPase gene deleted null control cells demonstrates that ATP synthase is a molecular target for thymoquinone. This also links the beneficial dietary based antimicrobial and anticancer effects of thymoquinone to its inhibitory action on ATP synthase.

  19. Thymoquinone Inhibits Escherichia coli ATP Synthase and Cell Growth

    PubMed Central

    Ahmad, Zulfiqar; Laughlin, Thomas F.; Kady, Ismail O.

    2015-01-01

    We examined the thymoquinone induced inhibition of purified F1 or membrane bound F1FO E. coli ATP synthase. Both purified F1 and membrane bound F1FO were completely inhibited by thymoquinone with no residual ATPase activity. The process of inhibition was fully reversible and identical in both membrane bound F1Fo and purified F1 preparations. Moreover, thymoquinone induced inhibition of ATP synthase expressing wild-type E. coli cell growth and non-inhibition of ATPase gene deleted null control cells demonstrates that ATP synthase is a molecular target for thymoquinone. This also links the beneficial dietary based antimicrobial and anticancer effects of thymoquinone to its inhibitory action on ATP synthase. PMID:25996607

  20. Blue light inhibits proliferation of melanoma cells

    NASA Astrophysics Data System (ADS)

    Becker, Anja; Distler, Elisabeth; Klapczynski, Anna; Arpino, Fabiola; Kuch, Natalia; Simon-Keller, Katja; Sticht, Carsten; van Abeelen, Frank A.; Gretz, Norbert; Oversluizen, Gerrit

    2016-03-01

    Photobiomodulation with blue light is used for several treatment paradigms such as neonatal jaundice, psoriasis and back pain. However, little is known about possible side effects concerning melanoma cells in the skin. The aim of this study was to assess the safety of blue LED irradiation with respect to proliferation of melanoma cells. For that purpose we used the human malignant melanoma cell line SK-MEL28. Cell proliferation was decreased in blue light irradiated cells where the effect size depended on light irradiation dosage. Furthermore, with a repeated irradiation of the melanoma cells on two consecutive days the effect could be intensified. Fluorescence-activated cell sorting with Annexin V and Propidium iodide labeling did not show a higher number of dead cells after blue light irradiation compared to non-irradiated cells. Gene expression analysis revealed down-regulated genes in pathways connected to anti-inflammatory response, like B cell signaling and phagosome. Most prominent pathways with up-regulation of genes were cytochrome P450, steroid hormone biosynthesis. Furthermore, even though cells showed a decrease in proliferation, genes connected to the cell cycle were up-regulated after 24h. This result is concordant with XTT test 48h after irradiation, where irradiated cells showed the same proliferation as the no light negative control. In summary, proliferation of melanoma cells can be decreased using blue light irradiation. Nevertheless, the gene expression analysis has to be further evaluated and more studies, such as in-vivo experiments, are warranted to further assess the safety of blue light treatment.

  1. Carcinoid tumors: CT and I-131 meta-iodo-benzylguanidine scintigraphy

    SciTech Connect

    Adolph, J.M.; Kimmig, B.N.; Georgi, P.; zum Winkel, K.

    1987-07-01

    The diagnostic value of computed tomography (CT) and iodine-131 meta-iodo-benzylguanidine (MIBG) scintiscanning was studied in nine patients with histologically proved carcinoid tumors of intestinal (n = 4), bronchial (n = 3), or thymic (n = 2) origin. CT scans clearly depicted the tumors and metastases in relation to surrounding vital structures but did not provide findings specific for carcinoids. The appearance on CT of an abdominal soft-tissue mass with a radiating pattern of linear densities was found to be highly suggestive of intestinal carcinoid tumors. I-131 MIBG scintiscans disclosed intense tracer uptake in the tumors and metastases in five patients. MIBG studies correctly depicted nine of nine tumor manifestations in intestinal carcinoids and four of six tumor manifestations in bronchus carcinoids. No MIBG concentration was found in thymus carcinoids. Because of its selective uptake mechanism, I-131 MIBG scintigraphy can allow specific detection and localization of neuroendocrine tumor tissue in patients with suspected carcinoid tumors. MIBG scintigraphy has diagnostic potential as a screening procedure in carcinoid tumors, especially those of intestinal origin.

  2. Late recurrent pulmonary typical carcinoid tumor: case report and review of the literature.

    PubMed

    Ciment, Ari; Gil, Joan; Teirstein, Alvin

    2006-10-01

    Carcinoid tumors are uncommon pulmonary neoplasms. They are classified histologically as either atypical or typical. Atypical carcinoids are aggressive malignancies that require radical surgical resection and have a guarded prognosis with a propensity to metastasize and recur. Typical carcinoids are low-grade malignancies with relatively less metastatic or recurring potential and are usually treated with simple excision. Recurrence of a typical pulmonary carcinoid tumor more than a decade after initial resection is very rare. A patient with recurrence of a typical carcinoid tumor 11 years after resection of the primary lesion with one involved lymph node is reported here. Late recurrences are rare in both atypical and typical varieties, but are much more common in atypical carcinoids. The patient reported here represents the fifth case of recurrence of a typical carcinoid tumor more than ten years after resection. This suggests that, after resection of a typical carcinoid neoplasm, patients should be monitored carefully, especially if lymph node metastases are present at the time of surgery.

  3. Cell proliferation inhibition in reduced gravity

    NASA Technical Reports Server (NTRS)

    Moos, P. J.; Fattaey, H. K.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Extended durations of spaceflight have been shown to be deleterious on an organismic level; however, mechanisms underlying cellular sensitivity to the gravitational environment remain to be elucidated. The majority of the gravitational studies to date indicates that cell regulatory pathways may be influenced by their gravitational environment. Still, few cell biology experiments have been performed in space flight and even fewer experiments have been repeated on subsequent flights. With flight opportunities on STS-50, 54, and 57, Sf9 cells were flown in the BioServe Fluids Processing Apparatus and cell proliferation was measured with and without exposure to a cell regulatory sialoglycopeptide (CeReS) inhibitor. Results from these flights indicate that the Sf9 cells grew comparable to ground controls, that the CeReS inhibitor bound to its specific receptor, and that its signal transduction cascade was not gravity sensitive.

  4. Cell proliferation inhibition in reduced gravity

    NASA Technical Reports Server (NTRS)

    Moos, P. J.; Fattaey, H. K.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Extended durations of spaceflight have been shown to be deleterious on an organismic level; however, mechanisms underlying cellular sensitivity to the gravitational environment remain to be elucidated. The majority of the gravitational studies to date indicates that cell regulatory pathways may be influenced by their gravitational environment. Still, few cell biology experiments have been performed in space flight and even fewer experiments have been repeated on subsequent flights. With flight opportunities on STS-50, 54, and 57, Sf9 cells were flown in the BioServe Fluids Processing Apparatus and cell proliferation was measured with and without exposure to a cell regulatory sialoglycopeptide (CeReS) inhibitor. Results from these flights indicate that the Sf9 cells grew comparable to ground controls, that the CeReS inhibitor bound to its specific receptor, and that its signal transduction cascade was not gravity sensitive.

  5. Myostatin inhibits proliferation of human urethral rhabdosphincter satellite cells.

    PubMed

    Akita, Yasuyuki; Sumino, Yasuhiro; Mori, Ken-ichi; Nomura, Takeo; Sato, Fuminori; Mimata, Hiromitsu

    2013-05-01

    Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of myogenesis in skeletal muscle. We examined the effect of myostatin and myostatin inhibition by an antagonistic agent, follistatin, on growth of human urethral rhabdosphincter satellite cells (muscle stem cells) to develop a new strategy for treatment of stress urinary incontinence. Rhabdosphincter satellite cells were cultured and selected by magnetic affinity cell sorting using an anti-neural cell adhesion molecule antibody. The cells were transfected with simian virus-40 antigen to extend their lifespan. A cell proliferation assay, a cell cycle analysis and an investigation of signal transduction were carried out. The autocrine action of endogenous myostatin by western blotting, real-time reverse transcription polymerase chain reaction and immunoneutralization using an anti-myostatin antibody was also evaluated. Selectively cultured cells expressed markers of striated muscles and successfully differentiated into myotubes. Myostatin inhibited proliferation of these cells through Smad2 phosphorylation and cell cycle arrest. Inhibitory effects of myostatin were reversed by addition of follistatin. However, rhabdosphincter satellite cells did not appear to use autocrine secretion of myostatin to regulate their proliferation. Inhibition of myostatin function might be a useful pathway in the development of novel strategies for stimulating rhabdosphincter cells regeneration to treat stress urinary incontinence. © 2012 The Japanese Urological Association.

  6. Boric acid inhibits human prostate cancer cell proliferation.

    PubMed

    Barranco, Wade T; Eckhert, Curtis D

    2004-12-08

    The role of boron in biology includes coordinated regulation of gene expression in mixed bacterial populations and the growth and proliferation of higher plants and lower animals. Here we report that boric acid, the dominant form of boron in plasma, inhibits the proliferation of prostate cancer cell lines, DU-145 and LNCaP, in a dose-dependent manner. Non-tumorigenic prostate cell lines, PWR-1E and RWPE-1, and the cancer line PC-3 were also inhibited, but required concentrations higher than observed human blood levels. Studies using DU-145 cells showed that boric acid induced a cell death-independent proliferative inhibition, with little effect on cell cycle stage distribution and mitochondrial function.

  7. Inhibition of cyclooxygenase (COX)-2 affects endothelial progenitor cell proliferation

    SciTech Connect

    Colleselli, Daniela; Bijuklic, Klaudija; Mosheimer, Birgit A.; Kaehler, Christian M. . E-mail: C.M.Kaehler@uibk.ac.at

    2006-09-10

    Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis. Further analyses revealed an implication of Akt phosphorylation and caspase-3 activation. Both COX-1 and COX-2 expression can be found in bone-marrow-derived endothelial progenitor cells in vitro. COX-2 inhibition leads to a significant reduction in proliferation of endothelial progenitor cells by an increase in apoptosis and cell cycle arrest. COX-2 inhibition leads further to an increased cleavage of caspase-3 protein and inversely to inhibition of Akt activation. Highly proliferating endothelial progenitor cells can be targeted by selective COX-2 inhibition in vitro. These results indicate that upcoming therapy strategies in cancer patients targeting COX-2 may be effective in inhibiting tumour vasculogenesis as well as angiogenic processes.

  8. Lithium inhibits tumor lymphangiogenesis and metastasis through the inhibition of TGFBIp expression in cancer cells.

    PubMed

    Maeng, Yong-Sun; Lee, Rina; Lee, Boram; Choi, Seung-Il; Kim, Eung Kweon

    2016-02-09

    Metastasis is the main cause of mortality in cancer patients. Although there are many anti-cancer drugs targeting tumor growth, anti-metastatic agents are rarely developed. Angiogenesis and lymphangiogenesis are crucial for cancer progression; in particular, lymphangiogenesis is pivotal for metastasis in cancer. Here we report that lithium inhibits colon cancer metastasis by blocking lymphangiogenesis. Lithium reduces the expression of transforming growth factor-β-induced protein (TGFBIp) in colon cancer cells by inhibiting Smad3 phosphorylation via GSK3β inactivation. Moreover, lithium inhibits lymphatic endothelial cell migration, which is increased upon TGFBIp expression in tumor cells. Lithium had no significant effect on SW620 tumor growth in vitro and in vivo; however, it inhibited lymphangiogenesis in tumors. In tumor xenografts model, lithium was found to prevent metastasis to the lungs, liver, and lymph nodes by inhibiting TGFBIp-induced tumor lymphangiogenesis. Collectively, our findings demonstrate a novel role of lithium in the inhibition of colon cancer metastasis by blocking TGFBIp expression, and thereby TGFBIp-induced lymphangiogenesis, in primary tumors.

  9. Lithium inhibits tumor lymphangiogenesis and metastasis through the inhibition of TGFBIp expression in cancer cells

    PubMed Central

    Maeng, Yong-Sun; Lee, Rina; Lee, Boram; Choi, Seung-il; Kim, Eung Kweon

    2016-01-01

    Metastasis is the main cause of mortality in cancer patients. Although there are many anti-cancer drugs targeting tumor growth, anti-metastatic agents are rarely developed. Angiogenesis and lymphangiogenesis are crucial for cancer progression; in particular, lymphangiogenesis is pivotal for metastasis in cancer. Here we report that lithium inhibits colon cancer metastasis by blocking lymphangiogenesis. Lithium reduces the expression of transforming growth factor-β-induced protein (TGFBIp) in colon cancer cells by inhibiting Smad3 phosphorylation via GSK3β inactivation. Moreover, lithium inhibits lymphatic endothelial cell migration, which is increased upon TGFBIp expression in tumor cells. Lithium had no significant effect on SW620 tumor growth in vitro and in vivo; however, it inhibited lymphangiogenesis in tumors. In tumor xenografts model, lithium was found to prevent metastasis to the lungs, liver, and lymph nodes by inhibiting TGFBIp-induced tumor lymphangiogenesis. Collectively, our findings demonstrate a novel role of lithium in the inhibition of colon cancer metastasis by blocking TGFBIp expression, and thereby TGFBIp-induced lymphangiogenesis, in primary tumors. PMID:26857144

  10. LncRNA SNHG12 promotes cell growth and inhibits cell apoptosis in colorectal cancer cells

    PubMed Central

    Wang, J.Z.; Xu, C.L.; Wu, H.; Shen, S.J.

    2017-01-01

    Several long non-coding RNA (lncRNA) might be correlated with the prognosis of colorectal cancer (CRC) and serve as a diagnostic and prognostic biomarker. However, the exact expression pattern of small nucleolar RNA host gene 12 (SNHG12) in colorectal cancer and its clinical significance remains unclear. The level of SNHG12 was detected by qRT-PCR in CRC tissues and CRC cells. MTT assay and colony formation assay were performed to examine the cell proliferation of CRC cells transfected with pcDNA-SNHG12 or si-SNHG12. Flow cytometry technology was used to detect cell cycle and cell apoptosis of CRC cells transfected with pcDNA-SNHG12 or si-SNHG12. The protein level of cell cycle progression-related molecules, including cyclin-dependent kinases (CDK4, CDK6), cyclin D1 (CCND1) and cell apoptosis-related molecule caspase 3 was detected by western blot. The effect of SNHG12 knockdown was examined in vivo. Increased levels of SNHG12 were observed in CRC tissues and in CRC cells. SNHG12 promoted the cell proliferation of CRC cells. In addition, SNHG12 overexpression boosted the cell cycle progression of SW480 cells transfected with pcDNA-SNHG12 and SNHG12 knockdown inhibited the cell cycle progression of HT29 cells transfected with si-SNHG12. SNHG12 also inhibited the cell apoptosis of CRC cells. We also found that SNHG12 increased the expression of cell cycle-related proteins and suppressed the expression of caspase 3. Our results suggest that SNHG12 promoted cell growth and inhibited cell apoptosis in CRC cells, indicating that SNHG12 might be a useful biomarker for colorectal cancer. PMID:28225893

  11. Intestinal ischaemia associated with carcinoid tumor: a case report with review of the pathogenesis.

    PubMed

    Yener, O

    2013-01-01

    Carcinoid tumors are rare, slow-growing neuroendocrine neoplasms that are often indolent and may not become clinically apparent until there is a metastatic spread or evidence of carcinoid syndrome. A 44-year-old man presented to our clinic department with a history of previous left colon cancer operation, chronic crampy left lower quadrant pain, mass and severe anemia. A MR scan was obtained which demonstrated a calcified mesenteric mass 12×8×10 cm diameter with surrounding left colon mesenteric infiltration. The liver was normal. A case of ischaemic ileal necrosis is reported. It was associated with elastic vascular sclerosis produced by mesenteric metastases of an ileal carcinoid tumor. It is postulated that intestinal ischaemia may be of more importance in the production of abdominal pain by carcinoid tumors than has been generally accepted, and that it is the result of functional and structural changes in and around the mesenteric blood vessels, caused by substances secreted by the carcinoid tumor.

  12. A case of carcinoid tumor of the terminal ileum and simultaneous ovarian dermoid cyst.

    PubMed

    Hamada, Hosam

    2011-04-01

    Carcinoid tumors are slow-growing malignant neoplasms associated with an indolent clinical course. About 60% of such tumors are located within the gastrointestinal tract. Here, we describe the first case, to our knowledge, of a carcinoid tumor of the terminal ileum and a simultaneous ovarian dermoid cyst. A 57-year-old woman was presented with abdominal pain, vomiting, and clinical signs of mechanical bowel obstruction. Radiograph and computed tomography scan of the abdomen showed hydroaeric levels. Laparotomy revealed a mass in the terminal ileum and a right ovarian cystic mass. Right hemicolectomy and right oopherectomy were performed. The histopathological workup showed a carcinoid tumor of the terminal ileum and ovarian dermoid cyst. Small intestinal carcinoid tumor, an uncommon disease, has been reported earlier to coincide with various neoplasms. No association between small intestinal carcinoid tumor and ovarian dermoid cyst has been reported earlier in the English literature.

  13. Renal carcinoid tumor with liver metastasis followed up postoperatively for 9 years.

    PubMed

    Ouyang, BinShen; Ma, XiaoMei; Yan, HongZhu; He, Jin; Xia, ChunYan; Yu, HongYu

    2015-10-06

    We describe a case of renal carcinoid tumor with liver metastasis followed up postoperatively for 9 years. A 33-year-old man presented with left flank dull ache. On the abdominal computed tomography, a solid renal mass in the upper portion of the left kidney was detected. The patient had no other abnormal findings, such as suspected distant metastasis or lymph node metastasis. Radical nephrectomy was performed on 14/9/2005. Histological examination and immunohistochemical staining confirm primary renal carcinoid tumor. 9 years after radical nephrectomy, computed tomography of the abdomen demonstrated a 2 cm × 1.8 cm cyst mass in the right liver. Similar pathologic characteristics were found between the renal carcinoid tumor and liver tumor. We present a primary renal carcinoid tumor with liver metastasis 9 years after radical nephrectomy. With literature review, renal carcinoid tumors exhibit heterogenous behavior.

  14. Primary Carcinoid Tumor of the Ileal Efferent Limb of an Ileovesicostomy: A Case Report

    PubMed Central

    Mellis, Adamantios M.; Parker, Daniel C.; Buethe, David D.; Slobodov, Gennady

    2011-01-01

    We report on the evaluation and management of a 47-year-old white male found to have primary carcinoid tumor of the ileal segment of his diverting ileovesicostomy thirty-five months after initial creation. Subsequent to presentation with intermittent gross hematuria, CT urogram highlights an 8 mm enhancing lesion near the enterovesical junction of urinary diversion. Office cystoscopy confirms presence of a lesion that was later endoscopically resected and found to be a well-differentiated carcinoid tumor. Evaluation with serum markers, direct visualization utilizing endoscopy, and imaging was without finding of alternate primary or metastatic lesions. The patient ultimately had the proximal ileal portion of his ileovesicostomy excised and the distal portion converted into an ileal conduit. After briefly discussing the carcinoid tumor and the carcinoid syndrome it may cause, we review the literature on the incidence of carcinoid tumors in a population requiring the use of intestine in the urinary tract. PMID:22606607

  15. Inhibition of cell proliferation by the Mad1 transcriptional repressor.

    PubMed Central

    Roussel, M F; Ashmun, R A; Sherr, C J; Eisenman, R N; Ayer, D E

    1996-01-01

    Mad1 is a basic helix-loop-helix-leucine zipper protein that is induced upon differentiation of a number of distinct cell types. Mad1 dimerizes with Max and recognizes the same DNA sequences as do Myc:Max dimers. However, Mad1 and Myc appear to have opposing functions. Myc:Max heterodimers activate transcription while Mad:Max heterodimers repress transcription from the same promoter. In addition Mad1 has been shown to block the oncogenic activity of Myc. Here we show that ectopic expression of Mad1 inhibits the proliferative response of 3T3 cells to signaling through the colony-stimulating factor-1 (CSF-1) receptor. The ability of over-expressed Myc and cyclin D1 to complement the mutant CSF-1 receptor Y809F (containing a Y-to-F mutation at position 809) is also inhibited by Mad1. Cell cycle analysis of proliferating 3T3 cells transfected with Mad1 demonstrates a significant decrease in the fraction of cells in the S and G2/M phases and a concomitant increase in the fraction of G1 phase cells, indicating that Mad1 negatively influences cell cycle progression from the G1 to the S phase. Mutations in Mad1 which inhibit its activity as a transcription repressor also result in loss of Mad1 cell cycle inhibitory activity. Thus, the ability of Mad1 to inhibit cell cycle progression is tightly coupled to its function as a transcriptional repressor. PMID:8649388

  16. Protein kinase C activators inhibit capillary endothelial cell growth

    SciTech Connect

    Doctrow, S.R.

    1986-05-01

    Phorbol 12,13-dibutyrate (PDBu) binds specifically to bovine capillary endothelial (BCE) cells (K/sub d/ = 8nM) and inhibits the proliferation (K/sub 50/ = 6 +/- 4 nM). Under similar conditions, PDBu does not inhibit the growth of bovine aortic endothelial or smooth muscle cells. PDBu markedly attenuates the response of BCE cells to purified human hepatoma-derived growth factor which, in the absence of PDBu, stimulates BCE cell growth by about 3-fold. Several observations suggest that the inhibition of BCE cell growth by PDBu is mediated by protein kinase C: (1) different phorbol compounds inhibit BCE cell growth according to the relative potencies as protein kinase C activators (12-tetradecanoylphorbol 13-acetate > PDBu >> phorbol 12,13-diacetate >>>..beta..-phorbol; ..cap alpha..-phorbol 12,13-didecanoate). (2) Specific binding of PDBu to BCE cells is displaced by sn-1,2-dioctanoylglycerol (diC/sub 8/), a protein kinase C activator and an analog of the putative second messenger activating this kinase in vivo. The weak protein kinase C activator, sn-1,2-dibutyrylglycerol, does not affect PDBu binding. (3) A cytosolic extract from BCE cells contains a Ca/sup 2 +//phosphatidylserine-dependent kinase that is activated by diC/sub 8/ and PDBu, but not by ..beta..-phorbol. These results support a role for protein kinase C in suppressing capillary endothelial cell growth and may therefore have implications in the intracellular regulation of angiogenesis.

  17. [Ectopic Adrenocorticotropic Hormone-producing Pulmonary Carcinoid Tumor Presenting as Cushing Syndrome].

    PubMed

    Taniguchi, Daisuke; Sawada, Takahiro; Ebisui, Osamu; Kito, Katsumi; Nagayasu, Takeshi

    2015-02-01

    The patient was a 57-year-old female who felt muscle weakness and visited a physician. Hypokalemia was pointed out, and she was referred to our hospital for detailed examination and treatment. Hormone-related tests and imaging were performed, and the patient was diagnosed as Cushing syndrome. Moreover, an ectopic adrenocorticotropic hormone (ACTH)-producing tumor was suspected. The whole body was examined to find a tumor, but no apparent lesion was found, except for a small nodule of 5-mm in size was present in the right middle pulmonary lobe on chest computed tomography (CT). It was decided to perform surgical resection for both diagnosis and treatment. Pathological diagnosis was a typical carcinoid. On immunostaining, ACTH-positive cells were detected, and the lesion was definitely diagnosed as an ectopic ACTH-producing tumor. Since the ACTH level after surgery returned to normal, the lesion was concluded to be completely excised.

  18. Mullerian inhibiting substance inhibits invasion and migration of epithelial cancer cell lines.

    PubMed

    Chang, Henry L; Pieretti-Vanmarcke, Rafael; Nicolaou, Fotini; Li, Xianlin; Wei, Xiaolong; MacLaughlin, David T; Donahoe, Patricia K

    2011-01-01

    Given the fact that Mullerian Inhibiting Substance (MIS) causes complex remodeling of the urogenital ridge and regression of the Mullerian ducts during male embryonic development, we examined whether MIS could affect similar cell properties such as migration and invasion that could contribute ultimately to micro-metastasis of cancers arising from Mullerian tissues. MIS receptor expressing cell lines found to be invasive and migratory in vivo are examined in an in vivo assay that is cost-effective. We designed in vitro and in vivo experiments to determine if MIS inhibited the movement of cancer lines IGROV-1, HEp3, MDA-MB-231, and HT1080 in cell culture invasion/migration chamber assays and in chick embryo metastasis assays. MIS, at concentrations below those that inhibit cell proliferation, blocked in vitro invasion and in vivo migration of epithelial cancer cells that express the MIS receptor. While our laboratory has previously established MIS as an inhibitor of cancer cell proliferation using in vitro assays and in vivo xenografts, we now show that MIS can also inhibit in vivo tumor migration. Copyright © 2010 Elsevier Inc. All rights reserved.

  19. Foxp3+ T cells inhibit antitumor immune memory modulated by mTOR inhibition.

    PubMed

    Wang, Yanping; Sparwasser, Tim; Figlin, Robert; Kim, Hyung L

    2014-04-15

    Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3(+) T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3(+) T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients. ©2014 AACR.

  20. Pediatric neuroendocrine carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center.

    PubMed

    Degnan, Andrew J; Tocchio, Shannon; Kurtom, Waleed; Tadros, Sameh S

    2017-09-01

    While neuroendocrine (carcinoid) tumors are increasingly recognized in the adult population, they are often not suspected in children. Retrospective review of all well-differentiated neuroendocrine (carcinoid) tumors was performed based on pathology reports from a quaternary pediatric medical center between January 2003 and June 2016. Clinical presentations, treatment approaches, imaging findings, and outcomes were reviewed and analyzed. A total of 45 cases of pathology-proven carcinoid tumor were reported with an average age of 14.1 years (range: 7-21 years, SD: 2.8 years). Of these cases, 80% (36) were appendiceal, 11% (5) bronchial, 2% (1) colonic, 2% (1) gastric, 2% (1) enteric, and 2% (1) testicular. Metastases were observed in one (3%) appendiceal, one (100%) enteric, and two (40%) bronchial cases. No recurrence was demonstrated in any appendiceal carcinoid cases. Recurrence was seen in one of three extra-appendiceal gastrointestinal tumors. Tumor site and size significantly correlated with metastases and recurrence. Contrary to recent epidemiological investigations in adults, appendiceal carcinoid tumors remain the most common site for pediatric carcinoid tumors. Appendiceal carcinoid tumors exhibited benign clinical courses without recurrence during short-term follow-up. Extra-appendiceal gastrointestinal carcinoid tumors exhibited much more aggressive behavior with greater metastases and recurrence. Bronchial carcinoid tumors demonstrated good clinical response to resection even in cases with mediastinal lymph node involvement. While increased use of urine 5-HIAA levels and somatostatin receptor-specific imaging might improve detection and guide management of extra-appendiceal carcinoid tumors, longer-term follow-up is needed. © 2017 Wiley Periodicals, Inc.

  1. Nesfatin-1 inhibits ovarian epithelial carcinoma cell proliferation in vitro

    SciTech Connect

    Xu, Yang; Pang, Xiaoyan; Dong, Mei; Wen, Fang Zhang, Yi

    2013-11-01

    Highlights: •Nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest. •Nesfatin-1 enhances HO-8910 cell apoptosis. •Nesfatin-1 inhibits HO-8910 cell proliferation via mTOR and RhoA/ROCK signaling pathway. •The first report of nesfatin-1-mediated proliferation in ovarian epithelial carcinoma. -- Abstract: Nesfatin-1, an 82-amino-acid peptide derived from a 396-amino-acid precursor protein nucleobindin 2 (NUCB2), was originally identified in hypothalamic nuclei involved in the regulation of food intake. It was recently reported that nesfatin-1 is a novel depot specific adipokine preferentially produced by subcutaneous tissue, with obesity- and food deprivation-regulated expression. Although a relation between ovarian cancer mortality and obesity has been previously established, a role of nesfatin-1 in ovarian epithelial carcinoma remains unknown. The aim of the present study is to examine the effect of nesfatin-1 on ovary carcinoma cells proliferation. We found that nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest, this inhibition could be abolished by nesfatin-1 neutralizing antibody. Nesfatin-1 enhances HO-8910 cell apoptosis, activation of mammalian target of rapamycin (mTOR) and RhoA/ROCK signaling pathway block the effects of nesfatin-1-induced apoptosis, therefore reverses the inhibition of HO-8910 cell proliferation by nesfatin-1. In conclusion, the present study demonstrated that nesfatin-1 can inhibit the proliferation in human ovarian epithelial carcinoma cell line HO-8910 cells through inducing apoptosis via mTOR and RhoA/ROCK signaling pathway. This study provides a novel regulatory signaling pathway of nesfatin-1-regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy, especially in obese patients.

  2. HEPES inhibits the conversion of prion protein in cell culture.

    PubMed

    Delmouly, Karine; Belondrade, Maxime; Casanova, Danielle; Milhavet, Ollivier; Lehmann, Sylvain

    2011-05-01

    HEPES is a well-known buffering reagent used in cell-culture medium. Interestingly, this compound is also responsible for significant modifications of biological parameters such as uptake of organic molecules, alteration of oxidative stress mechanisms or inhibition of ion channels. While using cell-culture medium supplemented with HEPES on prion-infected cells, it was noticed that there was a significant concentration-dependent inhibition of accumulation of the abnormal isoform of the prion protein (PrP(Sc)). This effect was present only in live cells and was thought to be related to modification of the PrP environment or biology. These results could modify the interpretation of cell-culture assays of prion therapeutic agents, as well as of previous cell biology results obtained in the field using HEPES buffers. This inhibitory effect of HEPES could also be exploited to prevent contamination or propagation of prions in cell culture.

  3. Cutting edge: inhibition of T cell activation by TIM-2.

    PubMed

    Knickelbein, Jared E; de Souza, Anjali J; Tosti, Richard; Narayan, Preeti; Kane, Lawrence P

    2006-10-15

    T cell Ig and mucin domain protein 2 (TIM-2) has been shown to regulate T cell activation in vitro and T cell-mediated disease in vivo. However, it is still not clear whether TIM-2 acts mainly to augment T cell function or to inhibit it. We have directly examined the function of TIM-2 in murine and human T cell lines. Our results indicate that expression of TIM-2 significantly impairs the induction of NFAT and AP-1 transcriptional reporters by not only TCR ligation but also by the pharmacological stimuli PMA and ionomycin. This does not appear to be due to a general effect on cell viability, and the block in NFAT activation can be bypassed by expression of activated alleles of Ras or calcineurin, or MEK kinase, in the case of AP-1. Thus, our data are consistent with a model whereby TIM-2 inhibits T cell activation.

  4. Inhibiting ice recrystallization and optimization of cell viability after cryopreservation.

    PubMed

    Chaytor, Jennifer L; Tokarew, Jacqueline M; Wu, Luke K; Leclère, Mathieu; Tam, Roger Y; Capicciotti, Chantelle J; Guolla, Louise; von Moos, Elisabeth; Findlay, C Scott; Allan, David S; Ben, Robert N

    2012-01-01

    The ice recrystallization inhibition activity of various mono- and disaccharides has been correlated with their ability to cryopreserve human cell lines at various concentrations. Cell viabilities after cryopreservation were compared with control experiments where cells were cryopreserved with dimethylsulfoxide (DMSO). The most potent inhibitors of ice recrystallization were 220 mM solutions of disaccharides; however, the best cell viability was obtained when a 200 mM d-galactose solution was utilized. This solution was minimally cytotoxic at physiological temperature and effectively preserved cells during freeze-thaw. In fact, this carbohydrate was just as effective as a 5% DMSO solution. Further studies indicated that the cryoprotective benefit of d-galactose was a result of its internalization and its ability to mitigate osmotic stress, prevent intracellular ice formation and/or inhibit ice recrystallization. This study supports the hypothesis that the ability of a cryoprotectant to inhibit ice recrystallization is an important property to enhance cell viability post-freeze-thaw. This cryoprotective benefit is observed in three different human cell lines. Furthermore, we demonstrated that the ability of a potential cryoprotectant to inhibit ice recrystallation may be used as a predictor of its ability to preserve cells at subzero temperatures.

  5. [Severe tricuspid insufficiency and primary carcinoid tumor of the ovary. Long term success after valve replacement. Apropos of a case].

    PubMed

    Herreman, F; Vernant, P; Cachera, J P; Monier, P

    1978-01-01

    The case is reported of carcinoid heart disease in a lady of 70 with intractable congestive cardiac failure 5 years after the removal of a primary carcinoid tumour of the ovary. The special features of primary carcinoid tumours of the ovary are recalled, with emphasis on their rarity and of the absence of liver metastases. The various features of carcinoid syndrome are recalled in the light of current knowledge of the pathogenesis. A review of the literature on cardiac involvement in primary carcinoid tumours of the ovary, amounting to 10 cases, is included. The possibility of surgical cure of the heart lesions in carcinoid tumour by a prosthetic tricuspid valve are discussed, in the light of the 6 reported cases and the present one. Our report is the first one of replacement of the valve after removal of a primary ovarien carcinoid tumour, and the excellent result has been maintained after three years.

  6. Metformin inhibits the proliferation of benign prostatic epithelial cells

    PubMed Central

    Ge, Rongbin; Li, Jijun; Johnson, Cameron W.; Rassoulian, Cyrus; Olumi, Aria F.

    2017-01-01

    Objective Benign prostatic hyperplasia (BPH) is the most common proliferative abnormality of the prostate affecting elderly men throughout the world. Epidemiologic studies have shown that diabetes significantly increases the risk of developing BPH, although whether anti-diabetic medications preventing the development of BPH remains to be defined. We have previously found that stromally expressed insulin-like growth factor 1 (IGF-1) promotes benign prostatic epithelial cell proliferation through paracrine mechanisms. Here, we seek to understand if metformin, a first line medication for the treatment of type 2 diabetes, inhibits the proliferation of benign prostatic epithelial cells through reducing the expression of IGF-1 receptor (IGF-1R) and regulating cell cycle. Methods BPE cell lines BPH-1 and P69, murine fibroblasts3T3 and primary human prostatic fibroblasts were cultured and tested in this study. Cell proliferation and the cell cycle were analyzed by MTS assay and flow cytometry, respectively. The expression of IGF-1R was determined by western-blot and immunocytochemistry. The level of IGF-1 secretion in culture medium was measured by ELISA. Results Metformin (0.5-10mM, 6-48h) significantly inhibited the proliferation of BPH-1 and P69 cells in a dose-dependent and time-dependent manner. Treatment with metformin for 24 hours lowered the G2/M cell population by 43.24% in P69 cells and 24.22% in BPH-1 cells. On the other hand, IGF-1 (100ng/mL, 24h) stimulated the cell proliferation (increased by 28.81% in P69 cells and 20.95% in BPH-1 cells) and significantly enhanced the expression of IGF-1R in benign prostatic epithelial cells. Metformin (5mM) abrogated the proliferation of benign prostatic epithelial cells induced by IGF-1. In 3T3 cells, the secretion of IGF-1 was significantly inhibited by metformin from 574.31pg/ml to 197.61pg/ml. The conditioned media of 3T3 cells and human prostatic fibroblasts promoted the proliferation of epithelial cells and the

  7. Lateral inhibition of Notch signaling in neoplastic cells

    PubMed Central

    Heth, Jason A.; Muraszko, Karin M.; Fan, Xing; Bar, Eli E.; Eberhart, Charles G.

    2015-01-01

    During normal development, heterogeneous expression of Notch ligands can result in pathway suppression in the signal-sending cell, a process known as lateral inhibition. It is unclear if an analogous phenomenon occurs in malignant cells. We observed significant induction of Notch ligands in glioblastoma neurospheres and pancreatic carcinoma cells cultured in low oxygen, suggesting that this phenomenon could occur around hypoxic regions. To model lateral inhibition in these tumors, the ligand Jagged1 was overexpressed in glioblastoma and pancreatic carcinoma cells, resulting in overall induction of pathway targets. However, when ligand high and ligand low cells from a single line were co-cultured and then separated, we noted suppression of Notch pathway targets in the former and induction in the latter, suggesting that neoplastic lateral inhibition can occur. We also found that repression of Notch pathway targets in signal-sending cells may occur through the activity of a Notch ligand intracellular domain, which translocates into the nucleus. Understanding how this neoplastic lateral inhibition process functions in cancer cells may be important in targeting ligand driven Notch signaling in solid tumors. PMID:25557173

  8. Thrombomodulin inhibits the activation of eosinophils and mast cells.

    PubMed

    Roeen, Ziaurahman; Toda, Masaaki; D'Alessandro-Gabazza, Corina N; Onishi, Masahiro; Kobayashi, Tetsu; Yasuma, Taro; Urawa, Masahito; Taguchi, Osamu; Gabazza, Esteban C

    2015-01-01

    Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low-dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells.

  9. Brain Cancer Stem Cells Display Preferential Sensitivity to Akt Inhibition

    PubMed Central

    Eyler, Christine E.; Foo, Wen-Chi; LaFiura, Katherine M.; McLendon, Roger E.; Hjelmeland, Anita B.; Rich, Jeremy N.

    2009-01-01

    Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer improved efficacy and reduced toxicity compared to conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biologies may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched non-stem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anti-cancer stem cell therapies. PMID:18802038

  10. Targeting Btk with ibrutinib inhibit gastric carcinoma cells growth

    PubMed Central

    Wang, Jin Dao; Chen, Xiao Ying; Ji, Ke Wei; Tao, Feng

    2016-01-01

    Bruton’s tyrosine kinase (Btk) is a member of the Tec-family non-receptor tyrosine kinases family. It has previously been reported to be expressed in B cells and has an important role in B-cell malignancies. While the roles of Btk in the pathogenesis of certain B-cell malignancies are well established, the functions of Btk in gastric carcinoma have never been investigated. Herein, we found that Btk is over-expressed in gastric carcinoma tissues and gastric cancer cells. Knockdown of Btk expression selectively inhibits the growth of gastric cancer cells, but not that of the normal gastric mucosa epithelial cell, which express very little Btk. Inhibition of Btk by its inhibitor ibrutinib has an additive inhibitory effect on gastric cancer cell growth. Treatment of gastric cancer cells, but not immortalized breast epithelial cells with ibrutinib results in effective cell killing, accompanied by the attenuation of Btk signals. Ibrutinib also induces apoptosis in gastric carcinoma cells as well as is a chemo-sensitizer for docetaxel (DTX), a standard of care for gastric carcinoma patients. Finally, ibrutinib markedly reduces tumor growth and increases tumor cell apoptosis in the tumors formed in mice inoculated with the gastric carcinoma cells. Given these promising preclinical results for ibrutinib in gastric carcinoma, a strategy combining Btk inhibitor warrants attention in gastric cancer. PMID:27508020

  11. Inhibition of cell adhesion by phosphorylated Ezrin/Radixin/Moesin.

    PubMed

    Tachibana, Kouichi; Haghparast, Seyed Mohammad Ali; Miyake, Jun

    2015-01-01

    Altered phosphorylation status of the C-terminal Thr residues of Ezrin/Radixin/Moesin (ERM) is often linked to cell shape change. To determine the role of phophorylated ERM, we modified phosphorylation status of ERM and investigated changes in cell adhesion and morphology. Treatment with Calyculin-A (Cal-A), a protein phosphatase inhibitor, dramatically augmented phosphorylated ERM (phospho-ERM). Cal-A-treatment or expression of phospho-mimetic Moesin mutant (Moesin-TD) induced cell rounding in adherent cells. Moreover, reattachment of detached cells to substrate was inhibited by either treatment. Phospho-ERM, Moesin-TD and actin cytoskeleton were observed at the plasma membrane of such round cells. Augmented cell surface rigidity was also observed in both cases. Meanwhile, non-adherent KG-1 cells were rather rich in phospho-ERM. Treatment with Staurosporine, a protein kinase inhibitor that dephosphorylates phospho-ERM, up-regulated the integrin-dependent adhesion of KG-1 cells to substrate. These findings strongly suggest the followings: (1) Phospho-ERM inhibit cell adhesion, and therefore, dephosphorylation of ERM proteins is essential for cell adhesion. (2) Phospho-ERM induce formation and/or maintenance of spherical cell shape. (3) ERM are constitutively both phosphorylated and dephosphorylated in cultured adherent and non-adherent cells.

  12. Anandamide inhibits adhesion and migration of breast cancer cells

    SciTech Connect

    Grimaldi, Claudia; Pisanti, Simona; Laezza, Chiara; Malfitano, Anna Maria; Santoro, Antonietta; Vitale, Mario; Caruso, Maria Gabriella; Notarnicola, Maria; Iacuzzo, Irma; Portella, Giuseppe; Di Marzo, Vincenzo . E-mail: vdimarzo@icmib.na.cnr.it; Bifulco, Maurizio . E-mail: maubiful@unina.it

    2006-02-15

    The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB{sub 1} receptors could induce a non-invasive phenotype in breast mtastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB{sub 1} antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB{sub 1} receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB{sub 1} receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo.

  13. Marine algal fucoxanthin inhibits the metastatic potential of cancer cells.

    PubMed

    Chung, Tae-Wook; Choi, Hee-Jung; Lee, Ji-Yeon; Jeong, Han-Sol; Kim, Cheorl-Ho; Joo, Myungsoo; Choi, Jun-Yong; Han, Chang-Woo; Kim, So-Yeon; Choi, Jae-Sue; Ha, Ki-Tae

    2013-10-04

    Metastasis is major cause of malignant cancer-associated mortality. Fucoxanthin has effect on various pharmacological activities including anti-cancer activity. However, the inhibitory effect of fucoxanthin on cancer metastasis remains unclear. Here, we show that fucoxanthin isolated from brown alga Saccharina japonica has anti-metastatic activity. To check anti-metastatic properties of fucoxanthin, in vitro models including assays for invasion, migration, actin fiber organization and cancer cell-endothelial cell interaction were used. Fucoxanthin inhibited the expression and secretion of MMP-9 which plays a critical role in tumor invasion and migration, and also suppressed invasion of highly metastatic B16-F10 melanoma cells as evidenced by transwell invasion assay. In addition, fucoxanthin diminished the expressions of the cell surface glycoprotein CD44 and CXC chemokine receptor-4 (CXCR4) which play roles in migration, invasion and cancer-endothelial cell adhesion. Fucoxanthin markedly suppressed cell migration in wound healing assay and inhibited actin fiber formation. The adhesion of B16-F10 melanoma cells to the endothelial cells was significantly inhibited by fucoxanthin. Moreover, in experimental lung metastasis in vivo assay, fucoxanthin resulted in significant reduction of tumor nodules. Taken together, we demonstrate, for the first time, that fucoxanthin suppresses metastasis of highly metastatic B16-F10 melanoma cells in vitro and in vivo.

  14. Development of effective prophylaxis against intraoperative carcinoid crisis.

    PubMed

    Woltering, Eugene A; Wright, Anne E; Stevens, Melissa A; Wang, Yi-Zarn; Boudreaux, John P; Mamikunian, Gregg; Riopelle, James M; Kaye, Alan D

    2016-08-01

    The prophylactic use of a preoperative, intraoperative, and postoperative high-dose continuous octreotide acetate infusion was evaluated for its ability to minimize the incidence of carcinoid crises during neuroendocrine tumor (NET) cytoreductive surgeries. A retrospective study was approved by the institutional review boards at Ochsner Medical Center-Kenner and Louisiana State University Health Sciences Center. Ochsner Medical Center-Kenner operating room and multispecialty NET clinic. One hundred fifty consecutive patients who underwent a total of 179 cytoreductive surgeries for stage IV, small bowel NETs. All patients received a 500-μg/h infusion of octreotide acetate preoperatively, intraoperatively, and postoperatively. Anesthesia and surgical records were reviewed. Carcinoid crisis was defined as a systolic blood pressure of less than 80mm Hg for greater than 10minutes. Patients who experienced intraoperative hypertension or hypotension, profound tachycardia, or a "crisis" according to the operative note were also reviewed. One hundred sixty-nine (169/179; 94%) patients had normal anesthesia courses. The medical records of 10 patients were further investigated for a potential intraoperative crisis using the aforementioned criteria. Upon review, 6 patients were determined to have had a crisis. The final incidence of intraoperative crisis was 3.4% (6/179). A continuous high-dose infusion of octreotide acetate intraoperatively minimizes the incidence of carcinoid crisis. We believe that the low cost and excellent safety profile of octreotide warrant the use of this therapy during extensive surgical procedures for midgut and foregut NETs. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Diffuse Neuroendocrine Cell Hyperplasia: Report of Two Cases

    PubMed Central

    Cansız Ersöz, Cevriye; Cangır, Ayten Kayı; Dizbay Sak, Serpil

    2016-01-01

    Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder characterised by a proliferation of neuroendocrine cells within the lung. It is believed that a minority of the patients with DIPNECH can develop carcinoid tumors. Here, we report two new cases of DIPNECH with coexisting carcinoid tumors. PMID:27293939

  16. MITF suppression by CH5552074 inhibits cell growth in melanoma cells.

    PubMed

    Aida, Satoshi; Sonobe, Yukiko; Yuhki, Munehiro; Sakata, Kiyoaki; Fujii, Toshihiko; Sakamoto, Hiroshi; Mizuno, Takakazu

    2017-06-01

    Although treatment of melanoma with BRAF inhibitors and immune checkpoint inhibitors achieves a high response rate, a subset of melanoma patients with intrinsic and acquired resistance are insensitive to these therapeutics, so to improve melanoma therapy other target molecules need to be found. Here, we screened our chemical library to identify an anti-melanoma agent and examined its action mechanisms to show cell growth inhibition activity. We screened a chemical library against multiple skin cancer cell lines and conducted ingenuity pathway analysis (IPA) to investigate the mechanisms of CH5552074 activity. Suppression of microphthalmia-associated transcription factor (MITF) expression levels was determined in melanoma cells treated with CH5552074. Cell growth inhibition activity of CH5552074 was evaluated in MITF-dependent melanoma cell lines. We identified an anti-melanoma compound, CH5552074, which showed remarkable cell growth inhibition activity in melanoma cell lines. The IPA results suggested that CH5552074-sensitive cell lines had activated MITF. In further in vitro studies in the melanoma cell lines, a knockdown of MITF with siRNA resulted in cell growth inhibition, which showed that CH5552074 inhibited cell growth by reducing the expression level of MITF protein. These results suggest that CH5552074 can inhibit cell growth in melanoma cells by reducing the protein level of MITF. MITF inhibition by CH5552074 would be an attractive option for melanoma treatment.

  17. Inhibition of DNA synthesis in Meth A cells by chlorpromazine.

    PubMed

    Mizushima, T; Natori, S; Sekimizu, K

    1993-10-01

    We examined the influence of chlorpromazine, a phenothiazine derivative, on DNA synthesis in Meth A cells. Pulse-labelling experiments with [3H]thymidine showed that chlorpromazine inhibited DNA synthesis in cells cultured in vitro. The drug also inhibited DNA synthesis in isolated nuclei. Observation by fluorescence microscopy of fibroblastic cells stained with chlorpromazine indicated that the drug was localized in the cytoplasm and nuclear membranes, suggesting that it inhibited DNA synthesis in a manner dependent on the interaction of replication proteins with nuclear membranes. Meth A sarcomas growing in the endoderm of BALB/c mice regressed on intra-tumor injection of chlorpromazine, indicating that the drug has an anticancer action.

  18. Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture

    PubMed Central

    Musser, Jeffrey M. B.; Heatley, J. Jill; Koinis, Anastasia V.; Suchodolski, Paulette F.; Guo, Jianhua; Escandon, Paulina; Tizard, Ian R.

    2015-01-01

    Parrot bornavirus 4 is an etiological agent of proventricular dilatation disease, a fatal neurologic and gastrointestinal disease of psittacines and other birds. We tested the ability of ribavirin, an antiviral nucleoside analog with antiviral activity against a range of RNA and DNA viruses, to inhibit parrot bornavirus 4 replication in duck embryonic fibroblast cells. Two analytical methods that evaluate different products of viral replication, indirect immunocytochemistry for viral specific nucleoprotein and qRT-PCR for viral specific phosphoprotein gene mRNA, were used. Ribavirin at concentrations between 2.5 and 25 μg/mL inhibited parrot bornavirus 4 replication, decreasing viral mRNA and viral protein load, in infected duck embryonic fibroblast cells. The addition of guanosine diminished the antiviral activity of ribavirin suggesting that one possible mechanism of action against parrot bornavirus 4 may likely be through inosine monophosphate dehydrogenase inhibition. This study demonstrates parrot bornavirus 4 susceptibility to ribavirin in cell culture. PMID:26222794

  19. Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture.

    PubMed

    Musser, Jeffrey M B; Heatley, J Jill; Koinis, Anastasia V; Suchodolski, Paulette F; Guo, Jianhua; Escandon, Paulina; Tizard, Ian R

    2015-01-01

    Parrot bornavirus 4 is an etiological agent of proventricular dilatation disease, a fatal neurologic and gastrointestinal disease of psittacines and other birds. We tested the ability of ribavirin, an antiviral nucleoside analog with antiviral activity against a range of RNA and DNA viruses, to inhibit parrot bornavirus 4 replication in duck embryonic fibroblast cells. Two analytical methods that evaluate different products of viral replication, indirect immunocytochemistry for viral specific nucleoprotein and qRT-PCR for viral specific phosphoprotein gene mRNA, were used. Ribavirin at concentrations between 2.5 and 25 μg/mL inhibited parrot bornavirus 4 replication, decreasing viral mRNA and viral protein load, in infected duck embryonic fibroblast cells. The addition of guanosine diminished the antiviral activity of ribavirin suggesting that one possible mechanism of action against parrot bornavirus 4 may likely be through inosine monophosphate dehydrogenase inhibition. This study demonstrates parrot bornavirus 4 susceptibility to ribavirin in cell culture.

  20. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration

    PubMed Central

    Detaille, D; Vial, G; Borel, A-L; Cottet-Rouselle, C; Hallakou-Bozec, S; Bolze, S; Fouqueray, P; Fontaine, E

    2016-01-01

    Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert-butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy. PMID:27551496

  1. Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis

    PubMed Central

    Kim, Eun Ho; Song, Hyo Sook; Yoo, Seung Hoon; Yoon, Myonggeun

    2016-01-01

    Treatment with alternating electric fields at an intermediate frequency (100–300 kHz), referred to as tumor treating fields (TTF) therapy, inhibits cancer cell proliferation. In the present study, we demonstrated that TTF application suppressed the metastatic potential of U87 and U373 glioblastoma cell lines via the NF-kB, MAPK and PI3K/AKT signaling pathways. Wound-healing and transwell assays showed that TTF suppressed cell migration and invasion compared with controls. Soft agar and three-dimensional culture assays showed that TTF inhibited both anchorage-dependent (cell proliferation) and anchorage-independent (colony formation) GBM cell growth. TTF dysregulated epithelial-to-mesenchymal transition-related genes, such as vimentin and E-cadherin, which partially accounted for TTF inhibition of cell migration and invasion. We further demonstrated that TTF application suppressed angiogenesis by downregulating VEGF, HIF1α and matrix metalloproteinases 2 and 9. TTF also inhibited NF-kB transcriptional activity. Collectively, our findings show that TTF represents a promising novel anti-invasion and anti-angiogenesis therapeutic strategy for use in GBM patients. PMID:27556184

  2. Expanding indications for ESD: submucosal disease (SMT/carcinoid tumors).

    PubMed

    Goto, Osamu; Uraoka, Toshio; Horii, Joichiro; Yahagi, Naohisa

    2014-04-01

    Endoscopic submucosal dissection (ESD) is useful for submucosal tumors (SMTs) within the superficial submucosal layer, but perforation frequently occurs during ESD for SMTs located at the deeper layer. Endoscopic resection for small esophageal SMTs is acceptable, although candidates for endoscopic removal are rare. Laparoscopic assistance will be effective for minimally invasive endoscopic local resection for certain types of gastric SMT. Endoscopic mucosal resection with a ligation device would be better than ESD for rectal carcinoid in terms of simplicity and effectiveness. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Pulmonary and tricuspid valvuloplasty in carcinoid heart disease.

    PubMed

    Karimi, Ashkan; Pourafshar, Negiin; Fudge, James C

    2016-12-28

    A 26-year-old female with carcinoid heart disease consisting of severe pulmonary and tricuspid valve stenosis was admitted with line associated sepsis. She recovered from sepsis with antibiotics and aggressive fluid resuscitation but became grossly volume overloaded with evidence of tense ascites and lower extremity edema. She developed worsening renal and hepatic function due to congestive nephropathy and hepatopathy, which did not respond to intravenous diuretics, and she was deemed too sick for surgical pulmonary and tricuspid valve replacement. Pulmonary and tricuspid valvuloplasty was performed as a rescue measure to alleviate her congestive symptoms and improve her candidacy for valve replacement. © 2016 Wiley Periodicals, Inc.

  4. Familial risk of small intestinal carcinoid and adenocarcinoma.

    PubMed

    Kharazmi, Elham; Pukkala, Eero; Sundquist, Kristina; Hemminki, Kari

    2013-08-01

    Small intestinal cancer (SIC) is rare, and its etiology is poorly understood. We compared clusters of families with SICs of different histologic subtypes. By using the nationwide family cancer data sets of Sweden and Finland, we identified a cohort of 9964 first-degree relatives of 1799 patients with SIC, diagnosed from 1961 through 2009. Data were collected from time periods as long as 47 years (mean, 35.4 y), and cancer incidence was determined. Standardized incidence ratios (SIRs) were calculated and stratified by sex, age, time period, and cancer type, using the incidence rates for the entire national population as the reference. Among the 1799 SIC cases, 1.1% had a sibling with SIC, so the SIR was 11.8 (95% confidence interval [CI], 7.2-18.2); 1.1% had a parent or child with SIC (SIR, 3.5; 95% CI, 2.0-5.6). The SIR of concordant carcinoid histology of SIC among siblings was 28.4 (95% CI, 14.7-49.6; n = 12) and in parent-child pairs was 9.9 (95% CI, 5.4-16.6; n = 14). The familial risk of concordant histologic subtypes increased for siblings diagnosed with adenocarcinoma, but only 2 familial cases were identified. In family members of patients with SIC of the adenocarcinoma subtype, risks of colorectal and bladder cancer were modestly but significantly increased compared with the general population. Family members of patients with SIC of the carcinoid subtype had an increased risk for kidney cancer and polycythemia vera. Based on data from our population-based study, first-degree relatives of patients with small intestinal carcinoid tumors have developed these tumors with high incidence. Because of the rareness of this tumor, the absolute risk remains moderate even within families. Gastroenterologists could inform patients with small intestinal carcinoids about the familial risk and encourage counseling for their first-degree relatives. Studies are needed to identify genetic factors that affect susceptibility to SIC. Copyright © 2013 AGA Institute. Published

  5. Refractory carcinoid syndrome: a review of treatment options

    PubMed Central

    Riechelmann, Rachel P.; Pereira, Allan A.; Rego, Juliana F. M.; Costa, Frederico P.

    2016-01-01

    Carcinoid syndrome (CSy) is a constellation of symptoms that may commonly present in patients with well differentiated neuroendocrine tumors (NETs), with somatostatin analogs (SSAs) being the first-line option for symptom management. However, symptomatic progression eventually occurs and in this scenario of a refractory CSy; several treatment options have been studied such as dose escalation of SSA, interferon and liver-directed therapies. Nevertheless, recent phase III trials have contributed to the understanding and management of this condition. We performed a comprehensive review of interventional studies examining refractory CSy to provide the evidence for current treatment options and propose a treatment sequence. PMID:28203303

  6. Rectal carcinoids are on the rise: early detection by screening endoscopy.

    PubMed

    Scherübl, H

    2009-02-01

    Rectal carcinoids are on the rise; in the United States the age-adjusted incidence has increased by 800% -1000% in the last 35 years. The incidence of carcinoids of the stomach, pancreas, or small bowels has also multiplied. The reasons for these epidemiological changes are not yet understood. Both screening sigmoidoscopy and screening colonoscopy lead to a shift to smaller-sized (< or =13 mm) rectal carcinoids and earlier tumor stages at diagnosis. During the last 35 years the overall 5-year survival of patients with rectal carcinoid disease has increased by almost 20% (in the US). Thus, endoscopic screening of the colorectum is effective in the early diagnosis not only of colorectal adenomas and adenocarcinomas but also of carcinoids. Rectal carcinoids that are 10.0 mm or less and do not infiltrate the muscularis propria can be removed endoscopically. If histological angioinvasion or lymph node metastases are found, surgical lymph node dissection has to be considered. Before deciding on definitive therapy, rectal carcinoids should be staged by means of endoscopic ultrasonography, CT, or MRI and somatostatin receptor scintigraphy.

  7. Lutein Inhibits the Migration of Retinal Pigment Epithelial Cells via Cytosolic and Mitochondrial Akt Pathways (Lutein Inhibits RPE Cells Migration)

    PubMed Central

    Su, Ching-Chieh; Chan, Chi-Ming; Chen, Han-Min; Wu, Chia-Chun; Hsiao, Chien-Yu; Lee, Pei-Lan; Lin, Victor Chia-Hsiang; Hung, Chi-Feng

    2014-01-01

    During the course of proliferative vitreoretinopathy (PVR), the retinal pigment epithelium (RPE) cells will de-differentiate, proliferate, and migrate onto the surfaces of the sensory retina. Several studies have shown that platelet-derived growth factor (PDGF) can induce migration of RPE cells via an Akt-related pathway. In this study, the effect of lutein on PDGF-BB-induced RPE cells migration was examined using transwell migration assays and Western blot analyses. We found that both phosphorylation of Akt and mitochondrial translocation of Akt in RPE cells induced by PDGF-BB stimulation were suppressed by lutein. Furthermore, the increased migration observed in RPE cells with overexpressed mitochondrial Akt could also be suppressed by lutein. Our results demonstrate that lutein can inhibit PDGF-BB induced RPE cells migration through the inhibition of both cytoplasmic and mitochondrial Akt activation. PMID:25110866

  8. Inhibition of Plasmodium sporozoites infection by targeting the host cell

    PubMed Central

    Leitao, Ricardo; Rodriguez, Ana

    2010-01-01

    There is a great need of new drugs against malaria because of the increasing spread of parasite resistance against the most commonly used drugs in the field. We found that monensin, a common veterinary antibiotic, has a strong inhibitory effect in Plasmodium berghei and P. yoelii sporozoites hepatocyte infection in vitro. Infection of host cells by another apicomplexan parasite with a similar mechanism of host cell invasion, Toxoplasma tachyzoites, was also inhibited. Treatment of mice with monensin abrogates liver infection with P. berghei sporozoites in vivo. We also found that at low concentrations monensin inhibits the infection of Plasmodium sporozoites by rendering host cells resistant to infection, rather than having a direct effect on sporozoites. Monensin effect is targeted to the initial stages of parasite invasion of the host cell with little or no effect on development, suggesting that this antibiotic affects an essential host cell component that is required for Plasmodium sporozoite invasion. PMID:20493847

  9. Carcinoid tumor associated with adjacent dysplastic columnar epithelium in the renal pelvis: A case report and literature review.

    PubMed

    Kim, Sung Sun; Choi, Chan; Kang, Taek Won; Choi, Yoo Duk

    2016-01-01

    Carcinoid tumors are well documented in the pulmonary and gastrointestinal systems, but very rare in the urinary tract, especially in the renal pelvis. We report on a 60-year-old female patient who presented with left flank pain and fever. Abdominal computed tomography demonstrated a heterogeneously enhancing mass in the left renal pelvis and a stone at the left proximal ureter. Multiple parenchymal lesions were also observed, which were identified as uneven caliectasis displaying air-fluid levels and renal parenchymal atrophy. The patient underwent simple nephro-ureterectomy. Macroscopically, a polypoid mass was observed in the renal pelvis. Microscopically, the tumor revealed acinar, tubular, and solid pattern and was composed of small, monotonous and hyperchromatic cells. Lining epithelia in renal pelvis and ureter revealed columnar epithelia with dysplastic change. The tumor cells were positive for chromogranin A, synaptophysin, CD56, and focally positive for cytokeratin. Immunohistochemical staining of synaptophysin and chromogranin A highlighted the neuroendocrine cells in the columnar epithelium. Ki-67 (1:50; MIB-1) labeling index was less than 1% in the area with highest uptake. We report here a case of carcinoid tumor of the renal pelvis that was associated with adjacent dysplastic columnar epithelium. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  10. Nivolumab effectively inhibit platinum-resistant ovarian cancer cells via induction of cell apoptosis and inhibition of ADAM17 expression.

    PubMed

    Sun, L-M; Liu, Y-C; Li, W; Liu, S; Liu, H-X; Li, L-W; Ma, R

    2017-03-01

    Nivolumab is an anti-PD-1 (anti-programmed death-1) monoclonal antibody. It has achieved an overall response rate of 17% in Phase 1 clinical trial for patient with platinum-resistant ovarian cancer (PROC). However, its underlying mechanism has not been fully explored yet. The aim of the study is to investigate the efficiency of nivolumab to inhibit PROC cells and its possible mechanism. Firstly, methylthiazolyl tetrazolium bromide (MTT) assay was performed to determine the IC50 values of cisplatin in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. The results showed that IC50 (half maximal inhibitory concentration) values of cisplatin were significantly decreased in a time-dependent manner in A2780, A2780/DDP, SKOV3, and SKOV3/DDP cells. Secondly, MMT assay was used once again to measure anti-tumor effects of nivolumab in A2780/DDP cells. The results showed that anti-tumor effects of nivolumab increased in a dose- and time-dependent manner. Thirdly, A2780/DDP cells were treated with nivolumab in combination with cisplatin for 48 h. The results demonstrated that nivolumab increased the anti-tumor effects of cisplatin in A2780/DDP cells. Notably, the combined treatment effectively reversed cisplatin resistance in PROC cells. Also, nivolumab induced cell apoptosis and cell-cycle arrest in G0/G1 phase in PROC cells. FACS and Western blot were performed to measure cell apoptosis and Bcl-2 and Bax expression respectively. The results showed that combined treatment significantly increased cell apoptosis rate, down-regulated Bcl-2, and unregulated Bax expression in PROC cells. Additionally, the expression levels of ADAM17 were significantly decreased in a dose-dependent manner in PROC cells, which were treated with nivolumab. Therefore, all the results demonstrated that the combined treatment with nivolumab and cisplatin effectively inhibited PROC cells via induction of cell apoptosis and inhibition of ADAM17 expression.

  11. B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins.

    PubMed

    Hauser, Jannek; Sveshnikova, Natalia; Wallenius, Anders; Baradaran, Sanna; Saarikettu, Juha; Grundström, Thomas

    2008-01-29

    Upon encountering antigens, B-lymphocytes can adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons. Activation-induced cytidine deaminase (AID) is the mutagenic antibody diversification enzyme that is essential for both somatic hypermutation and CSR. The mutagenic AID enzyme has to be tightly controlled. Here, we show that engagement of the membrane-bound antibodies of the B-cell receptor (BCR), which signals that good antibody affinity has been reached, inhibits AID gene expression and that calcium (Ca(2+)) signaling is essential for this inhibition. Moreover, we show that overexpression of the Ca(2+) sensor protein calmodulin inhibits AID gene expression, and that the transcription factor E2A is required for regulation of the AID gene by the BCR. E2A mutated in the binding site for calmodulin, and thus showing calmodulin-resistant DNA binding, makes AID expression resistant to the inhibition through BCR activation. Thus, BCR activation inhibits AID gene expression through Ca(2+)/calmodulin inhibition of E2A.

  12. FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells.

    PubMed

    Rellinger, Eric J; Craig, Brian T; Alvarez, Alexandra L; Dusek, Haley L; Kim, Kwang W; Qiao, Jingbo; Chung, Dai H

    2017-03-01

    The MYC family of proteins promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells. We surveyed 3 MYCN-single copy and 5 MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression. Cell viability was measured with FX11 using a tetrazolium-based assay. Cell cycle analysis using propidium iodide with flow cytometry was performed to evaluate for growth arrest. Immunoblotting demonstrated PARP and Caspase 3 cleavage as evidence of apoptosis. LDHA is frequently expressed in both MYCN--amplified and MYCN-single copy cell lines. N-MYC and C-MYC protein levels did not correlate with LDHA protein expression. FX11 inhibits aerobic glycolysis and growth in three MYCN-amplified and one MYCN-single copy neuroblastoma cell lines. FX11 induces modest G1 cell cycle arrest with selective induction of apoptosis. Small molecule LDHA inhibition is capable of blocking aerobic glycolysis and growth of neuroblastoma cell lines in vitro and merits further in vivo evaluation of its preclinical efficacy in neuroblastomas. Copyright © 2016. Published by Elsevier Inc.

  13. Inhibition of Telomerase Recruitment and Cancer Cell Death*

    PubMed Central

    Nakashima, Mai; Nandakumar, Jayakrishnan; Sullivan, Kelly D.; Espinosa, Joaquín M.; Cech, Thomas R.

    2013-01-01

    Continued proliferation of human cells requires maintenance of telomere length, usually accomplished by telomerase. Telomerase is recruited to chromosome ends by interaction with a patch of amino acids (the TEL patch, for TPP1 glutamate (E) and leucine (L)-rich patch) on the surface of telomere protein TPP1. In previous studies, interruption of this interaction by mutation prevented telomere extension in HeLa cells, but the cell culture continued to grow. We now show that the telomerase inhibitor BIBR1532 acts together with TEL patch mutations to inhibit the growth of HeLa cell lines and that apoptosis is a prominent mechanism of death of these cells. Survivor cells take over the population beginning around 40 days in culture. These cells no longer express the TEL patch mutant TPP1, apparently because of silencing of the expression cassette, a survival mechanism that would not be available to cancer cells. These results provide hope that inhibiting the binding of telomerase to the TEL patch of TPP1, perhaps together with a modest inhibition of the telomerase enzyme, could comprise an effective anticancer therapy for the ∼90% of human tumors that are telomerase-positive. PMID:24097987

  14. Diversity of fate outcomes in cell pairs under lateral inhibition.

    PubMed

    Guisoni, Nara; Martinez-Corral, Rosa; Garcia Ojalvo, Jordi; de Navascués, Joaquín

    2017-02-07

    Cell fate determination by lateral inhibition via Notch/Delta signalling has been extensively studied. Most formalised models consider Notch/Delta interactions in fields of cells, with parameters that typically lead to symmetry breaking of signalling states between neighbouring cells, commonly resulting in salt-and-pepper fate patterns. Here we consider the case of signalling between isolated cell pairs, and find that the bifurcation properties of a standard mathematical model of lateral inhibition can lead to stable symmetric signalling states. We apply this model to the adult intestinal stem cell (ISC) of Drosophila, whose fate is stochastic but dependent on the Notch/Delta pathway. We observe a correlation between signalling state in cell pairs and their contact area. We interpret this behaviour in terms of the properties of our model in the presence of population variability in contact areas, which affects the effective signalling threshold of individual cells. Our results suggest that the dynamics of Notch/Delta signalling can contribute to explain stochasticity in stem cell fate decisions, and that the standard model for lateral inhibition can account for a wider range of developmental outcomes than previously considered.

  15. Regulatory T cells inhibit CD34+ cell differentiation into NK cells by blocking their proliferation

    PubMed Central

    Pedroza-Pacheco, Isabela; Shah, Divya; Domogala, Anna; Luevano, Martha; Blundell, Michael; Jackson, Nicola; Thrasher, Adrian; Madrigal, Alejandro; Saudemont, Aurore

    2016-01-01

    Graft versus Host Disease (GvHD) remains one of the main complications after hematopoietic stem cell transplantation (HSCT). Due to their ability to suppress effector cells, regulatory T cells (Tregs) have been proposed as a cellular therapy to prevent GvHD, however they also inhibit the functions of natural killer (NK) cells, key effectors of the Graft versus Leukemia effect. In this study, we have explored whether a Tregs therapy will also impact on NK cell differentiation. Using an in vitro model of hematopoietic stem cell (HSC) differentiation into NK cells, we found that activated Tregs led to a 90% reduction in NK cell numbers when added at the time of commitment to the NK cell lineage. This effect was contact dependent and was reversible upon Tregs depletion. The few NK cells that developed in these cultures were mature and exhibited normal functions. Furthermore, adoptive transfer of activated Tregs in rag-/- γc-/- mice abrogated HSC differentiation into NK cells thus confirming our in vitro findings. Collectively, these results demonstrate for the first time that activated Tregs can inhibit NK cell differentiation from HSC under specific conditions. PMID:26915707

  16. Regulatory T cells inhibit CD34+ cell differentiation into NK cells by blocking their proliferation.

    PubMed

    Pedroza-Pacheco, Isabela; Shah, Divya; Domogala, Anna; Luevano, Martha; Blundell, Michael; Jackson, Nicola; Thrasher, Adrian; Madrigal, Alejandro; Saudemont, Aurore

    2016-02-26

    Graft versus Host Disease (GvHD) remains one of the main complications after hematopoietic stem cell transplantation (HSCT). Due to their ability to suppress effector cells, regulatory T cells (Tregs) have been proposed as a cellular therapy to prevent GvHD, however they also inhibit the functions of natural killer (NK) cells, key effectors of the Graft versus Leukemia effect. In this study, we have explored whether a Tregs therapy will also impact on NK cell differentiation. Using an in vitro model of hematopoietic stem cell (HSC) differentiation into NK cells, we found that activated Tregs led to a 90% reduction in NK cell numbers when added at the time of commitment to the NK cell lineage. This effect was contact dependent and was reversible upon Tregs depletion. The few NK cells that developed in these cultures were mature and exhibited normal functions. Furthermore, adoptive transfer of activated Tregs in rag(-/-) γc(-/-) mice abrogated HSC differentiation into NK cells thus confirming our in vitro findings. Collectively, these results demonstrate for the first time that activated Tregs can inhibit NK cell differentiation from HSC under specific conditions.

  17. Chemotherapy and irradiation for locally advanced and metastatic pulmonary carcinoid tumors

    PubMed Central

    Chong, Curtis R.; Wirth, Lori J.; Nishino, Mizuki; Chen, Aileen B.; Sholl, Lynette M.; Kulke, Matthew H.; McNamee, Ciaran J.; Jänne, Pasi A.; Johnson, Bruce E.

    2015-01-01

    Objectives The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined. Materials and methods A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990 and 2012. Results 300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stages I–III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4–32), compared to 3 (1%) patients with typical carcinoid (range, 8–12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum–etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5-year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 month median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 month median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6–72 months). Conclusions These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy. PMID:25218177

  18. TACE (ADAM17) inhibits Schwann cell myelination.

    PubMed

    La Marca, Rosa; Cerri, Federica; Horiuchi, Keisuke; Bachi, Angela; Feltri, M Laura; Wrabetz, Lawrence; Blobel, Carl P; Quattrini, Angelo; Salzer, James L; Taveggia, Carla

    2011-06-12

    Tumor necrosis factor-α-converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.

  19. Pirin Inhibits Cellular Senescence in Melanocytic Cells

    PubMed Central

    Licciulli, Silvia; Luise, Chiara; Scafetta, Gaia; Capra, Maria; Giardina, Giuseppina; Nuciforo, Paolo; Bosari, Silvano; Viale, Giuseppe; Mazzarol, Giovanni; Tonelli, Chiara; Lanfrancone, Luisa; Alcalay, Myriam

    2011-01-01

    Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression. PMID:21514450

  20. Resveratrol Inhibited Non-small Cell Lung Cancer Through Inhibiting STAT-3 Signaling.

    PubMed

    Li, Xin; Wang, Dan; Zhao, Qing Chun; Shi, Tao; Chen, Jun

    2016-11-01

    Resveratrol has demonstrated many beneficial effects against cancers; however, the mechanism remains unclear. Non-small cell lung cancer accounts for 80% of lung cancers. The present study was designed to observe the effects and related mechanisms of resveratrol on non-small cell lung cancer in in vitro A549 cells. The anticancer effects of resveratrol were analyzed on cell viability, migration and invasion, proliferation and apoptosis. Cell viability was determined by sulphorhodamine B assays. Cell proliferation and apoptosis were determined by flow cytometry and migration and invasion by transwell chamber analysis. Expression of STAT-3 was examined by real-time polymerase chain reaction and western blot. Overexpressing vector of STAT-3 was also constructed and transfected into A549 cells to observe the effects of resveratrol on STAT-3 signaling. The results showed that resveratrol displayed a dose-dependent and time-dependent cytotoxicity action on A549 cell viability. Resveratrol also inhibited proliferation, migration and invasion and promoted apoptosis in a time-dependent manner from 0-72 hours. Further study showed that resveratrol inhibited the messenger RNA and protein expression of STAT-3, and overexpressed STAT-3 abolished the effects of resveratrol on proliferation, apoptosis, migration and invasion totally or in part. These results suggest that the anticancer effects of resveratrol are mediated by STAT-3 signaling. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  1. Telmisartan inhibits human urological cancer cell growth through early apoptosis

    PubMed Central

    MATSUYAMA, MASAHIDE; FUNAO, KIYOAKI; KURATSUKURI, KATSUYUKI; TANAKA, TOMOAKI; KAWAHITO, YUTAKA; SANO, HAJIME; CHARGUI, JAMEL; TOURAINE, JEAN-LOUIS; YOSHIMURA, NORIO; YOSHIMURA, RIKIO

    2010-01-01

    Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agents. In addition, studies have provided evidence that ARBs have the potential to inhibit the growth of several types of cancer cells. It was reported that telmisartan (a type of ARB) has peroxisome proliferator-activated receptor (PPAR)-γ activation activity. We previously reported that the PPAR-γ ligand induces growth arrest in human urological cancer cells through apoptosis. In this study, we evaluated the effects of telmisartan and other ARBs on cell proliferation in renal cell carcinoma (RCC), bladder cancer (BC), prostate cancer (PC) and testicular cancer (TC) cell lines. The inhibitory effects of telmisartan and other ARBs (candesartan, valsartan, irbesartan and losartan) on the growth of the RCC, BC, PC and TC cell lines was investigated using an MTT assay. Flow cytometry and Hoechst staining were used to determine whether the ARBs induced apoptosis. Telmisartan caused marked growth inhibition in the urological cancer cells in a dose- and time-dependent manner. Urological cancer cells treated with 100 μM telmisartan underwent early apoptosis and DNA fragmentation. However, the other ARBs had no effect on cell proliferation in any of the urological cancer cell lines. Telmisartan may mediate potent anti-proliferative effects in urological cancer cells through PPAR-γ. Thus, telmisartan is a potent target for the prevention and treatment of human urological cancer. PMID:22993542

  2. Zedoary oil (Ezhu You) inhibits proliferation of AGS cells

    PubMed Central

    2013-01-01

    Background Zedoary (Curcumae Rhizoma, Ezhu), a Chinese medicinal herb, has been reported to show anticancer activity. This study aims to investigate the effect of zedoary oil (Ezhu You) on the proliferation of AGS cells which is one gastric cancer cell line. Methods The main ingredients of the herb were detected by GC-MS for herbal quality control. Cell viability was measured by MTT assay and cell proliferation was investigated by immunocytochemical staining for proliferating cell nuclear antigen (PCNA) protein. In addition, the cell cycle distributions were detected by flow cytometry with propidium iodine (PI) staining and the apoptosis rates were evaluated by flow cytometry with annexin V/PI double-staining. The morphological changes associated with apoptosis were observed by Hoechst 33342/PI double-staining. Protein expression was determined by western blot analysis. Results The main ingredients of the herb, including curzerene (26.45%), eucalyptol (12.04%), curcumol (9.04%), pyridine (7.97%), germacrone (7.89%), β-elemene (7.36%), τ-elemene (4.11%) and 28 other ingredients, including curdione, were consistent with the chemical profiles of zedoary. Zedoary oil significantly decreased the cell viability of AGS cells (P < 0.01) and MGC 803 cells (P < 0.01), and the inhibitory effects were attenuated by elevated concentrations of FBS. At high concentrations (≥90 μg/mL), zedoary oil killed GES-1 cells. At low concentrations (≤60 μg/mL), zedoary oil was less inhibitory toward normal gastric epithelial cells than gastric cancer cell lines. In AGS cells, zedoary oil inhibited cell proliferation in a dose- and time-dependent manner, with decreased PCNA protein expression in the zedoary oil-treated cells, and arrested the cell cycle at S, G2/M and G0/G1 stages after treatment for 6–48 h. At concentrations of 30, 60 and 90 μg/mL, which resulted in significant inhibition of proliferation and cell cycle arrest, zedoary oil induced cell apoptosis. In

  3. Parasitic inhibition of cell death facilitates symbiosis.

    PubMed

    Pannebakker, Bart A; Loppin, Benjamin; Elemans, Coen P H; Humblot, Lionel; Vavre, Fabrice

    2007-01-02

    Symbiotic microorganisms have had a large impact on eukaryotic evolution, with effects ranging from parasitic to mutualistic. Mitochondria and chloroplasts are prime examples of symbiotic microorganisms that have become obligate for their hosts, allowing for a dramatic extension of suitable habitats for life. Out of the extraordinary diversity of bacterial endosymbionts in insects, most are facultative for their hosts, such as the ubiquitous Wolbachia, which manipulates host reproduction. Some endosymbionts, however, have become obligatory for host reproduction and/or survival. In the parasitoid wasp Asobara tabida the presence of Wolbachia is necessary for host oogenesis, but the mechanism involved is yet unknown. We show that Wolbachia influences programmed cell death processes (a host regulatory feature typically targeted by pathogens) in A. tabida, making its presence essential for the wasps' oocytes to mature. This suggests that parasite strategies, such as bacterial regulation of host apoptosis, can drive the evolution of host dependence, allowing for a swift transition from parasitism to mutualism.

  4. Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

    PubMed Central

    Duguid, Ian; Branco, Tiago; Chadderton, Paul; Arlt, Charlotte; Powell, Kate; Häusser, Michael

    2015-01-01

    Classical feed-forward inhibition involves an excitation–inhibition sequence that enhances the temporal precision of neuronal responses by narrowing the window for synaptic integration. In the input layer of the cerebellum, feed-forward inhibition is thought to preserve the temporal fidelity of granule cell spikes during mossy fiber stimulation. Although this classical feed-forward inhibitory circuit has been demonstrated in vitro, the extent to which inhibition shapes granule cell sensory responses in vivo remains unresolved. Here we combined whole-cell patch-clamp recordings in vivo and dynamic clamp recordings in vitro to directly assess the impact of Golgi cell inhibition on sensory information transmission in the granule cell layer of the cerebellum. We show that the majority of granule cells in Crus II of the cerebrocerebellum receive sensory-evoked phasic and spillover inhibition prior to mossy fiber excitation. This preceding inhibition reduces granule cell excitability and sensory-evoked spike precision, but enhances sensory response reproducibility across the granule cell population. Our findings suggest that neighboring granule cells and Golgi cells can receive segregated and functionally distinct mossy fiber inputs, enabling Golgi cells to regulate the size and reproducibility of sensory responses. PMID:26432880

  5. Receptor tyrosine kinase inhibition by regorafenib/sorafenib inhibits growth and invasion of meningioma cells.

    PubMed

    Tuchen, Marcus; Wilisch-Neumann, Annette; Daniel, Evelyn A; Baldauf, Lisa; Pachow, Doreen; Scholz, Johannes; Angenstein, Frank; Stork, Oliver; Kirches, Elmar; Mawrin, Christian

    2017-03-01

    Systemic chemotherapeutic treatment for unresectable and/or aggressive meningiomas is still unsatisfying. PDGF receptor (PDGFR)-mediated activation of mitogenic signalling has been shown to be active in meningiomas. Therefore, we evaluate in vitro and in vivo the effects of inhibiting PDGFR using the clinically well-characterised tyrosine kinase inhibitors sorafenib or regorafenib in meningioma models. IOMM-Lee meningioma cells were used to assess cytotoxic effects, inhibition of proliferation, induction of apoptosis, as well as inhibition of migration and motility by sorafenib and regorafenib. Using an orthotopic mouse xenograft model, growth inhibition as monitored by magnetic resonance imaging, and overall survival of sorafenib- or regorafenib-treated mice compared with control animals was determined. Treatment of malignant IOMM-Lee cells resulted in significantly reduced cell survival and induction of apoptosis following regorafenib and sorafenib treatment. Western blots showed that both drugs target phosphorylation of p44/42 ERK via downregulation of the PDGFR. Both drugs additionally showed significant inhibition of cell motility and invasion. In vivo, mice with orthotopic meningioma xenografts showed a reduced volume (n.s.) of signal enhancement in MRI (mainly tumour) following sorafenib and regorafenib treatment. This was translated in a significantly increased overall survival time (p ≤ 0.05) for regorafenib-treated mice. Analyses of in vivo-grown tumours demonstrated again reduced PDGFR expression and expression/phosphorylation of p44/42. Sorafenib and regorafenib show antitumour activity in vitro and in vivo by targeting PDGFR and p44/42 ERK signalling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. [Somatotropic pituitary tumor in a patient with a previous ovarian strumal carcinoid. Report of one case].

    PubMed

    Riedemann, Erick; Rojas, Claudio; Quevedo, Iván

    2004-07-01

    Strumal carcinoid is an unusual form of monodermal ovarian teratoma with thyroid-like follicles mixed with typical carcinoid tumor patterns. We report a 49 years old woman presenting with an acromegaly. At the age of 45, an ovarian strumal carcinoid was excised and at three years of follow up, she complained of finger and feet growth. Laboratory showed an elevated serum IGF-1 and a sella turcica magnetic resonance imaging showed an 8 mm microadenoma. She was subjected to a transphenoidal excision and the pathological study disclosed a solid acidophilic pituitary adenoma. Two months after surgery, there was a significant decrease in serum IGT-I levels.

  7. Diode Laser in Management of Tracheobronchial Typical Carcinoid: A Case Report with Review of Literature

    PubMed Central

    Bhambhani, Navin; Masurkar, Vishwanath; Thombre, Sonal

    2015-01-01

    Tracheobronchial carcinoids are relatively uncommon neoplasms with malignant (though indolent) potential and variable behavior. Clinical presentation is usually similar to any obstructive tracheobronchial lesions or rarely with presentation of carcinoid syndrome. Management varies from Pneumonectomy to use of lung sparing bronchoscoplastic techniques. We report the case of a 32-year-old male patient diagnosed with carcinoid of left main bronchus. Patient was successfully treated with trans-bronchoscopic diode laser. At 24 months of follow up patient remains asymptomatic and recurrence-free. PMID:26500999

  8. Atypical Carcinoid Tumor with Anaplastic Lymphoma Kinase (ALK) Rearrangement Successfully Treated by an ALK Inhibitor.

    PubMed

    Nakajima, Masayuki; Uchiyama, Naoki; Shigemasa, Rie; Matsumura, Takeshi; Matsuoka, Ryota; Nomura, Akihiro

    This is the first report in which crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, reduced an atypical carcinoid tumor with ALK rearrangement. A 70-year-old man developed a tumor in the left lung and multiple metastases to the lung and brain. The pathology of transbronchial biopsied specimens demonstrated an atypical carcinoid pattern. Combined with immunohistochemical findings, we diagnosed the tumor as atypical carcinoid. ALK gene rearrangement was observed by both immunohistochemical (IHC) and fluorescence in situ hybridization. He was treated with chemotherapy as first-line therapy, however, the tumor did not respond to chemotherapy. Thereafter, he was treated with crizotinib, which successfully reduced the tumors.

  9. Whole abdominal radiation in the management of metastatic gastrointestinal carcinoid tumor

    SciTech Connect

    Keane, T.J.; Rider, W.D.; Harwood, A.R.; Thomas, G.M.; Cummings, B.J.

    1981-11-01

    Twenty-eight patients with metastatic gastrointestinal carcinoid tumor were treated with whole abdominal radiation. Twenty-one of these patients had the carcinoid syndrome. The prescribed mid-line tumor dose was 2000 to 2500 rad in 20 to 25 fractions in 4 to 5 weeks. The overall 5 year survival was 35% (median survival 2.5 years). A marked survival difference was noted in those patients with carcinoid syndrome compared to the non-functioning group. None of the syndrome patients survived five years (median survival 1.7 years) whereas six of the seven non-syndrome patients are five year survivors.

  10. Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1 in Cells

    PubMed Central

    Zhang, Feiran; Bhat, Shridhar; Gabelli, Sandra B.; Chen, Xiaochun; Miller, Michelle S.; Nacev, Benjamin A.; Cheng, Yim Ling; Meyers, David J.; Tenney, Karen; Shim, Joong Sup; Crews, Phillip; Amzel, L. Mario; Ma, Dawei; Liu, Jun O.

    2013-01-01

    Methionine aminopeptidases (MetAPs) which remove the initiator methionine from nascent peptides are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1–4). But all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1–4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells. PMID:23634668

  11. Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells.

    PubMed

    Zhang, Feiran; Bhat, Shridhar; Gabelli, Sandra B; Chen, Xiaochun; Miller, Michelle S; Nacev, Benjamin A; Cheng, Yim Ling; Meyers, David J; Tenney, Karen; Shim, Joong Sup; Crews, Phillip; Amzel, L Mario; Ma, Dawei; Liu, Jun O

    2013-05-23

    Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1-4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1-4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells.

  12. Sphingosylphosphorylcholine inhibits macrophage adhesion to vascular smooth muscle cells.

    PubMed

    Wirrig, Christiane; McKean, Jenny S; Wilson, Heather M; Nixon, Graeme F

    2016-09-01

    Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically stimulated by cytokines such as tumour necrosis factor-α (TNF). The aim of this study was to determine the effect of the sphingolipid sphingosylphosphorylcholine (SPC) on the interaction of monocytes/macrophages with vascular smooth muscle cells. Rat aortic smooth muscle cells and rat bone marrow-derived macrophages were co-cultured using an in vitro assay following incubation with sphingolipids to assess inter-cellular adhesion. We reveal that SPC inhibits the TNF-induced adhesion of macrophages to smooth muscle cells. This anti-adhesive effect was the result of SPC-induced changes to the smooth muscle cells (but not the macrophages) and was mediated, at least partly, via the sphingosine 1-phosphate receptor subtype 2. Lipid raft domains were also required. Although SPC did not alter expression or membrane distribution of the adhesion proteins intercellular adhesion molecule-1 and vascular cellular adhesion protein-1 in smooth muscle cells, SPC preincubation inhibited the TNF-induced increase in inducible nitric oxide synthase (NOS2) resulting in a subsequent decrease in nitric oxide production. Inhibiting NOS2 activation in smooth muscle cells led to a decrease in the adhesion of macrophages to smooth muscle cells. This study has therefore delineated a novel pathway which can inhibit the interaction between macrophages and vascular smooth muscle cells via SPC-induced repression of NOS2 expression. This mechanism could represent a potential drug target in vascular disease. Copyright © 2016. Published by Elsevier Inc.

  13. Memory Antitumor T-Cells Resist Inhibition by Immune Suppressor Cells.

    PubMed

    Gao, Yanhua; Whitaker-Dowling, Patricia; Bergman, Ira

    2015-09-01

    Cancer immune therapy is difficult partly because several classes of suppressor cells, including regulatory T-cells and macrophage-derived suppressor cells, inhibit the antitumor T-cell response. We used treatment studies of implanted tumors in mice to demonstrate that the same inhibitory cells that abrogated an acute therapeutic T-cell response to established tumor did not inhibit the therapeutic response produced by memory T-cells. Generating antitumor memory T-cells may be a highly potent strategy against cancer with late developing metastases. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  14. Atorvastatin inhibits myocardin expression in vascular smooth muscle cells.

    PubMed

    Li, Jingjing; Jiang, Jixin; Yin, Hao; Wang, Lifeng; Tian, Ruijuan; Li, Haijie; Wang, Zengyong; Li, Dong; Wang, Yuebing; Gui, Yu; Walsh, Michael P; Zheng, Xi-Long

    2012-07-01

    Atorvastatin (ATV), an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, is widely prescribed as a lipid-lowering drug. It also inhibits the RhoA-Rho-associated kinase pathway in vascular smooth muscle (SM) cells and critically inhibits SM function. Myocardin is a coactivator of serum response factor, which upregulates SM contractile proteins. The RhoA-Rho-associated kinase pathway, which directly triggers SM contraction, also increases myocardin gene expression. Therefore, we investigated whether ATV inhibits myocardin gene expression in SM cells. In mice injected with ATV (IP 20 μg/g per day) for 5 days, myocardin gene expression was significantly downregulated in aortic and carotid arterial tissues with decreased expression of myocardin target genes SM α-actin and SM22. Correspondingly, the contractility of aortic rings in mice treated with ATV or the Rho-associated kinase inhibitor Y-27632 was reduced in response to treatment with either KCl or phenylephrine. In cultured mouse and human aortic SM cells, KCl treatment stimulated the expression of myocardin, SM α-actin, and SM22. These stimulatory effects were prevented by ATV treatment. ATV-induced inhibition of myocardin expression was prevented by pretreatment with either mevalonate or geranylgeranylpyrophosphate but not farnesylpyrophosphate. Treatment with Y-27632 mimicked ATV effects on the gene expression of myocardin, SM α-actin, and SM22, further suggesting a role for the RhoA-Rho-associated kinase pathway in ATV effects. Furthermore, ATV treatment inhibited RhoA membrane translocation and activation; these effects were prevented by pretreatment with mevalonate. We conclude that ATV inhibits myocardin gene expression in vivo and in vitro, suggesting a novel mechanism for ATV inhibition of vascular contraction.

  15. Single Granule Cells Excite Golgi Cells and Evoke Feedback Inhibition in the Cochlear Nucleus

    PubMed Central

    Yaeger, Daniel B.

    2015-01-01

    In cerebellum-like circuits, synapses from thousands of granule cells converge onto principal cells. This fact, combined with theoretical considerations, has led to the concept that granule cells encode afferent input as a population and that spiking in individual granule cells is relatively unimportant. However, granule cells also provide excitatory input to Golgi cells, each of which provide inhibition to hundreds of granule cells. We investigated whether spiking in individual granule cells could recruit Golgi cells and thereby trigger widespread inhibition in slices of mouse cochlear nucleus. Using paired whole-cell patch-clamp recordings, trains of action potentials at 100 Hz in single granule cells was sufficient to evoke spikes in Golgi cells in ∼40% of paired granule-to-Golgi cell recordings. High-frequency spiking in single granule cells evoked IPSCs in ∼5% of neighboring granule cells, indicating that bursts of activity in single granule cells can recruit feedback inhibition from Golgi cells. Moreover, IPSPs mediated by single Golgi cell action potentials paused granule cell firing, suggesting that inhibitory events recruited by activity in single granule cells were able to control granule cell firing. These results suggest a previously unappreciated relationship between population coding and bursting in single granule cells by which spiking in a small number of granule cells may have an impact on the activity of a much larger number of granule cells. PMID:25788690

  16. Caerulomycin A Suppresses Immunity by Inhibiting T Cell Activity

    PubMed Central

    Chauhan, Arun; Khatri, Neeraj; Vohra, Rakesh M.; Jolly, Ravinder S.; Agrewala, Javed N.

    2014-01-01

    Background Caerulomycin A (CaeA) is a known antifungal and antibiotic agent. Further, CaeA is reported to induce the expansion of regulatory T cell and prolongs the survival of skin allografts in mouse model of transplantation. In the current study, CaeA was purified and characterized from a novel species of actinomycetes, Actinoalloteichus spitiensis. The CaeA was identified for its novel immunosuppressive property by inhibiting in vitro and in vivo function of T cells. Methods Isolation, purification and characterization of CaeA were performed using High Performance Flash Chromatography (HPFC), NMR and mass spectrometry techniques. In vitro and in vivo T cell studies were conducted in mice using flowcytometry, ELISA and thymidine-[methyl-3H] incorporation. Results CaeA significantly suppressed T cell activation and IFN-γ secretion. Further, it inhibited the T cells function at G1 phase of cell cycle. No apoptosis was noticed by CaeA at a concentration responsible for inducing T cell retardation. Furthermore, the change in the function of B cells but not macrophages was observed. The CaeA as well exhibited substantial inhibitory activity in vivo. Conclusion This study describes for the first time novel in vitro and in vivo immunosuppressive function of CaeA on T cells and B cells. CaeA has enough potential to act as a future immunosuppressive drug. PMID:25286329

  17. Endothelins inhibit mineralization of rat calvarial osteoblast-like cells.

    PubMed

    Hiruma, Y; Inoue, A; Shiohama, A; Otsuka, E; Hirose, S; Yamaguchi, A; Hagiwara, H

    1998-01-01

    We examined the effects of members of the endothelin (ET) family on mineralization of rat calvarial osteoblast-like cells. The accumulation of calcium in cells and cell layers was attenuated by ETs with the rank order of potency ET-1 = ET-2 > ET-3. We stained the mineralized nodules by von Kossa staining and measured the number and area of mineralized nodules. The inhibitory effects of ET-1 and ET-2 on the formation of mineralized nodules were stronger than those of ET-3. Our data suggest that ET-1 may inhibit the mineralization process of osteoblastic cells through the ETA receptor.

  18. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.

    PubMed

    Nelson, Erik A; Walker, Sarah R; Kepich, Alicia; Gashin, Laurie B; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C; Frank, David A

    2008-12-15

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival.

  19. Arachidonic acid inhibits glycine transport in cultured glial cells.

    PubMed Central

    Zafra, F; Alcantara, R; Gomeza, J; Aragon, C; Gimenez, C

    1990-01-01

    The effects of arachidonic acid on glycine uptake, exchange and efflux in C6 glioma cells were investigated. Arachidonic acid produced a dose-dependent inhibition of high-affinity glycine uptake. This effect was not due to a simple detergent-like action on membranes, as the inhibition of glycine transport was most pronounced with cis-unsaturated long-chain fatty acids, whereas saturated and trans-unsaturated fatty acids had relatively little or no effect. Endogenous unsaturated non-esterified fatty acids may exert a similar inhibitory effect on the transport of glycine. The mechanism for this inhibitory effect has been examined in a plasma membrane vesicle preparation derived from C6 cells, which avoids metabolic or compartmentation interferences. The results suggest that part of the selective inhibition of glycine transport by arachidonic acid could be due to the effects of the arachidonic acid on the lipid domain surrounding the carrier. PMID:2121132

  20. Cell growth inhibition by sequence-specific RNA minihelices.

    PubMed

    Hipps, D; Schimmel, P

    1995-08-15

    RNA minihelices which reconstruct the 12 base pair acceptor-T psi C domains of transfer RNAs interact with their cognate tRNA synthetases. These substrates lack the anticodons of the genetic code and, therefore, cannot participate in steps of protein synthesis subsequent to aminoacylation. We report here that expression in Escherichia coli of either of two minihelices, each specific for a different amino acid, inhibited cell growth. Inhibition appears to be due to direct competition between the minihelix and its related tRNA for binding to their common synthetase. This competition, in turn, sharply lowers the pool of the specific charged tRNA for protein synthesis. Inhibition is relieved by single nucleotide changes which disrupt the minihelix-synthetase interaction. The results suggest that sequence-specific RNA minihelix substrates bind to cognate synthetases in vivo and can, in principle, act as cell growth regulators. Naturally occurring non-tRNA substrates for aminoacylation may serve a similar purpose.

  1. Duodenal and Ampullary Carcinoid Tumors: Size Predicts Necessity for Lymphadenectomy.

    PubMed

    Dogeas, Epameinondas; Cameron, John L; Wolfgang, Cristopher L; Hirose, Kenzo; Hruban, Ralph H; Makary, Martin A; Pawlik, Timothy A; Choti, Michael A

    2017-08-01

    Unlike other neuroendocrine tumors of the gastrointestinal tract, management of duodenal and periampullary carcinoids remains controversial. We aimed to determine the metastatic potential and optimal choice of therapy for these neoplasms. A retrospective review of all patients treated at the Johns Hopkins Hospital between 1996 and 2012 was conducted. Clinicopathologic factors associated with lymph nodal involvement and clinical outcomes were evaluated. A total of 101 patients were identified. Eighty (79.2%) tumors arose from the duodenum and 21 (20.8%) from the periampullary area. Thirty-five (34.7%) patients underwent pancreaticoduodenectomy (PD), 12 (11.9%) local resection, 38 (37.6%) endoscopic excision, and 16 (15.8%) patients harbored incidental tumors identified in the specimen after PD for another indication. Lymph node (LN) pathologic evaluation was done in 56 patients, among which 27 (48%) had positive LN. Specifically, LN positivity (LN+) for tumors <1 cm in size was 4.5% (1/22), for tumors 1-2 cm 72% (13/18), and for tumors >2 cm 81% (13/16). Tumor size was the only factor associated with LN+ (p = 0.029). Lymph nodal involvement is common for duodenal and periampullary carcinoid tumors, particularly among those >1 cm in size; therefore, resection with lymphadenectomyfor these larger tumors is recommended.

  2. Combined adenocarcinoma-carcinoid tumor of transverse colon.

    PubMed

    Bhattacharjee, Prosanta Kumar; Halder, Shyamal

    2013-01-01

    A 65-year-old male presented with painless hematochezia associated with episodic cramps in upper abdomen, watery diarrhea, and a slowly growing mass in upper abdomen. Examination revealed a firm 6 x 5 cm, intra-abdominal, epigastric mass. Colonoscopy up to 90 cm showed a stenosing, ulcero-proliferative lesion in the transverse colon. No synchronous lesion was detected. Biopsy revealed mucin secreting adenocarcinoma. Exploration showed the growth involving the transverse colon proximal to the splenic flexure with a part of ileum, approximately three feet proximal to ileo-caecal junction, adherent to it. No significant mesenteric lymph node enlargement was evident. The patient underwent resection of the growth along with the segment of adherent ileum. Continuity was re-established by a colo-colic and ileo-ileal anastomosis respectively. Patient received adjuvant chemotherapy. Post-operative histopathology demonstrated a composite histological pattern with an admixture of carcinoid tumor and adenocarcinoma, invasion of ileal serosa and adenocarcinomatous deposits in mesocolic lymph nodes, the tumor staging being (T4, N0, M0/Stage II) for carcinoid and (T4, N1, M0/Stage III) for adenocarcinoma. Patient was followed-up for a year and was doing well without any evidence of recurrence.

  3. Complications from carcinoid syndrome: review of the current evidence

    PubMed Central

    Mota, José Mauricio; Sousa, Luana Guimarães; Riechelmann, Rachel P

    2016-01-01

    Patients with well-differentiated neuroendocrine tumours may develop carcinoid syndrome (CS), which is characterised by flushing, abdominal cramps, diarrhoea, and bronchospasms. In this scenario, long-term secretion of vasoactive substances—serotonin, tachynins, and others, may induce fibrogenic responses in local or distant tissues, leading to complications such as carcinoid heart disease (CHD), mesenteric and/or retroperitoneal fibrosis. Rare cases of lung/pleural fibrosis and scleroderma have also been described. Despite it not being well described yet, current evidence suggests the pathogenesis of such fibrogenic complications relies on signalling through 5-HT2B and TGF-β1. Medical management is still very limited and lacks prospective and randomised studies for definitive recommendations. Surgical procedures remain the best definitive treatment option for CHD and abdominal fibrosis. Recently, cognitive impairment has also been described as a potential consequence of CS. This review critically discusses the literature concerning the epidemiology, pathogenesis, clinical features, diagnosis, and treatment options for CS-related long-term complications. PMID:27594907

  4. Rectal carcinoid tumor metastasis to a skull base meningioma

    PubMed Central

    Huang, Jennifer; Gupta, Amit; Badve, Chaitra; Cohen, Mark L; Wolansky, Leo J

    2016-01-01

    Carcinoid tumors are rare, slow-growing neuroendocrine tumors that most frequently develop in the gastrointestinal tract or lungs and have high potential for metastasis. Metastasis to the brain is rare, but to another intracranial tumor is extremely rare. Of the intracranial tumors, meningiomas are the most common to host metastases, which may be related to its rich vascularity and E-cadherin expression. We describe the case of a 65-year-old female with active chemotherapy-treated neuroendocrine carcinoma who presented with left-sided facial numbness, headaches, and blurry vision. Initial imaging revealed a 1 cm irregular dural-based left petrous apex mass suggestive of a meningioma that was re-imaged four months later as a rapidly enlarging, extra-axial, mass extending into the cavernous sinus, effacing Meckel’s cave that resembled a trigeminal schwannoma. Pathology revealed a carcinoid tumor metastatic to meningioma. While the mass displayed characteristic imaging findings of a schwannoma, rapid growth in the setting of known active malignancy should prompt the clinician to consider mixed pathology from metastatic disease or a more aggressive meningioma. PMID:26825133

  5. Rottlerin inhibits cell growth and invasion via down-regulation of Cdc20 in glioma cells

    PubMed Central

    Wang, Lixia; Hou, Yingying; Yin, Xuyuan; Su, Jingna; Zhao, Zhe; Ye, Xiantao; Zhou, Xiuxia; Zhou, Li; Wang, Zhiwei

    2016-01-01

    Rottlerin, isolated from a medicinal plant Mallotus phillippinensis, has been demonstrated to inhibit cellular growth and induce cytoxicity in glioblastoma cell lines through inhibition of calmodulin-dependent protein kinase III. Emerging evidence suggests that rottlerin exerts its antitumor activity as a protein kinase C inhibitor. Although further studies revealed that rottlerin regulated multiple signaling pathways to suppress tumor cell growth, the exact molecular insight on rottlerin-mediated tumor inhibition is not fully elucidated. In the current study, we determine the function of rottlerin on glioma cell growth, apoptosis, cell cycle, migration and invasion. We found that rottlerin inhibited cell growth, migration, invasion, but induced apoptosis and cell cycle arrest. Mechanistically, the expression of Cdc20 oncoprotein was measured by the RT-PCR and Western blot analysis in glioma cells treated with rottlerin. We observed that rottlerin significantly inhibited the expression of Cdc20 in glioma cells, implying that Cdc20 could be a novel target of rottlerin. In line with this, over-expression of Cdc20 decreased rottlerin-induced cell growth inhibition and apoptosis, whereas down-regulation of Cdc20 by its shRNA promotes rottlerin-induced anti-tumor activity. Our findings indicted that rottlerin could exert its tumor suppressive function by inhibiting Cdc20 pathway which is constitutively active in glioma cells. Therefore, down-regulation of Cdc20 by rottlerin could be a promising therapeutic strategy for the treatment of glioma. PMID:27626499

  6. ATF3 inhibits PPARγ-stimulated transactivation in adipocyte cells

    SciTech Connect

    Jang, Min-Kyung; Jung, Myeong Ho

    2015-01-02

    Highlights: • ATF3 inhibits PPARγ-stimulated transcriptional activation. • ATF3 interacts with PPARγ. • ATF3 suppresses p300-mediated transcriptional coactivation. • ATF3 decreases the binding of PPARγ and recruitment of p300 to PPRE. - Abstract: Previously, we reported that activating transcription factor 3 (ATF3) downregulates peroxisome proliferator activated receptor (PPARγ) gene expression and inhibits adipocyte differentiation in 3T3-L1 cells. Here, we investigated another role of ATF3 on the regulation of PPARγ activity. ATF3 inhibited PPARγ-stimulated transactivation of PPARγ responsive element (PPRE)-containing reporter or GAL4/PPARγ chimeric reporter. Thus, ATF3 effectively repressed rosiglitazone-stimulated expression of adipocyte fatty acid binding protein (aP2), PPARγ target gene, in 3T3-L1 cells. Coimmunoprecipitation and GST pulldown assay demonstrated that ATF3 interacted with PPARγ. Accordingly, ATF3 prevented PPARγ from binding to PPRE on the aP2 promoter. Furthermore, ATF3 suppressed p300-mediated transcriptional coactivation of PPRE-containing reporter. Chromatin immunoprecipitation assay showed that overexpression of ATF3 blocked both binding of PPARγ and recruitment of p300 to PPRE on aP2 promoter induced by rosiglitazone treatment in 3T3-L1 cells. Taken together, these results suggest that ATF3 interacts with PPARγ and represses PPARγ-mediated transactivation through suppression of p300-stimulated coactivation in 3T3-L1 cells, which may play a role in inhibition of adipocyte differentiation.

  7. Fluoxetine regulates cell growth inhibition of interferon-α.

    PubMed

    Lin, Yu-Min; Yu, Bu-Chin; Chiu, Wen-Tai; Sun, Hung-Yu; Chien, Yu-Chieh; Su, Hui-Chen; Yen, Shu-Yang; Lai, Hsin-Wen; Bai, Chyi-Huey; Young, Kung-Chia; Tsao, Chiung-Wen

    2016-10-01

    Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.

  8. Clodronate inhibits PGE(2) production in compressed periodontal ligament cells.

    PubMed

    Liu, L; Igarashi, K; Kanzaki, H; Chiba, M; Shinoda, H; Mitani, H

    2006-08-01

    Periodontal ligament (PDL) cells play an essential role in orthodontic tooth movement. We recently reported that clodronate, a non-N-containing bisphosphonate, strongly inhibited tooth movement in rats, and thus could be a useful adjunct for orthodontic treatment. However, it is not clear how clodronate affects the responses of PDL cells to orthodontic force. In this study, we hypothesized that clodronate prevents the mechanical stress-induced production of prostaglandin E(2) (PGE(2)), interleukin-1beta (IL-1beta), and nitric oxide (NO) in human PDL cells. A compressive stimulus caused a striking increase in PGE(2) production, while the responses of IL-1beta and NO were less marked. Clodronate concentration-dependently inhibited the stress-induced production of PGE(2). Clodronate also strongly inhibited stress-induced gene expression for COX-2 and RANKL. These results suggest that the inhibitory effects of clodronate on tooth movement and osteoclasts may be due, at least in part, to the inhibition of COX-2-dependent PGE(2) production and RANKL expression in PDL cells.

  9. Lysyl oxidase propeptide inhibits smooth muscle cell signaling and proliferation

    SciTech Connect

    Hurtado, Paola A.; Vora, Siddharth; Sume, Siddika Selva; Yang, Dan; Hilaire, Cynthia St.; Guo Ying; Palamakumbura, Amitha H.; Schreiber, Barbara M.; Ravid, Katya; Trackman, Philip C.

    2008-02-01

    Lysyl oxidase is required for the normal biosynthesis and maturation of collagen and elastin. It is expressed by vascular smooth muscle cells, and its increased expression has been previously found in atherosclerosis and in models of balloon angioplasty. The lysyl oxidase propeptide (LOX-PP) has more recently been found to have biological activity as a tumor suppressor, and it inhibits Erk1/2 Map kinase activation. We reasoned that LOX-PP may have functions in normal non-transformed cells. We, therefore, investigated its effects on smooth muscle cells, focusing on important biological processes mediated by Erk1/2-dependent signaling pathways including proliferation and matrix metalloproteinase-9 (MMP-9) expression. In addition, we investigated whether evidence for accumulation of LOX-PP could be found in vivo in a femoral artery injury model. Recombinant LOX-PP was expressed and purified, and was found to inhibit primary rat aorta smooth muscle cell proliferation and DNA synthesis by more than 50%. TNF-{alpha}-stimulated MMP-9 expression and Erk1/2 activation were both significantly inhibited by LOX-PP. Immunohistochemistry studies carried out with affinity purified anti-LOX-PP antibody showed that LOX-PP epitopes were expressed at elevated levels in vascular lesions of injured arteries. These novel data suggest that LOX-PP may provide a feedback control mechanism that serves to inhibit properties associated with the development of vascular pathology.

  10. Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

    SciTech Connect

    Nishida, Yoshihiro . E-mail: ynishida@med.nagoya-u.ac.jp; Knudson, Warren; Knudson, Cheryl B.; Ishiguro, Naoki

    2005-07-01

    Osteosarcoma is a common malignant bone tumor associated with childhood and adolescence. The results of numerous studies have suggested that hyaluronan plays an important role in regulating the aggressive behavior of various types of cancer cells. However, no studies have addressed hyaluronan with respect to osteosarcomas. In this investigation, the mRNA expression copy number of three mammalian hyaluronan synthases (HAS) was determined using competitive RT-PCR in the osteoblastic osteosarcoma cell line, MG-63. MG-63 are highly malignant osteosarcoma cells with an abundant hyaluronan-rich matrix. The results demonstrated that HAS-2 is the predominant HAS in MG-63. Accumulation of intracellular hyaluronan increased in association with the proliferative phase of these cells. The selective inhibition of HAS-2 mRNA in MG-63 cells by antisense phosphorothioate oligonucleotides resulted in reduced hyaluronan accumulation by these cells. As expected, the reduction in hyaluronan disrupted the assembly of cell-associated matrices. However, of most interest, coincident with the reduction in hyaluronan, there was a substantial decrease in cell proliferation, a decrease in cell motility and a decrease in cell invasiveness. These data suggest that hyaluronan synthesized by HAS-2 in MG-63 plays a crucial role in osteosarcoma cell proliferation, motility, and invasion.

  11. Fermented red ginseng extract inhibits cancer cell proliferation and viability.

    PubMed

    Oh, Jisun; Jeon, Seong Bin; Lee, Yuri; Lee, Hyeji; Kim, Ju; Kwon, Bo Ra; Yu, Kang-Yeol; Cha, Jeong-Dan; Hwang, Seung-Mi; Choi, Kyung-Min; Jeong, Yong-Seob

    2015-04-01

    Red ginseng (Panax ginseng C.A. Meyer) is the most widely recognized medicinal herb due to its remedial effects in various disorders, such as cancers, diabetes, and heart problems. In this study, we investigated the anticancer effect of fermented red ginseng extract (f-RGE; provided by Jeonju Biomaterials Institute, Jeonju, South Korea) in a parallel comparison with the effect of nonfermented red ginseng extract (nf-RGE; control) on several cancer cell lines--MCF-7 breast cancer cells, HepG2 hepatocellular carcinoma cells, and reprogrammed MCF-7 cells (mimicking cancer stem cells). Cells were cultured at various concentrations of RGE (from 0.5 up to 5 mg/mL) and their viabilities and proliferative properties were examined. Our data demonstrate the following: (1) nf-RGE inhibited cell viability at ≥1 mg/mL for MCF-7 cells and ≥2 mg/mL for HepG2 cells, (2) in the presence of a carcinogenic agent, 12-O-tetradecanoylphorbol-13-acetate (TPA), nf-RGE treatment in combination with paclitaxel synergistically decreased MCF-7 as well as HepG2 cell viability, (3) f-RGE (which contained a greater level of Rg3 content) more effectively decreased the viability of MCF-7 and HepG2 cells compared to nf-RGE, and (4) f-RGE appeared more potent for inhibiting cancerous differentiation of reprogrammed MCF-7 cells in a synergistic fashion with paclitaxel, especially in the presence of TPA, compared to nf-RGE. These findings suggest that f-RGE treatment may be more effective for decreasing cancer cell survival by inducing apoptotic cell death and also presumably for preventing cancer stem cell differentiation compared to nf-RGE.

  12. A Novel LZAP-binding Protein, NLBP, Inhibits Cell Invasion*

    PubMed Central

    Kwon, Junhye; Cho, Hyun Jung; Han, Seung Hun; No, Jin Gu; Kwon, Jae Young; Kim, Hongtae

    2010-01-01

    LXXLL/leucine zipper-containing alternative reading frame (ARF)-binding protein (LZAP) was recently shown to function as a tumor suppressor through inhibition of the NF-κB signaling pathway. LZAP is also known as a negative regulator of cell invasion, and its expression was demonstrated to be reduced in several tumor tissues. However, the molecular mechanism of the negative effect of LZAP on cell invasion is unclear. In this study, we identify NLBP as a novel LZAP-binding protein using tandem affinity purification. We demonstrate the negative effects of NLBP on cell invasion and the NF-κB signaling pathway. NLBP expression was not detected in hepatocellular carcinoma cells with strong invasive activity, whereas its expression was detected in a hepatocellular carcinoma cell line with no invasive activity. We also demonstrate that these two proteins mutually affect the stability of each other by inhibiting ubiquitination of the other protein. Based on these results, we suggest that NLBP may act as a novel tumor suppressor by inhibiting cell invasion, blocking NF-κB signaling, and increasing stability of the LZAP protein. PMID:20164180

  13. A novel LZAP-binding protein, NLBP, inhibits cell invasion.

    PubMed

    Kwon, Junhye; Cho, Hyun Jung; Han, Seung Hun; No, Jin Gu; Kwon, Jae Young; Kim, Hongtae

    2010-04-16

    LXXLL/leucine zipper-containing alternative reading frame (ARF)-binding protein (LZAP) was recently shown to function as a tumor suppressor through inhibition of the NF-kappaB signaling pathway. LZAP is also known as a negative regulator of cell invasion, and its expression was demonstrated to be reduced in several tumor tissues. However, the molecular mechanism of the negative effect of LZAP on cell invasion is unclear. In this study, we identify NLBP as a novel LZAP-binding protein using tandem affinity purification. We demonstrate the negative effects of NLBP on cell invasion and the NF-kappaB signaling pathway. NLBP expression was not detected in hepatocellular carcinoma cells with strong invasive activity, whereas its expression was detected in a hepatocellular carcinoma cell line with no invasive activity. We also demonstrate that these two proteins mutually affect the stability of each other by inhibiting ubiquitination of the other protein. Based on these results, we suggest that NLBP may act as a novel tumor suppressor by inhibiting cell invasion, blocking NF-kappaB signaling, and increasing stability of the LZAP protein.

  14. Myc inhibits JNK-mediated cell death in vivo.

    PubMed

    Huang, Jiuhong; Feng, Yu; Chen, Xinhong; Li, Wenzhe; Xue, Lei

    2017-04-01

    The proto-oncogene Myc is well known for its roles in promoting cell growth, proliferation and apoptosis. However, in this study, we found from a genetic screen that Myc inhibits, rather than promotes, cell death triggered by c-Jun N-terminal kinase (JNK) signaling in Drosophila. Firstly, expression of Drosophila Myc (dMyc) suppresses, whereas loss of dMyc enhances, ectopically activated JNK signaling-induced cell death. Secondly, dMyc impedes physiologically activated JNK pathway-mediated cell death. Thirdly, loss of dMyc triggers JNK pathway activation and JNK-dependent cell death. Finally, the mammalian cMyc gene, when expressed in Drosophila, impedes activated JNK signaling-induced cell death. Thus, besides its well-studied apoptosis promoting function, Myc also antagonizes JNK-mediated cell death in Drosophila, and this function is likely conserved from fly to human.

  15. [Garlic oil inhibits cyclin E expression in gastric adenocarcinoma cells].

    PubMed

    Liang, Wei-Jiang; Yan, Xi; Zhang, Wan-Dai; Luo, Rong-Cheng

    2007-08-01

    To explore the inhibitory effect of garlic oil on cyclin E expression in gastric adenocarcinoma cells. Human gastric adenocarcinoma SGC7901 cells were cultured routinely and the expressions of transforming growth factor alpha (TGFalpha) and epidermal growth factor receptor (EGFR) are detected by immunofluorescent staining and flow cytometry. The SGC7901 cells were also cultured with RPMI 1640 without calf serum for 48 h, followed by further culture with RPMI 1640 in the presence of 2.5% calf serum before treatment with TGFalpha, garlic oil, or their combination, and cyclin E expression of the cells was then detected by immunofluorescent staining and flow cytometry. The positivity rates of TGFalpha and EGFR expressions were 46.80% and 57.78 % respectively in SGC7901 cells cultured routinely for 48 h. The positivity rate of cyclin E expression was increased by 7.06% (P<0.001) in SGC7901 cells treated with 30 microg/L TGFalpha for 5 h, decreased by 11.75% (P<0.001) following a 5-hour treatment with 10% garlic oil, and decreased further by 17.11% (Plt;0.001) after treatment with both 30 microg/L TGFalpha and 10% garlic oil for 5 h. The gastric adenocarcinoma SGC7901 cells express TGFalpha and EGFR and possess TGFalpha autocrine and paracrine loops to promote cell proliferation. Garlic oil inhibits cyclin E expression in routinely cultured SGC7901 cells and also in TGFalpha-treated ones, suggesting that garlic oil can inhibit the TGFalpha autocrine and paracrine loops, which can be one of the pathways of garlic oil to inhibit cancer cell proliferation.

  16. Spreading of embryologically distinct urothelial cells is inhibited by SPARC.

    PubMed

    Hudson, Amber E; Feng, Waldo C; Delostrinos, Catherine F; Carmean, Nicole; Bassuk, James A

    2005-02-01

    The AON epitope of secreted protein acidic and rich in cysteine (SPARC) is a conserved motif expressed by human SPARC in a variety of human cell types. Through the use of a monoclonal antibody that recognizes this epitope, transitional epithelium was found to restrict expression of SPARC to the suprabasal and intermediate layer. Such intracellular expression was defined by immunoreactive signals that localized to the apical plasma membranes of suprabasal and intermediate cells. Polarization of SPARC to apical plasma membranes of suprabasal cells was retained in vitro by a subpopulation of cells that exhibited characteristics of suprabasal cells--cell-cycle quiescence, large cell volumes, and multiple nuclei. In contrast, the basal layer of transitional epithelium in vivo and cycling cells in vitro did not exhibit this apical staining pattern, but instead sequestered the SPARC polypeptide within urothelial cytoplasm and/or nuclei, as revealed by immunohistochemical analysis. Elution of soluble proteins and DNA from urothelial cells revealed the presence of SPARC within the nuclear matrix--and that SPARC colocalized with the nuclear matrix Ki-67 antigen. rSPARC activity was demonstrated and quantified with a rounding assay whereby the spreading of freshly plated cells was inhibited by recombinant SPARC in a concentration- and time-dependent manner. Inhibition of spreading was observed in urothelial cells derived from endoderm (bladder) and mesoderm (ureter) germ layers. Statistically significant differences were seen between urothelial cells from these two layers. Mesodermal cells recovered more slowly from the inhibitory effects of rSPARC, such that at hour 6 endodermal cells underwent significantly more spreading, as shown by a rounding index (RI). These experiments provide new insights about the matricellular trafficking of SPARC and suggest that intra- and extra-cellular localization patterns influence the development, homeostasis, and differentiation of

  17. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells

    PubMed Central

    Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

    2015-01-01

    B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process. PMID:26265439

  18. Inhibition of host cell apoptosis by Eimeria bovis sporozoites.

    PubMed

    Lang, Mirjam; Kann, Michael; Zahner, Horst; Taubert, Anja; Hermosilla, Carlos

    2009-03-09

    Sophisticated evasion strategies of obligate intracellular parasites, in particular prevention of host cell apoptosis, are necessary to ensure successful replication. To study the ability of Eimeria bovis in this regard, in vitro experiments were performed applying bovine foetal gastrointestinal cells (BFGC), bovine umbilical vein endothelial cells (BUVEC) and African green monkey kidney cells (VERO) as host cells. BUVEC and BFGC allow maturation of sporozoites to macromeronts, in VERO cells sporozoites survive for weeks without showing further development. In highly infected BUVEC monolayers, infected cells survived until merozoite release whereas uninfected cells underwent apoptosis. Light microscopy and TUNEL assays performed 3-10 days p.i. showed that, within infected BFGC and VERO cell monolayers, uninfected cells underwent programmed cell death after application of various inducers of apoptosis, whereas infected cells survived. Incidentally, the anti-apoptotic efficacies in infected cells were independent of the drugs and the host cell type. We could not demonstrate significant differences between infected and uninfected cells after colchicin treatment in terms of translation of phosphatidylserines to the host cell surface, caspase 3 activity and cytochrome c release, probably since obtainable infection rates were too low. However, we could show by laser scanning confocal microscopy on single cell levels that the expression of the anti-apoptotic factors cellular Flice inhibitory protein (c-FLIP) and cellular inhibition of apoptosis protein 1 (c-IAP1) were enhanced in E. bovis infected cells after application of colchicin, in the latter case also in non-infected cells directly neighbouring infected ones. Our data show that E. bovis protects its host cell from apoptosis by increasing expression of c-IAP1 and c-FLIP.

  19. Equine mesenchymal stem cells inhibit T cell proliferation through different mechanisms depending on tissue source.

    PubMed

    Carrade Holt, Danielle D; Wood, Joshua A; Granick, Jennifer L; Walker, Naomi J; Clark, Kaitlin C; Borjesson, Dori L

    2014-06-01

    Mesenchymal stem cells (MSCs) are used in both human clinical trials and veterinary medicine for the treatment of inflammatory and immune-mediated diseases. MSCs modulate inflammation by decreasing the cells and products of the inflammatory response. Stimulated equine MSCs from bone marrow (BM), adipose tissue (AT), cord blood (CB), and umbilical cord tissue (CT) inhibit lymphocyte proliferation and decrease inflammatory cytokine production. We hypothesized that equine MSCs inhibit T cell proliferation through secreted mediators and that MSCs from different tissue sources decrease T cell proliferation through different mechanisms. To test our hypotheses, we inhibited interleukin-6 (IL-6), nitric oxide (NO), and prostaglandin E2 (PGE2) to determine their impact on stimulated T cell proliferation. We also determined how equine MSCs modulate lymphocyte proliferation either via cell cycle arrest or apoptosis. Inhibition of IL-6 or NO did not reverse the immunomodulatory effect of MSCs on activated T cells. In contrast, inhibition of PGE2 restored T cell proliferation, restored the secretion of tumor necrosis factor-α and interferon-γ, and increased IL-10 levels. MSCs from solid-tissue-derived sources, AT and CT, inhibited T cell proliferation through induction of lymphocyte apoptosis while blood-derived MSCs, BM and CB, induced lymphocyte cell cycle arrest. Equine MSCs from different tissue sources modulated immune cell function by both overlapping and unique mechanisms. MSC tissue source may determine immunomodulatory properties of MSCs and may have very practical implications for MSC selection in the application of MSC therapy.

  20. Inhibition of osteogenic differentiation of human mesenchymal stem cells

    PubMed Central

    Moioli, Eduardo K.; Hong, Liu; Mao, Jeremy J.

    2010-01-01

    Mesenchymal stem cells (hMSCs) have been shown to differentiate into osteoblasts that, in turn, are capable of forming tissues analogous to bone. The present study was designed to investigate the inhibition of osteogenesis by hMSCs. Bone marrow-derived hMSCs were treated with transforming growth factor β-3 (TGFβ3) at various doses during or after their differentiation into osteogenic cells. TGFβ3 was encapsulated in poly(DL-lactic-co-glycolic acid) (PLGA) microspheres and released via controlled delivery in the osteogenic culture of hMSCs and hMSC-derived osteoblasts for up to 28 days. Controlled release of TGFβ3 inhibited the osteogenic differentiation of hMSCs, as evidenced by significantly reduced alkaline phosphatase activity and staining, as well as decreased mineral deposition. After hMSCs had been differentiated into osteoblasts, controlled release of TGFβ3 further inhibited not only alkaline phosphatase and mineral deposition but also osteocalcin expression. These findings demonstrate the potential for sustained modulation of the behavior of stem cells and/or stem cell-derived lineage-specific cells via controlled release of growth factor(s). The attenuation of osteogenic differentiation of MSCs may facilitate understanding not only the regulation and patterning of osteogenesis in development but also several pathological models such as osteopetrosis, craniosynostosis, and heart valve calcification. PMID:17537129

  1. Hugl-1 inhibits glioma cell growth in intracranial model.

    PubMed

    Liu, Xuejiao; Lu, Dong; Ma, Peng; Liu, Huaqiang; Cao, Yuewen; Sang, Ben; Zhu, Xianlong; Shi, Qiong; Hu, Jinxia; Yu, Rutong; Zhou, Xiuping

    2015-10-01

    Drosophila lethal (2) giant larvae (lgl) has been reported as a tumor suppressor and could regulate the Drosophila hippo signaling. Human giant larvae-1(Hugl-1), one human homologue of Drosophila lgl, also has been reported to be involved in the development of some human cancers. However, whether Hugl-1 is associated with the pathogenesis of malignant gliomas remains poorly understood. In the present work, we examined the effect of Hugl-1 on glioma cell growth both in vitro and in vivo. Firstly, we found that Hugl-1 protein levels decreased in the human glioma tissues, suggesting that Hugl-1 is involved in glioma progression. Unfortunately, either stably or transiently over-expressing Hugl-1 did not affect glioma cell proliferation in vitro. In addition, Hugl-1 over-expression did not regulate hippo signaling pathway. Interestingly, over-expression of Hugl-1 not only inhibited gliomagenesis but also markedly inhibited cell proliferation and promoted the apoptosis of U251 cells in an orthotopic model of nude mice. Taken together, this study provides the evidence that Hugl-1 inhibits glioma cell growth in intracranial model of nude mice, suggesting that Hugl-1 might be a potential tumor target for glioma therapy.

  2. A 12-mm carcinoid tumor of the minor duodenal papilla with lymph node metastases.

    PubMed

    Fukami, Yasuyuki; Kurumiya, Yasuhiro; Mizuno, Keisuke; Sekoguchi, Ei; Kobayashi, Satoshi; Ito, Akira; Tomida, Akihiro; Onishi, Sakura; Shirotsuki, Ryo; Okubo, Kenji; Narita, Michihiko

    2013-01-01

    Carcinoid tumors located in the minor duodenal papilla are extremely rare, with only a few cases reported in the literature. Herein, we report the case of a 71-year-old man with a 12-mm carcinoid tumor at the minor duodenal papilla with lymph node metastases. Multidetector-row computed tomography with contrast enhancement revealed a 12-mm well-enhanced tumor in the duodenum. Upper gastrointestinal endoscopy showed a 12-mm submucosal tumor at the minor papilla of the duodenum. Biopsy specimens revealed a carcinoid tumor, and a subtotal stomach-preserving pancreatoduodenectomy was performed. Carcinoid tumors at the minor duodenal papilla have a high prevalence of nodal disease, even for tumors <2 cm in diameter. Therefore, we believe that radical resection with tumor-free margins (i.e. pancreatoduodenectomy) is the treatment of choice.

  3. Concurrent small bowel adenocarcinoma and carcinoid tumor in Crohn's disease--case report and literature review.

    PubMed

    Boltin, Doron; Levi, Zohar; Halpern, Marisa; Fraser, Gerald M

    2011-10-01

    Adenocarcinomas of the large and small bowel, as well as intestinal carcinoid tumors have been reported at increased rates in Crohn's disease. We herein report a rare case of concurrent adenocarcinoma and carcinoid tumor of the small bowel presenting as intestinal obstruction and found incidentally at laparotomy in a 55 year old male with longstanding ileal Crohn's disease. We performed a Medline Pubmed search for cases of synchronous or composite adenocarcinoma and carcinoid tumor in the setting of Crohn's disease and identified four similar cases. Concurrent adenocarcinoma and carcinoid tumor occurred both in newly diagnosed and longstanding Crohn's disease, most commonly involved the terminal ileum and presented with symptoms mimicking Crohn's disease. Diagnosis was made incidentally at laparotomy in all cases. Lymph node involvement was variable. Clinicians should be aware of this rare entity for expeditious surgical intervention.

  4. A carcinoid tumor of the ampulla of Vater treated by endoscopic snare papillectomy.

    PubMed

    Pyun, Dae-Keun; Moon, Gyoo; Han, Jimin; Kim, Myung-Hwan; Lee, Sang Soo; Seo, Dong-Wan; Lee, Sung-Koo

    2004-12-01

    Here, a case of a patient with incidental finding of a carcinoid tumor of the ampulla of Vater, who was treated with endoscopic snare papillectomy, is reported. A 62-year-old male was admitted to our hospital due to a carcinoid tumor of the ampulla of Vater, which was found during follow-up endoscopy after an endoscopic mucosal resection of early gastric cancer. No lymphadenopathy or visceral metastasis was found on an abdominal CT scan, In-111 octerotide scan and EUS. The ampulla was then en bloc removed by endoscopic snare papillectomy. The resected specimen revealed a 0.7 x 0.5 x 0.1 cm sized carcinoid tumor. All margins of resection were negative for tumor. After six months of follow-up, there was no evidence of recurrence and metastasis, either endoscopically or radiologically. To our knowledge, this case is the first report of an ampullary carcinoid tumor treated by endoscopic snare papillectomy in Korea.

  5. Primary carcinoid tumor of medulla spinalis: case report and review of the literature.

    PubMed

    Zhang, Xian-feng; Zhang, Yan; Yan, Xu; Bie, Li

    2014-12-19

    Carcinoid tumors are slow growing neuroendocrine tumors which can originate from various sites within the body. A carcinoid tumor originating in the medulla spinalis has not previously been reported in the literature. We report a case of a 33-year-old man, presenting with a five-month history of bilateral lower extremity pain, as well as paresthesia, and mild weakness in one lateral lower extremity. A lumbar laminectomy of L3 to L5 and en bloc resection of the tumor was performed. Postoperative histopathology and immunohistochemical analysis of the tumor were consistent with that of a carcinoid tumor. There were no clinical or radiological signs of tumor recurrence or metastasis at the patient's two year postoperative follow-up. During the differential diagnosis of medulla spinalis tumors, the possibility of a primary carcinoid tumor originating within the medulla spinalis should be considered. An accurate tumor classification is imperative to ensure that the most effective course of treatment is pursued.

  6. Treatment of solitary gastric carcinoid tumor by endoscopic polypectomy in a patient with pernicious anemia

    PubMed Central

    Kadikoylu, Gurhan; Yavasoglu, Irfan; Yukselen, Vahit; Ozkara, Esra; Bolaman, Zahit

    2006-01-01

    Type I gastric carcinoid tumors result from hypergastrinemia in 1%-7% of patients with pernicious anemia. We diagnosed pernicious anemia in a 48-year-old female patient with complaint of fatigue for three months. She had no gastrointestinal symptoms. Endoscopic examination ot the upper gastrointestinal tract revealed atrophic gastritis and a polypoid lesion in the corpus of 3-4 mm in size. Endoscopic polypectomy was performed. Histopathological examination of the specimen revealed positive chromogranin A and synaptophysin stainings compatible with the diagnosis of a carcinoid tumor. Serum gastrin level was increased, urinary 5-hydroxyindoleacetic acid was within the normal range. There was no other symptom, sign, or laboratory finding of a carcinoid syndrome in the patient. No metastasis was found with indium-111 octreotide scan, computed tomographies of abdomen and thorax. Type I gastric carcinoid tumors are only rarely solitary and patients with tumors < 1 cm in size may benefit from endoscopic polypectomy. PMID:16830392

  7. Sex steroids inhibit osmotic swelling of retinal glial cells.

    PubMed

    Neumann, Florian; Wurm, Antje; Linnertz, Regina; Pannicke, Thomas; Iandiev, Ianors; Wiedemann, Peter; Reichenbach, Andreas; Bringmann, Andreas

    2010-04-01

    Osmotic swelling of glial cells may contribute to the development of retinal edema. We investigated whether sex steroids inhibit the swelling of glial somata in acutely isolated retinal slices and glial cells of the rat. Superfusion of retinal slices or cells from control animals with a hypoosmolar solution did not induce glial swelling, whereas glial swelling was observed in slices of postischemic and diabetic retinas. Progesterone, testosterone, estriol, and 17beta-estradiol prevented glial swelling with half-maximal effects at approximately 0.3, 0.6, 6, and 20 microM, respectively. The effect of progesterone was apparently mediated by transactivation of metabotropic glutamate receptors, P2Y1, and adenosine A1 receptors. The data suggest that sex steroids may inhibit cytotoxic edema in the retina.

  8. Astaxanthin Inhibits Proliferation and Induces Apoptosis and Cell Cycle Arrest of Mice H22 Hepatoma Cells

    PubMed Central

    Shao, Yiye; Ni, Yanbo; Yang, Jing; Lin, Xutao; Li, Jun; Zhang, Lixia

    2016-01-01

    Background It is widely recognized that astaxanthin (ASX), a member of the carotenoid family, has strong biological activities including antioxidant, anti-inflammation, and immune-modulation activities. Previous studies have confirmed that ASX can effectively inhibit hepatoma cells in vitro. Material/Methods MTT was used to assay proliferation of mice H22 cells, and flow cytometry was used to determine apoptosis and cell cycle arrest of H22 cells in vitro and in vivo. Moreover, anti-tumor activity of ASX was observed in mice. Results ASX inhibited the proliferation of H22 cells, promoted cell necrosis, and induced cell cycle arrest in G2 phase in vitro and in vivo. Conclusions This study indicated that ASX can inhibit proliferation and induce apoptosis and cell cycle arrest in mice H22 hepatoma cells in vitro and in vivo. PMID:27333866

  9. Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death

    PubMed Central

    Kim, Hyun-Ji

    2016-01-01

    Paclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, and used as an anticancer agent. Paclitaxel prevents cancer cell division by inhibiting spindle fiber function, inducing cell death. A recent study demonstrated that paclitaxel binds to myeloid differentiation protein-2 of Toll-like receptor 4 and prevents the signal transduction of lipopolysaccharide (LPS). Paclitaxel converts immune cells hypo-responsive to LPS. In this study, we investigated whether paclitaxel can inhibit the phenotype and function of immune cells. To accomplish this, we used spleen cells, a major type of immune cell, LPS, a representative inflammatory agent and a mitogen for B lymphocytes. LPS profoundly increased the activation and cytokine production of spleen cells. However, paclitaxel significantly inhibited LPS-induced hyper-activation of spleen cells. Furthermore, we found that paclitaxel induced cell death of LPS-treated spleen cells. These results suggest that paclitaxel can inhibit the hyper-immune response of LPS in spleen cells via a variety of mechanisms. These findings suggest that paclitaxel can be used as a modulating agent for diseases induced by hyper-activation of B lymphocytes. Taken together, these results demonstrate that paclitaxel inhibits the function of spleen cells activated by LPS, and further induces cell death. PMID:27030196

  10. Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death.

    PubMed

    Kim, Hyun-Ji; Joo, Hong-Gu

    2016-12-30

    Paclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, and used as an anticancer agent. Paclitaxel prevents cancer cell division by inhibiting spindle fiber function, inducing cell death. A recent study demonstrated that paclitaxel binds to myeloid differentiation protein-2 of Toll-like receptor 4 and prevents the signal transduction of lipopolysaccharide (LPS). Paclitaxel converts immune cells hypo-responsive to LPS. In this study, we investigated whether paclitaxel can inhibit the phenotype and function of immune cells. To accomplish this, we used spleen cells, a major type of immune cell, LPS, a representative inflammatory agent and a mitogen for B lymphocytes. LPS profoundly increased the activation and cytokine production of spleen cells. However, paclitaxel significantly inhibited LPS-induced hyper-activation of spleen cells. Furthermore, we found that paclitaxel induced cell death of LPS-treated spleen cells. These results suggest that paclitaxel can inhibit the hyper-immune response of LPS in spleen cells via a variety of mechanisms. These findings suggest that paclitaxel can be used as a modulating agent for diseases induced by hyper-activation of B lymphocytes. Taken together, these results demonstrate that paclitaxel inhibits the function of spleen cells activated by LPS, and further induces cell death.

  11. Contact inhibition of locomotion determines cell-cell and cell-substrate forces in tissues.

    PubMed

    Zimmermann, Juliane; Camley, Brian A; Rappel, Wouter-Jan; Levine, Herbert

    2016-03-08

    Cells organized in tissues exert forces on their neighbors and their environment. Those cellular forces determine tissue homeostasis as well as reorganization during embryonic development and wound healing. To understand how cellular forces are generated and how they can influence the tissue state, we develop a particle-based simulation model for adhesive cell clusters and monolayers. Cells are contractile, exert forces on their substrate and on each other, and interact through contact inhibition of locomotion (CIL), meaning that cell-cell contacts suppress force transduction to the substrate and propulsion forces align away from neighbors. Our model captures the traction force patterns of small clusters of nonmotile cells and larger sheets of motile Madin-Darby canine kidney (MDCK) cells. In agreement with observations in a spreading MDCK colony, the cell density in the center increases as cells divide and the tissue grows. A feedback between cell density, CIL, and cell-cell adhesion gives rise to a linear relationship between cell density and intercellular tensile stress and forces the tissue into a nonmotile state characterized by a broad distribution of traction forces. Our model also captures the experimentally observed tissue flow around circular obstacles, and CIL accounts for traction forces at the edge.

  12. Sulforaphane Inhibits Mammary Adipogenesis by Targeting Adipose Mesenchymal Stem Cells

    PubMed Central

    Li, Qinglin; Xia, Jixiang; Yao, Yuan; Gong, Da-wei; Shi, Hongfei; Zhou, Qun

    2013-01-01

    It is now well accepted that tumor cells actively communicate with the tumor microenvironment (e.g., adipocytes) leading to the progression of breast cancer and other malignancies. It is also known that adipose mesenchymal stem cells (MSCs) have the ability to differentiate into mature adipocytes and initiate cytokine signaling within the tumor microenvironment. Here, we examine the role of MSC-differentiated adipocytes on breast cancer cell migration, and test the effects of sulforaphane (SFN, a dietary chemoprevention agent) on adipocyte-breast cancer cell interaction. Our results demonstrate that SFN promotes MSC self-renewal and inhibits adipogenic differentiation. Subsequently, SFN-treatment of adipocytes considerably hinders cytokine communication with breast cancer cells, thereby decreasing breast cancer cell migration and tumor formation. PMID:24002734

  13. Sulforaphane inhibits mammary adipogenesis by targeting adipose mesenchymal stem cells.

    PubMed

    Li, Qinglin; Xia, Jixiang; Yao, Yuan; Gong, Da-Wei; Shi, Hongfei; Zhou, Qun

    2013-09-01

    It is now well accepted that tumor cells actively communicate with the tumor microenvironment (e.g., adipocytes) leading to the progression of breast cancer and other malignancies. It is also known that adipose mesenchymal stem cells (MSCs) have the ability to differentiate into mature adipocytes and initiate cytokine signaling within the tumor microenvironment. Here, we examine the role of MSC-differentiated adipocytes on breast cancer cell migration, and test the effects of sulforaphane (SFN, a dietary chemoprevention agent) on adipocyte-breast cancer cell interaction. Our results demonstrate that SFN promotes MSC self-renewal and inhibits adipogenic differentiation. Subsequently, SFN treatment of adipocytes considerably hinders cytokine communication with breast cancer cells, thereby decreasing breast cancer cell migration and tumor formation.

  14. Estrogen inhibits cell cycle progression and retinoblastoma phosphorylation in rhesus ovarian surface epithelial cell culture

    SciTech Connect

    Wright, Jay W.; Stouffer, Richard L.; Rodland, Karin D.

    2003-10-31

    Estrogen promotes the growth of some ovarian cancer cells at nanomolar concentrations, but has been shown to inhibit growth of normal ovarian surface epithelial (OSE) cells at micromolar concentrations (1μg/ml). OSE cells express the estrogen receptor (ER)-α, and are the source of 90% of various cancers. The potential sensitivity of OSE cells to estrogen stresses the importance of understanding the estrogen-dependent mechanisms at play in OSE proliferation and transformation, as well as in anticancer treatment. We investigated the effects of estradiol on cell proliferation in vitro, and demonstrate an intracellular locus of action of estradiol in cultured rhesus ovarian surface epithelial (RhOSE) cells. We show that ovarian and breast cells are growth-inhibited by micromolar concentration of estradiol and that this inhibition correlates with estrogen receptor expression. We further show that normal rhesus OSE cells do not activate ERK or Akt in response to estradiol nor does estradiol block the ability of serum to stimulate ERK or induce cyclin D expression. Contrarily, estradiol inhibits serum-dependent retinoblastoma protein (Rb) phosphorylation and blocks DNA synthesis. This inhibition does not formally arrest cells and is reversible within hours of estrogen withdrawal. Our data are consistent with growth inhibition by activation of Rb and indicate that sensitivity to hormone therapy in anticancer treatment can be modulated by cell cycle regulators downstream of the estrogen receptor.

  15. Medial hypertrophy of the ovarian vein: a novel type of vascular pathology associated with a primary ovarian carcinoid tumor.

    PubMed

    Dessauvagie, Benjamin F; Lai, Patrick H; Oost, Ebo; Thomas, Anitha; Stewart, Colin J R

    2015-01-01

    Primary carcinoid tumors of the ovary are rare accounting for only 1% of neoplasms that are associated with the carcinoid syndrome. However, the carcinoid syndrome can occur in the absence of hepatic metastases due to the release of vasoactive peptides directly into the systemic circulation via the ovarian vein. We present a 69-yr-old woman presenting with carcinoid valvular disease and congestive cardiac failure who was found to have a primary left ovarian carcinoid tumor. At operation it was noted that the left ovarian vein had an unusually firm and thickened appearance, and histologic examination revealed marked fibromuscular medial hypertrophy with luminal compression. There was no associated vascular elastosis. This ovarian venous alteration appears to represent a novel addition to the spectrum of cardiovascular injuries associated with carcinoid tumors.

  16. Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth.

    PubMed

    Pal, Krishnendu; Pletnev, Alexandre A; Dutta, Shamit K; Wang, Enfeng; Zhao, Ruizhi; Baral, Aradhita; Yadav, Vinod Kumar; Aggarwal, Suruchi; Krishnaswamy, Soundararajan; Alkharfy, Khalid M; Chowdhury, Shantanu; Spaller, Mark R; Mukhopadhyay, Debabrata

    2014-10-01

    Endoglin, a 180-kDa disulfide-linked homodimeric transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a coreceptor of TβRII that binds TGFβ and is important for vascular development, and consequently has become a compelling target for antiangiogenic therapies. A few recent studies in gastrointestinal stromal tumor (GIST), breast cancer, and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. We analyzed the antiproliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable antiproliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the antitumor effect of both RNAi-based and competitive inhibitor-based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells. ©2014 American Association for Cancer Research.

  17. Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth

    PubMed Central

    Pal, Krishnendu; Pletnev, Alexandre A.; Dutta, Shamit K.; Wang, Enfeng; Zhao, Ruizhi; Baral, Aradhita; Yadav, Vinod Kumar; Aggarwal, Suruchi; Krishnaswamy, Soundararajan; Alkharfy, Khalid M.; Chowdhury, Shantanu; Spaller, Mark R.; Mukhopadhyay, Debabrata

    2014-01-01

    Endoglin, a 180 kDa disulfide-linked homodimeric, transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a co-receptor of TβRII that binds Transforming Growth Factor-β (TGF-β) and is important for vascular development, and consequently has become a compelling target for anti-angiogenic therapies. A few recent studies in Gastrointestinal Stromal Tumor (GIST), breast cancer and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond anti-angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. We analyzed the anti-proliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable anti-proliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the anti-tumor effect of both RNAi based and competitive inhibitor based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells. PMID:25125675

  18. Quercetin Inhibits Cell Migration and Invasion in Human Osteosarcoma Cells.

    PubMed

    Lan, Haifeng; Hong, Wei; Fan, Pan; Qian, Dongyang; Zhu, Jianwei; Bai, Bo

    2017-09-21

    Osteosarcoma is a malignant tumor associated with high mortality; however, no effective therapies for the disease have been developed. Several studies have focused on elucidating the pathogenesis of osteosarcoma and have aimed to develop novel therapies for the disease. Quercetin is a vital dietary flavonoid that has been shown to have a variety of anticancer effects, as it induces cell cycle arrest, apoptosis, and differentiation and is involved in cell adhesion, metastasis and angiogenesis. Herein, we aimed to investigate the effects of quercetin on osteosarcoma migration and invasion in vitro and in vivo and to explore the molecular mechanisms underlying its effects on osteosarcoma migration and invasion. Cell viability, cell cycle activity and cell apoptosis were measured using CCK-8 assay and flow cytometry, and cell migration and invasion were evaluated by wound healing and transwell assays, respectively. The mRNA and protein expression levels of several proteins of interest were assessed by real-time quantitative PCR and western blotting, respectively. Moreover, a nude mouse model of human osteosarcoma lung metastasis was established to assess the anti-metastatic effects of quercetin in vivo. We noted no significant differences in cell cycle activity and apoptosis between HOS and MG63 cells and control cells. Treatment with quercetin significantly attenuated cell migration and invasion in HOS and MG63 cells compared with treatment with control medium. Moreover HIF-1α, VEGF, MMP2, and MMP9 mRNA and protein expression levels were significantly downregulated in HOS cells treated with quercetin compared with HOS cells treated with controls. Additionally, treatment with quercetin attenuated metastatic lung tumor formation and growth in the nude mouse model of osteosarcoma compared with treatment with controls. Our findings regarding the inhibitory effects of quercetin on cell migration and invasion suggest that quercetin may have potential as a therapy for human

  19. Residual ovarian tissue mimicking malignancy in a patient with mucinous carcinoid tumor of the ovary. A case report.

    PubMed

    Burke, M; Talerman, A; Carlson, J A; Bibbo, M

    1997-01-01

    Mucinous carcinoid tumor of the ovary is an uncommon lesion in reproductive-age women. If a patient status post total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) for this tumor presents with a pelvic mass, recurrence of the tumor must be considered, as must the presence of residual ovarian tissue producing physiologic cysts with mass effect, termed the "ovarian remnant syndrome." Benign ovarian follicle cysts may have cellular atypia and mimic malignancy. A female, one year status post TAH-BSO for mucinous carcinoid tumor of the ovary, presented with pelvic mass. Clinical and radiologic evidence supported the diagnosis of recurrent tumor. Aspiration biopsy material was compatible with malignancy, and immunocytochemical stains supported a neuroendocrine origin of the cells. Surgical excision and histologic examination of the mass revealed ovarian tissue with features of corpus luteum and follicular cyst. Numerous pitfalls exist when considering an unusual tumor. While the patient's history, clinical impressions and immunocytochemistry may strongly suggest malignancy, more common benign entities may mimic malignancy and should be considered in the differential diagnosis.

  20. Resection of Carcinoid Tumor Metastatic to the Right Ventricle and Tricuspid Valve.

    PubMed

    Williams, Adam R; Wang, Andrew; Kim, Han; Milano, Carmelo A

    2015-12-01

    Carcinoid tumors rarely metastasize to the heart, and previous reports involved the myocardium only. We present a case of carcinoid tumor metastatic to the right ventricle (RV) and tricuspid valve. Preoperative cardiac magnetic resonance imaging (CMR) showed the tumor arising from the right ventricular free wall and involving the tricuspid valve apparatus. The tumor was resected through a right atriotomy and required tricuspid valve replacement.

  1. Increased accumulation of N-isopropyl-(I-123)p-iodoamphetamine in bronchial carcinoid tumor

    SciTech Connect

    Nishizawa, S.; Higa, T.; Kuroda, Y.; Sano, A.; Murakami, M.; Takahashi, Y. )

    1990-02-01

    Radionuclide imaging with N-isopropyl-(I-123)p-iodoamphetamine (({sup 123}I)IMP) was performed in a patient with recurrent bronchial carcinoid tumor. Increased accumulation of ({sup 123}I)IMP was observed in the known lesions of the brain and neck on both tomographic and planar images. Scintigraphy also revealed unknown metastatic lesions of the paraaortic lymph nodes, which were later confirmed on x-ray CT. Iodine-123-IMP may have a potential role in evaluating carcinoid tumors.

  2. Sickle erythrocytes inhibit human endothelial cell DNA synthesis

    SciTech Connect

    Weinstein, R.; Zhou, M.A.; Bartlett-Pandite, A.; Wenc, K. )

    1990-11-15

    Patients with sickle cell anemia experience severe vascular occlusive phenomena including acute pain crisis and cerebral infarction. Obstruction occurs at both the microvascular and the arterial level, and the clinical presentation of vascular events is heterogeneous, suggesting a complex etiology. Interaction between sickle erythrocytes and the endothelium may contribute to vascular occlusion due to alteration of endothelial function. To investigate this hypothesis, human vascular endothelial cells were overlaid with sickle or normal erythrocytes and stimulated to synthesize DNA. The erythrocytes were sedimented onto replicate monolayers by centrifugation for 10 minutes at 17 g to insure contact with the endothelial cells. Incorporation of 3H-thymidine into endothelial cell DNA was markedly inhibited during contact with sickle erythrocytes. This inhibitory effect was enhanced more than twofold when autologous sickle plasma was present during endothelial cell labeling. Normal erythrocytes, with or without autologous plasma, had a modest effect on endothelial cell DNA synthesis. When sickle erythrocytes in autologous sickle plasma were applied to endothelial monolayers for 1 minute, 10 minutes, or 1 hour and then removed, subsequent DNA synthesis by the endothelial cells was inhibited by 30% to 40%. Although adherence of sickle erythrocytes to the endothelial monolayers was observed under these experimental conditions, the effect of sickle erythrocytes on endothelial DNA synthesis occurred in the absence of significant adherence. Hence, human endothelial cell DNA synthesis is partially inhibited by contact with sickle erythrocytes. The inhibitory effect of sickle erythrocytes occurs during a brief (1 minute) contact with the endothelial monolayers, and persists for at least 6 hours of 3H-thymidine labeling.

  3. Salinomycin inhibits osteosarcoma by targeting its tumor stem cells.

    PubMed

    Tang, Qing-Lian; Zhao, Zhi-Qiang; Li, Jin-Chun; Liang, Yi; Yin, Jun-Qiang; Zou, Chang-Ye; Xie, Xian-Biao; Zeng, Yi-Xin; Shen, Jing-Nan; Kang, Tiebang; Wang, Jin

    2011-12-01

    Osteosarcoma is the most common primary bone tumor in children and adolescents and is typically associated with a poor prognosis. Tumor stem cells (TSCs) are presumed to drive tumor initiation and tumor relapse or metastasis. Hence, the poor prognosis of osteosarcoma likely results from a failure to target the osteosarcoma stem cells. Here, we have utilized three different methods to enrich TSCs in osteosarcoma and further evaluated whether salinomycin could selectively target TSCs in osteosarcoma. Our results indicated that sarcosphere selection, chemotherapy selection and stem cell marker OCT4 or SOX2 over-expression are all effective in the enrichment of TSCs from osteosarcoma cell lines. Further investigation found that salinomycin inhibited osteosarcoma by selectively targeting its stem cells both in vitro and in vivo without severe side effects, and the Wnt/β-catenin signaling pathway may be involved in this inhibition of salinomycin. Taken together, we have identified that salinomycin is an effective inhibitor of osteosarcoma stem cells, supporting the use of salinomycin for elimination of osteosarcoma stem cells and implying a need for further clinical evaluation.

  4. Ethylene Inhibits Cell Proliferation of the Arabidopsis Root Meristem.

    PubMed

    Street, Ian H; Aman, Sitwat; Zubo, Yan; Ramzan, Aleena; Wang, Xiaomin; Shakeel, Samina N; Kieber, Joseph J; Schaller, G Eric

    2015-09-01

    The root system of plants plays a critical role in plant growth and survival, with root growth being dependent on both cell proliferation and cell elongation. Multiple phytohormones interact to control root growth, including ethylene, which is primarily known for its role in controlling root cell elongation. We find that ethylene also negatively regulates cell proliferation at the root meristem of Arabidopsis (Arabidopsis thaliana). Genetic analysis indicates that the inhibition of cell proliferation involves two pathways operating downstream of the ethylene receptors. The major pathway is the canonical ethylene signal transduction pathway that incorporates CONSTITUTIVE TRIPLE RESPONSE1, ETHYLENE INSENSITIVE2, and the ETHYLENE INSENSITIVE3 family of transcription factors. The secondary pathway is a phosphorelay based on genetic analysis of receptor histidine kinase activity and mutants involving the type B response regulators. Analysis of ethylene-dependent gene expression and genetic analysis supports SHORT HYPOCOTYL2, a repressor of auxin signaling, as one mediator of the ethylene response and furthermore, indicates that SHORT HYPOCOTYL2 is a point of convergence for both ethylene and cytokinin in negatively regulating cell proliferation. Additional analysis indicates that ethylene signaling contributes but is not required for cytokinin to inhibit activity of the root meristem. These results identify key elements, along with points of cross talk with cytokinin and auxin, by which ethylene negatively regulates cell proliferation at the root apical meristem.

  5. Paromomycin inhibits Cryptosporidium infection of a human enterocyte cell line.

    PubMed

    Marshall, R J; Flanigan, T P

    1992-04-01

    Cryptosporidium parvum is a protozoan parasite that causes severe enteritis in patients with AIDS for which there is no effective therapy. Paromomycin is a nonabsorbable aminoglycoside that is effective in the treatment of other intestinal protozoa. The ability of paromomycin to inhibit C. parvum infection of a differentiated human enterocyte cell line was evaluated in vitro. Paromomycin concentrations ranging from 50 to 5000 micrograms/ml inhibited infection at 24 h in a dose-dependent fashion. Concentrations greater than 1000 micrograms/ml, which are theoretically achievable in the bowel lumen, inhibited infection by greater than 85% (P less than .001). Prospective clinical trials of paromomycin for the treatment of cryptosporidiosis in patients with AIDS are warranted.

  6. Scintigraphic detection of carcinoid tumors with a cost effectiveness analysis

    PubMed Central

    Dimitroulopoulos, Dimitris; Xynopoulos, Dimitris; Tsamakidis, Klisthenis; Paraskevas, Emmanouel; Zisimopoulos, Athanassios; Andriotis, Efthymios; Fotopoulou, Ekaterini; Kontis, Marios; Paraskevas, Ioannis

    2004-01-01

    AIM: To evaluate the diagnostic sensitivity and accuracy and the cost-effectiveness of this technique in the detection of gastroenteropancreatic carcinoid tumors and their metastases in comparison with conventional imaging methods. METHODS: Somatostatin receptor scintigraphy (SRS) was performed in 24 patients with confirmed carcinoids and 7 under investigation. The results were compared with those of conventional imaging methods (chest X-ray, upper abdominal ultrasound, chest CT, upper and lower abdominal CT). Also a cost-effectiveness analysis was performed comparing the cost in Euro of several combinations of SRS with conventional imaging modalities. RESULTS: SRS visualized primary or metastatic sites in 71.0% of cases and 61.3% of conventional imagings. The diagnostic sensitivity of the method was higher in patients with suspected lesions (85.7% vs 57.1%). SRS was less sensitive in the detection of metastatic sites (78.9% vs 84.2%). The undetectable lesions by SRS metastatic sites were all in the liver. Between several imaging combinations, the combinations of chest X-ray/upper abdominal CT/SRS and chest CT/upper abdominal CT/SRS showed the highest sensitivity (88.75%) in terms of the number of detected lesions. The combinations of chest X-ray/upper abdominal US/SRS and chest CT/upper abdominal ultrasound/SRS yielded also a quite similar sensitivity (82%). Compared to the cost of the four sensitive combinations the combination of chest X-ray/upper abdominal ultrasound/SRS presented the lower cost, 1183.99 Euro vs 1251.75 Euro for chest CT/upper abdominal ultrasound/SRS, 1294.93 Euro for chest X/ray/upper abdominal CT/SRS and 1362.75 Euro for chest CT/upper abdominal CT/SRS. CONCLUSION: SRS imaging is a very sensitive method for the detection of gastroenteropancreatic carcinoids but is less sensitive than ultrasound and CT in the detection of liver metastases. Between several imaging combinations, the combination of chest X-ray/upper abdominal CT/SRS shows the

  7. [Multidetector computed tomography assessment of the degree of differentiation of bronchial carcinoid tumors].

    PubMed

    Bueno Palomino, A; Zurera Tendero, L; Espejo Herrero, J J; Espejo Pérez, S; Villar Pastor, C

    2013-01-01

    To define the CT findings for bronchial carcinoid tumors and to determine whether these findings enable these tumors to be classified as typical or atypical. We reviewed the chest CT studies performed between 1 January 2001 and 31 December 2009 in patients at our hospital diagnosed with bronchial carcinoid tumors. The sample consisted of 52 patients (23 women and 29 men) with a mean age of 47 years (range 11-77 years). The 52 cases were classified as typical or atypical on the basis of the following radiological findings: size, location, focality, type of growth, calcifications, signs secondary to bronchial obstruction, and the presence of significant lymph node enlargement or metastases. These findings were then compared with the histological findings. Typical carcinoid tumors were the most prevalent (46 cases). The variables associated with atypical tumors were: male sex, advanced age at onset, and size >3cm. The accuracy of CT in classifying atypical tumors correctly increased with the number of variables indicative of atypical carcinoid tumors. A negative result for atypical nature made it possible to rule out an atypical carcinoid tumor in 95% of the cases. CT is useful for defining and characterizing carcinoid tumors into typical or atypical, although a precise formula for differentiating between the two types remains to be defined. Copyright © 2011 SERAM. Published by Elsevier Espana. All rights reserved.

  8. Primary neuroendocrine tumor (carcinoid tumor) of the testis: a case report with review of literature.

    PubMed

    Lubana, Sandeep Singh; Singh, Navdeep; Chan, Hon Cheung; Heimann, David

    2015-05-31

    The term carcinoid (Karzinoide) was coined by German pathologist Oberndorfer in 1907. Primary testicular carcinoid tumors (TCT) are rare, constituting 0.23% of all testicular tumors. In this report we describe a case of primary TCT of the testis and present the results of an extensive literature review to cover all the aspects of carcinoid tumor, including the definition, classification, origin, presentation, diagnostic evaluation, management, prognosis, and follow-up. A 34-year-old male presented with chronic right scrotal swelling with recent onset of pain. Radical orchiectomy revealed a solid intratesticular tumor confined to the testis and epididymis, without lymphovascular invasion. Histology was consistent with neuroendocrine carcinoma. The tumor was staged as pT1 N0 M0 S2. Immunohistochemistry was positive for neuroendocrine markers. An extratesticular carcinoid tumor was ruled out. Urinary excretion of 5-hydroxyindoleacetic acid and Chromogranin A were within normal range. It is important to follow serotonin levels since the elevated levels of serotonin can cause carcinoid heart disease. If metastatic lesions are not accessible for resection, a trial of octreotide therapy can be given. This case also adds to the rare reports in the literature of primary carcinoid tumors of the testis having low malignant potential. The literature review highlights new diagnostic and therapeutic interventions and stresses the importance of long-term follow-up due to evidence of delayed metastasis or recurrences and also due to emergence of new complications as a result of improved prognosis and prolonged survival.

  9. Partial abdominal evisceration and intestinal autotransplantation to resect a mesenteric carcinoid tumor

    PubMed Central

    2011-01-01

    Background Midgut carcinoids are neuroendocrine tumors that commonly metastasize to the intestinal mesentery, where they predispose to intestinal obstruction, ischemia and/or congestion. Because of their location, many mesenteric carcinoid tumors are deemed unresectable due to the risk of uncontrollable bleeding and prolonged intestinal ischemia. Case Presentation We report the case of a 60-year-old male with a mesenteric carcinoid tumor obstructing his superior mesenteric vein, resulting in intestinal varices and severe recurrent GI bleeds. While his tumor was thought to be unresectable by conventional techniques, it was successfully resected using intestinal autotransplantation to safely gain access to the tumor. This case is the first described application of this technique to carcinoid tumors. Conclusions Intestinal autotransplantation can be utilized to safely resect mesenteric carcinoid tumors from patients who were not previously thought to be surgical candidates. We review the literature concerning both carcinoid metastases to the intestinal mesentery and the use of intestinal autotransplantation to treat lesions involving the mesenteric root. PMID:21281518

  10. Carcinoid tumor of the minor papilla in complete pancreas divisum presenting as recurrent abdominal pain

    PubMed Central

    2010-01-01

    Background Tumors of the minor papilla of the duodenum are extremely rare, and they are mostly neuroendocrine tumors, such as somatostatinomas and carcinoid tumors. However, true incidence of carcinoid tumors in minor papilla might be much higher, because patients with minor papillary tumors usually remain asymptomatic. We report a very unusual case of carcinoid tumor in a patient with complete pancreas divisum with a review of the literature. Case presentation A 56-year-old female patient was referred for evaluation of pancreatic duct dilatation noted on abdominal ultrasonography and computerized tomography. She complained of intermittent epigastric pain for 6 months. A MRCP and ERCP revealed complete pancreas divisum with dilatation of the main pancreatic duct. On duodenoscopy, a small, yellows, subepithelial nodule was visualized at the minor papilla; biopsy of this lesion revealed a carcinoid tumor. She underwent a pylorus-preserving pancreaticoduodenectomy. The histologic evaluation showed a single nodule, 1 cm in diameter, in the submucosa with duodenal and vascular invasion and metastasis to the regional lymph nodes. Conclusion Although the size of the carcinoid tumor was small and the tumor was hormonally inactive, the concomitant pancreas divisum led to an early diagnosis, the tumor had aggressive behavior. Carcinoid tumors of the minor papilla should be included in the differential diagnosis of recurrent abdominal pain or pancreatitis of unknown cause. PMID:20149263

  11. Carcinoid tumor of the minor papilla in complete pancreas divisum presenting as recurrent abdominal pain.

    PubMed

    Kim, Yong Gil; Kim, Tae Nyeun; Kim, Kyeong Ok

    2010-02-12

    Tumors of the minor papilla of the duodenum are extremely rare, and they are mostly neuroendocrine tumors, such as somatostatinomas and carcinoid tumors. However, true incidence of carcinoid tumors in minor papilla might be much higher, because patients with minor papillary tumors usually remain asymptomatic. We report a very unusual case of carcinoid tumor in a patient with complete pancreas divisum with a review of the literature. A 56-year-old female patient was referred for evaluation of pancreatic duct dilatation noted on abdominal ultrasonography and computerized tomography. She complained of intermittent epigastric pain for 6 months. A MRCP and ERCP revealed complete pancreas divisum with dilatation of the main pancreatic duct. On duodenoscopy, a small, yellows, subepithelial nodule was visualized at the minor papilla; biopsy of this lesion revealed a carcinoid tumor. She underwent a pylorus-preserving pancreaticoduodenectomy. The histologic evaluation showed a single nodule, 1 cm in diameter, in the submucosa with duodenal and vascular invasion and metastasis to the regional lymph nodes. Although the size of the carcinoid tumor was small and the tumor was hormonally inactive, the concomitant pancreas divisum led to an early diagnosis, the tumor had aggressive behavior. Carcinoid tumors of the minor papilla should be included in the differential diagnosis of recurrent abdominal pain or pancreatitis of unknown cause.

  12. Inhibition of mast cell-dependent anaphylaxis by sodium salicylate

    PubMed Central

    Kim, H M; Shin, H Y; Choo, Y K; Park, J K

    1999-01-01

    Sodium salicylate (NaSal) is a commonly used agent with a wide pharmacological spectrum. The objective of the present study was to investigate the effect of NaSal on anaphylaxis. NaSal (10−1 and 1 mm) significantly inhibited systemic anaphylaxis induced by compound 48/80 in rats. NaSal also significantly inhibited local anaphylaxis activated by anti-dinitrophenyl (DNP) immunoglobulin E (IgE). NaSal (10−1 and 1 mm) significantly inhibited histamine release from rat peritoneal mast cells (RPMC) activated by compound 48/80 or anti-DNP IgE. Northern-blot analysis demonstrated that a significantly reduced level of the mRNA of l-histidine decarboxylase was expressed in mast cells treated with NaSal, compared with that without NaSal. NaSal (10−2 and 10−1 mm) had a significant inhibitory effect on anti-DNP IgE-induced tumour necrosis factor-α secretion from RPMC. The level of cyclic AMP in RPMC, when NaSal (1 mm) was added, transiently and significantly increased about sixfold compared with that of basal cells. These results suggest a possible use of NaSal in managing mast cell-dependent anaphylaxis. PMID:10233741

  13. Prolyl hydroxylase 3 inhibited the tumorigenecity of gastric cancer cells.

    PubMed

    Cui, Lei; Qu, Jianguo; Dang, Shengchun; Mao, Zhengfa; Wang, Xuqing; Fan, Xin; Sun, Kang; Zhang, Jianxin

    2014-09-01

    Gastric cancer is one of the most common malignancies and the second leading cause of cancer-related death in the world, and it is very urgent to develop novel therapeutic strategies. Although HIF-1α is the most highly characterized target of prolyl hydroxylase 3 (PHD3), PHD3 has been shown to regulate several signal pathways independent of HIF-1α. Here, we found that the expression of PHD3 was decreased in the clinical gastric cancer samples and reversely correlated with tumor size and tumor stage. Over-expression of PHD3 in the gastric cancer cells significantly inhibited cell growth in vitro and in vivo, while knockdown the expression of PHD3 promoted the tumorigenecity of gastric cancer cells. Mechanistically, it showed that PHD3 downregulated the expression of beta-catenin and inhibited beta-catenin/T-cell factor (TCF) signaling. Taken together, our findings demonstrate that PHD3 inhibits gastric cancer by suppressing the beta-catenin/TCF signaling and PHD3 might be an important therapeutic target in gastric cancer.

  14. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia.

    PubMed Central

    Law, R E; Meehan, W P; Xi, X P; Graf, K; Wuthrich, D A; Coats, W; Faxon, D; Hsueh, W A

    1996-01-01

    Vascular smooth muscle cell (VSMC) proliferation and migration are responses to arterial injury that are highly important to the processes of restenosis and atherosclerosis. In the arterial balloon injury model in the rat, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are induced in the vessel wall and regulate these VSMC activities. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit insulin and epidermal growth factor-induced growth of VSMCs. We hypothesized that these agents might also inhibit the effect of PDGF and bFGF on cultured VSMCs and intimal hyperplasia in vivo. Troglitazone (1 microM), a member of the thiazolidinedione class, produced a near complete inhibition of both bFGF-induced DNA synthesis as measured by bromodeoxyuridine incorporation (6.5+/-3.9 vs. 17.6+/-4.3% cells labeled, P < 0.05) and c-fos induction. This effect was associated with an inhibition (by 73+/-4%, P < 0.01) by troglitazone of the transactivation of the serum response element, which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via a blockade of the MAP kinase pathway at a point downstream of MAP kinase activation by MAP kinase kinase. At this dose, troglitazone also inhibited PDGF-BB-directed migration of VSMC (by 70+/-6%, P < 0.01). These in vitro effects were operative in vivo. Quantitative image analysis revealed that troglitazone-treated rats had 62% (P < 0.001) less neointima/media area ratio 14 d after balloon injury of the aorta compared with injured rats that received no troglitazone. These results suggest troglitazone is a potent inhibitor of VSMC proliferation and migration and, thus, may be a useful agent to prevent restenosis and possibly atherosclerosis. PMID:8878442

  15. Inhibition of Skp2 sensitizes lung cancer cells to paclitaxel

    PubMed Central

    Huang, Tonghai; Yang, Lin; Wang, Guangsuo; Ding, Guanggui; Peng, Bin; Wen, Yuxin; Wang, Zheng

    2017-01-01

    S-phase kinase-associated protein 2 (Skp2) is an E3 ubiquitin ligase and plays an important role in the control of cell cycle progression. Skp2 is upregulated in several cancers, including lung cancers, but the role of Skp2 in the tumorigenesis and anticancer drug resistance in human lung cancer remains to be determined. We report here that Skp2 positively regulated mitotic arrest deficient 2 (MAD2) expression and that inhibition of Skp2 sensitizes human lung cancer cells to paclitaxel. Knockdown of Skp2 by small interfering RNA (siRNA) decreased Mad2 messenger RNA (mRNA) and protein levels in A549 and NCI-H1975 cells, accompanied with upregulation of p27 but decrease of the phosphorylation of retinoblastoma (Rb). In contrast, ectopic overexpression of Skp2 increased Mad2 mRNA and protein levels and phosphorylation of Rb, while it decreased p27. Pharmacological inhibition of CDK1/2 by flavopiridol or E2F1 with HLM006474 led to downregulation of Mad2 expression and prevented the increase of Mad2 expression by Skp2. Most importantly, pharmacological inhibition of Skp2 sensitized A549 and NCI-H1299 cells to paclitaxel. Our results demonstrated that SKP2 positively regulates the gene expression of MAD2 through p27-CDKs-E2F1 signaling pathway and that inhibition of Skp2 sensitizes A549 and NCI-H1299 cells to paclitaxel, suggesting that small molecule inhibitors of Skp2 are potential agents for the treatment of lung cancer with upregulation of Skp2. PMID:28176922

  16. Inhibition of Skp2 sensitizes lung cancer cells to paclitaxel.

    PubMed

    Huang, Tonghai; Yang, Lin; Wang, Guangsuo; Ding, Guanggui; Peng, Bin; Wen, Yuxin; Wang, Zheng

    2017-01-01

    S-phase kinase-associated protein 2 (Skp2) is an E3 ubiquitin ligase and plays an important role in the control of cell cycle progression. Skp2 is upregulated in several cancers, including lung cancers, but the role of Skp2 in the tumorigenesis and anticancer drug resistance in human lung cancer remains to be determined. We report here that Skp2 positively regulated mitotic arrest deficient 2 (MAD2) expression and that inhibition of Skp2 sensitizes human lung cancer cells to paclitaxel. Knockdown of Skp2 by small interfering RNA (siRNA) decreased Mad2 messenger RNA (mRNA) and protein levels in A549 and NCI-H1975 cells, accompanied with upregulation of p27 but decrease of the phosphorylation of retinoblastoma (Rb). In contrast, ectopic overexpression of Skp2 increased Mad2 mRNA and protein levels and phosphorylation of Rb, while it decreased p27. Pharmacological inhibition of CDK1/2 by flavopiridol or E2F1 with HLM006474 led to downregulation of Mad2 expression and prevented the increase of Mad2 expression by Skp2. Most importantly, pharmacological inhibition of Skp2 sensitized A549 and NCI-H1299 cells to paclitaxel. Our results demonstrated that SKP2 positively regulates the gene expression of MAD2 through p27-CDKs-E2F1 signaling pathway and that inhibition of Skp2 sensitizes A549 and NCI-H1299 cells to paclitaxel, suggesting that small molecule inhibitors of Skp2 are potential agents for the treatment of lung cancer with upregulation of Skp2.

  17. CD101 inhibits the expansion of colitogenic T cells

    PubMed Central

    Schey, Regina; Dornhoff, Heike; Baier, Julia L.C.; Purtak, Martin; Opoka, Robert; Koller, Anna Katharina; Atreya, Raya; Rau, Tilman T.; Daniel, Christoph; Amann, Kerstin; Bogdan, Christian; Mattner, Jochen

    2015-01-01

    CD101 exerts negative-costimulatory effects in vitro, but its function in vivo remains poorly defined. CD101 is abundantly expressed on lymphoid and myeloid cells in intestinal tissues, but absent from naïve splenic T cells. Here, we assessed the impact of CD101 on the course of inflammatory bowel disease (IBD). Using a T cell transfer model of chronic colitis, we found that in recipients of naïve T cells from CD101+/+ donors up to 30% of the recovered lymphocytes expressed CD101, correlating with an increased IL-2-mediated FoxP3-expression. Transfer of CD101−/− T cells caused more severe colitis and was associated with an expansion of IL-17-producing T cells and an enhanced expression of IL-2Rα/β independently of FoxP3. The co-transfer of naïve and regulatory T cells (Treg) protected most effectively from colitis, when both donor and recipient mice expressed CD101. While the expression of CD101 on T cells was sufficient for Treg-function and the inhibition of T cell proliferation, sustained IL-10-production required additional CD101-expression by myeloid cells. Finally, in patients with IBD a reduced CD101-expression on peripheral and intestinal monocytes and CD4+ T cells correlated with enhanced IL-17-production and disease activity. Thus, CD101-deficiency is a novel marker for progressive colitis and potential target for therapeutic intervention. PMID:26813346

  18. Hydrogen peroxide inhibits photosynthetic electron transport in cells of cyanobacteria.

    PubMed

    Samuilov, V D; Bezryadnov, D B; Gusev, M V; Kitashov, A V; Fedorenko, T A

    2001-06-01

    The effect of H2O2 on photosynthetic O2 evolution and photosynthetic electron transfer in cells of cyanobacteria Anabaena variabilis and Anacystis nidulans was studied. The following experiments were performed: 1) directly testing the effect of exogenous H2O2; 2) testing the effect of intracellular H2O2 generated with the use of methyl viologen (MV); 3) testing the effect of inhibiting intracellular H2O2 decomposition by salicylic acid (SA) and 3-amino-1,2,4-triazole (AT). H2O2 inhibited photosynthetic O2 evolution and light-induced reduction of p-benzoquinone (BQ) + ferricyanide (FeCy) in the Hill reaction. The I50 value for H2O2 was ~0.75 mM. Photosynthetic electron transfer in the cells treated with H2O2 was not maintained by H2O2, NH2OH, 1,5-diphenylcarbazide, tetraphenylboron, or butylated hydroxytoluene added as artificial electron donors for Photosystem (PS) II. The H2O --> CO2, H2O --> MV (involving PSII and PSI) and H2O --> BQ + FeCy (chiefly dependent on PSII) electron transfer reactions were inhibited upon incubation of the cells with MV, SA, or AT. The N,N,N,N-tetramethyl-p-phenylenediamine --> MV (chiefly dependent on PSI) electron transfer was inhibited by SA and AT but was resistant to MV. The results show that H2O2 inhibits photosynthetic electron transfer. It is unlikely that H2O2 could be a physiological electron donor in oxygenic photosynthesis.

  19. Quercetin protects against atherosclerosis by inhibiting dendritic cell activation.

    PubMed

    Lin, Weiqun; Wang, Wenting; Wang, Dongliang; Ling, Wenhua

    2017-09-01

    Quercetin is a typical flavonol with atheroprotective effects, but the effect of quercetin on dendritic cell (DC) maturation in relation to atherosclerosis has not yet been clearly defined. Thus, we investigated whether quercetin can inhibit DC maturation and evaluated its potential value in atherosclerosis progression in ApoE(-/-) mice. Quercetin consumption inhibited DC activation, inflammatory response and suppressed the progression of atherosclerosis in ApoE(-/-) mice. Subsequently, quercetin treatment inhibited the phenotypic and functional maturation of DCs, as evidenced not only by downregulation of CD80, CD86, MHC-II, IL-6 and IL-12 but also by a reduction in the ability to stimulate T cell allogeneic proliferation. Finally, an in vitro study demonstrated that quercetin inhibited DC maturation via upregulation of Dabs, which then downregulated the Src/PI3K/Akt-NF-κB-inflammatory pathways. Our data indicate that quercetin attenuates atherosclerosis progression by regulating DC activation via Dab2 protein expression. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Rapamycin inhibits poly(ADP-ribosyl)ation in intact cells

    SciTech Connect

    Fahrer, Joerg; Wagner, Silvia; Buerkle, Alexander; Koenigsrainer, Alfred

    2009-08-14

    Rapamycin is an immunosuppressive drug, which inhibits the mammalian target of rapamycin (mTOR) kinase activity inducing changes in cell proliferation. Synthesis of poly(ADP-ribose) (PAR) is an immediate cellular response to genotoxic stress catalyzed mostly by poly(ADP-ribose) polymerase 1 (PARP-1), which is also controlled by signaling pathways. Therefore, we investigated whether rapamycin affects PAR production. Strikingly, rapamycin inhibited PAR synthesis in living fibroblasts in a dose-dependent manner as monitored by immunofluorescence. PARP-1 activity was then assayed in vitro, revealing that down-regulation of cellular PAR production by rapamycin was apparently not due to competitive PARP-1 inhibition. Further studies showed that rapamycin did not influence the cellular NAD pool and the activation of PARP-1 in extracts of pretreated fibroblasts. Collectively, our data suggest that inhibition of cellular PAR synthesis by rapamycin is mediated by formation of a detergent-sensitive complex in living cells, and that rapamycin may have a potential as therapeutic PARP inhibitor.

  1. Inhibition of cancer cell invasion and metastasis by genistein

    PubMed Central

    Pavese, Janet M.; Farmer, Rebecca L.

    2010-01-01

    Genistein is a small, biologically active flavonoid that is found in high amounts in soy. This important compound possesses a wide variety of biological activities, but it is best known for its ability to inhibit cancer progression. In particular, genistein has emerged as an important inhibitor of cancer metastasis. Consumption of genistein in the diet has been linked to decreased rates of metastatic cancer in a number of population-based studies. Extensive investigations have been performed to determine the molecular mechanisms underlying genistein’s antimetastatic activity, with results indicating that this small molecule has significant inhibitory activity at nearly every step of the metastatic cascade. Reports have demonstrated that, at high concentrations, genistein can inhibit several proteins involved with primary tumor growth and apoptosis, including the cyclin class of cell cycle regulators and the Akt family of proteins. At lower concentrations that are similar to those achieved through dietary consumption, genistein can inhibit the prometastatic processes of cancer cell detachment, migration, and invasion through a variety of mechanisms, including the transforming growth factor (TGF)-β signaling pathway. Several in vitro findings have been corroborated in both in vivo animal studies and in early-phase human clinical trials, demonstrating that genistein can both inhibit human cancer metastasis and also modulate markers of metastatic potential in humans, respectively. Herein, we discuss the variety of mechanisms by which genistein regulates individual steps of the metastatic cascade and highlight the potential of this natural product as a promising therapeutic inhibitor of metastasis. PMID:20730632

  2. A pilot randomized control study to evaluate endoscopic resection using a ligation device for rectal carcinoid tumors

    PubMed Central

    Sakata, Hiroyuki; Iwakiri, Ryuichi; Ootani, Akifumi; Tsunada, Seiji; Ogata, Shinichi; Ootani, Hibiki; Shimoda, Ryo; Yamaguchi, Kanako; Sakata, Yasuhisa; Amemori, Sadahiro; Mannen, Kotaro; Mizuguchi, Masanobu; Fujimoto, Kazuma

    2006-01-01

    AIM: Rectal carcinoid tumors smaller than 10 mm can be resected with local excision using endoscopy. In order to remove rectal carcinoid tumors completely, we evaluated endoscopic mucosal resection with a ligation device in this pilot control randomized study. METHODS: Fifteen patients were diagnosed with rectal carcinoid tumor (less than 10 mm) in our hospital from 1993 to 2002. There were 9 males and 6 females, with a mean age 61.5 years (range, 34-77 years). The patients had no complaints of carcinoid syndrome symptoms. Fifteen patients were randomly divided into 2 groups: 7 carcinoid tumors were treated by conventional endoscopic resection, and 8 carcinoid tumors were treated by endoscopic resection using a ligation device. RESULTS: All rectal carcinoid tumors were located at the middle to distal rectum. The size of the tumors varied from 3 mm to 10 mm and background characteristics of the patients were not different in the two groups. The rate of complete removal of carcinoid tumors using a ligation device (100%, 8/8) was significantly higher than that of conventional endoscopic resection (57.1%, 4/7). The three patients had tumor involvement of deep margin, for which additional treatment was performed. No complications occurred during or after endoscopic resection using a ligation device. All patients in the both groups were alive during the 3-year observation period. CONCLUSION: Endoscopic resection using a ligation device is a useful and safe method for resection of small rectal carcinoid tumors. PMID:16810752

  3. Angiopoietin1 Inhibits Mast Cell Activation and Protects against Anaphylaxis

    PubMed Central

    Li, Meng-Tao; Liu, Yi-Nan; He, Qi-Hua; Xiao, Jun-Jun; Bai, Yun

    2014-01-01

    Since morbidity and mortality rates of anaphylaxis diseases have been increasing year by year, how to prevent and manage these diseases effectively has become an important issue. Mast cells play a central regulatory role in allergic diseases. Angiopoietin1 (Ang-1) exhibits anti-inflammatory properties by inhibiting vascular permeability, leukocyte migration and cytokine production. However, Ang-1's function in mast cell activation and anaphylaxis diseases is unknown. The results of our study suggest that Ang-1 decreased lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production of mast cells by suppressing IκB phosphorylation and NF-κB nuclear translocation. Ang-1 also strongly inhibited compound 48/80 induced and FcεRI-mediated mast cells degranulation by decreasing intracellular calcium levels in vitro. In vivo lentivirus-mediated delivery of Ang-1 in mice exhibited alleviated leakage in IgE-dependent passive cutaneous anaphylaxis (PCA). Furthermore, exogenous Ang-1 intervention treatment prevented mice from compound 48/80-induced mesentery mast cell degranulation, attenuated increases in pro-inflammatory cytokines, relieved lung injury, and improved survival in anaphylaxis shock. The results of our study reveal, for the first time, the important role of Ang-1 in the activation of mast cells, and identify a therapeutic effect of Ang-1 on anaphylaxis diseases. PMID:24586553

  4. Ponicidin Inhibits Monocytic Leukemia Cell Growth by Induction of Apoptosis

    PubMed Central

    Liu, Jia-Jun; Zhang, Yong; Guang, Wei-Bin; Yang, Hong-Zhi; Lin, Dong-Jun; Xiao, Ruo-Zhi

    2008-01-01

    In this study two monocytic leukemia cell lines, U937 and THP-1 cells, were used to investigate the anti-proliferation effects caused by ponicidin. Cell viability was measured by an MTT assay. Cell apoptosis was assessed by flow cytometry as well as DNA fragmentation analysis. Cell morphology was observed using an inverted microscope and Hoechst 33258 staining. RT-PCR and Western blot analysis were used to detect survivin as well as Bax and Bcl-2 expressions after the cells were treated with different concentrations of ponicidin. The results revealed that ponicidin could inhibit the growth of U937 and THP-1 cells significantly by induction of apoptosis. The suppression was in both time- and dose-dependent manner. Marked morphological changes of cell apoptosis were observed clearly after the cells were treated with ponicidin for 48∼72 h. RT-PCR and Western blot analysis demonstrated that both survivin and Bcl-2 expressions were down-regulated remarkably while Bax expression remained constant before and after apoptosis occurred. We therefore conclude that ponicidin has significant anti-proliferation effects by inducing apoptosis on leukemia cells in vitro, downregulation of survivin as well as Bcl-2 expressions may be the important apoptosis inducing mechanisms. The results suggest that ponicidin may serve as potential therapeutic agent for leukemia. PMID:19330074

  5. Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells.

    PubMed

    Mamo, Tewodros; Mladek, Ann C; Shogren, Kris L; Gustafson, Carl; Gupta, Shiv K; Riester, Scott M; Maran, Avudaiappan; Galindo, Mario; van Wijnen, Andre J; Sarkaria, Jann N; Yaszemski, Michael J

    2017-04-29

    Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PKCS), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PKCS in osteosarcoma tissue specimens and cell lines was examined. Moreover, the small molecule DNA-PKCS inhibitor, KU60648, was investigated as a radiosensitizing strategy for osteosarcoma cells in vitro. DNA-PKCS was consistently expressed in the osteosarcoma tissue specimens and cell lines studied. Additionally, KU60648 effectively sensitized two of those osteosarcoma cell lines (143B cells by 1.5-fold and U2OS cells by 2.5-fold). KU60648 co-treatment also altered cell cycle distribution and enhanced DNA damage. Cell accumulation at the G2/M transition point increased by 55% and 45%, while the percentage of cells with >20 γH2AX foci were enhanced by 59% and 107% for 143B and U2OS cells, respectively. These results indicate that the DNA-PKCS inhibitor, KU60648, is a promising radiosensitizing agent for osteosarcoma. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Gamma-Glutamylcysteine Inhibits Oxidative Stress in Human Endothelial Cells

    DTIC Science & Technology

    2012-01-01

    γ-Glutamylcysteine inhibits oxidative stress in human endothelial cells Yukiko K. Nakamura a, Michael A. Dubick b, Stanley T. Omaye a,⁎ a Department...n f o Article history: Received 12 July 2011 Accepted 16 October 2011 Keywords: γ-Glutamylcysteine Glutathione Glutathione synthetase Oxidative stress...include reducing risks of oxidative stress-related injuries and diseases. The ob- jective of this studywas to investigate the efficacy of GGC on GSH

  7. Ivermectin Inhibits Growth of Chlamydia trachomatis in Epithelial Cells

    PubMed Central

    Pettengill, Matthew A.; Lam, Verissa W.; Ollawa, Ikechukwu; Marques-da-Silva, Camila; Ojcius, David M.

    2012-01-01

    Ivermectin is currently approved for treatment of both clinical and veterinary infections by nematodes, including Onchocerca cervicalis in horses and Onchocerca volvulus in humans. However, ivermectin has never been shown to be effective against bacterial pathogens. Here we show that ivermectin also inhibits infection of epithelial cells by the bacterial pathogen, Chlamydia trachomatis, at doses that could be envisioned clinically for sexually-transmitted or ocular infections by Chlamydia. PMID:23119027

  8. Lovastatin inhibited the growth of gastric cancer cells.

    PubMed

    Cheng-Qian, Yang; Xin-Jing, Wei; Wei-Xinbing; Zhuang-Lei, Gao; Hong-Peng, Zhao; Songde, Xu; Pei-Lin, Wang

    2014-01-01

    Gastric cancer cells required large amount of cholesterol to grow and proliferate. The objective of this study was to examine whether the growth of gastric cancer cells was inhibited in vivo by using lovastatin, an effective cholesterol-lowing drug. The mice models for gastric cancer cells MKN45 were divided into two groups, the control and experimental group. Lovastatin was administered orally to the experimental group, while saline given to the control group. We measured the volume and weight of tumors, and calculated RTV (relative tumor volume), T/C (relative added value of tumor) and the inhibition rate. Then the expression levels of PCNA in gastric cancer tissues were examined immunohistochemically. The volume of tumors in the control and experimental groups was 3.801 +/- 1.078 and 3.325 +/- 0.745, respectively (p > 0.05), while RTV was 49.684 +/- 12.250 and 42.506 +/- 10.515, respectively (p > 0.05). T/C, an indication of antitumor, was 85.55%. The weight of tumors of the mice in control and experimental group was 3.23 +/- 0.43 and 2.65 +/- 0.58, respectively (p < 0.05). The inhibition rate was 20.48%. The PCNA index in the lovastatin group was 32.35 +/- 6.43%, while in the control group was 91.24 +/- 6.59%. The PCNA index of lovastatin group was much lower (P < 0.01). Lovastatin inhibited the growth of gastric cancer cells.

  9. Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition

    SciTech Connect

    Ju, Yeun-Jin; Shin, Hyun-Jin; Park, Jeong-Eun; Juhn, Kyoung-Mi; Woo, Seon Rang; Kim, Hee-Young; Han, Young-Hoon; Hwang, Sang-Gu; Hong, Sung-Hee; Kang, Chang-Mo; Yoo, Young-Do; Park, Won-Bong; Cho, Myung-Haing; Park, Gil Hong; Lee, Kee-Ho

    2010-11-12

    Research highlights: {yields} In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. {yields} The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. {yields} The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. {yields} P53 status is not associated with the occurrence of unsensitized clone. {yields} Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC{sup -/-} cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC{sup -/-} clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

  10. Cannabinoids inhibit cellular respiration of human oral cancer cells.

    PubMed

    Whyte, Donna A; Al-Hammadi, Suleiman; Balhaj, Ghazala; Brown, Oliver M; Penefsky, Harvey S; Souid, Abdul-Kader

    2010-01-01

    The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs. A phosphorescence analyzer that measures the time-dependence of O(2) concentration in cellular or mitochondrial suspensions was used for this purpose. A rapid decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to the cells. The inhibition was concentration-dependent, and Delta(9)-THC was the more potent of the two compounds. Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Delta(9)-THC and Delta(8)-THC were not mediated by the cannabinoidreceptors. Inhibition of O(2) consumption by cyanide confirmed the oxidations occurred in the mitochondrial respiratory chain. Delta(9)-THC inhibited the respiration of isolated mitochondria from beef heart. These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.

  11. Barium inhibits arsenic-mediated apoptotic cell death in human squamous cell carcinoma cells.

    PubMed

    Yajima, Ichiro; Uemura, Noriyuki; Nizam, Saika; Khalequzzaman, Md; Thang, Nguyen D; Kumasaka, Mayuko Y; Akhand, Anwarul A; Shekhar, Hossain U; Nakajima, Tamie; Kato, Masashi

    2012-06-01

    Our fieldwork showed more than 1 μM (145.1 μg/L) barium in about 3 μM (210.7 μg/L) arsenic-polluted drinking well water (n = 72) in cancer-prone areas in Bangladesh, while the mean concentrations of nine other elements in the water were less than 3 μg/L. The types of cancer include squamous cell carcinomas (SCC). We hypothesized that barium modulates arsenic-mediated biological effects, and we examined the effect of barium (1 μM) on arsenic (3 μM)-mediated apoptotic cell death of human HSC-5 and A431 SCC cells in vitro. Arsenic promoted SCC apoptosis with increased reactive oxygen species (ROS) production and JNK1/2 and caspase-3 activation (apoptotic pathway). In contrast, arsenic also inhibited SCC apoptosis with increased NF-κB activity and X-linked inhibitor of apoptosis protein (XIAP) expression level and decreased JNK activity (antiapoptotic pathway). These results suggest that arsenic bidirectionally promotes apoptotic and antiapoptotic pathways in SCC cells. Interestingly, barium in the presence of arsenic increased NF-κB activity and XIAP expression and decreased JNK activity without affecting ROS production, resulting in the inhibition of the arsenic-mediated apoptotic pathway. Since the anticancer effect of arsenic is mainly dependent on cancer apoptosis, barium-mediated inhibition of arsenic-induced apoptosis may promote progression of SCC in patients in Bangladesh who keep drinking barium and arsenic-polluted water after the development of cancer. Thus, we newly showed that barium in the presence of arsenic might inhibit arsenic-mediated cancer apoptosis with the modulation of the balance between arsenic-mediated promotive and suppressive apoptotic pathways.

  12. Honokiol inhibits melanoma stem cells by targeting notch signaling.

    PubMed

    Kaushik, Gaurav; Venugopal, Anand; Ramamoorthy, Prabhu; Standing, David; Subramaniam, Dharmalingam; Umar, Shahid; Jensen, Roy A; Anant, Shrikant; Mammen, Joshua M V

    2015-12-01

    Melanoma is an aggressive disease with limited therapeutic options. Here, we determined the effects of honokiol (HNK), a biphenolic natural compound on melanoma cells and stemness. HNK significantly inhibited melanoma cell proliferation, viability, clonogenicity and induced autophagy. In addition, HNK significantly inhibited melanosphere formation in a dose dependent manner. Western blot analyses also demonstrated reduction in stem cell markers CD271, CD166, Jarid1b, and ABCB5. We next examined the effect of HNK on Notch signaling, a pathway involved in stem cell self-renewal. Four different Notch receptors exist in cells, which when cleaved by a series of enzymatic reactions catalyzed by Tumor Necrosis Factor-α-Converting Enzyme (TACE) and γ-secretase protein complex, results in the release of the Notch intracellular domain (NICD), which then translocates to the nucleus and induces target gene expression. Western blot analyses demonstrated that in HNK treated cells there is a significant reduction in the expression of cleaved Notch-2. In addition, there was a reduction in the expression of downstream target proteins, Hes-1 and cyclin D1. Moreover, HNK treatment suppressed the expression of TACE and γ-secretase complex proteins in melanoma cells. To confirm that suppression of Notch-2 activation is critical for HNK activity, we overexpressed NICD1, NICD2, and performed HNK treatment. NICD2, but not NICD1, partially restored the expression of Hes-1 and cyclin D1, and increased melanosphere formation. Taken together, these data suggest that HNK is a potent inhibitor of melanoma cells, in part, through the targeting of melanoma stem cells by suppressing Notch-2 signaling.

  13. Fucoidan inhibits angiogenesis induced by multiple myeloma cells.

    PubMed

    Liu, Fen; Luo, Guoping; Xiao, Qing; Chen, Liping; Luo, Xiaohua; Lv, Jinglong; Chen, Lixue

    2016-10-01

    Multiple myeloma (MM) remains an incurable hematological neoplasms. Our previous studies showed that Fucoidan possessed anti-myeloma effect by inducing apoptosis and inhibiting invasion of myeloma cells. In this study, we evaluated the effect of Fucoidan on angiogenesis induced by human myeloma cells and elucidated its possible mechanisms. Multiple myeloma cells were treated with Fucoidan at different concentrations, then the conditioned medium (CM) was collected. The levels of VEGF in the CM were tested by ELISA. The results showed that Fucoidan significantly decreased VEGF secretion by RPMI-8226 and U266 cells. The tube formation assay and migration test on human umbilical vein endothelial cells (HUVECs) were used to examine the effect of Fucoidan on angiogenesis induced by human myeloma cells. The results showed that Fucoidan decreased HUVECs formed tube structures and inhibited HUVECs migration, and suppressed the angiogenic ability of multiple myeloma RPMI-8226 and U266 cells in a dose-dependent manner. The study also showed that Fucoidan downregulated the expression of several kinds of proteins, which may be correlated with the reduction of angiogenesis induced by myeloma cells. Moreover, results were compared from normoxic and hypoxic conditions, they showed that Fucoidan had anti-angiogenic activity. Furthermore, in a multiple myeloma xenograft mouse model, it indicated that Fucoidan negatively affected tumor growth and angiogenesis in vivo. In conclusion, our results demonstrate that Fucoidan was able to interfere with angiogenesis of multiple myeloma cells both in vitro and in vivo and may have a substantial potential in the treatment of MM.

  14. Honokiol Inhibits Melanoma Stem Cells by Targeting Notch Signaling

    PubMed Central

    Kaushik, Gaurav; Venugopal, Anand; Ramamoorthy, Prabhu; Standing, David; Subramaniam, Dharmalingam; Umar, Shahid; Jensen, Roy A.; Anant, Shrikant; Mammen, Joshua M.V.

    2016-01-01

    Melanoma is an aggressive disease with limited therapeutic options. Here, we determined the effects of honokiol (HNK), a biphenolic natural compound on melanoma cells and stemness. HNK significantly inhibited melanoma cell proliferation, viability, clonogenicity and induced autophagy. In addition, HNK significantly inhibited melanosphere formation in a dose dependent manner. Western blot analyses also demonstrated reduction in stem cell markers CD271, CD166, Jarid1b, and ABCB5. We next examined the effect of HNK on Notch signaling, a pathway involved in stem cell self-renewal. Four different Notch receptors exist in cells, which when cleaved by a series of enzymatic reactions catalyzed by Tumor Necrosis Factor-α-Converting Enzyme (TACE) and γ-secretase protein complex, results in the release of the Notch intracellular domain (NICD), which then translocates to the nucleus and induces target gene expression. Western blot analyses demonstrated that in HNK treated cells there is a significant reduction in the expression of cleaved Notch-2. In addition, there was a reduction in the expression of downstream target proteins, Hes-1 and cyclin D1. Moreover, HNK treatment suppressed the expression of TACE and γ-secretase complex proteins in melanoma cells. To confirm that suppression of Notch-2 activation is critical for HNK activity, we overexpressed NICD1, NICD2, and performed HNK treatment. NICD2, but not NICD1, partially restored the expression of Hes-1 and cyclin D1, and increased melanosphere formation. Taken together, these data suggest that HNK is a potent inhibitor of melanoma cells, in part, through the targeting of melanoma stem cells by suppressing Notch-2 signaling. PMID:25491779

  15. Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma

    SciTech Connect

    Hui Zhouguang; Tretiakova, Maria; Zhang Zhongfa; Li Yan; Wang Xiaozhen; Zhu, Julie Xiaohong; Gao Yuanhong; Mai Weiyuan; Furge, Kyle; Qian Chaonan; Amato, Robert; Butler, E. Brian

    2009-01-01

    Purpose: Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. Methods and Materials: The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. Results: STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10{sup -8} for clear cell; and p = 3.6 x 10{sup -4} for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. Conclusion: This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.

  16. Belatacept Does Not Inhibit Follicular T Cell-Dependent B-Cell Differentiation in Kidney Transplantation

    PubMed Central

    de Graav, Gretchen N.; Hesselink, Dennis A.; Dieterich, Marjolein; Kraaijeveld, Rens; Verschoor, Wenda; Roelen, Dave L.; Litjens, Nicolle H. R.; Chong, Anita S.; Weimar, Willem; Baan, Carla C.

    2017-01-01

    Humoral alloreactivity has been recognized as a common cause of kidney transplant dysfunction. B-cell activation, differentiation, and antibody production are dependent on IL-21+CXCR5+follicular T-helper (Tfh) cells. Here, we studied whether belatacept, an inhibitor of the costimulatory CD28-CD80/86-pathway, interrupts the crosstalk between Tfh- and B-cells more efficiently than the calcineurin inhibitor tacrolimus. The suppressive effects of belatacept and tacrolimus on donor antigen-driven Tfh–B-cell interaction were functionally studied in peripheral blood mononuclear cells from 40 kidney transplant patients randomized to a belatacept- or tacrolimus-based immunosuppressive regimen. No significant differences in uncultured cells or donor antigen-stimulated cells were found between belatacept- and tacrolimus-treated patients in the CXCR5+Tfh cell generation and activation (upregulation of PD-1). Belatacept and tacrolimus in vitro minimally inhibited Tfh-cell generation (by ~6–7%) and partially prevented Tfh-cell activation (by ~30–50%). The proportion of IL-21+-activated Tfh-cells was partially decreased by in vitro addition of belatacept or tacrolimus (by ~60%). Baseline expressions and proportions of activated CD86+ B-cells, plasmablasts, and transitional B-cells after donor antigen stimulation did not differ between belatacept- and tacrolimus-treated patients. Donor antigen-driven CD86 upregulation on memory B-cells was not fully prevented by adding belatacept in vitro (~35%), even in supratherapeutic doses. In contrast to tacrolimus, belatacept failed to inhibit donor antigen-driven plasmablast formation (~50% inhibition vs. no inhibition, respectively, p < 0.0001). In summary, donor antigen-driven Tfh-B-cell crosstalk is similar in cells obtained from belatacept- and tacrolimus-treated patients. Belatacept is, however, less potent in vitro than tacrolimus in inhibiting Tfh-cell-dependent plasmablast formation. PMID:28620390

  17. Extended monod kinetics for substrate, product, and cell inhibition.

    PubMed

    Han, K; Levenspiel, O

    1988-08-05

    A generalized form of Monod kinetics is proposed to account for all kinds of product, cell, and substrate inhibition. This model assumes that there exists a critical inhibitor concentration above which cells cannot grow, and that the constants of the Monod equation are functions of this limiting inhibitor concentration. Methods for evaluating the constants of this rate form are presented. Finally the proposed kinetic form is compared with the available data in the literature, which unfortunately is very sparse. In all cases, this equation form fitted the data very well.

  18. Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

    PubMed

    Huang, Jiangrong; Yang, Xiaoyu; Peng, Xiaochun; Huang, Wei

    2017-09-22

    Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells.

    PubMed

    Li, Jingjun; Ma, Jing; Meng, Guofeng; Lin, Hong; Wu, Sharon; Wang, Jamie; Luo, Jie; Xu, Xiaohong; Tough, David; Lindon, Matthew; Rioja, Inmaculada; Zhao, Jing; Mei, Hongkang; Prinjha, Rab; Zhong, Zhong

    2016-09-01

    Neural stem cells and progenitor cells (NPCs) are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis. BET bromodomain proteins, Brd2, Brd3, and Brd4 were found to be downregulated in NPCs upon differentiation, while their levels remain unaltered in proliferating NPCs. Consistent with the pharmacological study using bromodomain selective inhibitor (+)-JQ-1, knockdown of each BET protein resulted in an increase in the number of neurons with simultaneous reduction in both astrocytes and oligodendrocytes. Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating brain injuries and neurodegenerative diseases. Copyright © 2016 Helmholtz Zentrum München. Published by Elsevier B.V. All rights reserved.

  20. Autophagy contributes to gefitinib-induced glioma cell growth inhibition

    SciTech Connect

    Chang, Cheng-Yi; Kuan, Yu-Hsiang; Ou, Yen-Chuan; Li, Jian-Ri; Wu, Chih-Cheng; Pan, Pin-Ho; Chen, Wen-Ying; Huang, Hsuan-Yi; Chen, Chun-Jung

    2014-09-10

    Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.

  1. HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma.

    PubMed

    Jacobson, Caron; Kopp, Nadja; Layer, Jacob V; Redd, Robert A; Tschuri, Sebastian; Haebe, Sarah; van Bodegom, Diederik; Bird, Liat; Christie, Amanda L; Christodoulou, Alexandra; Saur, Amy; Tivey, Trevor; Zapf, Stefanie; Bararia, Deepak; Zimber-Strobl, Ursula; Rodig, Scott J; Weigert, Oliver; Weinstock, David M

    2016-11-24

    The Bruton tyrosine kinase (BTK) inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma (MCL). Intrinsic resistance can occur through activation of the nonclassical NF-κB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer heat shock protein 90 (HSP90) inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IκB kinase α in MCL lines and CD40-dependent B cells, with downstream loss of MAPK and nonclassical NF-κB signaling. A proteome-wide analysis in MCL lines and an MCL patient-derived xenograft identified a restricted set of targets from HSP90 inhibition that were enriched for factors involved in B-cell receptor and JAK/STAT signaling, the nonclassical NF-κB pathway, cell-cycle regulation, and DNA repair. Finally, multiple HSP90 inhibitors potently killed MCL lines in vitro, and the clinical agent AUY922 was active in vivo against both patient-derived and cell-line xenografts. Together, these findings define the HSP90-dependent proteome in MCL. Considering the disappointing clinical activity of HSP90 inhibitors in other contexts, trials in patients with MCL will be essential for defining the efficacy of and mechanisms of resistance after ibrutinib failure. © 2016 by The American Society of Hematology.

  2. Oxidative stress inhibits distant metastasis by human melanoma cells

    PubMed Central

    Piskounova, Elena; Agathocleous, Michalis; Murphy, Malea M.; Hu, Zeping; Huddlestun, Sara E.; Zhao, Zhiyu; Leitch, A. Marilyn; Johnson, Timothy M.; DeBerardinis, Ralph J.; Morrison, Sean J.

    2015-01-01

    Solid cancer cells commonly enter the blood and disseminate systemically but are highly inefficient at forming distant metastases for poorly understood reasons. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficient metastasizers. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo. PMID:26466563

  3. The human asparaginase enzyme (ASPG) inhibits growth in leukemic cells

    PubMed Central

    Belviso, Stefania; Amato, Rosario; Perrotti, Nicola; Menniti, Miranda

    2017-01-01

    The human protein ASPG is an enzyme with a putative antitumor activity. We generated in bacteria and then purified a recombinant GST-ASPG protein that we used to characterize the biochemical and cytotoxic properties of the human ASPG. We demonstrated that ASPG possesses asparaginase and PAF acetylhydrolase activities that depend on a critical threonine residue at position 19. Consistently, ASPG but not its T19A mutant showed cytotoxic activity in K562, NALM-6 and MOLT-4 leukemic cell lines but not in normal cells. Regarding the mechanism of action of ASPG, it was able to induce a significant apoptotic death in K562 cells. Taken together our data suggest that ASPG, combining different enzymatic activities, should be considered a promising anti-cancer agent for inhibiting the growth of leukemia cells. PMID:28542249

  4. Ozone Inhibits Guard Cell K+ Channels Implicated in Stomatal Opening

    NASA Astrophysics Data System (ADS)

    Torsethaugen, Gro; Pell, Eva J.; Assmann, Sarah M.

    1999-11-01

    Ozone (O3) deleteriously affects organisms ranging from humans to crop plants, yet little is understood regarding the underlying mechanisms. In plants, O3 decreases CO2 assimilation, but whether this could result from direct O3 action on guard cells remained unknown. Potassium flux causes osmotically driven changes in guard cell volume that regulate apertures of associated microscopic pores through which CO2 is supplied to the photosynthetic mesophyll tissue. We show in Vicia faba that O3 inhibits (i) guard cell K+ channels that mediate K+ uptake that drives stomatal opening; (ii) stomatal opening in isolated epidermes; and (iii) stomatal opening in leaves, such that CO2 assimilation is reduced without direct effects of O3 on photosynthetic capacity. Direct O3 effects on guard cells may have ecological and agronomic implications for plant productivity and for response to other environmental stressors including drought.

  5. Simulated microgravity inhibits cell wall regeneration of Penicillium decumbens protoplasts

    NASA Astrophysics Data System (ADS)

    Zhao, C.; Sun, Y.; Yi, Z. C.; Rong, L.; Zhuang, F. Y.; Fan, Y. B.

    2010-09-01

    This work compares cell wall regeneration from protoplasts of the fungus Penicillium decumbens under rotary culture (simulated microgravity) and stationary cultures. Using an optimized lytic enzyme mixture, protoplasts were successfully released with a yield of 5.3 × 10 5 cells/mL. Under simulated microgravity conditions, the protoplast regeneration efficiency was 33.8%, lower than 44.9% under stationary conditions. Laser scanning confocal microscopy gave direct evidence for reduced formation of polysaccharides under simulated conditions. Scanning electron microscopy showed the delayed process of cell wall regeneration by simulated microgravity. The delayed regeneration of P. decumbens cell wall under simulated microgravity was likely caused by the inhibition of polysaccharide synthesis. This research contributes to the understanding of how gravitational loads affect morphological and physiological processes of fungi.

  6. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    PubMed

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  7. Mifepristone inhibits GRβ-coupled prostate cancer cell proliferation

    PubMed Central

    Ligr, Martin; Li, Yirong; Logan, Susan K.; Taneja, Semir; Melamed, Jonathan; Lepor, Hebert; Garabedian, Michael J.; Lee, Peng

    2013-01-01

    Purpose The glucocorticoid receptor (GR) gene produces GRα and GRβ isoforms by alternative splicing of a C-terminal exon. GRα binds glucocorticoids, modulates transcription in a glucocorticoid-dependent manner, and plays a growth inhibitory role in prostate cells. Due to this role, glucocorticoids are often used to treat androgen-independent prostate cancer. By contrast, GRβ possesses intrinsic transcriptional activity and binds mifepristone (RU486), but not glucocorticoids, to control gene expression. The role of GRβ in prostate cell proliferation is unknown. Materials and Methods We determined the levels of GRβ in various prostate cancer cell lines by RT-PCR and western blotting. The effect of GRβ on the kinetics of prostate cancer cell growth was determined by cell counting and flow cytometry upon mifepristone and dexamethasone treatment. Cell proliferation was also examined following siRNA-mediated knock-down and overexpression of GRβ. Results GRβ mRNA and protein were upregulated in LNCaP cells overexpressing the androgen receptor co-factor ARA70β. Treatment of LNCaP-ARA70β with mifepristone or siRNA targeting GRβ inhibited proliferation, compared to parental LNCaP cells. An immortal but non-tumorigenic (RC165) prostate cell line, as well as a tumorigenic (DU145) prostate cell line with endogenous GRβ also showed partial growth reduction upon depletion of GRβ, albeit to a lesser extent than LNCaP-ARA70β cells. The growth-stimulatory effect of ARA70β on LNCaP cells is, in part, GRβ-dependent, as is the proliferation of RC165 and, to a lesser extent, DU145 cells. Conclusions These results suggest that patients whose primary tumors express GRβ and ARA70β may benefit from mifepristone treatment. PMID:22819113

  8. FH535 inhibited migration and growth of breast cancer cells.

    PubMed

    Iida, Joji; Dorchak, Jesse; Lehman, John R; Clancy, Rebecca; Luo, Chunqing; Chen, Yaqin; Somiari, Stella; Ellsworth, Rachel E; Hu, Hai; Mural, Richard J; Shriver, Craig D

    2012-01-01

    There is substantial evidence indicating that the WNT signaling pathway is activated in various cancer cell types including breast cancer. Previous studies reported that FH535, a small molecule inhibitor of the WNT signaling pathway, decreased growth of cancer cells but not normal fibroblasts, suggesting this pathway plays a role in tumor progression and metastasis. In this study, we tested FH535 as a potential inhibitor for malignant phenotypes of breast cancer cells including migration, invasion, and growth. FH535 significantly inhibited growth, migration, and invasion of triple negative (TN) breast cancer cell lines (MDA-MB231 and HCC38) in vitro. We demonstrate that FH535 was a potent growth inhibitor for TN breast cancer cell lines (HCC38 and MDA-MB-231) but not for other, non-TN breast cancer cell lines (MCF-7, T47D or SK-Br3) when cultured in three dimensional (3D) type I collagen gels. Western blotting analyses suggest that treatment of MDA-MB-231 cells with FH535 markedly inhibited the expression of NEDD9 but not activations of FAK, Src, or downstream targets such as p38 and Erk1/2. We demonstrated that NEDD9 was specifically associated with CSPG4 but not with β1 integrin or CD44 in MDA-MB-231 cells. Analyses of gene expression profiles in breast cancer tissues suggest that CSPG4 expression is higher in Basal-type breast cancers, many of which are TN, than any other subtypes. These results suggest not only a mechanism for migration and invasion involving the canonical WNT-signaling pathways but also novel strategies for treating patients who develop TN breast cancer.

  9. Inhibition of FAK kinase activity preferentially targets cancer stem cells

    PubMed Central

    Kolev, Vihren N.; Tam, Winnie F.; Wright, Quentin G.; McDermott, Sean P.; Vidal, Christian M.; Shapiro, Irina M.; Xu, Qunli; Wicha, Max S.; Pachter, Jonathan A.; Weaver, David T.

    2017-01-01

    Because cancer stem cells (CSCs) have been implicated in chemo-resistance, metastasis and tumor recurrence, therapeutic targeting of CSCs holds promise to address these clinical challenges to cancer treatment. VS-4718 and VS-6063 are potent inhibitors of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates cell signals transmitted by integrins and growth factor receptors. We report here that inhibition of FAK kinase activity by VS-4718 or VS-6063 preferentially targets CSCs, as demonstrated by a panel of orthogonal CSC assays in cell line models and surgically resected primary breast tumor specimens cultured ex vivo. Oral administration of VS-4718 or VS-6063 to mice bearing xenograft models of triple-negative breast cancer (TNBC) significantly reduced the proportion of CSCs in the tumors, as evidenced by a reduced tumor-initiating capability upon re-implantation in limiting dilutions of cells prepared from these tumors. In contrast, the cytotoxic chemotherapeutic agents, paclitaxel and carboplatin, enriched for CSCs, consistent with previous reports that these cytotoxic agents preferentially target non-CSCs. Importantly, VS-4718 and VS-6063 attenuated the chemotherapy-induced enrichment of CSCs in vitro and delayed tumor regrowth following cessation of chemotherapy. An intriguing crosstalk between FAK and the Wnt/β-catenin pathway was revealed wherein FAK inhibition blocks β-catenin activation by reducing tyrosine 654 phosphorylation of β-catenin. Furthermore, a constitutively active mutant form of β-catenin reversed the preferential targeting of CSCs by FAK inhibition, suggesting that this targeting is mediated, at least in part, through attenuating β-catenin activation. The preferential targeting of cancer stem cells by FAK inhibitors provides a rationale for the clinical development of FAK inhibitors aimed to increase durable responses for cancer patients. PMID:28881682

  10. Isoliquiritigenin inhibits cell proliferation and induces apoptosis in human hepatoma cells.

    PubMed

    Hsu, Ya-Ling; Kuo, Po-Lin; Lin, Liang-Tzung; Lin, Chun-Ching

    2005-02-01

    Isoliquiritigenin (4,2',4'-trihydroxychalcone, ISL) is a natural pigment with a simple chalcone structure. In this study, we report the ISL-induced inhibition on the growth of human hepatoma cells (Hep G2) for the first time. The cell growth inhibition achieved by ISL treatment resulted in programmed cell death in a caspase activation-dependent manner, with an IC50 of 10.51 microg/mL. Outcomes of ISL treatment included the up-regulation of IkappaBalpha expression in the cytoplasm, and the decrease of NF-kappaB level as well as its activity in the nucleus. In addition, ISL also suppressed the expression of Bcl-XL and c-IAP1/2 protein, the downstream target molecule of NF-kappaB. These results demonstrated that ISL treatment inhibited the NF-kappaB cell survival-signaling pathway and induced apoptotic cell death in Hep G2 cells.

  11. Inhibition of B-Cell Proliferation and Antibody Production by Mesenchymal Stromal Cells Is Mediated by T Cells

    PubMed Central

    Bernardo, Maria Ester; Scarsella, Marco; Conforti, Antonella; Giorda, Ezio; Biagini, Simone; Cascioli, Simona; Rossi, Francesca; Guzzo, Isabella; Vivarelli, Marina; Dello Strologo, Luca; Emma, Francesco; Locatelli, Franco; Carsetti, Rita

    2015-01-01

    Bone marrow (BM)-derived mesenchymal stromal cells (MSCs), endowed with immunosuppressive and anti-inflammatory properties, represent a promising tool in immunoregulatory and regenerative cell therapy. Clarifying the interactions between MSCs and B-lymphocytes may be crucial for designing innovative MSC-based strategies in conditions in which B cells play a role, including systemic lupus erythematosus (SLE) and rejection of kidney transplantation. In this study, we show that, both in healthy subjects and in patients, in vitro B-cell proliferation, plasma-cell differentiation, and antibody production are inhibited by BM-derived MSCs when peripheral blood lymphocytes are stimulated with CpG, but not when sorted B cells are cultured with MSCs+CpG. Inhibition is restored in CpG+MSC cocultures when sorted T cells are added to sorted B cells, suggesting that this effect is mediated by T cells, with both CD4+ and CD8+ cells playing a role. Moreover, cell–cell contact between MSCs and T cells, but not between MSCs and B cells, is necessary to inhibit B-cell proliferation. Thus, the presence of functional T cells, as well as cell–cell contact between MSCs and T cells, are crucial for B-cell inhibition. This information can be relevant for implementing MSC-based therapeutic immune modulation in patients in whom T-cell function is impaired. PMID:25036865

  12. 3-Methyladenine suppresses cell migration and invasion of HT1080 fibrosarcoma cells through inhibiting phosphoinositide 3-kinases independently of autophagy inhibition.

    PubMed

    Ito, Shingo; Koshikawa, Nobuko; Mochizuki, Shigenobu; Takenaga, Keizo

    2007-08-01

    3-Methyladenine (3-MA) inhibits class III phosphoinositide 3-kinase (PI3K) and is widely used as an inhibitor of autophagy. 3-MA has also been shown to stimulate cell death of tumor cells under nutrient-starved conditions by inhibiting autophagy. To explore the possibility of this type of autophagy inhibitors as anticancer drugs, we examined the effects of 3-MA on the phenotypes of highly metastatic human fibrosarcoma HT1080 cells. We report here that although 3-MA did not markedly affect cell survival of the cells under either normal or amino acid-starved conditions, it strongly inhibited the invasiveness of the cells. 3-MA rapidly suppressed actin rich membrane ruffle and/or lamellipodia formation under normal conditions, leading to inhibition of cell migration and invasion of the cells without substantial inhibitions of small GTPase Rac activity and the production of matrix metalloproteinases MMP-2 and MMP-9. 3-MA abolished class I and class II PI3Ks in in vitro lipid kinase assays, and suppressed cell motility of the cells more strongly than the other PI3K inhibitors wortmannin and LY294002. Downregulation of Beclin 1, a protein required for autophagic body formation, by transfection of Beclin 1 siRNA did not inhibit membrane ruffle formation and cell migration. These results suggest that 3-MA suppresses the invasion of HT1080 cells, independently of autophagy inhibition, through inhibition of type I and II PI3Ks and possibly other molecules.

  13. Inhibition of murine erythroleukemia cell differentiation by 3-deazaadenosine.

    PubMed

    Sherman, M L; Shafman, T D; Spriggs, D R; Kufe, D W

    1985-11-01

    Recent studies have demonstrated that 5'-methylthioadenosine, an inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, blocks induction of murine erythroleukemia cell (MEL) differentiation. The nucleoside analogue 3-deazaadenosine (c3Ado) is both an efficient substrate and a potent inhibitor of AdoHcy hydrolase. The present study was undertaken to determine whether c3Ado would similarly inhibit MEL differentiation. The results demonstrate that c3Ado inhibits induction of MEL differentiation by dimethyl sulfoxide, hexamethylene bisacetamide, butyric acid, and diazapam. c3Ado blocks the appearance of the differentiated MEL phenotype by inhibiting both MEL heme synthesis and transcription of alpha- and beta-globin RNA. The inhibitory effect of c3Ado on MEL differentiation is concentration dependent, reversible, and potentiated by L-homocysteine thiolactone. Furthermore the AdoHcy/AdoMet ratio increases nearly 3.5-fold after 24 h of treatment with 50 microM c3Ado. In contrast, this c3Ado effect is not associated with polyamine depletion or cytostasis. These findings indicate that c3Ado blocks the induction of MEL differentiation at a transcriptional level and that this effect may be related to inhibition of AdoHcy hydrolase.

  14. Dendritic cell MST1 inhibits Th17 differentiation

    PubMed Central

    Li, Chunxiao; Bi, Yujing; Li, Yan; Yang, Hui; Yu, Qing; Wang, Jian; Wang, Yu; Su, Huilin; Jia, Anna; Hu, Ying; Han, Linian; Zhang, Jiangyuan; Li, Simin; Tao, Wufan; Liu, Guangwei

    2017-01-01

    Although the differentiation of CD4+T cells is widely studied, the mechanisms of antigen-presenting cell-dependent T-cell modulation are unclear. Here, we investigate the role of dendritic cell (DC)-dependent T-cell differentiation in autoimmune and antifungal inflammation and find that mammalian sterile 20-like kinase 1 (MST1) signalling from DCs negatively regulates IL-17 producing-CD4+T helper cell (Th17) differentiation. MST1 deficiency in DCs increases IL-17 production by CD4+T cells, whereas ectopic MST1 expression in DCs inhibits it. Notably, MST1-mediated DC-dependent Th17 differentiation regulates experimental autoimmune encephalomyelitis and antifungal immunity. Mechanistically, MST1-deficient DCs promote IL-6 secretion and regulate the activation of IL-6 receptor α/β and STAT3 in CD4+T cells in the course of inducing Th17 differentiation. Activation of the p38 MAPK signal is responsible for IL-6 production in MST1-deficient DCs. Thus, our results define the DC MST1–p38MAPK signalling pathway in directing Th17 differentiation. PMID:28145433

  15. GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

    PubMed Central

    Cao, Yanan; Xuan, Binbin; Fan, Yingchao; Sheng, Huiming; Zhuang, Wenfang

    2017-01-01

    Drug resistance constitutes one of the main obstacles for clinical recovery of acute myeloid leukemia (AML) patients. Therefore, the treatment of AML requires new strategies, such as adding a third drug. To address whether GATA2 could act as a regulator of chemotherapy resistance in human leukemia cells, we observed KG1a cells and clinical patients’ AML cells with a classic drug (Cerubidine) and Gefitinib. After utilizing chemotherapy, the expression of GATA2 and its target genes (EVI, SCL and WT1) in surviving AML cells and KG1a cells were significantly enhanced to double and quadrupled compared to its original level respectively. Furthermore, with continuous chemotherapeutics, AML cells with GATA2 knockdown or treated with GATA2 inhibitor (K1747) almost eliminated with dramatically reduced expression of WT1, SCL, EVI, and significantly increased apoptotic population. Therefore, we propose that reducing GATA2 expression or inhibition of its transcription activity can relieve the drug resistance of acute myeloid leukemia cells and it would be helpful for eliminating the leukemia cells in patients. PMID:28114350

  16. Cinnamon effectively inhibits the activity of leukemia stem cells.

    PubMed

    Guan, X; Su, M C; Zhao, R B; Ouyang, H M; Dong, X D; Hu, P; Pei, Q; Lu, J; Li, Z F; Zhang, C R; Yang, T-H

    2016-08-19

    Cinnamon is the main component of Sanyangxuedai, which is one of the effective traditional Chinese medicines for treating malignancies. Leukemia is a prevalent malignant disease that Sanyangxuedai has been used to treat. Although successful in several studies, there is a lack of solid evidence as to why Sanyangxuedai has an effect on leukemia, and little is known about the underlying mechanisms. In this study, the active ingredients of cinnamon were isolated, purified, and identified. The transwell transport pool formed with the Caco-2 cell model was used to filter the active ingredients of cinnamon by simulating the gastrointestinal barrier in vitro. Moreover, the cell morphology, cell cycle status, apoptosis status, and antigenic variation of the cell surface antigens were observed and measured in K562 cells after treatment with the active ingredients of cinnamon. Our results showed that 50-75 μM was a safe concentration of cinnamon extract for treatment of K562 cells for 72 h. The cinnamon extract caused growth inhibition of K562 cells. Cinnamon extract seemed to arrest the cells at the G1 stage and increased the apoptosis rate significantly. Interestingly, cinnamon extract treatment upregulated the expression of erythroid and myeloid differentiation antigens and downregulated that of the megakaryocytic differentiation antigens in a dose-dependent manner. Our findings indicate that cinnamon extract from Sanyangxuedai may be effective for treating leukemia.

  17. Ubenimex inhibits cell proliferation, migration and invasion by inhibiting the expression of APN and inducing autophagic cell death in prostate cancer cells.

    PubMed

    Wang, Xiaoqing; Niu, Zhihong; Jia, Yang; Cui, Meng; Han, Liping; Zhang, Yongfei; Liu, Zheng; Bi, Dongbin; Liu, Shuai

    2016-04-01

    Prostate cancer is the second most frequently diagnosed cancer in males worldwide and is commonly associated with metastasis. Moreover, in prostate cancer, aminopeptidase N (APN) expression is closely correlated with metastasis. Ubenimex, an APN inhibitor, is widely used as an adjunct therapy for cancer, enhancing the function of immunocompetent cells and conferring antitumor effects. However, due to the low expression of APN, it is rarely used to treat prostate cancer. Recently, the induction of autophagy as a molecular mechanism has been strongly connected with tumor cell death. Thus, we investigated whether ubenimex could inhibit cell proliferation, migration and invasion by downregulating APN expression to induce autophagic cell death in prostate cancer cells. The LNCaP and PC-3 cell lines were treated with different doses of ubenimex. Cell viability was measured using growth curve analysis and WST-8 proliferation assay. Autophagic cell death was assessed using fluorescence microscopy and acridine orange/ethidium bromide (AO/EB) staining. Protein expression was assessed by immunofluorescence and western blot analyses. Autophagosomes were evaluated using transmission electron microscopy. Wound-healing migration assays were performed to determine the migratory ability of the PC-3 cells. In addition, nude mice were used in the present study to examine PC-3 cell proliferation in vivo. The results revealed that APN expression differed between the metastatic and non-metastatic prostate cancer cells. In addition, ubenimex inhibited APN expression in the prostate cancer cells. Ubenimex increased prostate cancer cell death, as determined using the lactate dehydrogenase (LDH) cytotoxicity assay. This effect was accompanied by increased levels of LC3B. Furthermore, ubenimex inhibited PC-3 cell proliferation in vivo and in vitro. Ubenimex inhibited the cell migration and invasion in prostate cancer cells by downregulating APN expression. Finally, ubenimex induced

  18. Bisphenol A Inhibits Cell Proliferation and Reduces the Motile Potential of Murine LM8 Osteosarcoma Cells.

    PubMed

    Kidani, Teruki; Yasuda, Rie; Miyawaki, Joji; Oshima, Yusuke; Miura, Hiromasa; Masuno, Hiroshi

    2017-04-01

    The aim of this study was to examine the effect of bisphenol A (BPA) on the proliferation and motility potential of murine LM8 osteosarcoma cells. LM8 cells were treated for 3 days with or without 80 μM BPA. The effect of BPA on cell proliferation was determined by DNA measurement in the cultures and 5-bromo-2'-deoxyuridine (BrdU) incorporation study. Ethanol-fixed cells were stained with hematoxylin-eosin (H&E) to visualize cell morphology. Cell motility was assayed using inserts with uncoated membranes in invasion chambers. Expression of cell division cycle 42 (CDC42) was determined by immunofluorescence staining and western blotting. BPA reduced the DNA content of cultures and the number of BrdU-positive cells. BPA induced a change in morphology from cuboidal with multiple filopodia on the cell surface to spindle-shaped with a smooth cell surface. BPA-treated cells expressed less CDC42 and were less motile than untreated cells. BPA inhibited DNA replication and cell proliferation. BPA inhibited filopodia formation and motile potential by inhibiting CDC42 expression in LM8 cells. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  19. Carbocisteine inhibits rhinovirus infection in human tracheal epithelial cells.

    PubMed

    Yasuda, H; Yamaya, M; Sasaki, T; Inoue, D; Nakayama, K; Yamada, M; Asada, M; Yoshida, M; Suzuki, T; Nishimura, H; Sasaki, H

    2006-07-01

    The aim of the study was to examine the effects of a mucolytic drug, carbocisteine, on rhinovirus (RV) infection in the airways. Human tracheal epithelial cells were infected with a major-group RV, RV14. RV14 infection increased virus titres and the cytokine content of supernatants. Carbocisteine reduced supernatant virus titres, the amount of RV14 RNA in cells, cell susceptibility to RV infection and supernatant cytokine concentrations, including interleukin (IL)-6 and IL-8, after RV14 infection. Carbocisteine reduced the expression of mRNA encoding intercellular adhesion molecule (ICAM)-1, the receptor for the major group of RVs. It also reduced the supernatant concentration of a soluble form of ICAM-1, the number and fluorescence intensity of acidic endosomes in the cells before RV infection, and nuclear factor-kappaB activation by RV14. Carbocisteine also reduced the supernatant virus titres of the minor group RV, RV2, although carbocisteine did not reduce the expression of mRNA encoding a low density lipoprotein receptor, the receptor for RV2. These results suggest that carbocisteine inhibits rhinovirus 2 infection by blocking rhinovirus RNA entry into the endosomes, and inhibits rhinovirus 14 infection by the same mechanism as well as by reducing intercellular adhesion molecule-1 levels. Carbocisteine may modulate airway inflammation by reducing the production of cytokines in rhinovirus infection.

  20. Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.

    PubMed

    Li, Wenjuan; Zhang, Chunjing; Ren, Amy; Li, Teena; Jin, Rong; Li, Guohong; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

    2015-01-01

    The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis.

  1. Cell growth inhibition by sequence-specific RNA minihelices.

    PubMed Central

    Hipps, D; Schimmel, P

    1995-01-01

    RNA minihelices which reconstruct the 12 base pair acceptor-T psi C domains of transfer RNAs interact with their cognate tRNA synthetases. These substrates lack the anticodons of the genetic code and, therefore, cannot participate in steps of protein synthesis subsequent to aminoacylation. We report here that expression in Escherichia coli of either of two minihelices, each specific for a different amino acid, inhibited cell growth. Inhibition appears to be due to direct competition between the minihelix and its related tRNA for binding to their common synthetase. This competition, in turn, sharply lowers the pool of the specific charged tRNA for protein synthesis. Inhibition is relieved by single nucleotide changes which disrupt the minihelix-synthetase interaction. The results suggest that sequence-specific RNA minihelix substrates bind to cognate synthetases in vivo and can, in principle, act as cell growth regulators. Naturally occurring non-tRNA substrates for aminoacylation may serve a similar purpose. Images PMID:7664744

  2. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    SciTech Connect

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

  3. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    PubMed Central

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2012-01-01

    Purpose Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of KrasG12D-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radio-sensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer. PMID:23182391

  4. Inhibition of steroidogenesis in Leydig cells by Müllerian-inhibiting substance.

    PubMed

    Fynn-Thompson, Eric; Cheng, Henry; Teixeira, Jose

    2003-12-15

    Müllerian-inhibiting substance (MIS), a member of the transforming growth factor-beta family of cytokines that signal through a heteromeric complex of single-transmembrane serine/threonine kinase receptors, is required for Müllerian duct regression and normal reproductive tract development in the male embryo. However, the continued expression of MIS at high levels in males until puberty and its induction in females after birth suggested other roles for MIS. Additionally, Leydig cell development and steroidogenic capacity and ovarian follicle recruitment were abnormal in MIS-knockout or MIS-overexpressing mice. We have shown that MIS inhibits the cAMP-induced expression of cytochrome P450 C17alpha-hydroxylase/C17-20 lyase (Cyp17) mRNA both in vitro and in vivo. Our current efforts are to understand the molecular mechanisms regulating both MIS type II receptor (MISRII) expression and its signaling in rodent Leydig cell lines. MISRII expression in R2C cells requires both steroidogenic factor-1 and an unknown protein to bind to its proximal promoter in the context of 1.6 kb 5'-flanking DNA. When bound by MIS, signaling by the receptor in MA-10 cells blocks the protein kinase A-mediated induction of Cyp17 expression by a cAMP regulatory element-binding protein independent mechanism. We continue to investigate the molecular mechanisms of MISRII expression and possible interactions between MIS-regulated SMAD activation and cAMP signaling. These studies will provide a better understanding of the role played by MIS during postnatal life.

  5. Myostatin inhibits cell proliferation and protein synthesis in C2C12 muscle cells.

    PubMed

    Taylor, W E; Bhasin, S; Artaza, J; Byhower, F; Azam, M; Willard, D H; Kull, F C; Gonzalez-Cadavid, N

    2001-02-01

    Myostatin mutations in mice and cattle are associated with increased muscularity, suggesting that myostatin is a negative regulator of skeletal muscle mass. To test the hypothesis that myostatin inhibits muscle cell growth, we examined the effects of recombinant myostatin in mouse skeletal muscle C2C12 cells. After verification of the expression of cDNA constructs in a cell-free system and in transfected Chinese hamster ovary cells, the human recombinant protein was expressed as the full-length (375-amino acid) myostatin in Drosophila cells (Mst375D), or the 110-amino acid carboxy-terminal protein in Escherichia coli (Mst110EC). These proteins were identified by immunoblotting and were purified. Both Mst375D and Mst110EC dose dependently inhibited cell proliferation (cell count and Formazan assay), DNA synthesis ([3H]thymidine incorporation), and protein synthesis ([1-14C]leucine incorporation) in C2C12 cells. The inhibitory effects of both proteins were greater in myotubes than in myoblasts. Neither protein had any significant effects on protein degradation or apoptosis. In conclusion, recombinant myostatin proteins inhibit cell proliferation, DNA synthesis, and protein synthesis in C2C12 muscle cells, suggesting that myostatin may control muscle mass by inhibiting muscle growth or regeneration.

  6. A revisited concept: Contact inhibition of growth. From cell biology to malignancy.

    PubMed

    Ribatti, Domenico

    2017-10-01

    In cell biology, contact inhibition refers to two different but closely related phenomena, contact inhibition of locomotion and contact inhibition of proliferation, exhibited by fibroblasts when in contact with one another. Normal fibroblasts migrate across the surface of a culture dish until they make contact with a neighboring cell. Further cell migration is then inhibited, and normal cells adhere to each other, forming an orderly array of cells on the culture dish surface. Tumor cells, in contrast, continue moving after contact with their neighbors, migrating over adjacent cells, and growing in disordered, multilayered patterns. Not only the movement but also the proliferation of many normal cells is inhibited by cell-cell contact, and cancer cells are characteristically insensitive to such contact inhibition. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Arginase inhibition enhances angiogenesis in endothelial cells exposed to hypoxia.

    PubMed

    Wang, Lin; Bhatta, Anil; Toque, Haroldo A; Rojas, Modesto; Yao, Lin; Xu, Zhimin; Patel, Chintan; Caldwell, Ruth B; Caldwell, R William

    2015-03-01

    Hypoxia-induced arginase elevation plays an essential role in several vascular diseases but influence of arginase on hypoxia-mediated angiogenesis is completely unknown. In this study, in vitro network formation in bovine aortic endothelial cells (BAEC) was examined after exposure to hypoxia for 24h with or without arginase inhibition. Arginase activity, protein levels of the two arginase isoforms, eNOS, and VEGF as well as production of NO and ROS were examined to determine the involvement of arginase in hypoxia-mediated angiogenesis. Hypoxia elevated arginase activity and arginase 2 expression but reduced active p-eNOS(Ser1177) and NO levels in BAEC. In addition, both VEGF protein levels and endothelial elongation and network formation were reduced with continued hypoxia, whereas ROS levels increased and NO levels decreased. Arginase inhibition limited ROS, restored NO formation and VEGF expression, and prevented the reduction of angiogenesis. These results suggest a fundamental role of arginase activity in regulating angiogenic function.

  8. Vitamin E inhibits retinal pigment epithelium cell proliferation in vitro.

    PubMed

    Mojon, D; Boscoboinik, D; Haas, A; Bohnke, M; Azzi, A

    1994-01-01

    Retinal pigment epithelium (RPE) cells migrating through the damaged retina play an important role in the pathogenesis of proliferative vitreoretinopathy (PVR). We found that alpha-tocopherol (vitamin E) inhibits proliferation of human RPE in culture without exerting cytotoxic effects. Maximal inhibition was achieved with 100 microM alpha-tocopherol. Our result could explain the observation that vitamin E supplements have an adverse effect on light-damaged retina and on the course of retinitis pigmentosa. Since it has been shown that supplemental oral administrations of vitamin E can raise the RPE concentration of alpha-tocopherol well above 100 microM and supplementation is not associated with any clinical relevant adverse effect, we believe that vitamin E could be beneficial in the treatment of PVR.

  9. A triterpenoid from wild bitter gourd inhibits breast cancer cells

    PubMed Central

    Bai, Li-Yuan; Chiu, Chang-Fang; Chu, Po-Chen; Lin, Wei-Yu; Chiu, Shih-Jiuan; Weng, Jing-Ru

    2016-01-01

    The antitumor activity of 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 μM, respectively, via a PPARγ−independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-κB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer. PMID:26926586

  10. A triterpenoid from wild bitter gourd inhibits breast cancer cells

    NASA Astrophysics Data System (ADS)

    Bai, Li-Yuan; Chiu, Chang-Fang; Chu, Po-Chen; Lin, Wei-Yu; Chiu, Shih-Jiuan; Weng, Jing-Ru

    2016-03-01

    The antitumor activity of 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 μM, respectively, via a PPARγ-independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-κB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer.

  11. A triterpenoid from wild bitter gourd inhibits breast cancer cells.

    PubMed

    Bai, Li-Yuan; Chiu, Chang-Fang; Chu, Po-Chen; Lin, Wei-Yu; Chiu, Shih-Jiuan; Weng, Jing-Ru

    2016-03-01

    The antitumor activity of 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 μM, respectively, via a PPARγ-independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-κB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer.

  12. Androglobin knockdown inhibits growth of glioma cell lines

    PubMed Central

    Huang, Bo; Lu, Yi-Sheng; Li, Xia; Zhu, Zhi-Chuan; Li, Kui; Liu, Ji-Wei; Zheng, Jing; Hu, Ze-Lan

    2014-01-01

    Globin family was famous for oxygen supply function of its members such as hemoglobin and myoglobin. With the progress of research, several members of this protein family have been proven to play roles in tumors including glioma. Androglobin (ADGB) is a recently identified member of globin family with very few studies about its function. In the present study, we show that ADGB plays an oncogene role in glioma. Lentiviral vector mediated ADGB knockdown inhibited the proliferation of glioma cell lines determined by MTT assay and colony formation assay. ADGB knockdown also increased the apoptosis of glioma cell line U251 assessed by flow cytometry. In addition, western blot showed that ADGB knockdown altered levels of several proteins related to proliferation, survival or apoptosis in U251 cells. These findings suggest ADGB is involved in the progression of glioma in vitro. PMID:24966926

  13. Polydatin Inhibits Formation of Macrophage-Derived Foam Cells

    PubMed Central

    Wu, Min; Liu, Meixia; Guo, Gang; Zhang, Wengao; Liu, Longtao

    2015-01-01

    Rhizoma Polygoni Cuspidati, a Chinese herbal medicine, has been widely used in traditional Chinese medicine for a long time. Polydatin, one of the major active ingredients in Rhizoma Polygoni Cuspidati, has been recently shown to possess extensive cardiovascular pharmacological activities. In present study, we examined the effects of Polydatin on the formation of peritoneal macrophage-derived foam cells in Apolipoprotein E gene knockout mice (ApoE−/−) and explored the potential underlying mechanisms. Peritoneal macrophages were collected from ApoE−/− mice and cultured in vitro. These cells sequentially were divided into four groups: Control group, Model group, Lovastatin group, and Polydatin group. Our results demonstrated that Polydatin significantly inhibits the formation of foam cells derived from peritoneal macrophages. Further studies indicated that Polydatin regulates the metabolism of intracellular lipid and possesses anti-inflammatory effects, which may be regulated through the PPAR-γ signaling pathways. PMID:26557864

  14. Beta-interferon inhibits cell infection by Trypanosoma cruzi

    NASA Technical Reports Server (NTRS)

    Kierszenbaum, F.; Sonnenfeld, G.

    1984-01-01

    Beta interferon has been shown to inhibit the capacity of bloodstream forms of the flagellate Trypanosoma cruzi, the causative agent of Chagas' disease, to associate with and infect mouse peritoneal macrophages and rat heart myoblasts. The inhibitory effect was abrogated in the presence of specific antibodies to the interferon. Pretreatment of the parasites with interferon reduced their infectivity for untreated host cells, whereas pretreament of either type of host cell did not affect the interaction. The effect of interferon on the trypanosomes was reversible; the extent of the inhibitory effect was significantly reduced afer 20 min, and was undetectable after 60 min when macrophages were used as host cells. For the myoblasts, 60 min elapsed before the inhibitory effect began to subside and 120 min elapsed before it became insignificant or undetectable.

  15. Honokiol inhibits androgen receptor activity in prostate cancer cells.

    PubMed

    Hahm, Eun-Ryeong; Karlsson, A Isabella; Bonner, Michael Y; Arbiser, Jack L; Singh, Shivendra V

    2014-04-01

    We have shown previously that honokiol (HNK), a bioactive component of the medicinal plant Magnolia officinalis, inhibits growth of human prostate cancer cells in vitro and in vivo. However, the effect of HNK on androgen receptor (AR) signaling has not been studied. LNCaP, C4-2, and TRAMP-C1 cells were used for various assays. Trypan blue dye exclusion assay or clonogenic assay was performed for determination of cell viability. The effects of HNK and/or its analogs on protein levels of AR and its target gene product prostate specific antigen (PSA) were determined by western blotting. RNA interference of p53 was achieved by transient transfection. Reverse transcription-polymerase chain reaction was performed for mRNA expression of AR. Nuclear level of AR was visualized by microscopy. Apoptosis was quantified by DNA fragmentation assay or flow cytometry after Annexin V-propidium iodide staining. HNK and its dichloroacetate analog (HDCA) were relatively more effective in suppressing cell viability and AR protein level than honokiol epoxide or biseugenol. Nuclear translocation of AR stimulated by a synthetic androgen (R1881) was markedly suppressed in the presence of HNK. Downregulation of AR protein resulting from HNK exposure was attributable to transcriptional repression as well as proteasomal degradation. HNK-mediated suppression of AR protein was maintained in LNCaP cells after knockdown of p53 protein. HNK-induced apoptosis was not affected by R1881 treatment. The present study demonstrates, for the first time, that HNK inhibits activity of AR in prostate cancer cells regardless of the p53 status. © 2013 Wiley Periodicals, Inc.

  16. Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells

    SciTech Connect

    Savion, N.; Disatnik, M.H.; Nevo, Z.

    1987-01-01

    Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells attach, invade, and penetrate confluent vascular endothelial cell monolayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the (/sup 35/S)O/sub 4//sup -/-labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The degradation of (/sup 35/S)O/sub 4//sup -/-labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10..mu..g/ml), arteparon (10..mu..g/ml), and heparin at a concentration of 3 ..mu..g/ml. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage haparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis.

  17. Migrastatin Analogues Inhibit Canine Mammary Cancer Cell Migration and Invasion

    PubMed Central

    Majchrzak, Kinga; Lo Re, Daniele; Gajewska, Małgorzata; Bulkowska, Małgorzata; Homa, Agata; Pawłowski, Karol; Motyl, Tomasz; Murphy, Paul V.; Król, Magdalena

    2013-01-01

    Background Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6) on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer. Results Our results showed that two of six fully synthetic analogues of migrastatin: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6) disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion. Conclusion Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6) were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs. However, further in

  18. Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated

    PubMed Central

    2010-01-01

    Purpose Inhibitors of epidermal growth factor receptor (EGFR) have shown dramatic results in a subset of patients with non-small cell lung cancer (NSCLC), and have also been shown to enhance the effect of ionizing radiation (IR). We investigated how gefitinib, an orally given EGFR inhibitor for NSCLC patients, can radiosensitize NSCLC cells. Experimental Design and Results In clonogenic survival assays performed in three NSCLC cell lines, gefitinib radiosensitized NCI-H460 and VMRC-LCD but not A549 cells. Gefitinib pretreatment induced multinucleated cells after IR exposure in NCI-H460 and VMRC-LCD, but not in A549 cells. Gefitinib also inhibited activation of ataxia telangiectasia mutated (ATM) after IR-exposure in NCI-H460 and VMRC-LCD, but not in A549 cells. An ATM specific inhibitor increased IR-induced multinucleated cells in both NCI-H460 and A549 cells. Gefitinib pretreatment inhibited the gradual decrease of γH2AX foci relative to time after IR exposure in NCI-H460 but not in A549 cells. Suppression of COX-2 in A549 cells induced multinucleated cells and caused radiosensitization after gefitinib+IR treatment. In contrast, COX-2 overexpression in NCI-H460 cells attenuated the induction of multinucleation and radiosensitization after the same treatment. Conclusions Our results suggest that gefitinib radiosensitizes NSCLC cells by inhibiting ATM activity and therefore inducing mitotic cell death, and that COX-2 overexpression in NSCLC cells inhibits this action of gefitinib. PMID:20731837

  19. Inhibition of human natural killer cell activity by Pseudomonas aeruginosa alkaline protease and elastase.

    PubMed Central

    Pedersen, B K; Kharazmi, A

    1987-01-01

    The present study was designed to examine the effect of Pseudomonas aeruginosa alkaline protease (AP) and elastase (Ela) on human natural killer (NK) cell activity in vitro. AP and Ela were found to inhibit NK cell function. Addition of alpha interferon and interleukin-2 did not abolish this inhibition of NK cell activity. Adhesion of effector to target cells was studied in a single-cell agarose assay of monocyte-depleted NK-cell-enriched cell populations. AP and Ela were shown to inhibit effector/target cell conjugate formation. Furthermore, AP and Ela inhibited the binding of the monoclonal antibody Leu-11, which reacts with the Fc receptor of NK cells. The inhibition of NK cell binding to the target cell by P. aeruginosa proteases is most likely due to proteolytic cleavage of the surface receptors involved in the binding of the effector cell to the target cell. PMID:3030937

  20. Xanthohumol inhibits proliferation of laryngeal squamous cell carcinoma.

    PubMed

    Li, Yan; Wang, Kai; Yin, Shankai; Zheng, Hongliang; Min, Daliu

    2016-12-01

    Xanthohumol is a flavonoid compound that exhibits antioxidant and anticancer effects, and is used to treat atherosclerosis. The aim of the present study was to investigate the effect of xanthohumol on the cell proliferation of laryngeal squamous cell carcinoma and to understand the mechanism of its action. The effects of xanthohumol on the cell viability and apoptosis rate of laryngeal squamous cell carcinoma SCC4 cells were assessed by Annexin V-fluorescein isothiocyanate/propidium iodide staining. In addition, the expression levels of pro-apoptotic proteins, caspase-3, caspase-8, caspase-9, poly ADP ribose polymerase (PARP) p53 and apoptosis-inducing factor (AIF), as well as anti-apoptotic markers, B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1), were analyzed by western blotting. The results revealed that treatment with 40 µM xanthohumol significantly inhibited the proliferation of SCC4 cells. Furthermore, xanthohumol treatment (40 µM) induced SCC4 cell apoptosis, as indicated by the significant increase in activity and expression of caspase-3, caspase-8, caspase-9, PARP, p53 and AIF. By contrast, the protein expression of Bcl-2 and Mcl-1 was significantly decreased following treatment with 40 µM xanthohumol. Taken together, the results of the present study indicated that xanthohumol mediates growth suppression and apoptosis induction, which was mediated via the suppression of Bcl-2 and Mcl-1 and activation of PARP, p53 and AIF signaling pathways. Therefore, future studies that investigate xanthohumol as a potential therapeutic agent for laryngeal squamous cell carcinoma are required.

  1. Norepinephrine inhibits the migratory activity of pancreatic cancer cells.

    PubMed

    Stock, Anna-Maria; Powe, Desmond G; Hahn, Stephan A; Troost, Gabriele; Niggemann, Bernd; Zänker, Kurt S; Entschladen, Frank

    2013-07-15

    We have shown previously that norepinephrine induces migratory activity of tumour cells from breast, colon and prostate tissue via activation of beta-2 adrenergic receptors. Consequently, this effect can be inhibited pharmacologically by clinically established beta-blockers. Tumour cell migration is a prerequisite for metastasis formation, and accordingly we and others have shown that breast cancer patients, which take beta-blockers due to hypertension, have reduced metastasis formation and increased survival probability as compared to patients without hypertension or using other anti-hypertensive medication. Unlike the aforementioned tumour cells, pancreatic cancer cells show a reduced migratory activity upon norepinephrine treatment. By means of our three-dimensional, collagen-based cell migration assay, we have investigated the signal transduction pathways involved in this phenomenon. We have found that this conflicting effect of norepinephrine on pancreatic cancer cells is due to an imbalanced activation of the two pathways that usually mediate a pro-migratory effect of norepinephrine in other tumour cell types. Firstly, the inhibitory effect results from activation of a pathway which causes a strong increase of the secondary cell signalling molecule, cAMP. In addition, activation of phospholipase C gamma and the downstream protein kinase C alpha were shown to be already activated in pancreatic cancer cells and cannot be further activated by norepinephrine. We hypothesize that this constitutive activation of the phospholipase C gamma pathway is due to a cross-talk with receptor tyrosine kinase signalling, and this might also deliver an explanation for the unusual high spontaneous migratory activity of pancreatic cancer cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Xanthohumol inhibits proliferation of laryngeal squamous cell carcinoma

    PubMed Central

    Li, Yan; Wang, Kai; Yin, Shankai; Zheng, Hongliang; Min, Daliu

    2016-01-01

    Xanthohumol is a flavonoid compound that exhibits antioxidant and anticancer effects, and is used to treat atherosclerosis. The aim of the present study was to investigate the effect of xanthohumol on the cell proliferation of laryngeal squamous cell carcinoma and to understand the mechanism of its action. The effects of xanthohumol on the cell viability and apoptosis rate of laryngeal squamous cell carcinoma SCC4 cells were assessed by Annexin V-fluorescein isothiocyanate/propidium iodide staining. In addition, the expression levels of pro-apoptotic proteins, caspase-3, caspase-8, caspase-9, poly ADP ribose polymerase (PARP) p53 and apoptosis-inducing factor (AIF), as well as anti-apoptotic markers, B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1), were analyzed by western blotting. The results revealed that treatment with 40 µM xanthohumol significantly inhibited the proliferation of SCC4 cells. Furthermore, xanthohumol treatment (40 µM) induced SCC4 cell apoptosis, as indicated by the significant increase in activity and expression of caspase-3, caspase-8, caspase-9, PARP, p53 and AIF. By contrast, the protein expression of Bcl-2 and Mcl-1 was significantly decreased following treatment with 40 µM xanthohumol. Taken together, the results of the present study indicated that xanthohumol mediates growth suppression and apoptosis induction, which was mediated via the suppression of Bcl-2 and Mcl-1 and activation of PARP, p53 and AIF signaling pathways. Therefore, future studies that investigate xanthohumol as a potential therapeutic agent for laryngeal squamous cell carcinoma are required. PMID:28105237

  3. Galectin-3 inhibition sensitizes human renal cell carcinoma cells to arsenic trioxide treatment

    PubMed Central

    Xu, Yangyang; Gu, Xin; Gong, Mancheng; Guo, Guiying; Han, Kaiyu; An, Ruihua

    2013-01-01

    The anti-tumor effects of arsenic trioxide (ATO) were well established in acute promyelocytic leukemia, but not in renal cell carcinoma (RCC). Recent evidences indicate that galectin-3 (Gal-3) plays an anti-apoptotic role in chemotherapy induced tumor cell death. This study was intended to clarify the exact roles of Gal-3 performed in ATO-induced apoptosis in RCC cells. Weak apoptosis was observed in Gal-3-positive RCC cells (Caki-1, Caki-2, 786-0, and ACHN) following ATO treatment. However, ATO treatment upregulated Gal-3 expression concurrently caused a Synexin-cooperated translocation of Gal-3 from the nucleus to the cytoplasm. Gal-3-knockdown cells were more sensitive to ATO treatment as indicated by a strong mitochondria-dependent apoptosis following ATO treatment. Meanwhile, Gal-3 was found to inhibit ATO-induced apoptosis through enhancing Bcl-2 expression and stabilizing mitochondria. To confirm the results obtained from genetic method, we employed a Gal-3 inhibitor, modified citrus prectin (MCP), and co-treated the RCC cells with ATO. The cells showed an increased apoptosis in the syngeneic application of Gal-3 inhibition and ATO compared with ATO application alone. Based on these results, we conclude that Gal-3 inhibition sensitizes human renal cell carcinoma cells to ATO treatment through increasing mitochondria-dependent apoptosis. Our studies implicate synergetic application of ATO and Gal-3 inhibition as a potential strategy for RCC treatment. PMID:23917726

  4. RNA interference targeting raptor inhibits proliferation of gastric cancer cells

    SciTech Connect

    Wu, William Ka Kei; Lee, Chung Wa; Cho, Chi Hin; Chan, Francis Ka Leung; Yu, Jun; Sung, Joseph Jao Yiu

    2011-06-10

    Mammalian target of rapamycin complex 1 (mTORC1) is dysregulated in gastric cancer. The biologic function of mTORC1 in gastric carcinogenesis is unclear. Here, we demonstrate that disruption of mTORC1 function by RNA interference-mediated downregulation of raptor substantially inhibited gastric cancer cell proliferation through induction of G{sub 0}/G{sub 1}-phase cell cycle arrest. The anti-proliferative effect was accompanied by concomitant downregulation of activator protein-1 and upregulation of Smad2/3 transcriptional activities. In addition, the expression of cyclin D{sub 3} and p21{sup Waf1}, which stabilizes cyclin D/cdk4 complex for G{sub 1}-S transition, was reduced by raptor knockdown. In conclusion, disruption of mTORC1 inhibits gastric cancer cell proliferation through multiple pathways. This discovery may have an implication in the application of mTORC1-directed therapy for the treatment of gastric cancer.

  5. Curcumin and anthocyanin inhibit pepsin-mediated cell damage and carcinogenic changes in airway epithelial cells.

    PubMed

    Samuels, Tina L; Pearson, Amy C S; Wells, Clive W; Stoner, Gary D; Johnston, Nikki

    2013-10-01

    Laryngopharyngeal reflux (LPR) is associated with inflammatory and neoplastic airway diseases. Gastric pepsin internalized by airway epithelial cells during reflux contributes to oxidative stress, inflammation, and carcinogenesis. Several plant extracts and compounds inhibit digestive enzymes and inflammatory or neoplastic changes to the esophagus in models of gastroesophageal reflux. This study examined the potential of chemoprotective phytochemicals to inhibit peptic activity and mitigate pepsin-mediated damage of airway epithelial cells. Cultured human laryngeal and hypopharyngeal epithelial cells were pretreated with curcumin (10 micromol/L), ecabet sodium (125 microg/mL), and anthocyanin-enriched black-raspberry extract (100 microg/mL) 30 minutes before treatment with pepsin (0.1 mg/mL; 1 hour; pH 7). Controls were treated with media pH 7 or pepsin pH 7 without phytochemicals. Cell damage and proliferative changes were assessed by electron microscopy, cell count, thymidine analog incorporation, and real-time polymerase chain reaction array. Pepsin inhibition was determined by in vitro kinetic assay. Micromolar concentrations of curcumin, ecabet sodium, and black-raspberry extract inhibited peptic activity and pepsin-induced mitochondrial damage and hyperproliferation. Curcumin abrogated pepsin-mediated depression of tumor suppressor gene expression and altered the subcellular localization of pepsin following endocytosis. Several phytochemicals inhibit the pepsin-mediated cell damage underlying inflammatory or neoplastic manifestations of LPR. Dietary supplementation or adjunctive therapy with phytochemicals may represent novel preventive or therapeutic strategies for LPR-attributed disease.

  6. Silencing of carboxypeptidase E inhibits cell proliferation, tumorigenicity, and metastasis of osteosarcoma cells

    PubMed Central

    Fan, Shuli; Li, Xu; Li, Leiming; Wang, Liguo; Du, Zhangzhen; Yang, Yan; Zhao, Jiansong; Li, Yan

    2016-01-01

    Carboxypeptidase E (CPE), a prohormone processing enzyme, has been implicated in the progression of multiple malignancies. However, the biological role and molecular mechanisms of CPE in osteosarcoma remain elusive. In this study, we assessed the effects of CPE on cell proliferation, tumorigenicity, migration, and invasion in osteosarcoma. Our results showed that silencing of CPE significantly inhibited cell proliferation, caused cell cycle arrest at G0/G1 phase, decreased the expression levels of cell cycle protein, cyclin D1, and inhibited tumorigenicity in vivo. Additionally, CPE downregulation repressed the migratory and invasive capacities of osteosarcoma cells in vitro. Furthermore, overexpression of CPE-ΔN (a splice variant of CPE) enhanced the cell growth, migration, and invasion of osteosarcoma cells. It is possible that both CPE forms are involved in the tumorigenesis and development of osteosarcoma, and therefore CPE may provide a promising biological target for osteosarcoma therapy. PMID:27274275

  7. Distinct patterns of chronic gastritis associated with carcinoid and cancer and their role in tumorigenesis.

    PubMed Central

    Solcia, E.; Rindi, G.; Fiocca, R.; Villani, L.; Buffa, R.; Ambrosiani, L.; Capella, C.

    1992-01-01

    A series of 60 gastric endocrine tumors comprised 44 body-fundus argyrophil carcinoids, of which 23 arose in a background of hypergastrinemia and type A chronic atrophic gastritis (A-CAG), mainly with histologic patterns suggestive of an autoimmune process. Only 22 percent (compared with 19 percent of 58 tumor-free A-CAG cases) of 36 carcinoids and 21 percent of 19 A-CAG carcinoids investigated had Helicobacter pylori (HP) colonization, against 50 percent of 14 CAG-associated neuroendocrine carcinomas or mixed endocrine-exocrine tumors, 84 percent of 150 cases with early gastric cancer (p < 0.001 versus carcinoids), mostly with B- or AB-type CAG, 76 percent of 97 tumor-free AB-CAG, and 95 percent of 151 tumor-free B-CAG cases. Secondary hypergastrinemia and local mechanisms activated by chronic autoimmune gastritis are among factors involved in the pathogenesis of relatively indolent CAG-associated carcinoids, whereas active HP gastritis in cooperation with environmental carcinogens may likely cause more severe epithelial transformation, leading to ordinary cancer and, possibly, to neuroendocrine carcinomas or mixed endocrine-exocrine tumors. Images FIG. 1 FIG. 2 FIG. 3 PMID:1341079

  8. Intradural Carcinoid Tumor Found in a Patient with No History of Cancer.

    PubMed

    Audlin, Jason R; Khullar, Gaurav; Deshaies, Eric M; Kurra, Swamy; Lavelle, William F

    2016-12-01

    Carcinoid tumors are rare neoplasms that often arise from the gastrointestinal or respiratory tracts. They often metastasize to bone tissue and pancreatic and hepatic sites. The central nervous system and most specifically the spinal cord are rarely involved. Primary carcinoid tumors of the central nervous system are even rarer. A 58-year-old man presented with progressive bilateral lower extremity weakness and a negative history of cancer. Imaging revealed an intradural mass at the L1 and L2 spinal levels. Surgical resection of the tumor via laminectomy was performed. The tumor was observed to have eroded through the dura and was compressing the spinal nerves. Histopathologically, the mass was observed to be of carcinoid origin. A subsequent octreoscan revealed no primary sites of carcinoid tumor. Postoperatively, the patient was followed for 1.5 years. The patient reported improvement in sensation to his lower extremities with no change in motor findings. Carcinoid tumors of the central nervous system are extremely rare, but they should remain in the differential diagnosis for patients experiencing extremity weakness and back or neck pain with an intradural mass and no primary source of the tumor identified or other manifestations of a primary tumor. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Comparison of Endoscopic Mucosal Resection With Circumferential Incision and Endoscopic Submucosal Dissection for Rectal Carcinoid Tumor.

    PubMed

    Chen, Ru; Liu, Xiang; Sun, Siyu; Wang, Sheng; Ge, Nan; Wang, Guoxin; Guo, Jintao

    2016-06-01

    Endoscopic submucosal dissection (ESD) has been a valuable treatment of choice for rectal carcinoid tumors that are endoscopically treatable because of its satisfactory resection rate and low recurrence rate. For treatment of small rectal carcinoids, endoscopic mucosal resection (EMR) is more often chosen by endoscopists because of its safety and time efficiency. We applied circumferential incision and endoscopic mucosal resection (CI-EMR), which is a modification of EMR, to treat rectal carcinoid tumors and compared their efficacy and safety. Between January 2008 and December 2013, we enrolled 66 patients (30 in the ESD group and 36 in the CI-EMR group) at Shengjing Hospital who were pathologically diagnosed with rectal carcinoid tumors <15 mm in diameter. We retrospectively analyzed en bloc resection rates, pathologic complete resection rates, incidences of complications, follow-up outcomes, and procedure times. The en bloc resection rate and the histologic complete resection rate were similar, but the procedure time was longer in the ESD group than in the CI-EMR group. In cases that were incompletely resected, neither local recurrence nor distant metastasis was detected during follow-up. Similarly minor bleeding occurred in both groups, and no perforation occurred after either procedure. CI-EMR showed comparable en bloc resection and histologically complete resection rates and is technically simpler and minimally invasive compared with ESD. Because of its easier performance and shorter procedure time, CI-EMR may be preferable to ESD for resection of rectal carcinoid tumors <15 mm in diameter without invasion or distant metastases.

  10. Management of sub-5 mm rectal carcinoids with lymph node metastases

    PubMed Central

    Toh, James Wei Tatt; Henderson, Christopher; Yabe, Takako Eva; Ong, Evonne; Chapuis, Pierre; Bokey, Les

    2015-01-01

    Minute (<5 mm) and small (5–10 mm) rectal carcinoids discovered during colonoscopy are generally considered to be non-aggressive, and the management and surveillance of patients with this entity are usually limited. We present the case of a 61-year-old Chinese female with multiple sub-5 mm carcinoid tumours in the rectum without any computed tomography (CT) evidence of lymph node or distant metastases. She underwent an ultra-low anterior resection for a sessile rectal polyp with the histological appearance of a moderately differentiated adenocarcinoma. Seven foci of minute carcinoids in the rectum and perirectal lymph node metastastic spread from the carcinoid tumours were also discovered on histopathology. There were no lymph node metastases originating from adenocarcinoma. This case report and review of the literature suggests that minute rectal carcinoids are at risk of metastasizing and that these patients should be investigated for lymph node and distant metastatic spread with CT and somatostatin receptor scintigraphy or its equivalent, as this would influence prognosis and surgical management of these patients. Findings relating to lymphovascular invasion, perineural invasion, high Ki-67, mitotic rate, depth of tumour invasion, central ulceration, multifocal tumours and size are useful in predicting metastases and may be used in scoring tools. Size alone is not a good predictor of metastastic spread. PMID:25342710

  11. Molecular mechanisms of cholangiocarcinoma cell inhibition by medicinal plants

    PubMed Central

    Leelawat, Surang; Leelawat, Kawin

    2017-01-01

    Cholangiocarcinoma (CCA) is one of the most common causes of cancer-associated mortality in Thailand. Certain phytochemicals have been demonstrated to modulate apoptotic signaling pathways, which may be targeted for the prevention and treatment of cancer. Therefore, the aim of the present study was to investigate the effect of specific medicinal plants on the inhibition of CCA cell proliferation, and to identify the molecular mechanisms underlying this. A WST-1 cell proliferation assay was performed using an RMCCA1 cell line, and apoptotic signaling pathways were also investigated using a PathScan Stress and Apoptosis Signaling Antibody Array Kit. The cell proliferation assay indicated that extracts from the Phyllanthus emblica fruit pulp (PEf), Phyllanthus emblica seed (PEs), Terminalia chebula fruit pulp (TCf), Terminalia chebula seed (TCs), Areca catechu seed (ACs), Curcuma longa (CL) and Moringa oleifera seed (MOs) exerted anti-proliferative activity in RMCCA1 cells. In addition, the PathScan assay revealed that certain pro-apoptotic molecules, including caspase-3, poly (ADP-ribose) polymerase, checkpoint kinase 2 and tumor protein 53, exhibited increased activity in RMCCA1 cells treated with the aforementioned selected plant extracts, with the exception of PEf. The mitogen-activated protein kinase (MAPK) pathways (including ERK1/2 and p38 MAPK) expression level was significantly increased in RMCCA1 cells pre-treated with extracts of PEs, TCf, CL and MOs. The activation of protein kinase B (Akt) was significantly demonstrated in RMCCA1 cells pre-treated with extracts of TCf, ACs and MOs. In summary, the present study demonstrated that extracts of PEs, TCf, TCs, ACs, CL and MOs exhibited anti-proliferative effects in CCA cells by inducing pro-apoptotic signals and modulating signal transduction molecules. Further studies in vivo are required to demonstrate the potential applications of specific plant extracts for the treatment of human cancer. PMID:28356985

  12. AP-2α inhibits hepatocellular carcinoma cell growth and migration.

    PubMed

    Huang, Wenhuan; Chen, Cheng; Liang, Zhongheng; Qiu, Junlu; Li, Xinxin; Hu, Xiang; Xiang, Shuanglin; Ding, Xiaofeng; Zhang, Jian

    2016-03-01

    Transcription factor AP-2α is involved in many types of human cancers, but its role in hepatocellular carcinogenesis is largely unknown. In this study, we found that expression of AP-2α was low in 40% of human hepatocellular cancers compared with adjacent normal tissues by immunohistochemical analysis. Moreover, AP-2α expression was low or absent in hepatocellular cancer cell lines (HepG2, Hep3B, SMMC-7721 and MHHC 97-H). Human liver cancer cell lines SMMC-7721 and Hep3B stably overexpressing AP-2α were established by lentiviral infection and puromycin screening, and the ectopic expression of AP-2α was able to inhibit hepatocellular cancer cell growth and proliferation by cell viability, MTT assay and liquid colony formation in vitro and in vivo. Furthermore, AP-2α overexpression decreased liver cancer cell migration and invasion as assessed by wound healing and Transwell assays, increasing the sensitivity of liver cancer cells to cisplatin analyzed by MTT assays. Also AP-2α overexpression suppressed the sphere formation and renewed the ability of cancer stem cells. Finally, we found that AP-2α is epigenetically modified and modulates the levels of phosphorylated extracellular signal-regulated protein kinase (ERK), β-catenin, p53, EMT, and CD133 expression in liver cancer cell lines. These results suggested that AP-2α expression is low in human hepatocellular cancers by regulating multiple signaling to affect hepatocellular cancer cell growth and migration. Therefore, AP-2α might represent a novel potential target in human hepatocellular cancer therapy.

  13. Bruceantin inhibits multiple myeloma cancer stem cell proliferation.

    PubMed

    Issa, Mark E; Berndt, Sarah; Carpentier, Gilles; Pezzuto, John M; Cuendet, Muriel

    2016-09-01

    Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.

  14. QSOX1 Inhibits Autophagic Flux in Breast Cancer Cells

    PubMed Central

    Poillet, Laura; Pernodet, Nicolas; Boyer-Guittaut, Michaël; Adami, Pascale; Borg, Christophe; Jouvenot, Michèle; Delage-Mourroux, Régis; Despouy, Gilles

    2014-01-01

    The QSOX1 protein (Quiescin Sulfhydryl oxidase 1) catalyzes the formation of disulfide bonds and is involved in the folding and stability of proteins. More recently, QSOX1 has been associated with tumorigenesis and protection against cellular stress. It has been demonstrated in our laboratory that QSOX1 reduces proliferation, migration and invasion of breast cancer cells in vitro and reduces tumor growth in vivo. In addition, QSOX1 expression has been shown to be induced by oxidative or ER stress and to prevent cell death linked to these stressors. Given the function of QSOX1 in these two processes, which have been previously linked to autophagy, we wondered whether QSOX1 might be regulated by autophagy inducers and play a role in this catabolic process. To answer this question, we used in vitro models of breast cancer cells in which QSOX1 was overexpressed (MCF-7) or extinguished (MDA-MB-231). We first showed that QSOX1 expression is induced following amino acid starvation and maintains cellular homeostasis. Our results also indicated that QSOX1 inhibits autophagy through the inhibition of autophagosome/lysosome fusion. Moreover, we demonstrated that inhibitors of autophagy mimic the effect of QSOX1 on cell invasion, suggesting that its role in this process is linked to the autophagy pathway. Previously published data demonstrated that extinction of QSOX1 promotes tumor growth in NOG mice. In this study, we further demonstrated that QSOX1 null tumors present lower levels of the p62 protein. Altogether, our results demonstrate for the first time a role of QSOX1 in autophagy in breast cancer cells and tumors. PMID:24475161

  15. QSOX1 inhibits autophagic flux in breast cancer cells.

    PubMed

    Poillet, Laura; Pernodet, Nicolas; Boyer-Guittaut, Michaël; Adami, Pascale; Borg, Christophe; Jouvenot, Michèle; Delage-Mourroux, Régis; Despouy, Gilles

    2014-01-01

    The QSOX1 protein (Quiescin Sulfhydryl oxidase 1) catalyzes the formation of disulfide bonds and is involved in the folding and stability of proteins. More recently, QSOX1 has been associated with tumorigenesis and protection against cellular stress. It has been demonstrated in our laboratory that QSOX1 reduces proliferation, migration and invasion of breast cancer cells in vitro and reduces tumor growth in vivo. In addition, QSOX1 expression has been shown to be induced by oxidative or ER stress and to prevent cell death linked to these stressors. Given the function of QSOX1 in these two processes, which have been previously linked to autophagy, we wondered whether QSOX1 might be regulated by autophagy inducers and play a role in this catabolic process. To answer this question, we used in vitro models of breast cancer cells in which QSOX1 was overexpressed (MCF-7) or extinguished (MDA-MB-231). We first showed that QSOX1 expression is induced following amino acid starvation and maintains cellular homeostasis. Our results also indicated that QSOX1 inhibits autophagy through the inhibition of autophagosome/lysosome fusion. Moreover, we demonstrated that inhibitors of autophagy mimic the effect of QSOX1 on cell invasion, suggesting that its role in this process is linked to the autophagy pathway. Previously published data demonstrated that extinction of QSOX1 promotes tumor growth in NOG mice. In this study, we further demonstrated that QSOX1 null tumors present lower levels of the p62 protein. Altogether, our results demonstrate for the first time a role of QSOX1 in autophagy in breast cancer cells and tumors.

  16. Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation.