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Sample records for stromal tumor cell

  1. Primary ovarian carcinoid tumor with luteinized stromal cells.

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    Engohan-Aloghe, Corinne; Buxant, F; Noël, J C

    2009-07-01

    Primary ovarian carcinoid tumors are rare. Distinct histologic patterns have been described in the literature as insular, trabecular, mucinous and mixed types. We describe a case of 71-year-old woman diagnosed with a left ovarian tumor. Frozen section examination identified the mass as a sex-cord stromal tumor. The surgically resected tumor was diagnosed as an insular carcinoid tumor with unusual luteinized stromal cells. Histologic diagnosis complied with results acquired by immunohistochemical with positivity of tumor cells for neuroendocrine markers and positivity of luteinized stromal cells for alpha-inhibin, calretinin and Melan A. Ovarian carcinoid tumor can be extremely heterogeneous. The purpose of our report was to show that the ovarian carcinoid tumor can be associated with stromal luteinization, mimicking a sex-cord stromal tumor.

  2. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth

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    Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make canc...

  3. Stromal cells in tumor microenvironment and breast cancer.

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    Mao, Yan; Keller, Evan T; Garfield, David H; Shen, Kunwei; Wang, Jianhua

    2013-06-01

    Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.

  4. Twist and Snail expression in tumor and stromal cells of epithelial odontogenic tumors.

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    Oh, Kyu-Young; Yoon, Hye-Jung; Lee, Jae-Il; Ahn, Sun-Ha; Hong, Seong-Doo

    2017-02-01

    The aims of this study were to evaluate expression of Twist and Snail in tumor and stromal cells of epithelial odontogenic tumors and to analyze relationships between Twist and Snail expression and between tumor and stromal expression. Immunohistochemistry was performed using Twist and Snail antibodies in 60 ameloblastomas (AMs; 20 solid/multicystic, 20 unicystic, and 20 recurrent), six ameloblastic carcinomas (ACs), 10 adenomatoid odontogenic tumors (AOTs), and six calcifying epithelial odontogenic tumors (CEOTs). A higher rate of tumor cells strongly positive for Twist was observed in AC compared to the other tumors (P = 0.019). The rate of tumor cells strongly positive for Snail tended to be higher in AC than in AM (P = 0.060). AM and AC showed a higher rate of Twist-positive stromal cells than AOT and CEOT (P Tumor cells of recurrent AM showed stronger expression of Twist (P tumor expression of Twist and Snail (r = 0.376, P = 0.001) and between tumor and stromal expression of Snail (r = 0.334, P = 0.002). Twist and Snail may affect the epithelial-mesenchymal transition in AC and be involved in recurrence of AM. Stromal Twist expression may be associated with aggressive clinical behavior of epithelial odontogenic tumors. A Twist-Snail pathway may participate in the development and progression of odontogenic tumors, and tumor-stroma interaction in odontogenic tumors may be mediated by Snail. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Gastrointestinal Stromal Cell Tumor (GIST) Presenting as an ...

    African Journals Online (AJOL)

    Background: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors that may mimic ovarian tumor on presurgical testing. These tumors are usually asymptomatic, often discovered accidentally during endoscopic or radiologic examinations,. Case Presentations: In first case a 50 years old woman presented ...

  6. Stromal p16 Overexpression in Adult Granulosa Cell Tumors of the Ovary.

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    Na, Kiyong; Sung, Ji-Youn; Kim, Hyun-Soo

    2017-05-01

    Adult granulosa cell tumor of the ovary is usually diagnosed at an early stage. However, most patients with advanced or recurrent disease will die of the disease due to limited treatment options. Data on the stromal p16 expression of ovarian adult granulosa cell tumors are limited. The aim of this study was to analyze the immunohistochemical p16 expression in the peritumoral stroma of primary and recurrent adult granulosa cell tumors and investigate whether there were significant differences in stromal p16 expression among nonpathological ovaries, benign sex cord-stromal tumors, and adult granulosa cell tumors. This study included 13 and 11 cases of primary and recurrent adult granulosa cell tumors, respectively. Non-pathological ovaries and benign sex cord-stromal tumors showed negative or weak positive expression, whereas most of the adult granulosa cell tumors showed diffuse and moderate-to-strong immunostaining. Primary adult granulosa cell tumors had significantly higher stromal p16 expression levels than nonpathological ovaries and benign sex cord-stromal tumors (padult granulosa cell tumors showed significantly elevated levels of stromal p16 expression compared to primary adult granulosa cell tumors (p=0.032). In contrast, the difference in stromal p16 expression between non-pathological ovaries and benign sex cord-stromal tumors was not statistically significant (p=0.522). Our observations suggest that stromal p16 expression may be involved in the development and progression of ovarian adult granulosa cell tumors. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  7. Perivascular epithelioid cell tumor of the liver coexisting with a gastrointestinal stromal tumor

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    Paiva, Carlos Eduardo; Moraes Neto, Francisco Alves; Agaimy, Abbas

    2008-01-01

    Approximately 10% of patients with gastrointestinal stromal tumors (GIST) develop other neoplasms, either synchronously or metachronously. In this report we describe coexistence of a gastrointestinal stromal tumor and a hepatic perivascular epithelioid cell tumor (PEComa) in a 51-year-old woman...... with no evidence of tuberous sclerosis. A subcapsular hepatic nodule (0.8 cm in diameter) was found during surgery for symptomatic gastric neoplasm (15 cm in diameter) arising from the lesser curvature. Both tumors revealed histomorphological and immunohistochemical features confirming a diagnosis of a small...... incidental hepatic PEComa and a high risky extramural gastric GIST, respectively. The patient remained disease-free 25 mo after surgery with no evidence of tumor recurrence or new neoplasms. To our knowledge, this is the first report of PEComa in a patient with GIST. Hepatic lesions detected synchronously...

  8. A role for ADAM12 in breast tumor progression and stromal cell apoptosis

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    Kveiborg, Marie; Frohlich, Camilla; Albrechtsen, Reidar

    2005-01-01

    of stromal fibroblasts in tumor initiation and progression has been elucidated. Here, we show that stromal cell apoptosis occurs in human breast carcinoma but is only rarely seen in nonmalignant breast lesions. Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast...... cancer, accelerates tumor progression in a mouse breast cancer model. ADAM12 does not influence tumor cell proliferation but rather confers both decreased tumor cell apoptosis and increased stromal cell apoptosis. This dual role of ADAM12 in governing cell survival is underscored by the finding that ADAM......12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. Together, these results show that the ability of ADAM12 to influence apoptosis may contribute to tumor progression....

  9. Expression of P450 Aromatase in Granulosa Cell Tumors and Sertoli-Stromal Cell Tumors of the Ovary: Which Cells Are Responsible for Estrogenesis?

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    Kato, Noriko; Uchigasaki, Shinya; Fukase, Masayuki; Kurose, Akira

    2016-01-01

    Granulosa cell tumors are representative of estrogenic ovarian tumors, and some Sertoli-stromal cell tumors are also estrogenic. The exact cells that are responsible for estrogenesis, however, have yet to be identified. In the present study, 25 sex cord-stromal tumors (20 granulosa cell tumors, 4 Sertoli-Leydig cell tumors, and a Sertoli cell tumor) were immunohistochemically examined for expression of P450 aromatase, which is critical for estrogenesis. All of the tumors had been evaluated for estrogenic function, including contemporaneous endometrial hyperplasia and/or elevation of serum estradiol. Eleven of 14 estrogenic granulosa cell tumors showed sparse or aggregated immunoreactivity for aromatase, whereas 5 of 6 nonestrogenic tumors did not. Aromatase was selectively expressed by plump granulosa cells with eosinophilic or vacuolated cytoplasm, resembling luteinized granulosa cells. Such a localization of aromatase is analogous to that in normal ovaries. Aromatase expression in primary tumors was recapitulated by recurrent tumors. In Sertoli-stromal cell tumors, either undifferentiated plump cells or well-differentiated Sertoli cells expressed aromatase. In conclusion, the expression of P450 aromatase corresponds to specific cell morphology in sex cord-stromal tumors, including recurrent tumors. Aromatase status in granulosa cell tumors provides helpful information on whether serum estradiol could be a marker for recurrence.

  10. Tumor and Stromal-Based Contributions to Head and Neck Squamous Cell Carcinoma Invasion

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    Markwell, Steven M.; Weed, Scott A., E-mail: scweed@hsc.wvu.edu [Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506 (United States)

    2015-02-27

    Head and neck squamous cell carcinoma (HNSCC) is typically diagnosed at advanced stages with evident loco-regional and/or distal metastases. The prevalence of metastatic lesions directly correlates with poor patient outcome, resulting in high patient mortality rates following metastatic development. The progression to metastatic disease requires changes not only in the carcinoma cells, but also in the surrounding stromal cells and tumor microenvironment. Within the microenvironment, acellular contributions from the surrounding extracellular matrix, along with contributions from various infiltrating immune cells, tumor associated fibroblasts, and endothelial cells facilitate the spread of tumor cells from the primary site to the rest of the body. Thus far, most attempts to limit metastatic spread through therapeutic intervention have failed to show patient benefit in clinic trails. The goal of this review is highlight the complexity of invasion-promoting interactions in the HNSCC tumor microenvironment, focusing on contributions from tumor and stromal cells in order to assist future therapeutic development and patient treatment.

  11. Tumor versus stromal cells in culture--survival of the fittest?

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    Krishna M Talasila

    Full Text Available Two of the signature genetic events that occur in human gliomas, EGFR amplification and IDH mutation, are poorly represented in experimental models in vitro. EGFR amplification, for example, occurs in 40 to 50% of GBM, and yet, EGFR amplification is rarely preserved in cell cultures derived from human tumors. To analyze the fate of EGFR amplified and IDH mutated cells in culture, we followed the development over time of cultures derived from human xenografts in nude rats enriched for tumor cells with EGFR amplification and of cultures derived from patient samples with IDH mutations, in serum monolayer and spheroid suspension culture, under serum and serum free conditions. We observed under serum monolayer conditions, that nestin positive or nestin and SMA double positive rat stromal cells outgrew EGFR amplified tumor cells, while serum spheroid cultures preserved tumor cells with EGFR amplification. Serum free suspension culture exhibited a more variable cell composition in that the resultant cell populations were either predominantly nestin/SOX2 co-expressing rat stromal cells or human tumor cells, or a mixture of both. The selection for nestin/SMA positive stromal cells under serum monolayer conditions was also consistently observed in human oligodendrogliomas and oligoastrocytomas with IDH mutations. Our results highlight for the first time that serum monolayer conditions can select for stromal cells instead of tumor cells in certain brain tumor subtypes. This result has an important impact on the establishment of new tumor cell cultures from brain tumors and raises the question of the proper conditions for the growth of the tumor cell populations of interest.

  12. Functional Imaging of Proteolysis: Stromal and Inflammatory Cells Increase Tumor Proteolysis

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    Mansoureh Sameni

    2003-07-01

    Full Text Available The underlying basement membrane is degraded during progression of breast and colon carcinoma. Thus, we imaged degradation of a quenched fluorescent derivative of basement membrane type IV collagen (DQ-collagen IV by living human breast and colon tumor spheroids. Proteolysis of DQ-collagen IV by HCT 116 and HKh-2 human colon tumor spheroids was both intracellular and pericellular. In contrast, proteolysis of DQ-collagen IV by BT20 human breast tumor spheroids was pericellular. As stromal elements can contribute to proteolytic activities associated with tumors, we also examined degradation of DQ-collagen IV by human monocytes/macrophages and colon and breast fibroblasts. Fibroblasts themselves exhibited a modest amount of pericellular degradation. Degradation was increased 4–17-fold in cocultures of fibroblasts and tumor cells as compared to either cell type alone. Inhibitors of matrix metalloproteinases, plasmin, and the cysteine protease, cathepsin B, all reduced degradation in the cocultures. Monocytes did not degrade DQ-collagen IV; however, macrophages degraded DQ-collagen IV intracellularly. In coculture of tumor cells, fibroblasts, and macrophages, degradation of DQ-collagen IV was further increased. Imaging of living tumor and stromal cells has, thus, allowed us to establish that tumor proteolysis occurs pericellularly and intracellularly and that tumor, stromal, and inflammatory cells all contribute to degradative processes.

  13. Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment.

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    Modiano, Jaime F; Lindborg, Beth A; McElmurry, Ron T; Lewellen, Mitzi; Forster, Colleen L; Zamora, Edward A; Schaack, Jerome; Bellgrau, Donald; O'Brien, Timothy D; Tolar, Jakub

    2015-11-01

    The potential of mesenchymal stromal cells (MSCs) to inhibit anti-tumor immunity is becoming increasingly well recognized, but the precise steps affected by these cells during the development of an anti-tumor immune response remain incompletely understood. Here, we examined how MSCs affect the steps required to mount an effective anti-tumor immune response following administration of adenovirus Fas ligand (Ad-FasL) in the Lewis lung carcinoma (LL3) model. Administration of bone marrow-derived MSCs with LL3 cells accelerated tumor growth significantly. MSCs inhibited the inflammation induced by Ad-FasL in the primary tumors, precluding their rejection; MSCs also reduced the consequent expansion of tumor-specific T cells in the treated hosts. When immune T cells were transferred to adoptive recipients, MSCs impaired, but did not completely abrogate the ability of these T cells to promote elimination of secondary tumors. This impairment was associated with a modest reduction in tumor-infiltrating T cells, with a significant reduction in tumor-infiltrating macrophages, and with a reorganization of the stromal environment. Our data indicate that MSCs in the tumor environment reduce the efficacy of immunotherapy by creating a functional and anatomic barrier that impairs inflammation, T cell priming and expansion, and T cell function-including recruitment of effector cells.

  14. Altered expression pattern of topoisomerase IIalpha in ovarian tumor epithelial and stromal cells after platinum-based chemotherapy.

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    Chekerov, Radoslav; Klaman, Irina; Zafrakas, Menelaos; Könsgen, Dominique; Mustea, Alexander; Petschke, Beate; Lichtenegger, Werner; Sehouli, Jalid; Dahl, Edgar

    2006-01-01

    The aim of this study was to evaluate the expression of topoisomerase IIalpha (TOP2A) in epithelial and stromal cells of ovarian cancer. TOP2A expression was analyzed prospectively in normal and tumor epithelial and adjacent stromal cells using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) after laser microdissection (n = 38), RNA in situ hybridization (n = 13), and immunohistochemistry (n = 69). TOP2A mRNA was detected by RNA in situ hybridization in all ovarian cancer samples, with stronger hybridization signals in tumor epithelial cells compared to adjacent stromal cells. The same expression pattern was found by immunohistochemistry (P = .0001). Very interestingly, specific change was found in recurrent ovarian cancer after platinum-based chemotherapy: TOP2A expression decreased in tumor epithelial cells of recurrent ovarian cancer compared to primary ovarian cancer (P = .056), whereas it increased in tumor-adjacent stromal cells in carboplatin-treated recurrent tumors compared to primary ovarian cancer (P = .023). TOP2A mRNA and protein expression in ovarian cancer exhibits specific patterns in tumor epithelial and adjacent stromal cells, which are differentially modulated after platinum-based chemotherapy. These data support the recently discovered importance of the stromal compartment in tumor progression and suggest that tumor stromal cells might be relevant to the development of chemotherapy resistance in ovarian cancer.

  15. Altered Expression Pattern of Topoisomerase IIα, in Ovarian Tumor Epithelial and Stromal Cells after Platinum-Based Chemotherapy

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    Radoslav Chekerov

    2006-01-01

    Full Text Available OBJECTIVE: The aim of this study was to evaluate the expression of topoisomerase IIα (TOP2A in epithelial and stromal cells of ovarian cancer. METHODS: TOP2A expression was analyzed in normal ovarian tissue and in laser-microdissected ovarian tumor epithelial and adjacent stromal cells using quantitative real time RT-PCR (n = 38, RNA in situ hybridization (n =13, and immunhistochemistry (n = 69. Results: TOP2A mRNA was detected by RNA in situ hybridization in all ovarian cancer samples, with stronger hybridization signals in tumor epithelial cells compared to adjacent stromal cells. The same expression pattern was found by immunohistochemistry (P = .0001. Very interestingly, specific changes of TOP2A were found in recurrent ovarian cancer after platinum-based chemotherapy: TOP2A expression decreased in tumor epithelial cells (P = .056 of recurrent ovarian cancer, whereas it increased in tumor adjacent stromal cells (P = .023 compared to primary ovarian cancer. CONCLUSION: TOP2A mRNA and protein expressions in ovarian cancer exhibit specific patterns in tumor epithelial and adjacent stromal cells, which are differentially modulated after platinum-based chemotherapy. These data support the possible importance of the stromal compartment in tumor progression and suggest that tumor stromal cells might be relevant to the development of chemotherapy resistance in ovarian cancer.

  16. Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

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    Alessandro Poggi

    2016-11-01

    Full Text Available The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT, a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

  17. Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment

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    Rattigan, Yanique I.; Patel, Brijesh B. [Graduate School of Biomedical Sciences, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); Department of Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); Ackerstaff, Ellen [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); Sukenick, George [Molecular Pharmacology and Chemistry Research Program, Sloan-Kettering Institute, 415 E 68th Street, New York, NY 10065 (United States); Koutcher, Jason A. [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); Glod, John W. [Graduate School of Biomedical Sciences, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); Department of Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); Department of Pediatric Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); and others

    2012-02-15

    Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O{sub 2}) than under 20% O{sub 2} and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our {sup 13}C NMR spectroscopic measurements indicate that {sup 13}C-lactate is converted to {sup 13}C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.

  18. Multipotent mesenchymal stromal cells in liver cancer: implications for tumor biology and therapy.

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    Hernanda, Pratika Y; Pedroza-Gonzalez, Alexander; Sprengers, Dave; Peppelenbosch, Maikel P; Pan, Qiuwei

    2014-12-01

    Remodeling of tumor microenvironment is a hallmark in the pathogenesis of liver cancer. Being a pivotal part of tumor stroma, multipotent mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells (MSCs), are recruited and enriched in liver tumors. Owing to their tumor tropism, MSCs are now emerging as vehicles for anticancer drug/gene delivery against liver cancer. However, the exact impact of MSCs on liver cancer remains elusive, as a variety of effects of these cells that have been reported included a plethora of tumor-promoting effects and anti-oncogenic properties. This review aims to dissect the mechanistic insight regarding this observed discrepancy in different experimental settings of liver cancer. Furthermore, we call for caution using MSCs to treat liver cancer or even premalignant liver diseases, before conclusive evidence for safety and efficacy having been obtained. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Ovarian enzymatically active stromal cells can be a promoter of ovarian surface epithelial tumor.

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    Song, Zhangjuan

    2011-09-01

    Surface epithelial tumors (SETs) are the most common neoplasms of the ovary. They are traditionally thought derived from the ovarian surface or, as a recent hypothesis suggests, from various sources outside of ovary. Enzymatically active stromal cells (EASCs) are scattered in stroma of ovary, and characterized by their steroid-producing ability. With my observation of the increased EASCs near the epithelial cells of SETs, I hypothesize the epithelial cells of SETs can cause the increase of EASCs by converse adjacent stromal cells to EASCs; and EASCs, as a positive feedback, can prompt the proliferation of their neighbouring epithelial cells of SETs by secreting steroid hormone. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. GASTROINTESTINAL STROMAL TUMOR (GIST

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    Luigi eTornillo

    2014-11-01

    Full Text Available Gastrointestinal stromal tumors are the most frequent mesenchymal tumors of the gastrointestinal tract. The discovery that these tumors, formerly thought of smooth muscle origin, are indeed better characterized by specific activating mutation in genes coding for the receptor tyrosine kinases CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with receptor tyrosine kinase inhibitors has made GISTs the typical example of the integration of basic molecular knowledge in the daily clinical activity. The information on the mutational status of these tumors is essential to predict (and subsequently to plan the therapy. As resistant cases are frequently wild-type, other possible oncogenic events, defining other entities, have been discovered (e.g. succinil dehydrogenase mutation/dysregulation, insuline growth factor expression, mutations in the RAS-RAF-MAPK pathway. The classification of disease must nowadays rely on the integration of the clinico-morphological characteristics with the molecular data.

  1. The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

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    Drenka Trivanović

    2016-01-01

    Full Text Available State of tumor microenvironment (TME is closely linked to regulation of tumor growth and progression affecting the final outcome, refractoriness, and relapse of disease. Interactions of tumor, immune, and mesenchymal stromal/stem cells (MSCs have been recognized as crucial for understanding tumorigenesis. Due to their outstanding features, stem cell-like properties, capacity to regulate immune response, and dynamic functional phenotype dependent on microenvironmental stimuli, MSCs have been perceived as important players in TME. Signals provided by tumor-associated chronic inflammation educate MSCs to alter their phenotype and immunomodulatory potential in favor of tumor-biased state of MSCs. Adjustment of phenotype to TME and acquisition of tumor-promoting ability by MSCs help tumor cells in maintenance of permissive TME and suppression of antitumor immune response. Potential utilization of MSCs in treatment of tumor is based on their inherent ability to home tumor tissue that makes them suitable delivery vehicles for immune-stimulating factors and vectors for targeted antitumor therapy. Here, we review data regarding intrusive effects of inflammatory TME on MSCs capacity to affect tumor development through modification of their phenotype and interactions with immune system.

  2. Neuroblastic and Schwannian stromal cells of neuroblastoma are derived from a tumoral progenitor cell.

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    Mora, J; Cheung, N K; Juan, G; Illei, P; Cheung, I; Akram, M; Chi, S; Ladanyi, M; Cordon-Cardo, C; Gerald, W L

    2001-09-15

    The coexistence of neuroblastic and Schwannian stromal (SS) cells in differentiating neuroblastoma (NB), and derivation of Schwannian-like cells from neuroblastic clones in vitro, were accepted previously as evidence of a common pluripotent tumor stem line. This paradigm was challenged when SS cells were suggested to be reactive in nature. The advent of microdissection techniques, PCR-based allelic analysis, and in situ fluorescent cytometry made possible the analysis of pure cell populations in fresh surgical specimens, allowing unequivocal determination of clonal origins of various cell subtypes. To overcome the complexity and heterogeneity of three-dimensional tissue structure, we used: (a) Laser-Capture Microdissection to obtain histologically homogeneous cell subtype populations for allelotype analysis at chromosomes 1p36, 11q23, 14q32, and 17q and study of MYCN copy number; (b) multiparametric analysis by Laser-Scanning Cytometry of morphology, DNA content, and immunophenotype of intact cells from touch imprints; and (c) bicolor fluorescence in situ hybridization on touch imprints from manually microdissected neuroblast and stroma-rich areas. Histologically distinct SS and neuroblastic cells isolated by Laser-Capture Microdissection had the same genetic composition in 27 of 28 NB analyzed by allelic imbalance and gene copy number. In all 20 cases studied by Laser-Scanning Cytometry, SS cells identified by morphology and S-100 immunostaining had identical DNA content and GD2-staining pattern as their neuroblastic counterparts. In 7 cases, fluorescence in situ hybridization demonstrated the same chromosomal makeup for SS and neuroblastic cells. These results provide unequivocal evidence that neuroblastic and SS cells in NB are derived from genetically identical neoplastic cells and support the classical paradigm that NB arises from tumoral cells capable of development along multiple lineages.

  3. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

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    Chan, Tze-Sian; Pai, Vincent C.; Tan, Kok-Tong; Yen, Chia-Jui; Hsu, Shu-Ching; Chen, Wei-Yu; Shan, Yan-Shen; Lee, Michael T.; Chu, Jui-Mei

    2016-01-01

    Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy–treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif–positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR+ chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy. PMID:27881732

  4. Extragastrointestinal Stromal Tumor during Pregnacy

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    Ilay Gözükara

    2012-01-01

    Full Text Available Extragastrointestinal stromal tumors (EGISTs are mesenchymal neoplasms without connection to the gastrointestinal tract. Gastrointestinal stromal tumors (GISTs and EGIST are similar according to their clinicopathologic and histomorphologic features. Both of them most often express immunoreactivity for CD-117, a c-kit proto-oncogene protein. The coexistence of GIST and pregnancy is very rare, with only two cases reported in the literature. In this paper, we presented the first EGIST case during pregnancy in the literature.

  5. Laminin-5 gamma 2 chain expression is associated with intensity of tumor budding and density of stromal myofibroblasts in oral squamous cell carcinoma.

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    Marangon Junior, Helvécio; Rocha, Valéria Nazaré; Leite, Camila Ferreira; de Aguiar, Maria Cássia Ferreira; Souza, Paulo Eduardo Alencar; Horta, Martinho Campolina Rebello

    2014-03-01

    Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide. Laminin-5 gamma 2 chain (laminin-5 γ2) is a protein associated to a migratory phenotype in epithelial neoplastic cells. Stromal myofibroblasts also play a significant role in tumor invasion, due to its ability to modify the extracellular matrix. Tumor budding is a morphologic marker of tumor invasion. The aim of this study was to evaluate the expression of laminin-5 γ2 in OSCC and its association with intensity of tumor budding and density of stromal myofibroblasts. Paraffin-embedded archival samples of 57 OSCC patients were evaluated. Immunohistochemistry was employed to detect laminin-5 γ2, alpha smooth muscle actin (marker of stromal myofibroblasts), and multicytokeratin (to identify OSCC cells in tumor budding evaluation). Laminin-5 γ2 expression and its association with intensity of tumor budding and density of stromal myofibroblasts were analyzed. Association among intensity of tumor budding and density of stromal myofibroblasts was also evaluated. Higher laminin-5 γ2 expression was associated with high-intensity tumor budding (P tumor budding was associated with higher density of stromal myofibroblasts (P tumor budding and with higher density of stromal myofibroblasts, suggesting that this expression is related to the establishment of an invasive phenotype of neoplastic cells and a permissive environment for tumor invasion in this neoplasia. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression

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    Frohlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar

    2011-01-01

    Expression of ADAM12 is low in most normal tissues, but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In the present study, we found...

  7. Ghrelin and gastrointestinal stromal tumors.

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    Zhu, Chang-Zhen; Liu, Dong; Kang, Wei-Ming; Yu, Jian-Chun; Ma, Zhi-Qiang; Ye, Xin; Li, Kang

    2017-03-14

    Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs.

  8. Altered Expression Pattern of Topoisomerase IIα in Ovarian Tumor Epithelial and Stromal Cells after Platinum-Based Chemotherapy1

    OpenAIRE

    Chekerov, Radoslav; Klaman, Irina; Zafrakas, Menelaos; Könsgen, Dominique; Mustea, Alexander; Petschke, Beate; Lichtenegger, Werner; Sehouli, Jalid; Dahl, Edgar

    2006-01-01

    OBJECTIVE: The aim of this study was to evaluate the expression of topoisomerase IIα (TOP2A) in epithelial and stromal cells of ovarian cancer. METHODS: TOP2A expression was analyzed in normal ovarian tissue and in laser-microdissected ovarian tumor epithelial and adjacent stromal cells using quantitative real time RT-PCR (n = 38), RNA in situ hybridization (n = 13), and immunhistochemistry (n = 69). Results: TOP2A mRNA was detected by RNA in situ hybridization in all ovarian cancer samples, ...

  9. Altered Expression Pattern of Topoisomerase IIα, in Ovarian Tumor Epithelial and Stromal Cells after Platinum-Based Chemotherapy

    OpenAIRE

    Chekerov, Radoslav; Klaman, Irina; Zafrakas, Menelaos; Könsgen, Dominique; Mustea, Alexander; Petschke, Beate; Lichtenegger, Werner; Sehouli, Jalid; Dahl, Edgar

    2006-01-01

    OBJECTIVE: The aim of this study was to evaluate the expression of topoisomerase IIα (TOP2A) in epithelial and stromal cells of ovarian cancer. METHODS: TOP2A expression was analyzed in normal ovarian tissue and in laser-microdissected ovarian tumor epithelial and adjacent stromal cells using quantitative real time RT-PCR (n = 38), RNA in situ hybridization (n =13), and immunhistochemistry (n = 69). Results: TOP2A mRNA was detected by RNA in situ hybridization in all ovarian cancer samples, w...

  10. Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor

    Science.gov (United States)

    2013-01-01

    Background Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. Methods Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. Results We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. Conclusions We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc. PMID:23433424

  11. Neurotensin receptor 1 is expressed in gastrointestinal stromal tumors but not in interstitial cells of Cajal.

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    Petra Gromova

    Full Text Available Gastrointestinal stromal tumors (GIST are thought to derive from the interstitial cells of Cajal (ICC or an ICC precursor. Oncogenic mutations of the KIT or PDGFRA receptor tyrosine kinases are present in the majority of GIST, leading to ligand-independent activation of the intracellular signal transduction pathways. We previously investigated the gene expression profile in the murine Kit(K641E GIST model and identified Ntsr1 mRNA, encoding the Neurotensin receptor 1, amongst the upregulated genes. Here we characterized Ntsr1 mRNA and protein expression in the murine Kit(K641E GIST model and in tissue microarrays of human GIST. Ntsr1 mRNA upregulation in Kit(K641E animals was confirmed by quantitative PCR. Ntsr1 immunoreactivity was not detected in the Kit positive ICC of WT mice, but was present in the Kit positive hyperplasia of Kit(K641E mice. In the normal human gut, NTSR1 immunoreactivity was detected in myenteric neurons but not in KIT positive ICC. Two independent tissue microarrays, including a total of 97 GIST, revealed NTSR1 immunoreactivity in all specimens, including the KIT negative GIST with PDGFRA mutation. NTSR1 immunoreactivity exhibited nuclear, cytoplasmic or mixed patterns, which might relate to variable levels of NTSR1 activation. As studies using radio-labeled NTSR1 ligand analogues for whole body tumor imaging and for targeted therapeutic interventions have already been reported, this study opens new perspectives for similar approaches in GIST.

  12. Bevacizumab in Treating Patients With Recurrent Sex Cord-Stromal Tumors of the Ovary

    Science.gov (United States)

    2017-02-03

    Malignant Ovarian Epithelial Tumor; Ovarian Granulosa Cell Tumor; Ovarian Gynandroblastoma; Ovarian Sertoli-Leydig Cell Tumor; Ovarian Sex Cord Tumor With Annular Tubules; Ovarian Sex Cord-Stromal Tumor; Ovarian Sex Cord-Stromal Tumor of Mixed or Unclassified Cell Types; Ovarian Steroid Cell Tumor

  13. Weight reduction and pioglitazone ameliorate polycystic ovary syndrome after removal of a Sertoli-stromal cell tumor

    Directory of Open Access Journals (Sweden)

    Saito T

    2012-11-01

    Full Text Available Tsuyoshi Baba,1 Toshiaki Endo,1 Keiko Ikeda,1 Ayumi Shimizu,1 Miyuki Morishita,1 Yoshika Kuno,1 Hiroyuki Honnma,2 Tamotsu Kiya,3 Shin-ichi Ishioka,1 Tsuyoshi Saito11Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo, 2Asada Ladies Clinic, Kasugai, Aichi, 3Ena Ladies Clinic, Ishikari, Hokkaido, JapanAbstract: This report presents an unusual case of Sertoli-stromal cell tumor and polycystic ovary syndrome successfully treated with weight reduction and an insulin-sensitizing agent. A 22-year-old woman, gravida 0, para 0, visited our hospital for the first time with a 12-year history of secondary amenorrhea and hypertrichosis. Transvaginal ultrasonography revealed a solid tumor in the right ovary. Right salpingo-oophorectomy was performed and pathological examination confirmed a Sertoli-stromal cell tumor. The patient's serum androgen levels declined postoperatively, but remained above normal. Pioglitazone treatment for 6 months also significantly reduced serum androgen levels, but they still remained above normal. However, after losing 12 kg of body weight, the patient's serum androgen levels declined to normal, and spontaneous menstruation became regular. Weight reduction with pioglitazone is an effective means of treating hyperandrogenism.Keywords: etiology, hyperandrogenism, pioglitazone, polycystic ovary syndrome, Sertoli-stromal cell tumor, weight reduction

  14. PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.

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    Watts, Tammara L; Cui, Ruwen; Szaniszlo, Peter; Resto, Vicente A; Powell, Don W; Pinchuk, Irina V

    2016-12-08

    The robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer. Moreover, the high recurrence rate and poor clinical response to chemotherapy and radiation treatment further underscores that the non-cancerous cells of the microenvironment, such as mesenchymal stromal cells (MSCs), cancer associated fibroblasts (CAFs), and pericytes, may be important in the pathophysiology of HNSCC. Confocal microscopy and immunohistomchemistry approaches were used to identify MSCs tumor microenvironment from patients with oral cavity and oral pharyngeal squamous cell carcinoma (SCC). In vitro Boyden chamber assays and multiplex magnetic bead assays were used to measure MSC chemotaxis and to identify the chemokines secreted by JHU-011, -012, -019, three cells lines derived from patients with oral pharyngeal SCC. We show here that MSCs reside in the tumor microenvironment of patients with oral cavity and oral pharyngeal SCC and are recruited via paracrine mediated tumor cell secretion of (platelet derived growth factor) PDGF-AA. The MSC markers CD90+, CD105+, and gremlin-1+ were found to co-localize on cells within the tumor microenvironment in oral cavity SCC specimens distinct from α-smooth muscle actin staining CAFs. The conditioned media from JHU-011, -012, and -019 caused a significant increase in MSC migration (>60%) and invasion (>50%; p oral keratinocyte (OKT) controls. Tumor cell induced MSC chemotaxis appears to be mediated through paracrine secretion of PDGF-AA as inhibition of the PDGF-AA receptor, PDGFR-α but not PDGFR-β, resulted in near arrest of MSC chemotaxis (p cell lung cancer and osteosarcoma. This is the first evidence that a similar signaling paradigm may be present in HNSCC. PDGFR-α inhibitors have not been studied as adjunctive treatment options in the management of HNSCC and may prove to be an important driver of the

  15. The role of p53 protein and MMP-2 tumor/stromal cells expression on progressive growth of ovarian neoplasms.

    Science.gov (United States)

    Grelewski, Piotr Grzegorz; Bar, Julia Krystyna

    2013-08-01

    The aim of our study was to evaluate p53 gene/protein status and MMP-2 expression in respect to ovarian tumors progress to define the role of these markers in the metastasis of ovarian carcinomas. MMP-2 and p53 alterations were evaluated on 80 malignant, 30 benign ovarian tumors, and 62 metastatic lesions by using HRM method for mutations in p53 gene and by using RT-PCR for mRNA MMP-2 level. Our data indicate that parallel expression of MMP-2 epithelial/stromal cells and p53 may enhance cells invasion and metastasis in ovarian carcinoma.

  16. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells.

    Science.gov (United States)

    Coffelt, Seth B; Marini, Frank C; Watson, Keri; Zwezdaryk, Kevin J; Dembinski, Jennifer L; LaMarca, Heather L; Tomchuck, Suzanne L; Honer zu Bentrup, Kerstin; Danka, Elizabeth S; Henkle, Sarah L; Scandurro, Aline B

    2009-03-10

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells.

  17. Extra - Intestinal Gastrointestinal Stromal Tumor of Omentum

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    S Basnet

    2014-09-01

    Full Text Available Gastrointestinal stromal tumors are rare tumors, constituting less than 3% of all gastrointestinal malignant neoplasms but are the most common mesenchymal tumors of the gastrointestinal tract. Approximately 10% of gastrointestinal stromal tumors are extraintestinal and mostly arise from the mesentery or omentum. Here we report a rare case of an extraintestinal gastrointestinal stromal tumor of mesentery. Morphological and immunohistochemical features led to a diagnosis of extra-gastrointestinal stromal tumor.DOI: http://dx.doi.org/10.3126/jpn.v4i8.11610 Journal of Pathology of Nepal; Vol.4,No. 8 (2014 682-684

  18. Hypertensive crisis during wide excision of gastrointestinal stromal cell tumor (GIST): Undiagnosed paraganglioma -A case report-.

    Science.gov (United States)

    Shinn, Helen Ki; Jung, Jong Kwon; Park, Jay Kim; Kim, Jong Hoon; Jung, In Young; Lee, Hong Sik

    2012-03-01

    Although paraganglioma (PGL), an extra-adrenal retroperitoneal pheochromocytoma (PHEO), is a rare catecholamine-secreting neuroendocrine tumor, it can cause severe hypertensive crisis during anesthesia or surgery if undiagnosed preoperatively. Extraluminal perigastric masses may be presumed to be gastrointestinal stromal tumors (GISTs) or soft tissue sarcomas even when histologic confirmation is not possible. Therefore, without a histologic diagnosis or symptoms of excessive catecholamine secretion, PGL may be mistaken for GIST. We report a case of preoperatively undiagnosed PGL which caused hypertensive crisis during anesthesia for retroperitoneal mass excision.

  19. Lymph Node Stromal Cells Enhance Drug-Resistant Colon Cancer Cell Tumor Formation through SDF-1α/CXCR4 Paracrine Signaling

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    David A. Margolin

    2011-09-01

    Full Text Available Colorectal cancer (CRC is the third most common malignancy and the second leading cause of cancer-related deaths in America. Nearly two thirds of newly diagnosed CRC cases include lymph node (LN involvement, and LN metastasis is one of the strongest negative prognostic factors for CRC. It is thought that CRC tumors contain a small population of drug-resistant CRC tumor-initiating cells (Co-TICs that may be responsible for cancer recurrence. To evaluate the effects of the LN stromal cells on Co-TICs, we established a unique xenoplant model using CRC cells isolated by enzymatic digestion from consented patient specimens, HT-29 cells, HCA-7 cells, and LN stromal cell line HK cells. We found that HK cells and HK cell-conditioned media enhanced CRC tumor formation and tumor angiogenesis. Cells expressing CD133+ and the stromal cell-derived factor 1α (SDF-1α receptor CXCR4 were enriched in chemotherapeutic-resistant CRC cells. CD133+CXCR4+ Co-TICs isolated from patient specimens are more tumorigenic than unsorted tumor cells. Furthermore, the inhibitors specific to HK cell-derived SDF-1α reduced tumor formation and tumor angiogenesis. Our results have demonstrated a role for Co-TICs in tumor growth and defined the influence of LN stromal cells on Co-TICs. We have identified a major Co-TIC/LN microenvironment-specific mechanism for CRC resistance to chemotherapeutic agents and established experimental platforms for both in vitro and in vivo testing, indicating that SDF-1α and its receptor, CXCR4, may be targets for clinical therapy.

  20. Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms.

    Science.gov (United States)

    Roth, Lawrence M; Lyu, Bingjian; Cheng, Liang

    2017-07-01

    Sex cord-stromal tumors (SCSTs) are the second most frequent category of testicular neoplasms, accounting for approximately 2% to 5% of cases. Both genetic and epigenetic factors account for the differences in frequency and histologic composition between testicular and ovarian SCSTs. For example, large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia occur in the testis but have not been described in the ovary. In this article, we discuss recently described diagnostic entities as well as inconsistencies in nomenclature used in the recent World Health Organization classifications of SCSTs in the testis and ovary. We also thoroughly review the topic of neoplasms composed of both germ cells and sex cord derivatives with an emphasis on controversial aspects. These include "dissecting gonadoblastoma" and testicular mixed germ cell-sex cord stromal tumor (MGC-SCST). The former is a recently described variant of gonadoblastoma that sometimes is an immediate precursor of germinoma in the dysgenetic gonads of patients with a disorder of sex development. Although the relationship of dissecting gonadoblastoma to the previously described undifferentiated gonadal tissue is complex and not entirely resolved, we believe that it is preferable to continue to use the term undifferentiated gonadal tissue for those cases that are not neoplastic and are considered to be the precursor of classical gonadoblastoma. Although the existence of testicular MGC-SCST has been challenged, the most recent evidence supports its existence; however, testicular MGC-SCST differs significantly from ovarian examples due to both genetic and epigenetic factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Bilateral testicular germ cell-sex cord-stromal tumor in a pekin duck (Anas platyrhynchos domesticus).

    Science.gov (United States)

    Leach, Stacey; Heatley, J Jill; Pool, Roy Ransom; Spaulding, Kathy

    2008-12-01

    An intact male white pekin duck (Anas platyrhynchos domesticus) was presented for examination because of respiratory distress and 2- to 3-month history of lameness and lethargy. Results of radiography, ultrasonography, and cytologic examination revealed a large neoplastic mass in the coelom. The duck was euthanatized, and results of necropsy revealed 2 large, lobulated masses in the coelom and a small nodule on the liver. Histopathologic examination of the large masses revealed a collision pattern testicular tumor consisting of Sertoli, seminoma, and interstitial cell components. The hepatic nodule was a metastatic lesion consistent with a Sertoli cell testicular tumor. This is the first reported case of a mixed germ cell-sex cord-stromal tumor in a duck.

  2. Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway.

    Science.gov (United States)

    Ide, Takao; Kitajima, Yoshihiko; Miyoshi, Atsushi; Ohtsuka, Takao; Mitsuno, Mayumi; Ohtaka, Kazuma; Koga, Yasuo; Miyazaki, Kohji

    2006-12-15

    The hypoxic environment in tumor is reported to play an important role in pancreatic cancer progression. The interaction between stromal and cancer cells also contributes to the malignant behavior of pancreatic cancer. In the present study, we investigated whether hypoxic stimulation affects stromal as well as pancreatic cancer cells. Our findings demonstrated that hypoxia remarkably elevated the HIF-1alpha expression in both pancreatic cancer (PK8) and fibroblast cells (MRC5). Hypoxic stimulation accelerated the invasive activity of PK8 cells, and invasiveness was thus further accelerated when the hypoxic PK8 cells were cultured with conditioned medium prepared from hypoxic MRC5 cells (hypoxic conditioned medium). MMP-2, MMP-7, MT1-MMP and c-Met expressions were increased in PK8 cells under hypoxia. Hypoxic stimulation also increased the hepatocyte growth factor (HGF) secretion from MRC5 cells, which led to an elevation of c-Met phosphorylation in PK8 cells. Conversely, the elevated cancer invasion, MMP activity and c-Met phosphorylation of PK8 cells were reduced by the removal of HGF from hypoxic conditioned medium. In immunohistochemical study, the HIF-1alpha expression was observed in surrounding stromal as well as pancreatic cancer cells, thus indicating hypoxia exists in both of cancer and stromal cells. Moreover, the stromal HGF expression was found to significantly correlate with not only the stromal HIF-1alpha expression but also the c-Met expression in cancer cells. These results indicate that the hypoxic environment within stromal as well as cancer cells activates the HGF/c-Met system, thereby contributing to the aggressive invasive features of pancreatic cancer. Copyright 2006 Wiley-Liss, Inc.

  3. Sex cord-gonadal stromal tumor of the rete testis.

    Science.gov (United States)

    Sajadi, Kamran P; Dalton, Rory R; Brown, James A

    2009-01-01

    A 34-year-old tetraplegic patient with suppurative epididymitis was found on follow-up examination and ultrasonography to have a testicular mass. The radical orchiectomy specimen contained an undifferentiated spindled sex cord-stromal tumor arising in the rete testis. Testicular sex cord-stromal tumors are far less common than germ cell neoplasms and are usually benign. The close relationship between sex cords and ductules of the rete testis during development provides the opportunity for these uncommon tumors to arise anatomically within the rete tesis. This undifferentiated sex cord-stromal tumor, occurring in a previously unreported location, is an example of an unusual lesion mimicking an intratesticular malignant neoplasm.

  4. Precocious puberty secondary to a mixed germ cell-sex cord-stromal tumor associated with an ovarian yolk sac tumor: a case report

    Directory of Open Access Journals (Sweden)

    Metwalley Kotb

    2012-06-01

    Full Text Available Abstract Introduction Ovarian tumors are the least common cause of sexual precocity in girls. Mixed germ cell-sex cord-stromal tumors associated with a yolk sac tumor of the ovary are rare neoplasms, of which only a small number of well-documented cases have been described so far. Here, we report precocious puberty in a four-year-old Egyptian girl caused by a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary. Case presentation A four-year-old Egyptian girl was referred to our pediatric endocrinology unit for evaluation of bilateral breast budding, pubic hair and vaginal bleeding. On examination, we found that her breast enlargement and pubic hair were compatible with Tanner III. A thorough workup revealed a large mass in her right ovary. Magnetic resonance imaging ofher brain showed that her pituitary gland was normal. A hormonal assay revealed high levels of estradiol, 280 to 375pmol/L; progesterone, 5.3 nmol/L; testosterone 38.9 pg/mL; and androstenedione, 4.1 ng/mL. Her basal and stimulated levels of luteinizing hormone and follicle-stimulating hormone were low. Tumor markers levels were high, with a total inhibin of 1,069U/L and an alpha-fetoprotein of 987 μg/L. Her chromosomes were normal (46XX. Our patient underwent an explorative laparotomy and a solid tumor localized to her right ovary was identified. A right salpingo-oophorectomy was performed and the histopathological diagnosis was a mixed germ cell-sex cord-stromal tumorwith a yolk sac tumor of the ovary. Postoperatively, she was started on treatment with chemotherapy. Our patient is doing well without evidence of tumor recurrence or metastasis during eight months of postoperative follow-up. Conclusion Although a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary is a rare occurrence, it should be considered in the differential diagnosis for a prepubescent girl with an abdominal mass and precocious puberty.

  5. Unusual ovarian stromal tumor with radiation changes mimicking carcinoma.

    Science.gov (United States)

    Bohn, Olga L; Zhao, Chengquan; Jones, Mirka W

    2011-04-27

    Radiation-related changes including fibrosis, nuclear enlargement, hyperchromasia and cytoplasmic vacuolization may alter the appearance of normal ovarian tissue and ovarian tumors. We describe radiation-related changes in ovarian stromal neoplasm with mixed features of sclerosing stromal tumor and fibrothecoma. The right ovarian mass was discovered in a 38 year-old woman with past history of invasive squamous cell carcinoma of the cervix treated with cone biopsy and brachytherapy. The low power architecture of cellular pseudolobules and small sheets of tumor cells with scattered hyaline plaques was consisted with the pattern of combined sclerosing stromal tumor and fibrothecoma. However, the presence of severe cytologic atypia, as well as clear cell and signet ring differentiation and arrangements of tumor cells in single files and nests, raised a possibility of primary or metastatic carcinoma. The tumor cells were positive for calretinin, vimentin, inhibin, and WT1 and negative for AE1/3, cytokeratin 7 and 20, CD99, estrogen and progesterone receptors, mammaglobin, chromogranin, and S100 protein. Based on the results of immunostains and a subsequently provided history of radiation, a diagnosis of sex cord stromal tumor with mixed fibrothecoma and sclerosing stromal differentiation was made. Radiation-related atypia and fibrosis in sex cord stromal tumor may create a pattern mimicking carcinoma and therefore, in the presence of unusual histology, the use of immunohistochemistry is recommended.

  6. Unusual Ovarian Stromal Tumor with Radiation Changes Mimicking Carcinoma

    Directory of Open Access Journals (Sweden)

    Olga L. Bohn, Chengquan Zhao, Mirka W. Jones

    2011-01-01

    Full Text Available Radiation-related changes including fibrosis, nuclear enlargement, hyperchromasia and cytoplasmic vacuolization may alter the appearance of normal ovarian tissue and ovarian tumors. We describe radiation-related changes in ovarian stromal neoplasm with mixed features of sclerosing stromal tumor and fibrothecoma. The right ovarian mass was discovered in a 38 year-old woman with past history of invasive squamous cell carcinoma of the cervix treated with cone biopsy and brachytherapy. The low power architecture of cellular pseudolobules and small sheets of tumor cells with scattered hyaline plaques was consisted with the pattern of combined sclerosing stromal tumor and fibrothecoma. However, the presence of severe cytologic atypia, as well as clear cell and signet ring differentiation and arrangements of tumor cells in single files and nests, raised a possibility of primary or metastatic carcinoma. The tumor cells were positive for calretinin, vimentin, inhibin, and WT1 and negative for AE1/3, cytokeratin 7 and 20, CD99, estrogen and progesterone receptors, mammaglobin, chromogranin, and S100 protein. Based on the results of immunostains and a subsequently provided history of radiation, a diagnosis of sex cord stromal tumor with mixed fibrothecoma and sclerosing stromal differentiation was made. Radiation-related atypia and fibrosis in sex cord stromal tumor may create a pattern mimicking carcinoma and therefore, in the presence of unusual histology, the use of immunohistochemistry is recommended.

  7. Genetic analysis of ovarian microcystic stromal tumor.

    Science.gov (United States)

    Lee, Jae Hoon; Kim, Hyun-Soo; Cho, Nam Hoon; Lee, Jung-Yun; Kim, Sunghoon; Kim, Sang Wun; Kim, Young Tae; Nam, Eun Ji

    2016-03-01

    Microcystic stromal tumor (MCST) of the ovary is a rare subtype of ovarian tumor first described in 2009. Although high nuclear expression of β-catenin and β-catenin gene (CTNNB1) mutation are related with ovarian MCST, the origin and genetic background of ovarian MCST remain unclear. In this study, two cases of ovarian MCST are presented. Microscopically, the tumors showed a microcystic pattern and regions with lobulated cellular masses with intervening hyalinized, fibrous stroma. Tumor cells of both cases were stained with CD10, vimentin, and Wilms tumor 1. Genetic analysis was performed and β-catenin gene (CTNNB1) mutation in exon 3 was detected in both cases. This is the first report in regards of detecting CTNNB1 mutation in ovarian MCST through the use of pyrosequencing (a novel sequencing technique).

  8. Gastrointestinal Stromal Tumors: A Case Report

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    Palankezhe Sashidharan

    2014-03-01

    Full Text Available Advances in the identification of gastrointestinal stromal tumors, its molecular and immunohiostochemical basis, and its management have been a watershed in the treatment of gastrointestinal tumors. This paradigm shift occurred over the last two decades and gastrointestinal stromal tumors have now come to be understood as rare gastrointestinal tract tumors with predictable behavior and outcome, replacing the older terminologies like leiomyoma, schwannoma or leiomyosarcoma. This report presents a case of gastric gastrointestinal stromal tumor operated recently in a 47-year-old female patient and the outcome, as well as literature review of the pathological identification, sites of origin, and factors predicting its behavior, prognosis and treatment.

  9. Expression of adrenomedullin in human ovaries, ovarian sex cord-stromal tumors and cultured granulosa-luteal cells.

    Science.gov (United States)

    Liu, Jianqi; Bützow, Ralf; Hydén-Granskog, Christel; Voutilainen, Raimo

    2009-02-01

    The aim of the present study was to characterise the expression pattern of the multifunctional vasoactive peptide adrenomedullin (ADM) in human ovarian tumors, and to find hormonal regulators of ADM expression in human ovaries. The expression of ADM messenger RNA (mRNA) was higher in granulosa cell tumors than in fibrothecomas and normal ovaries, as analysed by Northern blots. In normal ovaries, ADM immunoreactivity was localised in both granulosa and thecal cells. Eight of the 90 granulosa cell tumors (9%) showed moderate and 53 (59%) weak ADM immunoreactivity, whereas 27% (11/41) of the fibrothecomas displayed weak ADM staining. FSH, protein kinase A activator (Bu)(2)cAMP, prostaglandin E(2) (PGE(2)), activin A and the broad protein kinase regulator staurosporine decreased ADM mRNA accumulation in cultured granulosa-luteal cells time- and dose-dependently. FSH, (Bu)(2)cAMP and PGE(2) increased progesterone secretion and the accumulation of the steroidogenic acute regulatory protein mRNA in these cells. In conclusion, ADM is expressed in normal human ovaries and sex cord-stromal tumors, particularly in those of granulosa cell origin. FSH, PGE(2,) (Bu)(2)cAMP and activin A suppress ADM gene expression in granulosa-luteal cells. Expression of ADM in human ovaries and its hormonal regulation in granulosa cells suggests a paracrine role for ADM in ovarian function.

  10. Regulation of IL-6 and IL-8 production by reciprocal cell-to-cell interactions between tumor cells and stromal fibroblasts through IL-1α in ameloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Fuchigami, Takao [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Kibe, Toshiro [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Koyama, Hirofumi; Kishida, Shosei; Iijima, Mikio [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Nishizawa, Yoshiaki [Kagoshima University Faculty of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Hijioka, Hiroshi; Fujii, Tomomi [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Ueda, Masahiro [Natural Science Centre for Research and Education, Kagoshima University, 1-21-24 Koorimoto, Kagoshima 890-8580 (Japan); Nakamura, Norifumi [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Kiyono, Tohru [Department of Virology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuouku, Tokyo 104-0045 (Japan); Kishida, Michiko, E-mail: kmichiko@m2.kufm.kagoshima-u.ac.jp [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan)

    2014-09-05

    Highlights: • We studied the interaction between tumor cells and fibroblasts in ameloblastoma. • AM-3 ameloblastoma cells secreted significantly high IL-1α levels. • IL-1α derived from AM-3 cells promoted IL-6 and IL-8 secretion of fibroblasts. • IL-6 and IL-8 activated the cellular motility and proliferation of AM-3 cells. - Abstract: Ameloblastoma is an odontogenic benign tumor that occurs in the jawbone, which invades bone and reoccurs locally. This tumor is treated by wide surgical excision and causes various problems, including changes in facial countenance and mastication disorders. Ameloblastomas have abundant tumor stroma, including fibroblasts and immune cells. Although cell-to-cell interactions are considered to be involved in the pathogenesis of many diseases, intercellular communications in ameloblastoma have not been fully investigated. In this study, we examined interactions between tumor cells and stromal fibroblasts via soluble factors in ameloblastoma. We used a human ameloblastoma cell line (AM-3 ameloblastoma cells), human fibroblasts (HFF-2 fibroblasts), and primary-cultured fibroblasts from human ameloblastoma tissues, and analyzed the effect of ameloblastoma-associated cell-to-cell communications on gene expression, cytokine secretion, cellular motility and proliferation. AM-3 ameloblastoma cells secreted higher levels of interleukin (IL)-1α than HFF-2 fibroblasts. Treatment with conditioned medium from AM-3 ameloblastoma cells upregulated gene expression and secretion of IL-6 and IL-8 of HFF-2 fibroblasts and primary-cultured fibroblast cells from ameloblastoma tissues. The AM3-stimulated production of IL-6 and IL-8 in fibroblasts was neutralized by pretreatment of AM-3 cells with anti-IL-1α antibody and IL-1 receptor antagonist. Reciprocally, cellular motility of AM-3 ameloblastoma cells was stimulated by HFF-2 fibroblasts in IL-6 and IL-8 dependent manner. In conclusion, ameloblastoma cells and stromal fibroblasts behave

  11. In silico ascription of gene expression differences to tumor and stromal cells in a model to study impact on breast cancer outcome.

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    Simen Myhre

    Full Text Available Breast tumors consist of several different tissue components. Despite the heterogeneity, most gene expression analyses have traditionally been performed without prior microdissection of the tissue sample. Thus, the gene expression profiles obtained reflect the mRNA contribution from the various tissue components. We utilized histopathological estimations of area fractions of tumor and stromal tissue components in 198 fresh-frozen breast tumor tissue samples for a cell type-associated gene expression analysis associated with distant metastasis. Sets of differentially expressed gene-probes were identified in tumors from patients who developed distant metastasis compared with those who did not, by weighing the contribution from each tumor with the relative content of stromal and tumor epithelial cells in their individual tumor specimen. The analyses were performed under various assumptions of mRNA transcription level from tumor epithelial cells compared with stromal cells. A set of 30 differentially expressed gene-probes was ascribed solely to carcinoma cells. Furthermore, two sets of 38 and five differentially expressed gene-probes were mostly associated to tumor epithelial and stromal cells, respectively. Finally, a set of 26 differentially expressed gene-probes was identified independently of cell type focus. The differentially expressed genes were validated in independent gene expression data from a set of laser capture microdissected invasive ductal carcinomas. We present a method for identifying and ascribing differentially expressed genes to tumor epithelial and/or stromal cells, by utilizing pathologic information and weighted t-statistics. Although a transcriptional contribution from the stromal cell fraction is detectable in microarray experiments performed on bulk tumor, the gene expression differences between the distant metastasis and no distant metastasis group were mostly ascribed to the tumor epithelial cells of the primary breast

  12. [Surgical resection of a gastrointestinal stromal cell tumor by double enterectomy and partial pancreatectomy on a 13-year-old mixed breed dog].

    Science.gov (United States)

    De Martin, Isabelle; Gagnon, Anne-Marie

    2006-04-01

    Surgical resection of a gastrointestinal stromal cell tumor by double enterectomy and partial pancreatectomy on a 13-year-old mixed breed dog. A 13 year-old, male, mixed breed dog, has been presented for an abdominal mass. The exam showed the presence of an ileo-caeco-colic mass adhered to the distal portion of the pancreas and the mid duodenum. A double enterectomy and a partial pancreatectomy were carried out and a diagnosis of gastrointestinal stromal cell tumor has been established.

  13. Skeletal (stromal) stem cells

    DEFF Research Database (Denmark)

    Abdallah, Basem M; Kermani, Abbas Jafari; Zaher, Walid

    2015-01-01

    Skeletal (marrow stromal) stem cells (BMSCs) are a group of multipotent cells that reside in the bone marrow stroma and can differentiate into osteoblasts, chondrocytes and adipocytes. Studying signaling pathways that regulate BMSC differentiation into osteoblastic cells is a strategy....../preadipocyte factor 1 (Dlk1/Pref-1), the Wnt co-receptor Lrp5 and intracellular kinases. This article is part of a Special Issue entitled: Stem Cells and Bone....

  14. Effect of water-soluble P-chitosan and S-chitosan on human primary osteoblasts and giant cell tumor of bone stromal cells

    Energy Technology Data Exchange (ETDEWEB)

    Tang, T; Zhang, G; PY Lau, Carol; Zheng, L Z; Xie, X H; Wang, X L; Patrick, Y; Qin, L; Kumta, Shekhar M [Department of Orthopaedics and Traumatology, Chinese University of Hong Kong (Hong Kong); Wang, X H; He, K, E-mail: kumta@cuhk.edu.hk [Department of Mechanical Engineering, Institute of Bio-manufacturing Engineering, Tsinghua University, Beijing (China)

    2011-02-15

    Water-soluble phosphorylated chitosan (P-chitosan) and disodium (1 {yields} 4)-2-deoxy-2-sulfoamino-{beta}-D-glucopyranuronan (S-chitosan) are two chemically modified chitosans. In this study, we found that P-chitosan significantly promotes cell proliferation of both human primary osteoblasts (OBs) and the OB like stromal cell component of the giant cell tumor of bone (GCTB) cells at the concentration from 125 to 1000 {mu}g ml{sup -1} at all time points of 1, 3, 5 and 7 days after treatment. Further investigation of the osteogenic effect of the P-chitosan suggested that it regulates the levels of osteoclastogenic factors, receptor activator of nuclear factor kappa B ligand and osteoprotegerin expression. An interesting finding is that S-chitosan at lower concentration (100 {mu}g ml{sup -1}) stimulates cell proliferation while a higher dose (1000 {mu}g ml{sup -1}) of S-chitosan inhibits it. The inhibitory effect of S-chitosan on human primary GCT stromal cells was greater than that of OBs (p < 0.05). Taken together, our findings elucidated the osteogenic effect of P-chitosan and the varying effects of S-chitosan on the proliferation of human primary OBs and GCT stromal cells and provided us the rationale for the construction of novel bone repair biomaterials with the dual properties of bone induction and bone tumor inhibition.

  15. An exceptional collision tumor: gastric calcified stromal tumor and ...

    African Journals Online (AJOL)

    An exceptional collision tumor: gastric calcified stromal tumor and pancreatic adenocarcinoma. Hicham Baba, Mohamed Elfahssi, Mohamed Said Belhamidi, Abderrahman Elhjouji, Ahmed Bounaim, Abdelmounaim Ait Ali, Khalid Sair, Aziz Zentar ...

  16. Circulating levels of cell adhesion molecule L1 as a prognostic marker in gastrointestinal stromal tumor patients

    Directory of Open Access Journals (Sweden)

    Schachner Melitta

    2011-05-01

    Full Text Available Abstract Background L1 cell adhesion molecule (CD171 is expressed in many malignant tumors and its expression correlates with unfavourable outcome. It thus represents a target for tumor diagnosis and therapy. An earlier study conducted by our group identified L1 expression levels in primary gastrointestinal stromal tumors (GIST as a prognostic marker. The aim of the current study was to compare L1 serum levels of GIST patients with those of healthy controls and to determine whether levels of soluble L1 in sera could serve as a prognostic marker. Methods Using a sensitive enzyme-linked immunosorbent assay (ELISA, soluble L1 was measured in sera of 93 GIST patients und 151 healthy controls. Soluble L1 levels were then correlated with clinicopathological data. Results Median levels of soluble L1 were significantly higher (p p Conclusion These results suggest that high soluble L1 levels predict poor prognosis and may thus be a promising tumor marker that can contribute to individualise therapy.

  17. Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity.

    Science.gov (United States)

    Rappa, Germana; Mercapide, Javier; Lorico, Aurelio

    2012-06-01

    Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow-derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells (MSCs) and two different breast carcinoma cell lines, MDA-MB-231 (MDA) and MA11. Hybrids showed predominantly mesenchymal morphological characteristics, mixed gene expression profiles, and increased DNA ploidy. Both MA11 and MDA hybrids were tumorigenic in immunodeficient mice, and some MDA hybrids had an increased metastatic capacity. Both in culture and as xenografts, hybrids underwent DNA ploidy reduction and morphological reversal to breast carcinoma-like morphological characteristics, while maintaining a mixed breast cancer-mesenchymal expression profile. Analysis of coding single-nucleotide polymorphisms by RNA sequencing revealed genetic contributions from both parental partners to hybrid tumors and metastasis. Because MSCs migrate and localize to breast carcinoma, our findings indicate that formation of MSC-breast cancer cell hybrids is a potential mechanism of the generation of invasive/metastatic breast cancer cells. Our findings reconcile the fusion theory of cancer progression with the common observation that breast cancer metastases are generally aneuploid, but not tetraploid, and are histopathologically similar to the primary neoplasm. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  18. A gastrointestinal stromal tumor (GIST masquerading as an ovarian mass

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    Beneduce Pasquale

    2004-05-01

    Full Text Available Abstract Background Malignant gastrointestinal stromal tumors (GIST are rare mesenchymal tumors originating in the wall of the gastrointestinal tract. Myogenic gastrointestinal stromal tumor, a distinctive morphologic variant is characterized by an unusually prominent myxoid stromal background. Case presentation We report a case of myxoid variant of GIST in a 42 years old woman presenting as an epigastric mass associated to an ovarian cyst and elevated CA-125. Histologically, the lesions was composed of a proliferation of spindle cells in an abundant myxoid stroma, without evidence of atypia or anaplasia. Immunohistochemical stains showed strong positive staining with muscle actin, positive staining with CD34 and weak positive staining with CD117, while showed negative for S-100. Conclusion At surgery every effort should be made to identify the origin of the tumor. A complete surgical removal of the tumor should be obtained, as this is the only established treatment that offers long term survival.

  19. Gastrointestinal stromal tumors. Analysis of 40 cases

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    Belén García

    2017-10-01

    Full Text Available Gastrointestinal stromal tumors represent less than 3% of all digestive tumors. They are primarily located in the stomach and the small intestine. The curative treatment is surgical resection. In the case of unresectable tumor or advanced disease, imatinib is the treatment of choice. The purpose of this retrospective study was to describe the characteristics of patients with gastrointestinal stromal tumors treated at our institution in the period 2000-2015. We analyzed 40 consecutive patients diagnosed with gastrointestinal stromal tumor (mean age 58-year old, range 33-84. The mean 5-year survival was 30.5%. At diagnosis, 30 patients had localized disease (75%; 14 of them received adjuvant imatinib and 15 follow-up on observation. In this group the disease-free interval was 55 months. In patients with advanced disease, the progression-free interval was 30 months

  20. Tumor-associated Endo180 requires stromal-derived LOX to promote metastatic prostate cancer cell migration on human ECM surfaces.

    Science.gov (United States)

    Caley, Matthew P; King, Helen; Shah, Neel; Wang, Kai; Rodriguez-Teja, Mercedes; Gronau, Julian H; Waxman, Jonathan; Sturge, Justin

    2016-02-01

    The diverse composition and structure of extracellular matrix (ECM) interfaces encountered by tumor cells at secondary tissue sites can influence metastatic progression. Extensive in vitro and in vivo data has confirmed that metastasizing tumor cells can adopt different migratory modes in response to their microenvironment. Here we present a model that uses human stromal cell-derived matrices to demonstrate that plasticity in tumor cell movement is controlled by the tumor-associated collagen receptor Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) and the crosslinking of collagen fibers by stromal-derived lysyl oxidase (LOX). Human osteoblast-derived and fibroblast-derived ECM supported a rounded 'amoeboid-like' mode of cell migration and enhanced Endo180 expression in three prostate cancer cell lines (PC3, VCaP, DU145). Genetic silencing of Endo180 reverted PC3 cells from their rounded mode of migration towards a bipolar 'mesenchymal-like' mode of migration and blocked their translocation on human fibroblast-derived and osteoblast-derived matrices. The concomitant decrease in PC3 cell migration and increase in Endo180 expression induced by stromal LOX inhibition indicates that the Endo180-dependent rounded mode of prostate cancer cell migration requires ECM crosslinking. In conclusion, this study introduces a realistic in vitro model for the study of metastatic prostate cancer cell plasticity and pinpoints the cooperation between tumor-associated Endo180 and the stiff microenvironment imposed by stromal-derived LOX as a potential target for limiting metastatic progression in prostate cancer.

  1. Sex Cord-Gonadal Stromal Tumor of the Rete Testis

    Directory of Open Access Journals (Sweden)

    Kamran P. Sajadi

    2009-01-01

    Full Text Available A 34-year-old tetraplegic patient with suppurative epididymitis was found on follow-up examination and ultrasonography to have a testicular mass. The radical orchiectomy specimen contained an undifferentiated spindled sex cord-stromal tumor arising in the rete testis. Testicular sex cord-stromal tumors are far less common than germ cell neoplasms and are usually benign. The close relationship between sex cords and ductules of the rete testis during development provides the opportunity for these uncommon tumors to arise anatomically within the rete tesis. This undifferentiated sex cord-stromal tumor, occurring in a previously unreported location, is an example of an unusual lesion mimicking an intratesticular malignant neoplasm.

  2. Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis*

    Science.gov (United States)

    Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

    2015-01-01

    The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1−/−) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4−/− mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. PMID:26475855

  3. Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis.

    Science.gov (United States)

    Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

    2015-12-11

    The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. SV40 Infection of Mesenchymal Stromal Cells From Wharton's Jelly Drives the Production of Inflammatory and Tumoral Mediators.

    Science.gov (United States)

    Cason, Carolina; Campisciano, Giuseppina; Zanotta, Nunzia; Valencic, Erica; Delbue, Serena; Bella, Ramona; Comar, Manola

    2017-11-01

    The Mesenchymal Stromal Cells from umbilical cord Wharton's jelly (WJSCs) are a source of cells with high potentiality for the treatment of human immunological disorders. Footprints of the oncogenic viruses Simian Virus 40 (SV40) and JC Virus (JCPyV) have been recently detected in human WJSCs specimens. The aim of this study is to evaluate if WJSCs can be efficiently infected by these Polyomaviruses and if they can potentially exert tumoral activity. Cell culture experiments indicated that WJSCs could sustain both SV40 and JCPyV infections. A transient and lytic replication was observed for JCPyV, while SV40 persistently infected WJSCs over a long period of time, releasing a viral progeny at low titer without evident cytopathic effect (CPE). Considering the association between SV40 and human tumors and the reported ability of the oncogenic viruses to drive the host innate immune response to cell transformation, the expression profile of a large panel of immune mediators was evaluated in supernatants by the Bioplex platform. RANTES, IL-3, MIG, and IL-12p40, involved in chronic inflammation, cells differentiation, and transformation, were constantly measured at high concentration comparing to control. These findings represent a new aspect of SV40 biological activity in the humans, highlighting its interaction with specific host cellular pathways. In view of these results, it seems to be increasingly urgent to consider Polyomaviruses in the management of WJSCs for their safely use as promising therapeutic source. J. Cell. Physiol. 232: 3060-3066, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

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    Kathrin Rupertus

    2012-01-01

    Full Text Available Background. Mobilization of c-Kit+ hematopoietic cells (HCs contributes to tumor vascularization. Whereas survival and proliferation of HCs are regulated by binding of the stem cell factor to its receptor c-Kit, migration of HCs is directed by stromal cell-derived factor (SDF-1. Therefore, targeting migration of HCs provides a promising new strategy of anti-tumor therapy. Methods. BALB/c mice (=16 were pretreated with an anti-c-Kit antibody followed by implantation of CT26.WT-GFP colorectal cancer cells into dorsal skinfold chambers. Animals (=8 additionally received a neutralizing anti-SDF-1 antibody. Animals (=8 treated with a control antibody served as controls. Investigations were performed using intravital fluorescence microscopy, immunohistochemistry, flow cytometry and western blot analysis. Results. Blockade of c-Kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. C-Kit blockade significantly increased VEGF and CXCR4 expression within the growing tumors. Neutralization of SDF-1 completely antagonized this anti-c-Kit-associated tumor growth by suppression of tumor neovascularization, inhibition of tumor cell proliferation and reduction of muscular infiltration. Conclusion. Our study indicates that bone marrow suppression via anti-c-Kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the SDF-1/CXCR4 pathway which is involved in HC-mediated tumor angiogenesis.

  6. Residual late radiation damage in mouse stromal tissue assessed by the tumor bed effect

    NARCIS (Netherlands)

    Haveman, Jaap; Rodermond, Hans; van Bree, Chris; Wondergem, Jan; Franken, Nicolaas A. P.

    2007-01-01

    Irradiation of murine subcutaneous stroma before implantation of tumor cells leads to retarded tumor growth. This effect is called Tumor Bed Effect (TBE) and can be used to assess the sensitivity of stromal tissue to radiation. We tested the ability of stromal tissue to recover from X-ray-induced

  7. The Role of Stromal Myofibroblast and Extracellular Matrix in Tumor Angiogenesis

    Science.gov (United States)

    Vong, Sylvia

    2011-01-01

    Tumor angiogenesis, the building of blood vessels in an expanding tumor mass, is an elegantly coordinated process that dictates tumor growth and progression. Stromal components of the tumor microenvironment, such as myofibroblasts and the extracellular matrix, collaborate with tumor cells in regulating development. Such myofibroblasts and the extracellular matrix have ever-expanding roles in the angiogenic process as well. This review summarizes how stromal myofibroblasts and the extracellular matrix can modulate tumor angiogenesis, highlighting recent findings. PMID:22866205

  8. Alfa-fetoprotein secreting ovarian sex cord-stromal tumor

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    Kusum D Jashnani

    2013-01-01

    Full Text Available Ovarian sex cord-stromal tumors are relatively infrequent neoplasms that account for approximately 8% of all primary ovarian tumors. They are a heterogeneous group of neoplasms composed of cells derived from gonadal sex cords (granulosa and Sertoli cells, specialized gonadal stroma (theca and Leydig cells, and fibroblasts. They may show androgenic or estrogenic manifestations. We report such a tumor associated with markedly raised serum alpha-fetoprotein (AFP levels in a young female presenting with a mass and defeminising symptoms. Serum AFP levels returned to normal on removal of tumor.

  9. Alfa-fetoprotein secreting ovarian sex cord-stromal tumor.

    Science.gov (United States)

    Jashnani, Kusum D; Hegde, Chandrashekar V; Munot, Shrutika P

    2013-01-01

    Ovarian sex cord-stromal tumors are relatively infrequent neoplasms that account for approximately 8% of all primary ovarian tumors. They are a heterogeneous group of neoplasms composed of cells derived from gonadal sex cords (granulosa and Sertoli cells), specialized gonadal stroma (theca and Leydig cells), and fibroblasts. They may show androgenic or estrogenic manifestations. We report such a tumor associated with markedly raised serum alpha-fetoprotein (AFP) levels in a young female presenting with a mass and defeminising symptoms. Serum AFP levels returned to normal on removal of tumor.

  10. Alerting the immune system via stromal cells is central to the prevention of tumor growth

    DEFF Research Database (Denmark)

    Navikas, Shohreh

    2013-01-01

    Anticancer immunotherapies are highly desired. Conversely, unwanted inflammatory or immune responses contribute to oncogenesis, tumor progression, and cancer-related death. For non-immunogenic therapies to inhibit tumor growth, they must promote, not prevent, the activation of anticancer immune...

  11. Ovarian serous cystadenofibroma with signet ring-stromal cells: report of 2 cases.

    Science.gov (United States)

    Shah, Rajeev; Shah, Varsha; McCluggage, W Glenn

    2010-09-01

    We report 2 ovarian serous cystadenofibromas with signet ring cells within the stromal component. The signet ring-stromal cells were widespread in 1 case and focal in the other. Immunohistochemically, they were negative with cytokeratin and other epithelial markers and positive with mesenchymal markers. The occurrence of signet ring-stromal cells in ovarian serous cystadenofibromas is an unusual pseudoneoplastic phenomenon, which has not been reported previously, although signet ring cells may occur within a variety of ovarian stromal neoplasms, including fibromas, sclerosing stromal tumors, and signet ring-stromal tumors. In reporting these cases, we review ovarian stromal neoplasms and other lesions with signet ring cells.

  12. [Myxoid mesenchymal tumors of uterus: endometrial stromal and smooth muscle tumors, myxoid variant].

    Science.gov (United States)

    Chesnais, Anne-Laure; Watkin, Emmanuel; Beurton, Daniel; Devouassoux-Shisheboran, Mojgan

    2011-06-01

    Four myxoid variant of uterine mesenchymal tumors are reported. One was a low grade stromal sarcoma with infiltrative margins and the others were well circumscribed tumors corresponding to an endometrial stromal nodule and two leiomyomas. They were hypocellular neoplasms composed of stellated cells with an abundant Alcian Blue positive myxoid matrix. The myxoid nature of the neoplasms obscured their cellular nature and made the distinction between smooth muscle and endometrial stromal tumors difficult. Endometrial stromal tumors, showed very focal areas of small basophilic cells, characteristic of endometrial stroma. The diagnosis was based on the presence of a spiral arteriolar network, a CD10 positivity as well as the absence of h-caldesmon and desmin expression. The two myxoid leiomyomas showed more spindle cells and a desmin expression while h-caldesmon was negative and CD10 focally positive in both cases. Myxoid variant of endometrial stromal tumors does not necessarily exhibit the typical morphology of endometrial stroma. They may demonstrate morphological features of smooth muscle tumors in the uterus. Also, myxoid changes in uterin smooth muscle tumors may modify the classical immunoreactivity of smooth muscle markers in these tumors and make it difficult to distinguish between benign and malignant neoplasms. An immunohistochemical panel of antibodies including CD10, h-caldesmon and desmin may help in establishing the correct diagnosis. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  13. Primary omental Gastrointestinal stromal tumor (GIST

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    Hirahara Nobutsune

    2007-06-01

    Full Text Available Abstract Background We report herein a rare case of primary omental gastrointestinal stromal tumor (GIST. Case presentation A 65 year-old man was referred to our hospital with a huge abdominal mass occupying the entire left upper abdomen as shown by sonography. On computed tomography (CT, this appeared as a heterogeneous low-density mass with faint enhancement. Abdominal angiography revealed that the right gastroepiploic artery supplied the tumor. With such an indication of gastric GIST, liposarcoma, leiomyosarcoma or mesothelioma laparotomy was performed and revealed that this large mass measured 20 × 17 × 6 cm, arising from the greater omentum. It was completely resected. Histopathologically, it was composed of proliferating spindle and epithelioid cells with an interlacing bundle pattern. Immunohistochemically, the tumor was positive for myeloid stem cell antigen (CD34, weakly positive for c-KIT (CD117 and slightly positive for neuron-specific enolase (NSE, but negative for cytokeratin (CK, alpha-smooth muscle actin (SMA and S-100 protein. A mutation was identified in the platelet-derived growth factor alpha (PDGFRA juxtamembrane domain (exon 12, codon561 and the tumor was diagnosed as an omental GIST. The postoperative course was uneventful. The patient is treated by Glevec® and is alive well with no sign of relapse. Conclusion Our case demonstrated a weak immunohistochemical expression of c-kit (CD117 and a point mutation in PDGFRA exon 12 resulting in an Asp for Val561 substitution. Imatinib therapy as an adjuvant to complete resection has been carried out safely. Because of the rarity of primary omental GISTs, it is inevitable to analyze accumulating data from case reports for a better and more detailed understanding of primary omental GISTs.

  14. Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model

    Directory of Open Access Journals (Sweden)

    Chen X-C

    2008-10-01

    Full Text Available Abstract Background Bone marrow-derived stromal cells (BMSCs are important for development, tissue cell replenishment, and wound healing in physiological and pathological conditions. BMSCs were found to preferably reach sites undergoing the process of cell proliferation, such as wound and tumor, suggesting that BMSCs may be used as a vehicle for gene therapy of tumor. Methods Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1. The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models. Results BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors. Conclusion We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.

  15. Gastrointestinal Stromal Tumor:A Rare Abdominal Tumor

    Directory of Open Access Journals (Sweden)

    Shagufta Shaheen

    2013-03-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare abdominal tumors which arise from the interstitial cells of Cajal in the gastrointestinal tract. Gastric GISTs are the most commonly seen GIST tumors and may grow to a very large size. They are often associated with abdominal pain, anorexia and weight loss. Most of them can be detected by CT. These tumors have been found to harbor mutations in CD117 which causes constitutional activation of the tyrosine kinase signaling pathway and is considered to be pathognomic. Tyrosine kinase inhibitors such as imatinib have revolutionized the treatment of these tumors, which are otherwise resistant to conventional chemotherapy and radiotherapy. Although surgical resection is the mainstay of treatment, tyrosine kinase inhibitors have been useful in prolonging the recurrence-free survival of these patients. Resistance to imatinib has been reported in GISTs with specific mutations. We present a case of gastric GIST which grew to a very large size and was associated with abdominal pain and weight loss. It was successfully resected and the patient was commenced on imatinib therapy.

  16. Ovarian Sex Cord-stromal Tumors With Melanin Pigment: Report of a Previously Undescribed Phenomenon.

    Science.gov (United States)

    Taylor, Jennifer; McCluggage, W Glenn

    2017-11-14

    We report 2 ovarian sex cord-stromal tumors, a luteinized adult granulosa cell tumor and a cellular fibroma, with melanin pigment. These occurred in 44 and 61-yr-old patients, respectively. As far as we are aware, melanin pigment has not been described previously in an ovarian sex cord-stromal tumor, although it has been reported in a testicular Sertoli cell tumor. We review ovarian neoplasms containing melanin pigment.

  17. Sclerosing stromal tumor of the ovary in a 4-year-old girl with characteristics of an ovarian signet-ring stromal tumor.

    Science.gov (United States)

    He, Ying; Yang, Kai-Xuan; Jiang, Wei; Wang, Dan-qing; Li, Lei

    2010-05-15

    Ovarian sclerosing stromal tumor (OSST) is an extremely rare neoplasm that primarily affects young women. Signet-ring stromal tumor is another rare non-functioning benign ovarian stromal neoplasm. We report a case of a right OSST with prominent characteristics of signet-ring stromal tumor in a 4-year-old girl with symptoms of premature thelarche. We describe the clinical, histopathological, and immunohistochemical findings and review the literature. To our knowledge, the 4-year-old patient presented here is the youngest case of OSST reported in premenarchal children. The presence of non-mucin/non-lipid obvious signet-ring-like cells in this case suggests a possible relationship between OSST and signet-ring stromal tumor of the ovary. (c) 2009. Published by Elsevier GmbH. All rights reserved.

  18. Bone and cementum as stromal features in Pindborg tumor.

    Science.gov (United States)

    Slootweg, P J

    1991-02-01

    A case of calcifying epithelial odontogenic tumor (CEOT) occurring in the left mandible of a 50-yr-old man was characterized by the presence of large masses of calcified collagen. Calcified amyloid acted as the nucleus for the deposition of this material. Because of the close association between both types of calcified material, it is presumed that the calcified amyloid is an inductive stimulus for the stromal cells to differentiate towards production of a collagenous matrix destined to calcify and resembling cementum. The stromal component of CEOT thus seems to be just as odontogenic as the epithelium is.

  19. Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors

    Science.gov (United States)

    2017-08-22

    Ovarian Granulosa Cell Tumor; Ovarian Gynandroblastoma; Ovarian Sertoli-Leydig Cell Tumor; Ovarian Sex Cord Tumor With Annular Tubules; Ovarian Sex Cord-Stromal Tumor; Ovarian Sex Cord-Stromal Tumor of Mixed or Unclassified Cell Types; Ovarian Steroid Cell Tumor

  20. Interferon-γ differentially modulates the impact of tumor necrosis factor-α on human endometrial stromal cells.

    Science.gov (United States)

    Spratte, Julia; Oemus, Anne; Zygmunt, Marek; Fluhr, Herbert

    2015-09-01

    The pro-inflammatory T helper (Th)-1 cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), are immunological factors relevant at the feto-maternal interface and involved in the pathophysiology of implantation disorders. The synergistic action of the two cytokines has been described with regard to apoptotic cell death and inflammatory responses in different cell types, but little is known regarding the human endometrium. Therefore, we examined the interaction of TNF-α and IFN-γ in human endometrial stromal cells (ESCs). ESCs were isolated from specimens obtained during hysterectomy and decidualized in vitro. Cells were incubated with TNF-α, IFN-γ or signaling-inhibitor. Insulin-like growth factor binding protein (IGFBP)-1, prolactin (PRL), leukemia inhibitory factor (LIF), interleukin (IL)-6, IL-8, regulated on activation normal T-cell expressed and secreted protein (RANTES) and monocyte chemotactic protein (MCP)-1 were measured using ELISA and real-time RT-PCR. Nuclear factor of transcription (NF)-κB and its inhibitor (IκBα) were analyzed by in-cell western assay and transcription factor assay. TNF-α inhibited and IFN-γ did not affect the decidualization of ESCs. In contrast, IFN-gamma differentially modulated the stimulating effect of TNF-alpha on cytokines by enhancing IL-6, RANTES and MCP-1 and attenuating LIF mRNA expression. These effects were time- and dose-dependent. IFN-γ had no impact on the initial activation of NF-κB signaling. Histone-deacetylase activity was involved in the modulating effect of IFN-γ on RANTES secretion. These observations showed a distinct pattern of interaction of the Th-1 cytokines, TNF-α and IFN-γ in the human endometrium, which could play an important role in the pathophysiology of implantation disorders. Copyright © 2015 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z

  1. Sclerosing Stromal Tumor of Ovary: A Case Report

    Directory of Open Access Journals (Sweden)

    Menka Khanna

    2012-01-01

    Full Text Available Sclerosing stromal tumor (SST is an extremely rare and distinctive sex cord stromal tumor which occurs predominantly in the second and third decades of life. We report a case of a 32-year-old woman who developed a sclerosing stromal tumor of ovary and presented with irregular menstruation and pelvic pain. Her hormonal status was normal but CA-125 was raised. She was suspected to have a malignant tumor on computed tomography and underwent bilateral salpingo-oopherectomy. It is therefore necessary to keep in mind the possibility of sclerosing stromal tumor in a young woman.

  2. Gastrointestinal Stromal Tumor – An Evolving Concept

    Science.gov (United States)

    Tornillo, Luigi

    2014-01-01

    Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. The discovery that these tumors, formerly thought of smooth muscle origin, are indeed better characterized by specific activating mutation in genes coding for the receptor tyrosine kinases (RTKs) CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with RTK inhibitors has made GISTs the typical example of the integration of basic molecular knowledge in the daily clinical activity. The information on the mutational status of these tumors is essential to predict (and subsequently to plan) the therapy. As resistant cases are frequently wild type, other possible oncogenic events, defining other “entities,” have been discovered (e.g., succinil dehydrogenase mutation/dysregulation, insuline growth factor expression, and mutations in the RAS-RAF-MAPK pathway). The classification of disease must nowadays rely on the integration of the clinico-morphological characteristics with the molecular data. PMID:25593916

  3. Gastrointestinal stromal tumor - an evolving concept.

    Science.gov (United States)

    Tornillo, Luigi

    2014-01-01

    Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. The discovery that these tumors, formerly thought of smooth muscle origin, are indeed better characterized by specific activating mutation in genes coding for the receptor tyrosine kinases (RTKs) CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with RTK inhibitors has made GISTs the typical example of the integration of basic molecular knowledge in the daily clinical activity. The information on the mutational status of these tumors is essential to predict (and subsequently to plan) the therapy. As resistant cases are frequently wild type, other possible oncogenic events, defining other "entities," have been discovered (e.g., succinil dehydrogenase mutation/dysregulation, insuline growth factor expression, and mutations in the RAS-RAF-MAPK pathway). The classification of disease must nowadays rely on the integration of the clinico-morphological characteristics with the molecular data.

  4. Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Yibin Kang

    2016-06-01

    Full Text Available Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1 in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.

  5. Expression of CD56 and WT1 in ovarian stroma and ovarian stromal tumors.

    Science.gov (United States)

    He, Huiying; Luthringer, Daniel J; Hui, Pei; Lau, Sean K; Weiss, Lawrence M; Chu, Peiguo G

    2008-06-01

    The immunophenotype of ovarian stroma and spindle cell tumors derived from ovarian stroma has not been well studied. We studied the expression of CD56, WT1, estrogen receptor-beta (ER-beta), progesterone receptor (PR), smooth muscle actin, S-100, CD34, and muscle specific actin in 16 normal ovaries, 17 ovarian fibromas, 11 ovarian cellular fibromas, 10 ovarian fibrothecomas, and 11 ovarian leiomyomas. In addition, we studied CD56 and WT1 expression in 7 cases of normal endometrium, 8 uterine smooth muscle tumors, 5 endometrial stromal tumors and 64 nongynecologic (GYN) spindle cell sarcomas. All normal ovaries, ovarian fibromas, fibrothecomas, and ovarian leiomyomas were positive for CD56 and WT1. Most of the normal ovaries, ovarian fibromas, ovarian fibrothecomas, and ovarian leiomyomata also expressed ER-beta and PR. Eight of 17 ovarian fibromas, 5 of 11 ovarian cellular fibromas, and 4 of 10 ovarian fibrothecoma with focal fibroblastic differentiation were positive for smooth muscle actin. A few cases of these tumors also expressed S-100 and CD34. Only rare cases of non-GYN spindle cell sarcomas expressed WT1. Our study results show that ovarian fibromas, fibrothecomas, and leiomyomas have a similar immunophenotype (positive for CD56, WT1, ER-beta, and PR) to that of ovarian stromal cells, supporting an ovarian stromal origin for these neoplasms. However, unlike normal ovarian stromal cells, ovarian fibromas, fibrothecomas, and leiomyomas can also show fibroblastic, smooth muscle, Schwannian, and solitary fibrous tumorlike differentiation. WT1 is a fairly specific marker for spindle cell tumors of gynecologic organs, including ovarian spindle cell tumors, endometrial stromal tumors, and uterine smooth muscle tumors. Non-GYN spindle cell sarcomas rarely express WT1. CD56 is strongly expressed in ovarian stromal cells but not in endometrial stromal cells. CD56 is often expressed by a wide variety of spindle cell sarcomas, thus, it has no value in differentiating

  6. Immortalized human fetal bone marrow-derived mesenchymal stromal cell expressing suicide gene for anti-tumor therapy in vitro and in vivo.

    Science.gov (United States)

    Lee, Wayne Y W; Zhang, Ting; Lau, Carol P Y; Wang, C C; Chan, Kai-Ming; Li, Gang

    2013-12-01

    Cancer is one of the greatest health challenges facing the world today with >10 million new cases of cancer every year. The self-renewal, tumor-homing ability and low immunogenicity of mesenchymal stromal cells (MSCs) make them potential delivery candidates for suicide genes for anti-tumor therapy. However, unstable supply and short life span of adult MSCs in vitro have limited this therapeutic potential. In this study, we aimed to evaluate if immortalization of human fetal bone marrow-derived mesenchymal stromal cells by simian virus 40 (SV40-hfBMSCs) could be a stable source of MSCs for clinical application of suicide gene therapy. Transduction of SV40 and herpes simplex virus thymidine kinase-IRES-green fluorescent protein (TK-GFP) did not cause significant change in the stem cell properties of hfBMSCs. The anti-tumor effect of SV40-TK-hfBMSCs in the presence of the prodrug ganciclovir was demonstrated in vitro and in nude mice bearing human prostate cancer cells, DU145 and PC3, which had been transduced with luciferase and GFP for imaging evaluation by an in vivo live imaging system (IVIS 200 imaging system; Caliper Life Sciences). Repeated injection of low doses (1 × 10(6) cells/kg) of SV40-TK-hfBMSCs was as effective as previously reported and did not cause observable harmful side effects in multiple organs. Mixed lymphocyte reaction showed that SV40-TK-hfBMSCs did not induce significant proliferation of lymphocytes isolated from healthy adults. Taken together, immortalized hfBMSCs represent a reliable and safe source of MSCs for further clinical translational study. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  7. Update on Gastrointestinal Stromal Tumors for Radiologists.

    Science.gov (United States)

    Tirumani, Sree Harsha; Baheti, Akshay D; Tirumani, Harika; O'Neill, Ailbhe; Jagannathan, Jyothi P

    2017-01-01

    The management of gastrointestinal stromal tumors (GISTs) has evolved significantly in the last two decades due to better understanding of their biologic behavior as well as development of molecular targeted therapies. GISTs with exon 11 mutation respond to imatinib whereas GISTs with exon 9 or succinate dehydrogenase subunit mutations do not. Risk stratification models have enabled stratifying GISTs according to risk of recurrence and choosing patients who may benefit from adjuvant therapy. Assessing response to targeted therapies in GIST using conventional response criteria has several potential pitfalls leading to search for alternate response criteria based on changes in tumor attenuation, volume, metabolic and functional parameters. Surveillance of patients with GIST in the adjuvant setting is important for timely detection of recurrences.

  8. Update on gastrointestinal stromal tumors for radiologists

    Energy Technology Data Exchange (ETDEWEB)

    Tirumani, Sree Harsha; O' Neill, Alibhe; Jagannathan, Jyothi P. [Dept. of Imaging, Dana-Farber Cancer Institute, Boston (United States); Baheti, Akahay D. [Dept. of Radiology, Tata Memorial Centre, Mumbai (India); Tirumani, Harika [Dept. of Radiology, University of Arkansas for Medical Sciences, Little Rock (United States)

    2017-01-15

    The management of gastrointestinal stromal tumors (GISTs) has evolved significantly in the last two decades due to better understanding of their biologic behavior as well as development of molecular targeted therapies. GISTs with exon 11 mutation respond to imatinib whereas GISTs with exon 9 or succinate dehydrogenase subunit mutations do not. Risk stratification models have enabled stratifying GISTs according to risk of recurrence and choosing patients who may benefit from adjuvant therapy. Assessing response to targeted therapies in GIST using conventional response criteria has several potential pitfalls leading to search for alternate response criteria based on changes in tumor attenuation, volume, metabolic and functional parameters. Surveillance of patients with GIST in the adjuvant setting is important for timely detection of recurrences.

  9. Adult Patient with Synchronous Gastrointestinal Stromal Tumor and Xp11 Translocation-Associated Renal Cell Carcinoma: A Unique Case Presentation with Discussion and Review of Literature

    Directory of Open Access Journals (Sweden)

    Vanda Farahmand Torous

    2015-01-01

    Full Text Available Gastrointestinal stromal tumor (GIST is the most common primary mesenchymal tumor of the gastrointestinal tract. This entity comprises a wide spectrum of tumors that vary from benign to overtly malignant, with the majority of these tumors harboring oncogenic mutations of the KIT receptor tyrosine kinase that can aid in diagnosis as well as in targeted therapy. Although the majority of GISTs are sporadic, there are forms that are associated with a variety of syndromes including Carney-Stratakis syndrome and neurofibromatosis type 1, as well as a subset of familial GIST syndromes that are caused by germline mutations in KIT or PDGFRA. Here, we describe an unusual case of a patient who was found to have a large abdominal GIST with an incidentally found Xp11 translocation-associated renal carcinoma. The karyotype of the renal carcinoma revealed an unbalanced rearrangement involving an (X;22 translocation at Xp11.2 and 22p11.2, which has not been reported in the literature. Although GISTs have shown an association with other primary malignant neoplasms, including simultaneous presence with unilateral clear cell renal cell carcinoma and bilateral papillary renal cell carcinomas, we describe the first reported case of synchronous GIST and Xp11 translocation-associated renal cell carcinoma.

  10. Gastrointestinal stromal tumor of the stomach with lymph node metastasis

    Directory of Open Access Journals (Sweden)

    Nalbant Olcay

    2008-09-01

    Full Text Available Abstract Background Lymph node (LN metastasis of gastrointestinal stromal tumors (GIST is unusual. Unlike gastric adenocarcinomas, routine lymphadenectomy is not recommended unless there is no suspicion for LN metastasis. Herein, we report a case of GIST of the stomach with LN metastasis treated with distal gastrectomy with perigastric LN dissection followed by adjuvant imatinib therapy. Case presentation A 32-year-old female presented with anemia. Diagnostic investigations including thoracoabdominopelvic computed tomography (CT scan and gastroscopy revealed a 8 cm gastric antral submucosal tumor without any metastasis. Enlarged periantral LNs were detected during laparotomy and patient underwent distal gastrectomy with en bloc perigastric LN dissection. Pathologic investigation revealed antral stromal tumor with high mitotic and Ki-67 index. Lymph node metastasis was observed in 7 of 12 resected perigastirc nodes. Immunohistochemically, tumor cells were positive for CD117. She was diagnosed as high grade gastric GIST due to the presence of LN metastasis, large tumor size and unfavorable histopathologic features thus underwent adjuvant imatinib treatment (400 mg, daily. No recurrence or metastasis has been detected during a 12-month of postoperative follow-up. Conclusion Surgery remains the mainstay of treatment in patients with localized, resectable GISTs. Although lymphatic metastasis rarely occurs in patients with GIST, LN dissection should be considered for patients with any suspicion of nodal metastasis. Adjuvant imatinib treatment is recommended according to the well defined prognostic factors.

  11. Gastrointestinal stromal tumor of the stomach with lymph node metastasis.

    Science.gov (United States)

    Canda, Aras Emre; Ozsoy, Yucel; Nalbant, Olcay Ak; Sagol, Ozgul

    2008-09-05

    Lymph node (LN) metastasis of gastrointestinal stromal tumors (GIST) is unusual. Unlike gastric adenocarcinomas, routine lymphadenectomy is not recommended unless there is no suspicion for LN metastasis. Herein, we report a case of GIST of the stomach with LN metastasis treated with distal gastrectomy with perigastric LN dissection followed by adjuvant imatinib therapy. A 32-year-old female presented with anemia. Diagnostic investigations including thoracoabdominopelvic computed tomography (CT) scan and gastroscopy revealed a 8 cm gastric antral submucosal tumor without any metastasis. Enlarged periantral LNs were detected during laparotomy and patient underwent distal gastrectomy with en bloc perigastric LN dissection. Pathologic investigation revealed antral stromal tumor with high mitotic and Ki-67 index. Lymph node metastasis was observed in 7 of 12 resected perigastirc nodes. Immunohistochemically, tumor cells were positive for CD117. She was diagnosed as high grade gastric GIST due to the presence of LN metastasis, large tumor size and unfavorable histopathologic features thus underwent adjuvant imatinib treatment (400 mg, daily). No recurrence or metastasis has been detected during a 12-month of postoperative follow-up. Surgery remains the mainstay of treatment in patients with localized, resectable GISTs. Although lymphatic metastasis rarely occurs in patients with GIST, LN dissection should be considered for patients with any suspicion of nodal metastasis. Adjuvant imatinib treatment is recommended according to the well defined prognostic factors.

  12. Ovarian microcystic stromal tumor: report of a new entity with immunohistochemical and ultrastructural studies.

    Science.gov (United States)

    Yang, Mary; Bhattacharjee, Meenakshi B

    2014-08-01

    Microcystic stromal tumor is a recently described rare subtype of ovarian tumor for which there has been no previously reported ultrastructural study. We report a case with the characteristic histological and immunohistochemical features and the first ultrastructural study. The immunohistochemical findings of strong and diffuse nuclear staining for beta catenin and P27 are suggestive of dysregulation of more than one genetic pathway. The ultrastructural findings are supportive of the previous postulation of an ovarian stromal origin of the neoplastic cells.

  13. Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival

    Science.gov (United States)

    Facco, Monica; Chiodin, Giorgia; Frezzato, Federica; Martini, Veronica; Gattazzo, Cristina; Lessi, Federica; Giorgi, Carlo Alberto; Visentin, Andrea; Castelli, Monica; Severin, Filippo; Zambello, Renato; Piazza, Francesco; Semenzato, Gianpietro; Trentin, Livio

    2015-01-01

    Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co-culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines. As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients. PMID:26517523

  14. Human stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Aldahmash, Abdullah; Zaher, Walid; Al-Nbaheen, May

    2012-01-01

    Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self......-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number...

  15. Synchronous Acromegaly and Gastrointestinal Stromal Tumor: A Case Report

    Directory of Open Access Journals (Sweden)

    Hüsniye Başer

    2014-06-01

    Full Text Available Acromegaly is a rare endocrine disorder characterized by the manifestations of sustained hypersecretion of growth hormone and concomitant elevations in circulating concentrations of insulin-like growth factor-1. It has been reported that patients with acromegaly are at the increased risk of developing malignant tumors, particularly colorectal cancer. Gastrointestinal stromal tumors are mesenchymal tumors of the digestive tract. An association between gastrointestinal stromal tumors and insulin-like growth factor system has been reported. Here, we report a patient diagnosed with synchronous acromegaly and gastrointestinal stromal tumor. A 59-year-old man with iron deficiency anemia presented with enlarged hands, coarse facial feature and several skin tags. Thyroid function tests were within normal range. Growth hormone was 5.14 ng/mL, insulin-like growth factor-1 was 820 ng/mL, and no growth hormone suppression was observed on 75g oral glucose tolerance test. Pituitary magnetic resonance imaging revealed microadenoma, and the patient was diagnosed with acromegaly. Upper gastrointestinal tract endoscopy revealed an ulcerovegetan mass in the duodenum and the results of the histopathologcal analysis was consistent with gastrointestinal stromal tumor. The association of synchronous and asynchronous gastrointestinal stromal tumors with other malignancies have been reported. The most common accompanying neoplasms are colorectal and gastric adenocarcinomas, as well as pancreatic tumors. However, in the literature, the number of reported cases of synchronous acromegaly and gastrointestinal stromal tumor are limited, and there are no sufficient data on this association. Turk Jem 2014; 2: 52-55

  16. [Gastrointestinal stromal tumors. A study of 5 cases].

    Science.gov (United States)

    Mouna, Bouraoui Ben Ammar; Asma, Kochlef en Zakour; Afef, Kilani; Dalila, Gargouri; Najet, Bel Hadj; Malika, Romani; Jamel, Kharrat; Abdeljabbar, Ghorbel; Olfa, Khayat; Achraf, Chedly; Mohamed, Ben Ayed; Slim, Khelifi; Abdelmajid, Letaïef

    2005-06-01

    GI stromal tumors are mesenchymatal tumors arising primarily from the digestive tract or from the omentum. Despite their rarity (less than 1% of digestive tumors). These tumors have become of current interest since the discovery of a treatment for metastatic and locally advanced tumors, the imatinib (Glivec). In this study we report 5 cases of stromal tumors. Patients were 42 years old an average. Abdominal mass was the revealing signal in 80% of cases, localisation- was obtained by endoscopy and ultrasonography in 60% cases. Total resection of the tumor was performed in all patients. Immuno-histochemical examination confirmed the diagnosis of stromal tumors. Based on these cases and on a review of literature, we insist on the diagnostic difficulties of this rare pathology, while trying to determine the histological prognostic parameters and the latest therapeutic methods.

  17. Interpretation of Pathologic Margin after Endoscopic Resection of Gastrointestinal Stromal Tumor

    OpenAIRE

    Kim, Sang Gyun

    2016-01-01

    Interpretation of the pathologic margin of a specimen from a resected tumor is important because local recurrence can be predicted by the presence of tumor cells in the resection margin. Although a sufficient resection margin is recommended in the resection of gastrointestinal adenocarcinoma, it is not usually regarded strictly in cases of mesenchymal tumor, especially gastrointestinal stromal tumor (GIST), because the tumor is usually encapsulated or well demarcated, and not infiltrative. Th...

  18. Functional role of the Ca{sup 2+}-activated Cl{sup −} channel DOG1/TMEM16A in gastrointestinal stromal tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Berglund, Erik, E-mail: erik.berglund@ki.se [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm (Sweden); Akcakaya, Pinar [Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm (Sweden); Berglund, David [Section for Transplantation Surgery, Department of Surgical Sciences, Uppsala University Hospital, Uppsala (Sweden); Karlsson, Fredrik [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm (Sweden); Vukojević, Vladana [Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Lee, Linkiat [Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm (Sweden); Bogdanović, Darko [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Lui, Weng-Onn; Larsson, Catharina [Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm (Sweden); Zedenius, Jan [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm (Sweden); Fröbom, Robin [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Bränström, Robert [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm (Sweden)

    2014-08-15

    DOG1, a Ca{sup 2+}-activated Cl{sup −} channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl{sup −} currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target. - Highlights: • Subcellular DOG1 localization varies between GIST cells. • DOG1 in GIST is voltage- and Ca{sup 2+}-activated. • Known TMEM16A modulators, like A01 and Eact, modulate DOG1. • DOG1 has small effects on cell viability and proliferation in vitro. • DOG1 impact early apoptotic GIST cells to undergo late apoptosis.

  19. Interaction of stromal and microvascular components in keratocystic odontogenic tumors.

    Science.gov (United States)

    Sousa-Neto, Ernesto Santos; Cangussu, Maria Cristina Teixeira; Gurgel, Clarissa Araújo; Guimarães, Vanessa Sousa; Ramos, Eduardo Antônio Gonçalves; Xavier, Flávia Caló Aquino; Cury, Patrícia Ramos; Carneiro Júnior, Braúlio; Leonardi, Rosalia; Dos Santos, Jean Nunes

    2016-09-01

    Little is known about the interaction of stromal components in odontogenic tumors. Thus, the aim of this study was to investigate mast cells (MCs), myofibroblasts, macrophages, and their possible association with angiogenesis and lymphangiogenesis in keratocystic odontogenic tumors (KCOTs). Thirty cases of KCOTs were included and analyzed by immunohistochemistry for mast cell tryptase, α-SMA, CD34, CD163, and D240. For comparative purpose, 15 radicular cysts (CRs) and 7 pericoronal follicles (PFs) were included. There was an increase in MCs for RCs and this difference was significant when they were compared to KCOTS and PFs. A significant increase in the density of MFs was observed for KCOTs when compared to RCs and PFs (P = 0.00). No significant difference in CD163-positive macrophages (P = 0.084) and CD34-positive vessels (P = 0.244) densities was observed between KCOTs, RCs, and PFs, although KCOTs showed a higher density of all proteins. Significant difference in lymphatic vessel density was observed for KCOTs when compared to RCs and PFs (P = 0.00). Positive correlation was observed between mast cell tryptase and CD34 in KCOTs (P = 0.025). A significant interaction between the MC population and CD34-positive vessels in KCOTs supported the hypothesis that MCs and blood vessels contribute to the stromal scaffold of KCOT. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. The role of stromal mast cells in the modification of CD4 CD25 Foxp3 regulatory T cells, Th17 lymphocytes and cytotoxic lymphocytes Tc1 in the development and progression of tumor

    Directory of Open Access Journals (Sweden)

    Katarzyna Starska

    2010-08-01

    Full Text Available Despite the lack of direct evidence that immune surveillance cells protect against tumor development, indirect clinical observations and experimental studies indicate activity in the immune response against cancer cells of various origin. Little is known about the effects of the stromal tumor mast cell (MC in the activity of immune cells, i.e. CD4[sup] [/sup]CD25[sup] [/sup]Foxp3[sup] [/sup] regulatory T cells, Th17 lymphocytes, cytotoxic lymphocytes Tc1 and their mutual modulatory function and regulation of the antitumor immune response. Factors synthesized by stromal tumor mast cells including histamine, COX-2, CXCL8 (IL-8, VEGF, IL-6, TNF, iNOS, MMP-8, and MMP-9 may, on the one hand, directly affect the activity of T lymphocyte subpopulations, i.e. iTreg, Tc1, and Th17, and thus regulate immunological processes occurring in the vicinity of the tumor. On the other hand, through effects on angiogenesis, apoptosis, the cell cycle, secretion of cytokines and the expression of adhesion molecules, they may indirectly determine the progression of the neoplasm. Understanding the regulatory mechanisms occurring in the system: tumor stroma mast cell → immune cells infiltrating the tumor (iTreg, Tc1, Th17 lymphocytes → expression of factors involved in angiogenesis, apoptosis, the cell cycle, and secretion of cytokines and adhesion molecules creates the future possibility of influencing the activation and regulation of selected proneoplastic and antineoplastic factors appearing in the neoplasm environment. Research on these mechanisms may be the beginning of a new approach to the fight against cancer growth and provide an opportunity to introduce new methods of treatment. The aim of this study was to present the current knowledge on the role of stromal tumor CD117[sup] [/sup] mast cells and factors secreted by these cells in the activation of T lymphocyte subpopulations, i.e. CD4[sup] [/sup]CD25[sup] [/sup]Foxp3[sup] [/sup]regulatory T cells, Th17

  1. Mesenchymal stromal cell delivery of full-length tumor necrosis factor-related apoptosis-inducing ligand is superior to soluble type for cancer therapy.

    Science.gov (United States)

    Yuan, ZhengQiang; Kolluri, Krishna K; Sage, Elizabeth K; Gowers, Kate H C; Janes, Sam M

    2015-07-01

    Mesenchymal stromal cell (MSC) delivery of pro-apoptotic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an attractive strategy for anticancer therapy. MSCs expressing full-length human TRAIL (flT) or its soluble form (sT) have previously been shown to be effective for cancer killing. However, a comparison between the two forms has never been performed, leaving it unclear which approach is most effective. This study addresses the issue for the possible clinical application of TRAIL-expressing MSCs in the future. MSCs were transduced with lentiviruses expressing flT or an isoleucine zipper-fused sT. TRAIL expression was examined and cancer cell apoptosis was measured after treatment with transduced MSCs or with MSC-derived soluble TRAIL. The transduction does not adversely affect cell phenotype. The sT-transduced MSCs (MSC-sT) secrete abundant levels of soluble TRAIL but do not present the protein on the cell surface. Interestingly, the flT-transduced MSCs (MSC-flT) not only express cell-surface TRAIL but also release flT into medium. These cells were examined for inducing apoptosis in 20 cancer cell lines. MSC-sT cells showed very limited effects. By contrast, MSC-flT cells demonstrated high cancer cell-killing efficiency. More importantly, MSC-flT cells can overcome some cancer cell resistance to recombinant TRAIL. In addition, both cell surface flT and secreted flT are functional for inducing apoptosis. The secreted flT was found to have higher cancer cell-killing capacity than either recombinant TRAIL or MSC-secreted sT. These observations demonstrate that MSC delivery of flT is superior to MSC delivery of sT for cancer therapy. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  2. Benign Mixed Epithelial and Stromal Tumor of the Kidney

    Directory of Open Access Journals (Sweden)

    A. Işin Doğan Ekici

    2006-01-01

    Full Text Available A 51-year-old, perimenopausal, female patient with 1-month history of right flank pain who was diagnosed with a renal mass and underwent nephron-sparing partial nephrectomy is presented. The renal mass was found to be a benign, biphasic tumor composed of an epithelial component, consisting of ducts of variable size scattered within a mesenchymal component, composed of spindle cells arranged in sheets and fascicles. No atypia, mitosis, or necrosis was found. The spindle component shows desmin, smooth muscle actin, and estrogen and progesterone receptor positivity immunohistochemically. The diagnosis of benign mixed epithelial and stromal tumor of the kidney is rendered. No recurrent disease has been detected during 2 years of follow up.

  3. Endometrial stromal tumors with sex cord-like elements: a case report

    African Journals Online (AJOL)

    Endometrial stromal nodules are rare. They represent less than a quarter of endometrial stromal tumors. Clement and Scully described as variants of endometrial stromal nodules two types of tumor ressembling ovarian sex cord tumors. Type I is tumor that resembles focally an ovarian sex cord tumor which can be ...

  4. Stromal cell contribution to human follicular lymphoma pathogenesis

    Directory of Open Access Journals (Sweden)

    Frédéric eMourcin

    2012-09-01

    Full Text Available Follicular lymphoma (FL is the prototypical model of indolent B-cell lymphoma displaying a strong dependence on a specialized cell microenvironment mimicking normal germinal center. Within malignant cell niches in invaded lymph nodes and bone marrow, external stimuli provided by infiltrating stromal cells make a pivotal contribution to disease development, progression, and drug resistance. The crosstalk between FL B cells and stromal cells is bidirectional, causing activation of both partners. In agreement, FL stromal cells exhibit specific phenotypic, transcriptomic, and functional properties. This review highlights the critical pathways involved in the direct tumor-promoting activity of stromal cells but also their role in the organization of FL cell niche through the recruitment of accessory immune cells and their polarization to a B-cell supportive phenotype. Finally, deciphering the interplay between stromal cells and FL cells provides potential new therapeutic targets with the aim to mobilize malignant cells outside their protective microenvironment and increase their sensitivity to conventional treatment.

  5. Genetics and genomics of ovarian sex cord-stromal tumors.

    Science.gov (United States)

    Fuller, P J; Leung, D; Chu, S

    2017-02-01

    Ovarian sex cord-stromal tumors (SCST) represent approximately 8% of malignant ovarian tumors. The most common are granulosa cell tumors (GCT) which account for approximately 90% of malignant SCST. Recent studies have unraveled the key genomic and genetic events contributing to their pathogenesis. SCST are found in the hereditary syndromes: Peutz-Jeghers syndrome, Ollier disease and Maffucci syndrome, and DICER1 syndrome. Genomic studies have largely been limited to GCT where a number of recurring chromosomal abnormalities (monsomy and trisomy) have been identified although their contribution to pathogenesis remains unclear. In addition to the recurrent DICER1 mutations reported in non-hereditary cases of Sertoli cell and Sertoli-Leydig cell tumors, recurrent somatic mutations in both the juvenile (j) and adult (a) forms of GCT have been reported. Approximately 30% of jGCT contain a somatic mutation, the gsp oncogene, while a further 60% have an activating mutation in the AKT gene. In the case of aGCT, a well characterized mutation in the FOXL2 transcription factor (FOXL2 C134W) is found in almost all cases, which arguably defines the disease, although the molecular events that determine the stage, behavior and prognosis of aGCT remain to be determined. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Esophageal Gastrointestinal Stromal Tumor: Diagnostic Complexity and Management Pitfalls

    Directory of Open Access Journals (Sweden)

    Charalampos G. Markakis

    2013-01-01

    Full Text Available Introduction. Gastrointestinal stromal tumors of the esophagus are rare. Case Presentation. This is a case of a 50-year-old male patient who was referred to our department complaining of atypical chest pain. A chest computed tomographic scan and endoscopic ultrasound revealed a submucosal esophageal tumor measuring 5 cm in its largest diameter. Suspecting a leiomyoma, we performed enucleation via right thoracotomy. The pathology report yielded a diagnosis of an esophageal gastrointestinal stromal tumor. The patient has shown no evidence of recurrence one year postoperatively. Conclusions. This report illustrates the complexity and dilemmas inherent in diagnosing and treating esophageal GISTs.

  7. The pathogenesis of ovarian myxoma: a neoplasm sometimes arising from other ovarian stromal tumors.

    Science.gov (United States)

    Roth, Lawrence M; Gaba, Arthur R; Cheng, Liang

    2013-07-01

    Ovarian myxoma is a rare distinctive benign ovarian stromal neoplasm that occurs predominantly in young women and is hormonally inactive. Although typically classified as an ovarian stromal tumor, its exact pathogenesis remains uncertain. We report 4 cases of ovarian myxoma, 3 of which were associated with another type or other types of ovarian stromal tumor and 1 occurred as a pure myxoma. In 2 cases, the myxoma arose from a sclerosing stromal tumor, and the third, most likely arose from a luteinized theca cell tumor (LTCT). Myxoid transformation of the connective tissue of the parent neoplasm appears to be a precursor of ovarian myxoma in some instances. We believe that the occurrence of trisomy 12 or other genetic abnormalities may play a role in this transformation. Whether or not associated with another type of ovarian stromal tumor, ovarian myxoma can be suspected macroscopically by its cystic gelatinous appearance and sharp circumscription. The most important differential diagnosis is a low-grade sarcoma with myxomatous features. We believe that myxomas arising from different anatomic sites likely are genetically, histologically, and biologically distinct. For purposes of classification, they should be considered as separate tumor types.

  8. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis

    DEFF Research Database (Denmark)

    Fluhr, Herbert; Krenzer, Stefanie; Stein, Gerburg M

    2007-01-01

    The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas...

  9. Immunohistochemical characterization of nonhuman primate ovarian sex cord-stromal tumors.

    Science.gov (United States)

    Durkes, A; Garner, M; Juan-Sallés, C; Ramos-Vara, J

    2012-09-01

    This study evaluates the immunoreactivity of 12 sex cord-stromal tumors of nonhuman primates (11 granulosa cell tumors and 1 luteoma). The markers selected are used in the characterization of gonadal tumors in dogs and other species, including cytokeratins AE1/AE3, GATA-4, inhibin-α, neuron-specific enolase, protein gene product 9.5, and vimentin. A normal nonhuman primate ovary was used as a control and to optimize immunolabeling. Staining was graded as follows: 0 (nonstaining), 1+ (cells), 2+ (10%-50% positive cells), and 3+ (> 50% positive cells). Calretinin, GATA-4, neuron-specific enolase, and vimentin were the most consistently expressed markers (12 of 12). Cytokeratins AE1/AE3 were also consistently expressed (11 of 12). Inhibin-α and protein gene product 9.5 were expressed in 8 and 10 sex cord-stromal tumors, respectively. Results indicate that immunoreactivity of nonhuman primate sex cord-stromal tumors is similar to that observed in other species and that calretinin, GATA-4, and neuron-specific enolase are the most consistently expressed markers in nonhuman primate sex cord-stromal tumors.

  10. Collagen reorganization at the tumor-stromal interface facilitates local invasion

    Directory of Open Access Journals (Sweden)

    Inman David R

    2006-12-01

    Full Text Available Abstract Background Stromal-epithelial interactions are of particular significance in breast tissue as misregulation of these interactions can promote tumorigenesis and invasion. Moreover, collagen-dense breast tissue increases the risk of breast carcinoma, although the relationship between collagen density and tumorigenesis is not well understood. As little is known about epithelial-stromal interactions in vivo, it is necessary to visualize the stroma surrounding normal epithelium and mammary tumors in intact tissues to better understand how matrix organization, density, and composition affect tumor formation and progression. Methods Epithelial-stromal interactions in normal mammary glands, mammary tumors, and tumor explants in three-dimensional culture were studied with histology, electron microscopy, and nonlinear optical imaging methodologies. Imaging of the tumor-stromal interface in live tumor tissue ex vivo was performed with multiphoton laser-scanning microscopy (MPLSM to generate multiphoton excitation (MPE of endogenous fluorophores and second harmonic generation (SHG to image stromal collagen. Results We used both laser-scanning multiphoton and second harmonic generation microscopy to determine the organization of specific collagen structures around ducts and tumors in intact, unfixed and unsectioned mammary glands. Local alterations in collagen density were clearly seen, allowing us to obtain three-dimensional information regarding the organization of the mammary stroma, such as radiating collagen fibers that could not have been obtained using classical histological techniques. Moreover, we observed and defined three tumor-associated collagen signatures (TACS that provide novel markers to locate and characterize tumors. In particular, local cell invasion was found predominantly to be oriented along certain aligned collagen fibers, suggesting that radial alignment of collagen fibers relative to tumors facilitates invasion. Consistent

  11. Sclerosing stromal tumor of the ovary: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Hyun Koo; Koh, Byung Hee; Rhim, Hyun Chul; Cho, On Koo; Kim, Yong Soo; Hahm, Chang Kok [School of Medicine, Hanyang Univ., Seoul (Korea, Republic of)

    2002-07-01

    Sclerosing stromal tumor of the ovary is a rare benign neoplasm, with distinctive clinical and pathologic features. It occurs predominantly in females during the second and third decades of life. Histologically, it is composed of cellular and acellular collagenized areas, and edematous stromal areas, and at ultrasonography and computed tomography is seen as a distinctive mixed solid and cystic mass lesion. We report a case of sclerosing stromal tumor of the ovary in a 15-year-old girl with a history of menorrhagia since menarche. Ultrasonography revealed the tumor as a well-defined, lobulated, heterogenous echogenic pelvic mass, while at CT, a huge pelvic mass 9 x 9 x 10 cm in size, was seen. This comprised a well-enhanced internal solid portion, a capsule, septa, and a non-enhanced cystic portion.

  12. Blocking of stromal interaction molecule 1 expression influence cell proliferation and promote cell apoptosis in vitro and inhibit tumor growth in vivo in head and neck squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Ping Li

    Full Text Available Calcium signal plays an important role in a variety of cancer cell metabolism, but knowledge on its role in head and neck squamous cell carcinoma (HNSCC is limited. Store-operated calcium entry (SOCE is the principal Ca2+ entry mechanism that maintains calcium concentration and produces calcium signal in non-excitable cells. SOCE is triggered by stromal interaction molecule 1 (STIM1, which is located in endoplasmic reticulum (ER as Ca2+ sensor. Although, many studies demonstrated that STIM1 and SOCE play important functions in the regulation of many cancer progressions, their clinical relevance in HNSCC remains unclear. In this study, STIM1 expression levels notably increased in 89% HNSCC tissues compared with those in adjacent normal tissues. Meanwhile, this overexpression was close associated with tumor size but not with neck lymph node metastasis. Thus, this study mainly focuses on STIM1 function in HNSCC tumor growth. Three HNSCC cell lines, namely, TSCCA (oral cancer cell line and Hep2 (laryngeal cell line with high STIM1 expression levels and Tb3.1 (oral cancer cell line with STIM1 expression level lower than previous two cell lines, were selected for in vitro study. Downregulated STIM1 expression levels in TSCCA and Hep2 arrested cells in G0/G1 stages, promoted cell apoptosis, and inhibited cell proliferation. By contrast, upregulated STIM1 expression in Tb3.1 inhibited cell apoptosis and promoted cell proliferation. Induced by thapsigargin (TG, ER stress was amplified when STIM1 expression was downregulated but was attenuated as STIM1 expression was upregulated. Furthermore, TSCCA cell xenograft models confirmed that STIM1 could promote HNSCC tumor growth in vivo. The present study provides new insight into HNSCC molecular mechanism and potential therapeutic target through targeting SOCE-dependent process. However, whether STIM1 participates in HNSCC metastasis requires further study.

  13. Significance of stromal-1 and stromal-2 signatures and biologic prognostic model in diffuse large B-cell lymphoma

    Science.gov (United States)

    Abdou, Asmaa Gaber; Asaad, Nancy; Kandil, Mona; Shabaan, Mohammed; Shams, Asmaa

    2017-01-01

    Objective : Diffuse Large B Cell Lymphoma (DLBCL) is a heterogeneous group of tumors with different biological and clinical characteristics that have diverse clinical outcomes and response to therapy. Stromal-1 signature of tumor microenvironment of DLBCL represents extracellular matrix deposition and histiocytic infiltrate, whereas stromal-2 represents angiogenesis that could affect tumor progression. Methods : The aim of the present study is to assess the significance of stromal-1 signature using SPARC-1 and stromal-2 signature using CD31 expression and then finally to construct biologic prognostic model (BPM) in 60 cases of DLBCL via immunohistochemistry. Results : Microvessel density (PBPM showed that 42 cases (70%) were of low biologic score (0–1) and 18 cases (30%) were of high biologic score (2–3). Low BPM cases showed less probability for splenic involvement (P=0.04) and a higher rate of complete response to therapy compared with high score cases (P=0.08). Conclusions : The DLBCL microenvironment could modulate tumor progression behavior since angiogenesis and SPARC positive stromal cells promote dissemination by association with spleen involvement and capsular invasion. Biologic prognostic models, including modified BPM, which considered cell origin of DLBCL and stromal signature pathways, could determine DLBCL progression and response to therapy. PMID:28607806

  14. Treatment of gastrointestinal stromal tumor (GIST during bariatric surgery

    Directory of Open Access Journals (Sweden)

    Fernando de Barros

    Full Text Available The gastrointestinal stromal tumor (GIST is a rare mesenchymal tumor. One should pay special attention when the GIST comes in obese patients during surgery. The laparoscopic resections with standard techniques, such as gastric bypass, have been described with good results. However, GIST resection associated sleeve gastrectomy for the treatment of obesity is rare, but can be done safely, depending on the location of the tumor.

  15. Pheochromocytoma and gastrointestinal stromal tumors in patients with neurofibromatosis type I

    NARCIS (Netherlands)

    Vlenterie, M.; Flucke, U.E.; Hofbauer, L.C.; Timmers, H.J.L.M.; Gastmeier, J.; Aust, D.E.; Graaf, W.T. van der; Wesseling, P.; Eisenhofer, G.; Lenders, J.W.M.

    2013-01-01

    BACKGROUND: Neurofibromatosis I may rarely predispose to pheochromocytoma and gastrointestinal stromal tumors. METHODS: A 59-year-old woman with neurofibromatosis I presented with pheochromocytoma of the left adrenal gland. During surgery, 3 gastrointestinal stromal tumors adjacent to the stomach

  16. Gastrointestinal stromal tumor presenting as a pelvic mass.

    Science.gov (United States)

    Zighelboim, Israel; Henao, Gwendolyn; Kunda, Anand; Gutierrez, Carolina; Edwards, Creighton

    2003-12-01

    Gastrointestinal stromal tumors (GISTs) are c-kit-positive tumors that may arise anywhere in the tubular gastrointestinal tract. Around 5% of the cases arise elsewhere in the abdominal cavity. Tumors originating in the omentum and mesentery have been reported.A 31-year-old woman presented with pelvic pain, a palpable pelvic mass, and elevated CA-125. Imaging showed innumerable pelvic and abdominal masses. Histopathology showed a GIST that was positive for c-kit and vimentin and negative for desmin and smooth muscle actin. The patient was started on imatinib mesylate. Six months after diagnosis the tumor has remained stable.GI stromal tumors (GIST) may initially present as pelvic mass with elevated CA-125. Imatinib mesylate is the current mainstay therapy for GISTs after surgery.

  17. Prostatic stromal tumor with fatal outcome in a young man: histopathological and immunohistochemical case presentation

    Directory of Open Access Journals (Sweden)

    Massimo Roncalli

    2010-12-01

    Full Text Available Stromal tumors of the prostate are rare and only a few cases have been described in the literature, including exceptional cases of stromal tumors with unknown malignant potential (STUMP and a fatal outcome in young patients. Morphologically distinguishing a STUMP from a stromal sarcoma of the prostate (PSS is still a challenge. We describe the histopathological and immunohistochemical findings in a 34-year-old man with a malignant specialized cell stromal tumor of the prostate that was diagnosed initially as STUMP, and he developed lung metastases within a few months. The patient attended our hospital because of lower urinary tract symptoms, after having excreted tissue through the urethra a few months before. Ultrasonography and urethrocystoscopy examinations showed a mass arising from the verumontanum, and a transurethral resection (TUR revealed a high-grade spindle cell sarcoma reminiscent of a phyllode tumor of the breast. The tumor cells were immunoreactive for vimentin, progesterone receptor and, focally, CD34. The preliminary histo­logical findings were subsequently confirmed after radical prostatectomy. The patient developed bilateral lung metastases and died 25 months after the initial diagnosis. Although rare in young patients, the challenging differential diagnosis of STUMP and PSS means that a prostate STUMP diagnosis made on the basis of biopsy or TUR specimens also requires urethrocystoscopic monitoring for the early detection of any progression to PSS. Radical prostatectomy should also be carefully considered.

  18. Endothelial cells are essential for ovarian stromal tissue restructuring after xenotransplantation of isolated ovarian stromal cells

    National Research Council Canada - National Science Library

    Dath, C; Dethy, A; Van Langendonckt, A; Van Eyck, A S; Amorim, C A; Luyckx, V; Donnez, J; Dolmans, M M

    2011-01-01

    .... To help improve the grafting technique, we investigated whether short-term xenografting of a suspension containing ovarian stromal and endothelial cells without follicles could enhance graft survival...

  19. Clinicopathological Characteristics of Ovarian Sclerosing Stromal Tumor with an Emphasis on TFE3 Overexpression.

    Science.gov (United States)

    Park, Cheol Keun; Kim, Hyun-Soo

    2017-10-01

    A sclerosing stromal tumor is a very rare benign sex cord-stromal tumor of the ovary. Because its clinical presentation and imaging findings are similar to those of borderline or malignant epithelial tumors and other sex cord-stromal tumors, accurate preoperative clinical diagnosis can be difficult. The aim of this study was to analyze the clinicopathological characteristics of SSTs and examine the immunohistochemical expression TFE3, which has not been studied in SSTs. Our study cohort consisted of 9 patients diagnosed as having SST; the median age was 36 years. Radiologically, SSTs presented as multiseptated cystic masses, mixed echoic masses, pseudolobular masses, solid pelvic masses, or uterine subserosal nodules. In 4 of the 9 cases, the preoperative clinical impression was a borderline or malignant ovarian tumor. SSTs displayed the following histopathological features: 1) relatively well-circumscribed cellular nodules that were randomly distributed in the fibrous or edematous stroma; 2) a characteristic alternating pattern of hypercellular and hypocellular areas; 3) a hemangiopericytoma-like vascular growth pattern in the cellular nodules; 4) bland-looking spindle-shaped cells and round or polygonal cells densely clustered around blood vessels; and 5) red blood cell-containing intracytoplasmic vacuole-like spaces in the tumor cell cytoplasm, possibly indicating epithelioid hemangioendothelioma. Immunohistochemically, the tumor cells exhibited diffuse and moderate-to-strong TFE3 expression in 7 of the 9 SSTs. TFE3 was strongly expressed in the nuclei of round or polygonal cells and lutein cells. In contrast, neither luteinized thecomas nor fibromas appreciably expressed TFE3. In summary, our study describes characteristic histopathological features that may be useful for differentiating SSTs from other sex-cord stromal tumors and demonstrates for the first time that SSTs show strong TFE3 expression. Further investigations are necessary to clarify the role of

  20. Gastrointestinal stromal tumor of the anal wall in a Nigerian ...

    African Journals Online (AJOL)

    Documented reports of gastrointestinal stromal tumors (GIST) are relatively few in the sub-Saharan continent. The body of evidence points towards anal wall involvement being a rarity indeed. In this article we document a 61 year old Nigerian man who presented with bleeding per rectum and in whom the histological ...

  1. Rare case of gastrointestinal stromal tumor of the anal canal

    Directory of Open Access Journals (Sweden)

    Madhu Kumar

    2013-01-01

    Full Text Available Gastrointestinal stromal tumor (GIST is a rare mesenchymal neoplasm of the gastrointestinal tract. GIST of anal canal is very rare representing only 3% of all anorectal mesenchymal tumors. We report an extremely rare case of GIST of the anal canal in 60-years-old man with history of irregular bowel habits with dark colored stool mixed with blood and constipation from 6 month. Diagnosis was made on the basis of histomorphological and immunohistochemical examination.

  2. Jejunojejunal Intussusception Induced by a Gastrointestinal Stromal Tumor

    Directory of Open Access Journals (Sweden)

    Ali H. Zakaria

    2012-01-01

    Full Text Available Background. Adult intussusception is a rare entity representing less than 1% of all intestinal obstructions. Diagnosis of the condition is difficult requiring a high index of suspicion and the utilization of imaging studies, especially CT scans. Diagnostic laparoscopy and/or exploratory laparotomy can be used as a diagnostic and therapeutic intervention. In over 90% of cases, an underlying lead point is identified. In the patient described here, it was a gastrointestinal stromal tumor (GIST, a relatively rare mesenchymal tumor comprising only 0.2–1.0% of the gastrointestinal tract neoplasms and believed to originate from neoplastic transformation of the interstitial cells of Cajal. GISTs may occur anywhere along the gastrointestinal tract, but most commonly arise in the stomach and small intestine. Literature review revealed only few cases reporting GISTs as a leading point of adult's intussusception. Case Presentation. In this report, we are presenting a rare case of jejunojejunal intussusception in a 78-year-old female patient with a GIST located in the terminal jejunum being the leading point, demonstrating the importance of imaging studies, especially CT scan, laparoscopy, and exploratory laparotomy as diagnostic and therapeutic interventions.

  3. Jejunojejunal intussusception induced by a gastrointestinal stromal tumor.

    Science.gov (United States)

    Zakaria, Ali H; Daradkeh, Salam

    2012-01-01

    Background. Adult intussusception is a rare entity representing less than 1% of all intestinal obstructions. Diagnosis of the condition is difficult requiring a high index of suspicion and the utilization of imaging studies, especially CT scans. Diagnostic laparoscopy and/or exploratory laparotomy can be used as a diagnostic and therapeutic intervention. In over 90% of cases, an underlying lead point is identified. In the patient described here, it was a gastrointestinal stromal tumor (GIST), a relatively rare mesenchymal tumor comprising only 0.2-1.0% of the gastrointestinal tract neoplasms and believed to originate from neoplastic transformation of the interstitial cells of Cajal. GISTs may occur anywhere along the gastrointestinal tract, but most commonly arise in the stomach and small intestine. Literature review revealed only few cases reporting GISTs as a leading point of adult's intussusception. Case Presentation. In this report, we are presenting a rare case of jejunojejunal intussusception in a 78-year-old female patient with a GIST located in the terminal jejunum being the leading point, demonstrating the importance of imaging studies, especially CT scan, laparoscopy, and exploratory laparotomy as diagnostic and therapeutic interventions.

  4. Extra-Gastrointestinal retroperitoneal giant stromal tumor complicated with intra-tumoral hemorrhage: case report and literature review

    Directory of Open Access Journals (Sweden)

    Suciu B.A.

    2015-02-01

    Full Text Available Gastrointestinal stromal tumors are an uncommon sarcomas with mesenchymal origin that arises in the gastrointestinal tract. Recently, most of the published reports describe such tumors located outside of the gastrointestinal tract, with similar pathological characteristics and are named extra-gastrointestinal stromal tumors. We report the case of a patient suffering for a giant retroperitoneal extra-gastrointestinal stromal tumor, complicated with intra-tumoral hemorrhage. The particularity of this case is the presence of the intra-tumoral hemorrhage in a retroperitoneal extragastrointestinal stromal tumor that grew rapidly in volume (in 1 week.

  5. Pathogenesis of Plexiform Neurofibroma: Tumor-Stromal/Hematopoietic Interactions in Tumor Progression

    Science.gov (United States)

    Staser, Karl; Yang, Feng-Chun; Clapp, D Wade

    2013-01-01

    Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, including myeloid leukemia, optic glioma, and plexiform neurofibroma formation. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, non-tumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals promoting vascular in-growth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system which depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and have clear relevance toward medical neurofibroma management. PMID:22077553

  6. Current management and prognostic features for gastrointestinal stromal tumor (GIST

    Directory of Open Access Journals (Sweden)

    Lamba Gurpreet

    2012-06-01

    Full Text Available Abstract Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI tract have undergone a remarkable evolution in how they are perceived, classified, approached, diagnosed and managed over the last 30 years. Gastrointestinal stromal tumors (GIST account for approximately 1% to 3% of all malignant GI tumors. The clinical features can vary depending on the anatomic location, size and aggressiveness of the tumor. Metastatic GIST represents a successful example of molecular targeted therapy. In this comprehensive review, we discuss the epidemiology, clinical features and diagnostic modalities for GIST. We also describe treatment options for early stage, locally advanced and metastatic GIST. Indications for neoadjuvant and adjuvant therapy along with duration of therapy are also explained. A brief discussion of latest biomarkers and updates from recent meetings is also provided.

  7. Borderline gastric stromal tumor: diagnosis by ultrasound and computed tomography; Tumor estromal borderline del estomago diagnostico por imagen en ecografia y TC

    Energy Technology Data Exchange (ETDEWEB)

    Feijoo, R.; Rubio, P. J.; Lopez, J. I.; Borderias, A.; Placeres, A. [Hospita San Jorge. Huesca (Spain)

    2000-07-01

    Gastrointestinal stromal tumors (GIST) are a type of undifferentiated stromal tumor that is recently being diagnosed more frequently owing to the introduction of new immunohistochemical techniques. Their main feature, indispensable for the definitive diagnosis, is immunohistochemical evidence of the presence of CD34-positive cells. We present a case of GIST of borderline malignancy involving the outer wall of the stomach, describing the ultrasound and computed tomography images and their correlation with the pathological features. (Author) 8 refs.

  8. Mouse endometrial stromal cells produce basement-membrane components

    DEFF Research Database (Denmark)

    Wewer, U M; Damjanov, A; Weiss, J

    1986-01-01

    During mouse pregnancy, uterine stromal cells transform into morphologically distinct decidual cells under the influence of the implanting embryo and a proper hormonal environment. Mechanical stimulation of hormonally primed uterine stromal cells leads to the same morphologic alterations. The dec...

  9. Epigenetic Regulation of CD133 in Gastrointestinal Stromal Tumors.

    Science.gov (United States)

    Geddert, Helene; Braun, Alexander; Kayser, Claudia; Dimmler, Arno; Faller, Gerhard; Agaimy, Abbas; Haller, Florian; Moskalev, Evgeny A

    2017-05-01

    This study ascertained the regulation of the stem cell marker CD133 and its potential applicability for prognostication of gastrointestinal stromal tumors (GISTs). A total of 95 resected GISTs were included in the study. CD133 protein expression was assessed immunohistochemically on tissue microarrays. Methylation percentage was quantified by pyrosequencing. Gene expression in cell lines GIST48b and GIST882 upon treatment with DNA demethylation agent 5-aza-2'-deoxycytidine was analyzed by quantitative polymerase chain reaction. The expression of hypermethylated CD133 could be reactivated in the GIST cell line upon hypomethylation with the drug. Similarly, in patient material, CD133 methylation percentage correlated inversely with the protein expression and reflected tumor size with hypermethylation in small (10 cm) GISTs. The gene's methylation percentage and expression level were clearly specific to anatomic sites and distinct driver mutations. KIT -mutant gastric GISTs exhibited significantly lower methylation degrees and concomitant high CD133 protein abundance compared with KIT -mutant GISTs from the small intestine. CD133 hypermethylation was documented in PDGFRA -mutant gastric GISTs along with low CD133 expression compared with KIT -mutant gastric GISTs. High CD133 expression was a prognosticator of shorter disease-free survival in all patients. In a subgroup of KIT -mutant gastric GISTs, low CD133 methylation degree was correlated with a shorter disease-free survival. Our results strongly suggest epigenetic regulation of CD133 expression by promoter methylation in GISTs. Pending further validation studies, high abundance of the protein can serve as a marker for malignant GISTs.

  10. Ovarian Microcystic Stromal Tumor: A Rare Clinical Manifestation of Familial Adenomatous Polyposis.

    Science.gov (United States)

    Liu, Cheng; Gallagher, Renee L; Price, Gareth R; Bolton, Elizabeth; Joy, Christopher; Harraway, James; Venter, Deon J; Armes, Jane E

    2016-11-01

    Microcystic stromal tumor (MST) is a rare tumor of presumed sex-cord stromal differentiation. We present a case of MST arising within a patient with constitutional 5q deletion syndrome, whose deletion encompassed the APC gene. Genomic analysis of the MST revealed a point mutation in the remaining APC allele, predicted to result in abnormal splicing of Exon 7. Subsequent clinical investigation revealed multiple gastrointestinal polyps qualifying for a diagnosis of familial adenomatous polyposis. This case emphasizes the importance of an aberrant Wnt/β-catenin pathway in the development of MST and adds credence to the inclusion of MST as a rare phenotype of familial adenomatous polyposis. In a search for additional genetic aberrations which may contribute to the development of this rare tumor, genomic analysis revealed a frameshift mutation in FANCD2, a protein which plays a key role in DNA repair. This protein is expressed in human ovarian stromal cells and FANCD2-knockout mice are known to develop sex cord-stromal tumors, factors which further support a possible role of aberrant FANCD2 in the development of MST.

  11. Expression of osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor-related apoptosis-inducing ligand, stromal cell-derived factor-1 and their receptors in epithelial metastatic breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Labovsky Vivian

    2012-06-01

    Full Text Available Abstract Background While breast cancer (BC is the major cause of death among women worldwide, there is no guarantee of better patient survival because many of these patients develop primarily metastases, despite efforts to detect it in its early stages. Bone metastasis is a common complication that occurs in 65-80 % of patients with disseminated disease, but the molecular basis underlying dormancy, dissemination and establishment of metastasis is not understood. Our objective has been to evaluate simultaneously osteoprotegerin (OPG, receptor activator of nuclear factor kappa B ligand (RANKL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, stromal cell-derived factor-1 (SDF-1, and their receptors (R in 2 human BC cell lines, MDA-MB-231 and MCF-7. Methods OPG, RANKL, TRAIL and SDF-1 expression and release, in addition to the expression of their receptors has been investigated using immunofluorescence, immunocytochemistry and ELISA analyses. Results MCF-7 cells released higher levels of OPG in conditioned media (CM than MDA-MB-231 cells; 100 % of both types of cell expressed OPG, RANKL, TRAIL and SDF-1. Moreover, 100 % in both lines expressed membrane RANKL and RANK, whereas only 50 % expressed CXCR4. Furthermore, 100 % expressed TRAIL-R1 and R4, 30-50 % TRAIL-R2, and 40-55 % TRAIL-R3. Conclusions MCF-7 and MDA-MB-231 cells not only released OPG, but expressed RANKL, TRAIL and SDF-1. The majority of the cells also expressed RANK, CXCR4 and TRAIL-R. Since these ligands and their receptors are implicated in the regulation of proliferation, survival, migration and future bone metastasis during breast tumor progression, assessment of these molecules in tumor biopsies of BC patients could be useful in identifying patients with more aggressive tumors that are also at risk of bone metastasis, which may thus improve the available options for therapeutic intervention.

  12. Jejunojejunal Intussusception Induced by a Gastrointestinal Stromal Tumor

    OpenAIRE

    Zakaria, Ali H.; Salam Daradkeh

    2012-01-01

    Background. Adult intussusception is a rare entity representing less than 1% of all intestinal obstructions. Diagnosis of the condition is difficult requiring a high index of suspicion and the utilization of imaging studies, especially CT scans. Diagnostic laparoscopy and/or exploratory laparotomy can be used as a diagnostic and therapeutic intervention. In over 90% of cases, an underlying lead point is identified. In the patient described here, it was a gastrointestinal stromal tumor (GIST),...

  13. Bone marrow-derived cells and tumor growth : Contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells

    NARCIS (Netherlands)

    Roorda, Berber D.; ter Elst, Arja; Kamps, Willem A.; de Bont, Eveline S. J. M.

    Research has provided evidence that tumor growth depends on the interaction of tumor cells with stromal cells, as already suggested in 1889 by Paget. Experimental and clinical studies have revealed that tumor stromal cells can be derived from bone marrow (BM)-derived progenitor cells, such as

  14. Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

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    Yue Yu

    Full Text Available Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood.Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels.Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1 and interlukin-6 (IL-6 by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion.Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

  15. Elevated expression of stromal palladin predicts poor clinical outcome in renal cell carcinoma.

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    Vivekanand Gupta

    Full Text Available The role that stromal renal cell carcinoma (RCC plays in support of tumor progression is unclear. Here we sought to determine the predictive value on patient survival of several markers of stromal activation and the feasibility of a fibroblast-derived extracellular matrix (ECM based three-dimensional (3D culture stemming from clinical specimens to recapitulate stromal behavior in vitro. The clinical relevance of selected stromal markers was assessed using a well annotated tumor microarray where stromal-marker levels of expression were evaluated and compared to patient outcomes. Also, an in vitro 3D system derived from fibroblasts harvested from patient matched normal kidney, primary RCC and metastatic tumors was employed to evaluate levels and localizations of known stromal markers such as the actin binding proteins palladin, alpha-smooth muscle actin (α-SMA, fibronectin and its spliced form EDA. Results suggested that RCCs exhibiting high levels of stromal palladin correlate with a poor prognosis, as demonstrated by overall survival time. Conversely, cases of RCCs where stroma presents low levels of palladin expression indicate increased survival times and, hence, better outcomes. Fibroblast-derived 3D cultures, which facilitate the categorization of stromal RCCs into discrete progressive stromal stages, also show increased levels of expression and stress fiber localization of α-SMA and palladin, as well as topographical organization of fibronectin and its splice variant EDA. These observations are concordant with expression levels of these markers in vivo. The study proposes that palladin constitutes a useful marker of poor prognosis in non-metastatic RCCs, while in vitro 3D cultures accurately represent the specific patient's tumor-associated stromal compartment. Our observations support the belief that stromal palladin assessments have clinical relevance thus validating the use of these 3D cultures to study both progressive RCC

  16. Gastric Schwannoma: A Benign Tumor Often Misdiagnosed as Gastrointestinal Stromal Tumor.

    Science.gov (United States)

    Shah, Apurva S; Rathi, Pravin M; Somani, Vaibhav S; Mulani, Astha M

    2015-09-28

    Gastric schwannomas are rare mesenchymal tumors that arise from the nerve plexus of gut wall. They present with nonspecific symptoms and are often detected incidentally. Preoperative investigation is not pathognomic and many are therefore misdiagnosed as gastrointestinal stromal tumors. We report a rare case of a 37-year old woman who underwent laparotomy for complex bilateral ovarian cyst with resection of gastric-gastrointestinal stromal tumor preoperatively, but confirmed to have a gastric schwannomas postoperatively. This case underscores the differential diagnosis of submucosal, exophytic gastric mass as schwannoma.

  17. Gastric schwannoma: a benign tumor often misdiagnosed as gastrointestinal stromal tumor

    Directory of Open Access Journals (Sweden)

    Apurva S. Shah

    2015-10-01

    Full Text Available Gastric schwannomas are rare mesenchymal tumors that arise from the nerve plexus of gut wall. They present with nonspecific symptoms and are often detected incidentally. Preoperative investigation is not pathognomic and many are therefore misdiagnosed as gastrointestinal stromal tumors. We report a rare case of a 37-year old woman who underwent laparotomy for complex bilateral ovarian cyst with resection of gastric-gastrointestinal stromal tumor preoperatively, but confirmed to have a gastric schwannomas postoperatively. This case underscores the differential diagnosis of submucosal, exophytic gastric mass as schwannoma.

  18. Hubungan antara Imunoekspresi Ki-67 dan Risiko Agresivitas Tumor pada Gastrointestinal Stromal Tumor

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    Herry Yulianti

    2015-12-01

    Full Text Available Gastrointestinal stromal tumor (GIST is the most common mesenchymal tumor of the gastrointestinal tract, and arises from intestinal cells of Cajal localized in the muscular layer of the digestive tract, which functions as pacemaker cells in regulating intestinal motility. The incidence of GIST is about 3−5% of all soft tissue sarcomas. Gastrointestinal stromal tumor can occur along the gastrointestinal tract and predominantly in middle-aged and older persons, with a median age between 50 and 60 years. Histologically, there are three categories of GIST morphology such as spindle cells, epitheloid, and mixed type. A spesific marker of GIST is cluster of differentiation (CD117, which has good sensitivity and immunoreactive in 95% of GIST. The expression of Ki-67 correlates with proliferative activities and can be detected in G1, S, G2, and M phases of cell cycle but not in G0 phase. The aim of this study was to assessthe correlation between the risk of aggressive behaviors and proliferative activities as measured by Ki-67 in tumors confirmed as GIST by CD117. The method of this study was cross-sectional, performed on 29 cases of GIST from the Department of Pathology Anatomy Dr. Hasan Sadikin General Hospital/Faculty of Medicine Universitas Padjadjaran, Santo Borromeus Hospital, Immanuel Hospital, and Santosa Hospital between 2007−2012. A section from paraffin embedded tissue of 55 cases of GIST was stained with hematoxylin eosin for histological and immunohistochemical evaluations using monoclonal antibody CD117 to confirm the diagnosis of GIST. There were 29 positive cases for CD117. Further staining was performed using monoclonal antibody Ki-67. The categorized positive cells of immunoexpression of CD117 showed brown particles inside cytoplasma and the immunoexpression of Ki-67 was assessed by identification of nuclear brown staining of neoplastic cells. The result showed that there were significant correlations between the risk of tumor

  19. Epithelial-stromal interaction 1 (EPSTI1) substitutes for peritumoral fibroblasts in the tumor microenvironment

    DEFF Research Database (Denmark)

    De Neergaard, Michala; Kim, Jiyoung; Villadsen, René

    2010-01-01

    Tumor cells can activate stroma, yet the implication of this activation in terms of reciprocal induction of gene expression in tumor cells is poorly understood. Epithelial Stromal Interaction 1 (EPSTI1) is an interferon response gene originally isolated from heterotypic recombinant cultures...... of human breast cancer cells and activated breast myofibroblasts. Here we describe the first immunolocalization of EPSTI1 in normal and cancerous breast tissue, and we provide evidence for a role of this molecule in the regulation of tumor cell properties and epithelial-mesenchymal transition. In general...... cell line and silenced endogenous EPSTI1 by RNA interference in another. Irrespective of the experimental approach, EPSTI1 expression led to an increase in tumorsphere formation-a property associated with breast stem/progenitor cells. Most remarkably, we show that EPSTI1, by conveying spread of tumor...

  20. Interpretation of Pathologic Margin after Endoscopic Resection of Gastrointestinal Stromal Tumor

    Science.gov (United States)

    Kim, Sang Gyun

    2016-01-01

    Interpretation of the pathologic margin of a specimen from a resected tumor is important because local recurrence can be predicted by the presence of tumor cells in the resection margin. Although a sufficient resection margin is recommended in the resection of gastrointestinal adenocarcinoma, it is not usually regarded strictly in cases of mesenchymal tumor, especially gastrointestinal stromal tumor (GIST), because the tumor is usually encapsulated or well demarcated, and not infiltrative. Therefore, margin positivity is not rare in the pathological evaluation of surgically or endoscopically resected GIST, and does not always indicate incomplete resection. Although a GIST may have a tumor-positive pathologic margin, complete resection may be achieved if no residual tumor is visible, and long-term survival can be predicted as in the cases with a negative pathologic margin. PMID:27055454

  1. Cell adhesion and apoptosis in ovarian stromal hyperplasia and hyperthecosis.

    Science.gov (United States)

    Sharabidze, N; Burkadze, G; Sabakhtarashvili, M

    2006-02-01

    The aim of our study was to investigate cell adhesion and apoptosis in ovarian stromal hyperplasia and hyperthecosis in reproductive women with and without polycystic ovarian disease. We have studied 104 patients with a histological diagnosis of ovarian stromal hyperthecosis and stromal hyperplasia. Paraffin sections were stained by hematoxylin-eosin, von Gieson and immunohistochemistry for Bcl-2 (anti-apoptotic protein) and E-cadherin (cell adhesion marker). We assessed the number of Bcl-2-positive and E-cadherin-positive cells. The patients were divided into 4 groups: group 1-33 patients with polycystic ovarian disease and coexistent stromal hyperthecosis, group 2-28 patients with polycystic ovarian disease and coexistent stromal hyperplasia, group 3-24 patients with ovarian stromal hyperthecosis, group 4-19 patients with ovarian stromal hyperplasia. Our results suggest that in ovarian stromal hyperthecosis and stromal hyperplasia coexistent with polycystic ovarian disease, E-cadherin-positivity in internal and external theca cells, and granulosa cells is associated with Bcl-2 expression. Therefore, ovarian cells expressing Bcl-2 and maintaining E-cadherin-positivity may be the viable cells that escape the apoptotic process. In ovarian stromal hyperthecosis without polycystic ovarian disease, luteinized stromal cells are potentially resistant to apoptosis as they are positive for Bcl-2. In ovarian stromal hyperplasia without polycystic ovarian disease, hyperplastic stromal cells are potentially susceptible to apoptosis as they are negative for Bcl-2. E-cadherin is negative both in stromal hyperthecosis and hyperplasia suggesting that E-cadherin expression in ovary is limited to granulosa and theca cells only. Described characteristics of cell adhesion and apoptosis may play a role in pathogenesis of ovarian stromal hyperthecosis and stromal hyperplasia with and without polycystic ovarian disease.

  2. Targeting MUC1-Mediated Tumor-Stromal Metabolic Interactions in Triple-Negative Breast Cancer

    Science.gov (United States)

    2015-09-01

    overexpression of MUC1 increased glucose uptake, lactate secretion and enhanced the expression of glycolytic enzymes. Therefore we hypothesized...reactive tumor microenvironment. Stromal cells can serve as a sink for the end-products of aerobic glycolysis (i.e, lactate ) and provide a source of...exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid. Lactic acid is mainly transported by two H+/ lactate symporters

  3. Innate lymphoid cells and their stromal microenvironments.

    Science.gov (United States)

    Kellermayer, Zoltán; Vojkovics, Dóra; Balogh, Péter

    2017-09-01

    In addition to the interaction between antigen presenting cells, T and B lymphocytes, recent studies have revealed important roles for a diverse set of auxiliary cells that profoundly influence the induction and regulation of immune responses against pathogens. Of these the stromal cells composed of various non-hematopoietic constituents are crucial for the creation and maintenance of specialized semi-static three-dimensional lymphoid tissue microenvironment, whereas the more recently described innate lymphoid cells are generated by the diversification of committed lymphoid precursor cells independently from clonally rearranged antigen receptor genes. Recent findings have revealed important contributions by innate lymphoid cells in inflammation and protection against pathogens in a tissue-specific manner. Importantly, lymphoid stromal cells also influence the onset of immune responses in tissue-specific fashion, raising the possibility of tissue-specific stromal - innate lymphoid cell collaboration. In this review we summarize the main features and interactions between these two cells types, with particular emphasis on ILC type 3 cells and their microenvironmental partners. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  4. The Bone Marrow-Derived Stromal Cells

    DEFF Research Database (Denmark)

    Tencerova, Michaela; Kassem, Moustapha

    2016-01-01

    diseases. BM stromal cells (also known as skeletal or mesenchymal stem cells) [bone marrow stromal stem cell (BMSC)] are multipotent stem cells located within BM stroma and give rise to osteoblasts and adipocytes. However, cellular and molecular mechanisms of BMSC lineage commitment to adipocytic lineage......Bone marrow (BM) microenvironment represents an important compartment of bone that regulates bone homeostasis and the balance between bone formation and bone resorption depending on the physiological needs of the organism. Abnormalities of BM microenvironmental dynamics can lead to metabolic bone...... and regulation of BM adipocyte formation are not fully understood. In this review, we will discuss recent findings pertaining to identification and characterization of adipocyte progenitor cells in BM and the regulation of differentiation into mature adipocytes. We have also emphasized the clinical relevance...

  5. A large gastrointestinal stromal tumor of duodenum: a case report

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    Hadi Ahmadi Amoli

    2014-01-01

    Case presentation: The patient is a forty six years old man. He complained of frequent colic pain in left upper quadrant of abdomen for two months before admitting to the hospital. The pain resolved spontaneously after a few hours. This situation almost has been repeated every week. The patient had severe repeated melena and faint for two weeks. As soon as the patient was entered the Sina Hospital in 2012, supportive care was started. Then upper gastrointestinal endoscopy was performed for him and the bleeding point was detected. Also abdominal and pelvic computed tomography with oral and intravenous contrast was done. Finally the patient was operated on tumor diagnosis in duodenal area according to classic Whipple procedure. Conclusion: Gastrointestinal bleeding is the most common symptom of gastrointestinal stromal tumors. The bleeding is minimal and chronic. It will be progress to sudden and severe bleeding. Diagnosis is done by upper gastrointestinal endoscopy and biopsy. The large tumors with high mitotic

  6. An unusual case of primary prostatic extragastrointestinal stromal tumor

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    Chao-Feng Chang

    2016-01-01

    Full Text Available Extragastrointestinal stromal tumors (EGISTs originate from several anatomic sites, except the digestive system. We describe an early prostatic EGIST case with lower urinary tract symptoms and a palpable lesion on digital examination. The patient received transrectal ultrasonography-guided biopsy of the prostate, and the pathological finding demonstrated positive staining for DOG-1 and CD117. Treatment included only imatinib, which shrank the tumor and led to complete remission. Because of enlarged prostate volume with tumor progression, the initial common manifestations are lower urinary tract symptoms. Surgical resection is the recommended management, particularly in bulky lesions. However, imatinib still plays an important role in long-term therapy. We also review the associated reported cases of prostatic EGISTs.

  7. Mesenchymal stromal cells: misconceptions and evolving concepts.

    Science.gov (United States)

    Phinney, Donald G; Sensebé, Luc

    2013-02-01

    Nearly half a century has passed since the publication of the first articles describing plastic-adherent cells from bone marrow, referred to initially as colony-forming unit fibroblasts, then marrow stromal cells, mesenchymal stem cells and most recently multipotent mesenchymal stromal cells (MSCs). As expected, our understanding of the nature and biologic functions of MSCs has undergone major paradigm shifts over this time. Despite significant advances made in deciphering their complex biology and therapeutic potential in both experimental animal models and human clinical trials, numerous misconceptions regarding the nature and function of MSCs have persisted in the field. Continued propagation of these misconceptions in some cases may significantly impede the advancement of MSC-based therapies in clinical medicine. We have identified six prevalent misconceptions about MSCs that we believe affect the field, and we attempt to rectify them based on current available data. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  8. Endothelial cells are essential for ovarian stromal tissue restructuring after xenotransplantation of isolated ovarian stromal cells.

    Science.gov (United States)

    Dath, C; Dethy, A; Van Langendonckt, A; Van Eyck, A S; Amorim, C A; Luyckx, V; Donnez, J; Dolmans, M M

    2011-06-01

    Grafting of isolated follicles represents an approach to prevent the risk of reimplanting malignant cells with cryopreserved ovarian fragments. Optimal conditions and cell types required to sustain human follicular growth need to be identified. To help improve the grafting technique, we investigated whether short-term xenografting of a suspension containing ovarian stromal and endothelial cells without follicles could enhance graft survival and revascularization. In human ovary, CD34 selectively labels endothelial cells of blood vessels. A CD34-replete ovarian stromal cell group, including stromal and endothelial cells, was obtained after enzymatic digestion of fresh human ovarian cortex. Magnetic-activated cell sorting was used to establish a CD34-depleted ovarian stromal cell group. Proportions of CD34-positive cells were evaluated by flow cytometry and immunocytochemistry. Cell suspensions were embedded in human plasma clots and grafted (n = 10 for each group, 7 days) to the ovarian bursa of nude mice. Angiogenesis was quantified after human/mouse CD34 immunostaining. CD34-replete grafts had a well-organized and vascularized stromal structure, containing tubular components staining for human CD34 and corresponding to functional vessels, as evidenced by intraluminal red blood cells. CD34-depleted grafts tended to be smaller than CD34-replete grafts and poorly vascularized with central necrosis. Global microvessel density was higher in the CD34-replete than depleted group (337.9 versus 187.3 vessels/mm(2), P ovarian endothelial and stromal cells to ensure the formation of a well-vascularized and structured ovarian-like stroma after short-term xenografting, for future application in the transplantation of isolated follicles.

  9. Update on imatinib for gastrointestinal stromal tumors: duration of treatment

    Directory of Open Access Journals (Sweden)

    Linch M

    2013-07-01

    Full Text Available Mark Linch,1,2 Jeroen Claus,2 Charlotte Benson1 1Sarcoma Unit, Royal Marsden Hospital, 2Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, London, United Kingdom Abstract: Gastrointestinal stromal tumors (GISTs are the most common sarcoma of the gastrointestinal tract, with transformation typically driven by activating mutations of c-KIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA. Successful targeting of c-KIT and PDGFRA with imatinib, a tyrosine kinase inhibitor (TKI, has had a major impact in advanced GIST and as an adjuvant and neoadjuvant treatment. If treatment with imatinib fails, further lines of TKI therapy have a role, but disease response is usually only measured in months, so strategies to maximize the benefit from imatinib are paramount. Here, we provide an overview of the structure and signaling of c-KIT coupled with a review of the clinical trials of imatinib in GIST. In doing so, we make recommendations about the duration of imatinib therapy and suggest how best to utilize imatinib in order to improve patient outcomes in the future. Keywords: adjuvant, c-KIT, mutations, resistance, treatment, gastrointestinal stromal tumors, imatinib

  10. [Resection of a Huge Gastrointestinal Stromal Tumor of the Stomach Following Neoadjuvant Chemotherapy with Imatinib].

    Science.gov (United States)

    Sato, Yoshihiro; Karasawa, Hideaki; Aoki, Takeshi; Imoto, Hirofumi; Tanaka, Naoki; Watanabe, Kazuhiro; Abe, Tomoya; Nagao, Munenori; Ohnuma, Shinobu; Musha, Hiroaki; Takahashi, Masanobu; Motoi, Fuyuhiko; Naitoh, Takeshi; Ishioka, Chikashi; Unno, Michiaki

    2016-11-01

    We report a case of a huge gastric gastrointestinal stromal tumor(GIST)that was safely resected followingpreoperative imatinib therapy. A 72-year-old woman was hospitalized with severe abdominal distension. Computed tomography revealed a 27×17 cm tumor in the left upper abdominal cavity. The patient was diagnosed with high risk GIST by EUS-FNA. We initiated preoperative adjuvant chemotherapy with imatinib to achieve a reduction of operative risks and functional preservation. After 6 months of chemotherapy, CT showed a reduction in the tumor size and the patient underwent partial gastrectomy and partial resection of the diaphragm. Histologically, most of the tumor cells were replaced by hyalinized collagen and viable cells were scattered only around the blood vessels. Neoadjuvant chemotherapy with imatinib has the potential to become an important therapeutic option for the treatment of huge GISTs.

  11. Stromal PDGFR-α Activation Enhances Matrix Stiffness, Impedes Mammary Ductal Development, and Accelerates Tumor Growth.

    Science.gov (United States)

    Hammer, Anisha M; Sizemore, Gina M; Shukla, Vasudha C; Avendano, Alex; Sizemore, Steven T; Chang, Jonathan J; Kladney, Raleigh D; Cuitiño, Maria C; Thies, Katie A; Verfurth, Quinn; Chakravarti, Arnab; Yee, Lisa D; Leone, Gustavo; Song, Jonathan W; Ghadiali, Samir N; Ostrowski, Michael C

    2017-06-01

    The extracellular matrix (ECM) is critical for mammary ductal development and differentiation, but how mammary fibroblasts regulate ECM remodeling remains to be elucidated. Herein, we used a mouse genetic model to activate platelet derived growth factor receptor-alpha (PDGFRα) specifically in the stroma. Hyperactivation of PDGFRα in the mammary stroma severely hindered pubertal mammary ductal morphogenesis, but did not interrupt the lobuloalveolar differentiation program. Increased stromal PDGFRα signaling induced mammary fat pad fibrosis with a corresponding increase in interstitial hyaluronic acid (HA) and collagen deposition. Mammary fibroblasts with PDGFRα hyperactivation also decreased hydraulic permeability of a collagen substrate in an in vitro microfluidic device assay, which was mitigated by inhibition of either PDGFRα or HA. Fibrosis seen in this model significantly increased the overall stiffness of the mammary gland as measured by atomic force microscopy. Further, mammary tumor cells injected orthotopically in the fat pads of mice with stromal activation of PDGFRα grew larger tumors compared to controls. Taken together, our data establish that aberrant stromal PDGFRα signaling disrupts ECM homeostasis during mammary gland development, resulting in increased mammary stiffness and increased potential for tumor growth. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Stromal PDGFR-α Activation Enhances Matrix Stiffness, Impedes Mammary Ductal Development, and Accelerates Tumor Growth

    Directory of Open Access Journals (Sweden)

    Anisha M. Hammer

    2017-06-01

    Full Text Available The extracellular matrix (ECM is critical for mammary ductal development and differentiation, but how mammary fibroblasts regulate ECM remodeling remains to be elucidated. Herein, we used a mouse genetic model to activate platelet derived growth factor receptor-alpha (PDGFRα specifically in the stroma. Hyperactivation of PDGFRα in the mammary stroma severely hindered pubertal mammary ductal morphogenesis, but did not interrupt the lobuloalveolar differentiation program. Increased stromal PDGFRα signaling induced mammary fat pad fibrosis with a corresponding increase in interstitial hyaluronic acid (HA and collagen deposition. Mammary fibroblasts with PDGFRα hyperactivation also decreased hydraulic permeability of a collagen substrate in an in vitro microfluidic device assay, which was mitigated by inhibition of either PDGFRα or HA. Fibrosis seen in this model significantly increased the overall stiffness of the mammary gland as measured by atomic force microscopy. Further, mammary tumor cells injected orthotopically in the fat pads of mice with stromal activation of PDGFRα grew larger tumors compared to controls. Taken together, our data establish that aberrant stromal PDGFRα signaling disrupts ECM homeostasis during mammary gland development, resulting in increased mammary stiffness and increased potential for tumor growth.

  13. Giant gastric gastrointestinal stromal tumor with severe peritoneal dissemination controlled by imatinib therapy following debulking surgery: a case report.

    Science.gov (United States)

    Fukuda, Shuichi; Fujiwara, Yoshinori; Wakasa, Tomoko; Kitani, Kotaro; Tsujie, Masanori; Yukawa, Masao; Ohta, Yoshio; Inoue, Masatoshi

    2017-02-07

    At the time of diagnosis, giant gastric gastrointestinal stromal tumors are sometimes associated with severe peritoneal dissemination. Unresectable gastrointestinal stromal tumors are considered a systemic disease; therefore, imatinib therapy is currently the primary treatment option in these cases. A 49-year-old Japanese woman was referred to our hospital with symptoms of anorexia, abdominal discomfort, and a palpable abdominal mass. Contrast-enhanced computed tomography revealed a huge mass with an irregular wall, approximately 22 cm in size, located between the posterior gastric wall and her pancreas. The tumor grew rapidly, and her abdominal symptoms worsened; therefore, a semi-urgent laparotomy was performed. The tumor had arisen from her upper stomach and was removed by wedge resection of her stomach. In addition, widely distributed multiple white nodules were noted, which were resected as far as possible. Immunohistochemical staining of the resected specimen was positive for KIT and CD34. The resected white nodules contained the same cells as the primary tumor. Based on these pathological findings, a final diagnosis of a gastric gastrointestinal stromal tumor with peritoneal dissemination was made. Imatinib was administered at 400 mg per day from 1 month postoperatively. The disease progression of the residual disseminated lesions was favorably controlled, and our patient is now doing well, 12 months after surgery. Imatinib therapy following debulking surgery can show dramatic effectiveness in giant gastric gastrointestinal stromal tumors with severe peritoneal dissemination.

  14. An unusual infiltrative basal cell carcinoma with osteoclastic stromal changes mimicking carcinosarcoma: a case report.

    Science.gov (United States)

    Gamsizkan, Mehmet; Naujokas, Agne; Simsek, Hasan Aktug; McCalmont, Timothy H

    2015-01-01

    A 91-year-old man presented with an ulcerated nodule on his left lower eyelid. The tumor showed an epithelial component composed of basaloid and clear cells and a stroma that contained many osteoclastic giant cells. Strong, diffuse expression for cytokeratin 17 and p63 was noted in the epithelial component, whereas no staining was present in the sarcomatoid stroma, suggesting that the osteoclast-rich stromal component represented an unusual benign stromal reaction to the carcinoma rather than a manifestation of carcinosarcoma. Further supporting this interpretation was the absence of mitotic figures and low Ki-67 proliferation index (of approximately 1%) in the stromal cells. We herein reported a case of unusual infiltrative basal cell carcinoma, accompanied by a clear cell carcinomatous features and concurrent benign osteoclastic stromal changes.

  15. A Pleural Solitary Fibrous Tumor, Multiple Gastrointestinal Stromal Tumors, Moyamoya Disease, and Hyperparathyroidism in a Patient Associated with NF1

    Directory of Open Access Journals (Sweden)

    Yoko Yamamoto

    2015-01-01

    Full Text Available Neurofibromatosis type 1 (NF1, also called von Recklinghausen’s disease, is a multisystemic disease caused by an alteration of the NF1 gene, a tumor suppressor located on the long arm of chromosome 17 (17q11.2. Loss of the gene function, due to a point mutation, leads to an increase in cell proliferation and the development of several tumors. We report a 60-year-old female patient manifesting hypercalcemia due to hyperparathyroidism, a solitary fibrous tumor (SFT of the pleura, multiple gastrointestinal stromal tumors (GISTs, and moyamoya disease associated with NF1. The SFT and GISTs were removed by staged operations. Then, hypercalcemia was successfully controlled after resection of the parathyroid adenoma. Based on a literature review, these combinations have never been reported, and the relevant literature is briefly discussed.

  16. Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Seshadri Ramakrishnan

    2009-01-01

    Full Text Available Aim : To study the role of neoadjuvant imatinib mesylate in downsizing tumors in patients with locally advanced nonmetastatic gastrointestinal stromal tumors (GISTs, thus improving the possibility of complete resection. Materials and Methods : We used neoadjuvant imatinib in six patients with locally advanced GISTs, at a dose of 400 mg daily, given orally in all patients for a median period of 3.5 months (range 1-20 months. All patients had a computerized tomography scan (CT scan once before starting the treatment and a repeat CT scan 1 month after starting imatinib. Some patients had another CT scan done at 3 months. The tumor volume was calculated using the formula V=4/3 πr 3 . Results : Following imatinib therapy, the median reduction in the tumor volume was 40% (range 20-50%. Four of the six patients underwent successful complete resection of the tumor following neoadjuvant imatinib for a median period of 2 months, and are disease free after a median follow-up of 10.5 months (range 3-20 months. Two patients in whom the tumors were deemed to be operable after downsizing refused surgery and are continuing imatinib. Imatinib did not produce serious toxicity in any patient. Conclusion : Neoadjuvant imatinib can be used successfully in patients with locally advanced nonmetastatic GISTs to improve the rates of complete resection and reduce the chance of tumor spill. The optimal duration of neoadjuvant treatment needs to be tailored based on response assessment at frequent intervals to identify the ideal window period for surgery.

  17. Leydig cell tumor

    Science.gov (United States)

    Tumor - Leydig cell; Testicular tumor - Leydig; Testicular neoplasm ... The cause of this tumor is unknown. There are no known risk factors for this tumor. Unlike germ cell tumors of the testicles, this tumor ...

  18. Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial)

    DEFF Research Database (Denmark)

    Qayyum, Abbas Ali; Haack-Sørensen, Mandana; Mathiasen, Anders Bruun

    2012-01-01

    . In addition, we give an introduction to the first-in-man clinical trial, MyStromalCell Trial, which is a prospective, randomized, double-blind, placebo-controlled study using culture-expanded ADSCs obtained from adipose-derived cells from abdominal adipose tissue and stimulated with VEGF-A(165) the week...

  19. Diagnosis and management of gastrointestinal stromal tumors: An up-to-date literature review.

    Science.gov (United States)

    El-Menyar, Ayman; Mekkodathil, Ahammed; Al-Thani, Hassan

    2017-01-01

    Gastrointestinal stromal tumors (GISTs) are rare life-threatening forms of cancer that may arise anywhere in the GI tract. Herein, we aimed to review the literature to describe the incidence, management, and outcomes of GISTs. We conducted a traditional narrative review using PubMed and EMBASE, searching for English-language publications for GISTs between January 2001 and January 2016 using keywords "gastrointestinal" "stromal tumors." Among 4582 retrieved articles, 50 articles were relevant over the last 15 years. Several risk stratification systems exist to predict the outcomes of GISTs based on certain criteria such as the primary site of occurrence, size of the tumor, mitotic activity, staining for proliferating cells, and tumor necrosis. Risk stratification is crucial in the management and outcomes of the disease. Surgical resection remains the gold standard option of GISTs treatment. Complete resection of the tumor is the main predictor of the postoperative patient's survival. Laparoscopic resections are associated with less intraoperative blood loss, early return of bowel function, early resumption of diet, and short hospital stay. However, laparoscopy is difficult to perform in large and unfavorably placed GISTs and may result in disease progression, recurrence, and poor survival. Robot-assisted laparoscopic resections provide instruments for surgeons to perform technically demanding operations. Moreover, extensive research work including large clinical trials is ongoing to establish promising role of the adjuvant and neo-adjuvant therapy for better disease- free survival in GIST patients.

  20. Pathological analysis of collision (double primary) cancer in the upper digestive tract concomitant with gastric stromal tumor: a case report.

    Science.gov (United States)

    Sun, Xun; Zou, Yabin; Hao, Yueming; Cheng, Hongjing; Zhou, Changli; Meng, Xiangwei

    2015-01-01

    Carcinoma of the esophagus and cardiac cancer are common malignancies, while multiple primary cancers in the esophagus and cardia is rarely encountered and easily misdiagnosed. Multiple primary cancers mean the same organs (tissues) or different organs (tissues) have two or more than two primary malignant tumors at the same time or in sequence in the same individual. The case below of two independent primary lesions is double primary carcinoma which meets the diagnosis standard of multiple primary cancers. Gastrointestinal stromal tumor is the most common stromal tumor, which is usually considered as originating from Cajal cells in the gastrointestinal tract or mesenchymal stem cells with the mutation of KIT or PDGFRA gene. Study on stromal tumor with digestive tract cancer is less both at home and abroad, while double primary carcinoma with stromal tumor is rare, which has not been reported at present. Although scholars have different viewpoints on the prognosis, but the full understanding of this disease can be as a warning for the future work and to avoid misdiagnosis.

  1. Single cell sequencing reveals heterogeneity within ovarian cancer epithelium and cancer associated stromal cells.

    Science.gov (United States)

    Winterhoff, Boris J; Maile, Makayla; Mitra, Amit Kumar; Sebe, Attila; Bazzaro, Martina; Geller, Melissa A; Abrahante, Juan E; Klein, Molly; Hellweg, Raffaele; Mullany, Sally A; Beckman, Kenneth; Daniel, Jerry; Starr, Timothy K

    2017-03-01

    The purpose of this study was to determine the level of heterogeneity in high grade serous ovarian cancer (HGSOC) by analyzing RNA expression in single epithelial and cancer associated stromal cells. In addition, we explored the possibility of identifying subgroups based on pathway activation and pre-defined signatures from cancer stem cells and chemo-resistant cells. A fresh, HGSOC tumor specimen derived from ovary was enzymatically digested and depleted of immune infiltrating cells. RNA sequencing was performed on 92 single cells and 66 of these single cell datasets passed quality control checks. Sequences were analyzed using multiple bioinformatics tools, including clustering, principle components analysis, and geneset enrichment analysis to identify subgroups and activated pathways. Immunohistochemistry for ovarian cancer, stem cell and stromal markers was performed on adjacent tumor sections. Analysis of the gene expression patterns identified two major subsets of cells characterized by epithelial and stromal gene expression patterns. The epithelial group was characterized by proliferative genes including genes associated with oxidative phosphorylation and MYC activity, while the stromal group was characterized by increased expression of extracellular matrix (ECM) genes and genes associated with epithelial-to-mesenchymal transition (EMT). Neither group expressed a signature correlating with published chemo-resistant gene signatures, but many cells, predominantly in the stromal subgroup, expressed markers associated with cancer stem cells. Single cell sequencing provides a means of identifying subpopulations of cancer cells within a single patient. Single cell sequence analysis may prove to be critical for understanding the etiology, progression and drug resistance in ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. CD117 expression in fibroblasts-like stromal cells indicates unfavorable clinical outcomes in ovarian carcinoma patients.

    Science.gov (United States)

    Huang, Ruixia; Wu, Dan; Yuan, Yuan; Li, Xiaoran; Holm, Ruth; Trope, Claes G; Nesland, Jahn M; Suo, Zhenhe

    2014-01-01

    The stem cell factor (SCF) receptor CD117 (c-kit), is widely used for identification of hematopoietic stem cells and cancer stem cells. Moreover, CD117 expression in carcinoma cells indicates a poor prognosis in a variety of cancers. However the potential expression in tumor microenvironment and the biological and clinical impact are currently not reported. The expression of CD117 was immunohistochemically evaluated in a serial of 242 epithelial ovarian cancer (EOC) cases. Thirty-eight out of 242 cases were CD117 positive in fibroblast-like stromal cells and 22 cases were positive in EOC cells. Four cases were both positive in fibroblast-like stromal cells and EOC cells for CD117. CD117 expression in fibroblast-like stromal cells in ovarian carcinoma was closely linked to advanced FIGO stage, poor differentiation grade and histological subtype (povarian carcinoma cells was not associated with these clinicopathological variables. The CD117 positive fibroblast-like stromal cells were all positive for mesenchymal stem/stromal cell (MSC) marker CD73 but negative for fibroblast markers fibroblast activation protein (FAP) and α smooth muscle actin (α-SMA), indicating that the CD117+/CD73+ fibroblast-like stromal cells are a subtype of mesenchymal stem cells in tumor stroma, although further characterization of these cells are needed. It is concluded herewith that the presence of CD117+/CD73+ fibroblast-like stromal cells in ovarian carcinoma is an unfavorable clinical outcome indication.

  3. β-catenin (CTNNB1) S33C mutation in ovarian microcystic stromal tumors.

    Science.gov (United States)

    Maeda, Daichi; Shibahara, Junji; Sakuma, Takahiko; Isobe, Masanori; Teshima, Shinichi; Mori, Masaya; Oda, Katsutoshi; Nakagawa, Shunsuke; Taketani, Yuji; Ishikawa, Shumpei; Fukayama, Masashi

    2011-10-01

    Microcystic stromal tumor (MCST) is a recently described subtype of ovarian tumor characterized by prominent microcystic histologic pattern and diffuse immunoreactivity for CD10 and vimentin. However, its pathobiology, particularly its histogenesis, remains largely unclear. Here, we report 2 cases of ovarian MCST, in which we have performed extensive histologic, immunohistochemical, and genetic investigations to determine its distinct nature among ovarian neoplasms. The patients were 32 and 41 years of age. Both tumors were solid and cystic masses involving the right ovary. Microscopically, tumor cells with generally bland, round-to-ovoid nuclei grew in microcystic, macrocystic, and solid patterns. Intervening thick fibrous stroma was observed. Immunohistochemically, tumor cells were diffusely and strongly positive for CD10, vimentin, and Wilms tumor 1. Furthermore, we detected aberrant nuclear expression of β-catenin protein in both cases. Of interest, mutation analyses revealed the presence of an identical point mutation, c.98C>G, in exon 3 of β-catenin (CTNNB1) in both tumors. This is an oncogenic mutation that causes replacement of serine with cysteine at codon 33, leading to the loss of a phosphorylation site in the β-catenin protein. The results of this study strongly suggest that dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the pathogenesis of ovarian MCST. Finally, by comparing the immunophenotype of MCST with its histologic mimics and other ovarian sex cord-stromal tumors, we were able to identify unique features of MCST and a panel of markers useful in differential diagnosis.

  4. Evidences of early senescence in multiple myeloma bone marrow mesenchymal stromal cells.

    Directory of Open Access Journals (Sweden)

    Thibaud André

    Full Text Available BACKGROUND: In multiple myeloma, bone marrow mesenchymal stromal cells support myeloma cell growth. Previous studies have suggested that direct and indirect interactions between malignant cells and bone marrow mesenchymal stromal cells result in constitutive abnormalities in the bone marrow mesenchymal stromal cells. DESIGN AND METHODS: The aims of this study were to investigate the constitutive abnormalities in myeloma bone marrow mesenchymal stromal cells and to evaluate the impact of new treatments. RESULTS: We demonstrated that myeloma bone marrow mesenchymal stromal cells have an increased expression of senescence-associated β-galactosidase, increased cell size, reduced proliferation capacity and characteristic expression of senescence-associated secretory profile members. We also observed a reduction in osteoblastogenic capacity and immunomodulatory activity and an increase in hematopoietic support capacity. Finally, we determined that current treatments were able to partially reduce some abnormalities in secreted factors, proliferation and osteoblastogenesis. CONCLUSIONS: We showed that myeloma bone marrow mesenchymal stromal cells have an early senescent profile with profound alterations in their characteristics. This senescent state most likely participates in disease progression and relapse by altering the tumor microenvironment.

  5. Transition of mesenchymal stem/stromal cells to endothelial cells

    NARCIS (Netherlands)

    M. Crisan (Mihaela)

    2013-01-01

    textabstractMesenchymal stem/stromal cells (MSCs) are heterogeneous. A fraction of these cells constitute multipotent cells that can self-renew and mainly give rise to mesodermal lineage cells such as adipocytes, osteocytes and chondrocytes. The ability of MSCs to differentiate into endothelial

  6. Targeting MUC1 mediated tumor stromal metabolic interaction in Triple negative Breast Cancer

    Science.gov (United States)

    2016-11-01

    AWARD NUMBER: W81XWH-13-1-0315 TITLE: Targeting MUC1-mediated tumor -stromal metabolic interaction in Triple- negative breast cancer PRINCIPAL...2013- 14 Aug 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0315 Targeting MUC1-mediated tumor -stromal metabolic...recurrence within 1-3 years and a high mortality rate [3]. Therefore, identifying factors that facilitate tumor growth and metastases have the

  7. Targeting MUC1-Mediated Tumor-Stromal Metabolic Interaction in Triple-Negative Breast Cancer

    Science.gov (United States)

    2016-11-01

    AWARD NUMBER: W81XWH-13-1-0315 TITLE: Targeting MUC1-mediated tumor -stromal metabolic interaction in Triple- negative breast cancer PRINCIPAL...2013- 14 Aug 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0315 Targeting MUC1-mediated tumor -stromal metabolic...recurrence within 1-3 years and a high mortality rate [3]. Therefore, identifying factors that facilitate tumor growth and metastases have the

  8. Microencapsulation of Neuroblastoma Cells and Mesenchymal Stromal Cells in Collagen Microspheres: A 3D Model for Cancer Cell Niche Study

    OpenAIRE

    Pan Yeung; Hoi Shun Sin; Shing Chan; Godfrey Chi Fung Chan; Barbara Pui Chan

    2015-01-01

    There is a growing trend for researchers to use in vitro 3D models in cancer studies, as they can better recapitulate the complex in vivo situation. And the fact that the progression and development of tumor are closely associated to its stromal microenvironment has been increasingly recognized. The establishment of such tumor supportive niche is vital in understanding tumor progress and metastasis. The mesenchymal origin of many cells residing in the cancer niche provides the rationale to in...

  9. Cryopreservation and revival of mesenchymal stromal cells

    DEFF Research Database (Denmark)

    Haack-Sørensen, Mandana; Kastrup, Jens

    2011-01-01

    Over the past few years, the pace of preclinical stem cell research is astonishing and adult stem cells have become the subject of intense research. Due to the presence of promising supporting preclinical data, human clinical trials for stem cell regenerative treatment of various diseases have been...... initiated. As there has been a precedent for the use of bone marrow stem cells in the treatment of hematological malignancies and ischemic heart diseases through randomized clinical safety and efficacy trials, the development of new therapies based on culture-expanded human mesenchymal stromal cells (MSCs......) opens up new possibilities for cell therapy. To facilitate these applications, cryopreservation and long-term storage of MSCs becomes an absolute necessity. As a result, optimization of this cryopreservation protocol is absolutely critical. The major challenge during cellular cryopreservation...

  10. Frequent gene dosage alterations in stromal cells of epithelial ovarian carcinomas.

    Science.gov (United States)

    Tuhkanen, Hanna; Anttila, Maarit; Kosma, Veli-Matti; Heinonen, Seppo; Juhola, Matti; Helisalmi, Seppo; Kataja, Vesa; Mannermaa, Arto

    2006-09-15

    Stromal cells are an active and integral part of epithelial neoplasms. We have previously observed allelic imbalance on chromosome 3p21 in both stromal and epithelial cells of ovarian tumors. This study was designed to explore gene dosage alterations throughout human chromosomes from stromal and epithelial cells of epithelial ovarian carcinomas. Thirteen stromal and 24 epithelial samples, microdissected from epithelial ovarian carcinomas, were analyzed using multiplex ligation-dependent probe amplification technique. Analysis covered 110 cancer related genes. Frequent genetic alterations were detected both in the stroma and epithelium of ovarian carcinomas. The mean number of altered genes per tumor was 10.8 in stroma and 23.6 in epithelium. In the stroma, the mean number of gains was 6.6 and of losses 4.2 and in the epithelium 13.7 and 9.9. The high number of changes associated with advanced tumor stage (p = 0.035) and death due to ovarian cancer (p = 0.032). The most frequent alteration was the deletion of the deleted in colorectal carcinoma (DCC) on chromosome 18q21.3 in 62% of samples. Loss of DCC was related to endometrioid subtype (p = 0.033). Large chromosomal aberrations were detected on the basis of alterations in adjacent genes. Most importantly, 38 genes showed similar genetic alterations (gain-gain or loss-loss) in stromal and epithelial compartments of 11 tumor pairs. Thus, frequent genetic alterations in stromal cells of epithelial ovarian carcinomas resembled those of malignant epithelial cells and may indicate a common precursor cell type. Epithelial-mesenchymal transition may generate transformed cancer cells and modify the tumor microenvironment with distinct properties.

  11. MiR-125b inhibits stromal cell proliferation in giant cell tumor of bone by targeting parathyroid hormone 1 receptor

    Directory of Open Access Journals (Sweden)

    Pan-Feng Wu

    2015-07-01

    Conclusion:Our results suggest that miR-125b acts as a tumor suppressor through suppression of the PTH1R/RANKL signaling pathway. These findings contribute to our understanding of the functions of miR-125b in GCT.

  12. Enhanced immunoreactivity of TIMP-2 in the stromal compartment of tumor as a marker of favorable prognosis in ovarian cancer patients.

    Science.gov (United States)

    Hałoń, Agnieszka; Nowak-Markwitz, Ewa; Donizy, Piotr; Matkowski, Rafal; Maciejczyk, Adam; Gansukh, Tserenchunt; Györffy, Balázs; Spaczyński, Marek; Zabel, Maciej; Lage, Hermann; Surowiak, Pawel

    2012-07-01

    Degradation of the extracellular matrix and basement membrane is a critical step in tumor progression. Matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP 2) act in a coordinated manner to form an integrated system involved in ovarian cancer (OC) progression. In this study, the authors describe the expression of TIMP-2 detected by immunohistochemistry in 6 OC cell lines and in 43 malignant epithelial ovarian tumors (in tumor and stromal compartments) in sections originating from primary laparotomies. No significant correlations between overall and progression-free survival and TIMP-2 expression in tumor compartment were observed. The analysis demonstrated a significant association between enhanced stromal expression of TIMP-2 and better clinical response to cisplatin- and paclitaxel-based chemotherapy. Increased expression of TIMP-2 in the stromal compartment and simultaneous overexpression in both stromal and tumor compartments strongly correlated with increased survival. No significant correlations were found in vitro between resistance to cisplatin, paclitaxel, or topotecan and the expression of TIMP-2 in the OC cell lines, suggesting stromal influences on tumor chemoresistance in the physiological environment. This study supports the concept of TIMP-2 expression in the stromal compartment of OC as a promising marker of prognosis and response to cisplatin- and paclitaxel-based chemotherapy in OC patients.

  13. Selective Targeting of Interferon gamma to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth

    NARCIS (Netherlands)

    Bansal, Ruchi; Tomar, Tushar; Ostman, Arne; Poelstra, Klaas; Prakash, Jai

    2012-01-01

    New approaches to block the function of tumor stromal cells such as cancer-associated fibroblasts and pericytes is an emerging field in cancer therapeutics as these cells play a crucial role in promoting angiogenesis and tumor growth via paracrine signals. Because of immunomodulatory and other

  14. Endogenous versus tumor-specific host response to breast carcinoma: a study of stromal response in synchronous breast primaries and biopsy site changes.

    Science.gov (United States)

    Wu, Julie M; Beck, Andrew H; Pate, Lisa L; Witten, Daniela; Zhu, Shirley X; Montgomery, Kelli D; Allison, Kimberly H; van de Rijn, Matt; West, Robert B

    2011-02-01

    We recently described two types of stromal response in breast cancer derived from gene expression studies of tenosynovial giant cell tumors and fibromatosis. The purpose of this study is to elucidate the basis of this stromal response--whether they are elicited by individual tumors or whether they represent an endogenous host reaction produced by the patient. Stromal signatures from patients with synchronous dual primaries were analyzed by immunohistochemistry on a tissue microarray (n = 26 pairs) to evaluate the similarity of stromal responses in different tumors within the same patient. We also characterized the extent to which the stromal signatures were conserved between stromal response to injury compared to the stromal response to carcinoma using gene expression profiling and tissue microarray immunohistochemistry. The two stromal response signatures showed divergent associations in synchronous primaries: the DTF fibroblast response is more likely to be similar in a patient with multiple breast primaries (permutation analysis P = 0.0027), whereas CSF1 macrophage response shows no significant concordance in separate tumors within a given patient. The DTF fibroblast signature showed more concordance across normal, cancer, and biopsy site samples from within a patient, than across normal, cancer, and biopsy site samples from a random group of patients, whereas the CSF1 macrophage response did not. The results suggest that the DTF fibroblast response is host-specific, whereas the CSF1 response may be tumor-elicited. Our findings provide further insight into stromal response and may facilitate the development of therapeutic strategies to target particular stromal subtypes. ©2010 AACR.

  15. Mesenchymal stromal cell therapy in ischemic stroke

    Directory of Open Access Journals (Sweden)

    Zhang Y

    2016-11-01

    Full Text Available Ye Zhang, Hong Deng, Chao Pan, Yang Hu, Qian Wu, Na Liu, Zhouping Tang Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China Abstract: Stroke is a clinical disease with high incidence, high disability rate, and high mortality. But effective and safe therapy for stroke remains limited. Adult mesenchymal stromal cells (MSCs perform a variety of therapeutic functions. MSC delivery improves neurological outcomes in ischemic stroke models via neurorestorative and neuroprotective effects such as angiogenic effects, promoting endogenous proliferation, and reducing apoptosis and inflammation. MSC secretome also showed powerful therapeutic effects as a cell-based therapy in animal experiments. Several clinical trials on MSC implantation via different routes have now been completed in patients with stroke. Although challenges such as immunogenicity of allo-MSCs and large-scale production strategies need to be overcome, MSCs can be considered as a promising potential therapy for ischemic stroke. Keywords: mesenchymal stromal cell, stroke, therapy, transplantation, exosomes

  16. Mixed epithelial and stromal tumors of the kidney. A report of 22 cases.

    Science.gov (United States)

    Michal, Michal; Hes, Ondrej; Bisceglia, Michele; Simpson, Roderick H W; Spagnolo, Dominic V; Parma, Alberto; Boudova, Ludmila; Hora, Milan; Zachoval, Roman; Suster, Saul

    2004-10-01

    Mixed epithelial and stromal tumor of the kidney (MESTK) is a recently described subset of renal neoplasm that tends to occur in middle-aged and older women and is characterized by a distinctive histological appearance. To further characterize this lesion, we report the clinicopathological and immunohistochemical features of 22 additional cases from our institutional files. Grossly, the tumors ranged in size from 1 cm to 14 cm (mean 6.7 cm), were well circumscribed but unencapsulated, and showed a cystic cut surface. The tumors were composed of a spindle cell proliferation that resembled ovarian stroma, as well as an epithelial component lining the cystic structures, which usually consisted of flat to hobnailed cells typical of collecting-duct epithelium. Areas displaying features of Mullerian differentiation were also documented in 6 cases, including epithelium of endometrioid, tubal, clear cell and squamous cell type as well as one case showing an architecture that closely resembled Mullerian adenofibroma and adenosarcoma. Follow-up in 14 patients (average 4.4 years) showed no evidence of recurrence or metastasis. We believe these tumors represent the renal counterpart of similar mixed epithelial and stromal neoplasms occurring in the biliary tract and pancreas, which is also characterized by cystic structures lined by epithelium, admixed with ovarian-type stroma. The differential diagnosis for these tumors includes cystic nephroma and cystic partially differentiated nephroblastoma, which we believe to represent clinically and morphologically distinct entities from MESTK. In particular, the distinction from cystic nephroma in adult male patients is emphasized, and two cases of this entity are included in the study for comparison.

  17. Obscure Gastrointestinal Bleed from a Gastrointestinal Stromal Tumor in a Jejunal Diverticulum: A Rare Case Report

    Directory of Open Access Journals (Sweden)

    A. Sadaf

    2010-01-01

    Full Text Available We present a case of small bowel diverticulum with gastrointestinal stromal tumor (GIST. This GIST in the diverticulum was confirmed by immunohistochemistry and was of low-grade malignant potential.

  18. All-trans retinoic acid inhibits KIT activity and induces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein

    Directory of Open Access Journals (Sweden)

    Taguchi Takahiro

    2010-12-01

    Full Text Available Abstract Background Imatinib, a selective tyrosine kinase inhibitor, has been used as a standard first-line therapy for irresectable and metastasized gastrointestinal stromal tumor (GIST patients. Unfortunately, most patients responding to imatinib will eventually exhibit imatinib-resistance, the cause of which is not fully understood. The serious clinical problem of imatinib-resistance demands alternative therapeutic strategy. This study was conducted to investigate the effect of all-trans retinoic acid (ATRA on GIST cell lines. Methods Cell proliferation was determined by trypan blue dye exclusion test. Western blot analysis was performed to test the expression of activated KIT, its downstream proteins, and apoptosis associated proteins. The cytotoxic interactions of imatinib with ATRA were evaluated using the isobologram of Steel and Peckham. Results and conclusion In this work, for the first time we have demonstrated that ATRA affected on cell proliferation of GIST-T1 and GIST-882 cell line through inhibition of cell growth in a dose dependent manner and induced apoptosis. High dose of ATRA induced morphologic change in GIST-T1 cells, rounded-up cells, and activated the caspase-3 protein. In further examination, we found that the ATRA-induced apoptosis in GIST-T1 cells was accompanied by the down-regulated expression of survivin and up-regulated expression of Bax protein. Moreover, ATRA suppressed the activity of KIT protein in GIST-T1 cells and its downstream signal, AKT activity, but not MAPK activity. We also have demonstrated that combination of ATRA with imatinib showed additive effect by isobologram, suggesting that the combination of ATRA and imatinib may be a novel potential therapeutic option for GIST treatment. Furthermore, the scracht assay result suggested that ATRA was a potential reagent to prevent the invasion or metastasis of GIST cells.

  19. Bilateral sclerosing stromal tumor of the ovary in a premenarchal girl

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Yun-Woo; Hong, Seong Sook [Soonchunhyang University Hospital, Department of Radiology, Yongsan-ku, Seoul (Korea); Jeen, Yoon-Mi [Soonchunhyang University Hospital, Department of Pathology, Seoul (Korea); Kim, Mi Kyung [Soonchunhyang University Hospital, Department of Gynecology, Seoul (Korea); Suh, Eun Sook [Soonchunhyang University Hospital, Department of Pediatrics, Seoul (Korea)

    2009-07-15

    Sclerosing stromal tumor (SST) is a rare benign ovarian neoplasm classified as a type of sex cord stromal tumor that occurs predominantly in young patients. Several reports have described the US, CT and MR features of SST, but there have been no reports of a bilateral calcified SST in a child. We present a case of a bilateral SST of the ovary with calcification in a 12-year-old premenarchal girl and describe the US, CT, MR and pathological findings. (orig.)

  20. Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice

    National Research Council Canada - National Science Library

    Simpson-Abelson, Michelle R; Sonnenberg, Gregory F; Takita, Hiroshi; Yokota, Sandra J; Conway, Jr, Thomas F; Kelleher, Jr, Raymond J; Shultz, Leonard D; Barcos, Maurice; Bankert, Richard B

    2008-01-01

    ...(null) mice consistently result in successful xenografts in which tissue architecture, including tumor-associated leukocytes, stromal fibroblasts, and tumor cells are preserved for prolonged periods...

  1. Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Martin G. Belinsky

    2013-05-01

    Full Text Available Gastrointestinal stromal tumors (GISTs in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15% of GISTs in adults, along with ~ 85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor (IGF1R, and exhibit deficiency in the succinate dehydrogenase (SDH enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological and clinical connections that link this group of SDH-deficient neoplasms, and offer a view towards understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.

  2. Gastrointestinal stromal tumors: correlation between symptoms at presentation, tumor location and prognostic factors in 47 consecutive patients

    Directory of Open Access Journals (Sweden)

    Cavallini Marco

    2011-02-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GIST are mesenchymal tumors of the gastrointestinal tract, usually kit-positive, that are believed to originate from interstitial cell of Cajal, or their related stem cells. The most common clinical presentation of these tumors is gastrointestinal bleeding, otherwise they may cause intestinal obstruction, abdominal pain, a palpable mass, or can be incidentally detected during surgery or endoscopic/radiological procedures. Prognosis is related to the size of the tumor and to the mitotic rate; other prognostic factors are tumor location, tumor resection margins, tumor rupture, and c-kit mutation that may interfere with molecular target therapy efficacy. Aim Primary aim of this study was to report our experience regarding GIST patients, correlating symptoms at presentation with tumor localization and risk factors. Patients and methods 47 consecutive patients undergone to surgical resection for GISTs were enrolled in a prospective study from December 1999 to March 2009. Patient's clinical and pathological features were collected and analysed. Results The most common symptom was abdominal pain. Bleeding in the digestive tract and abdominal pain were more frequent in gastric GISTs (58% and 61%; acute abdominal symptoms were more frequent in jejunal and ileal GISTs (40% and 60%, p We observed an higher prevalence of symptomatic patients in the "high risk/malignant group" of both the Fletcher's and Miettines's classification (p Conclusion According with our findings symptoms correlate to tumor location, to class risk criteria as mitotic index and risk classifications, however we cannot conclude that symptoms are per se predictive of survival or patient's outcome.

  3. Mesenchymal stromal cells in myeloid malignancies.

    Science.gov (United States)

    Schroeder, Thomas; Geyh, Stefanie; Germing, Ulrich; Haas, Rainer

    2016-12-01

    Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal myeloid disorders characterized by hematopoietic insufficiency. As MDS and AML are considered to originate from genetic and molecular defects of hematopoietic stem and progenitor cells (HSPC), the main focus of research in this field has focused on the characterization of these cells. Recently, the contribution of BM microenvironment to the pathogenesis of myeloid malignancies, in particular MDS and AML has gained more interest. This is based on a better understanding of its physiological role in the regulation of hematopoiesis. Additionally, it was demonstrated as a 'proof of principle' that genetic disruption of cells of the mesenchymal or osteoblastic lineage can induce MDS, MPS or AML in mice. In this review, we summarize the current knowledge about the contribution of the BM microenvironment, in particular mesenchymal stromal cells (MSC) to the pathogenesis of AML and MDS. Furthermore, potential models integrating the BM microenvironment into the pathophysiology of these myeloid disorders are discussed. Finally, strategies to therapeutically exploit this knowledge and to interfere with the crosstalk between clonal hematopoietic cells and altered stem cell niches are introduced.

  4. SDHB immunohistochemistry: A useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors

    NARCIS (Netherlands)

    J. Gaal (José); C.A. Stratakis (Constantine); J.A. Carney (J. Aidan); E.R. Ball (Evan R.); E. Korpershoek (Esther); M.B. Lodish (Maya Beth); I. Levy (Isaac); P. Xekouki (Paraskevi); F.H. van Nederveen (Francien); M.A. den Bakker (Michael); M.J. O'Sullivan (Maureen); W.N.M. Dinjens (Winand); R.R. de Krijger (Ronald)

    2011-01-01

    textabstractMutations in the tumor suppressor genes SDHB, SDHC, and SDHD (or collectively SDHx) cause the inherited paraganglioma syndromes, characterized by pheochromocytomas and paragangliomas. However, other tumors have been associated with SDHx mutations, such as gastrointestinal stromal tumors

  5. Cystic nephroma/mixed epithelial stromal tumor: a benign neoplasm with potential for recurrence.

    Science.gov (United States)

    Sun, Belinda L; Abern, Michael; Garzon, Steven; Setty, Suman

    2015-05-01

    Cystic nephroma (CN) is a rare, benign, renal neoplasm composed of epithelial and stromal elements. Only about 200 cases have been reported since 1892 and recurrence has rarely been observed. We report a 32-year-old Hispanic woman, with a history of a right, complex cystic, renal mass treated by robotic decortication 2 years ago, who presented with flank pain, hematuria, and recurrent urinary tract infection. A magnetic resonance imaging study showed a 3.4-cm multicystic lesion with thickened septa and enhancement at the right kidney. The partial nephrectomy specimen revealed a well-circumscribed, multicystic tumor abutting the renal pelvis, with thick septa and smooth walls, filled with clear fluid. Microscopic examination showed variably sized cysts lined by cuboidal epithelium with focal hobnailing, without significant cytologic atypia and mitosis. The epithelial lining was positive for CK19, high molecular weight cytokeratin, and α-methylacyl-CoA racemase suggesting a primitive tubular epithelial phenotype. Primitive glomeruli-like structures were also present. The ovarian-like stroma was condensed around the cysts and was variably cellular with areas of muscle differentiation and thick-walled vessels. The stroma was positive for desmin, estrogen receptor, progesterone receptor, and CD10. We suggest that CN represents a variable mixture of epithelial and stromal elements, immature glomerular, tubular, muscle, and vascular elements, which may be present in variable proportions creating a spectrum of lesions previously described as CN and mixed epithelial and stromal tumors (MEST). This case emphasizes that CN/MEST clinically/radiologically mimics other cystic renal neoplasms, especially cystic renal cell carcinoma and tubulocystic carcinoma, necessitating histopathological examination and immunohistochemial studies for definitive diagnosis. Additionally, CN has the tendency to recur when not completely excised initially. © The Author(s) 2014.

  6. Gut Mesenchymal Stromal Cells in Immunity

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    Valeria Messina

    2017-01-01

    Full Text Available Mesenchymal stromal cells (MSCs, first found in bone marrow (BM, are the structural architects of all organs, participating in most biological functions. MSCs possess tissue-specific signatures that allow their discrimination according to their origin and location. Among their multiple functions, MSCs closely interact with immune cells, orchestrating their activity to maintain overall homeostasis. The phenotype of tissue MSCs residing in the bowel overlaps with myofibroblasts, lining the bottom walls of intestinal crypts (pericryptal or interspersed within intestinal submucosa (intercryptal. In Crohn’s disease, intestinal MSCs are tightly stacked in a chronic inflammatory milieu, which causes their enforced expression of Class II major histocompatibility complex (MHC. The absence of Class II MHC is a hallmark for immune-modulator and tolerogenic properties of normal MSCs and, vice versa, the expression of HLA-DR is peculiar to antigen presenting cells, that is, immune-activator cells. Interferon gamma (IFNγ is responsible for induction of Class II MHC expression on intestinal MSCs. The reversal of myofibroblasts/MSCs from an immune-modulator to an activator phenotype in Crohn’s disease results in the formation of a fibrotic tube subverting the intestinal structure. Epithelial metaplastic areas in this context can progress to dysplasia and cancer.

  7. Epigenetic Classification of Human Mesenchymal Stromal Cells

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    Danilo Candido de Almeida

    2016-02-01

    Full Text Available Standardization of mesenchymal stromal cells (MSCs is hampered by the lack of a precise definition for these cell preparations; for example, there are no molecular markers to discern MSCs and fibroblasts. In this study, we followed the hypothesis that specific DNA methylation (DNAm patterns can assist classification of MSCs. We utilized 190 DNAm profiles to address the impact of tissue of origin, donor age, replicative senescence, and serum supplements on the epigenetic makeup. Based on this, we elaborated a simple epigenetic signature based on two CpG sites to classify MSCs and fibroblasts, referred to as the Epi-MSC-Score. Another two-CpG signature can distinguish between MSCs from bone marrow and adipose tissue, referred to as the Epi-Tissue-Score. These assays were validated by site-specific pyrosequencing analysis in 34 primary cell preparations. Furthermore, even individual subclones of MSCs were correctly classified by our epigenetic signatures. In summary, we propose an alternative concept to use DNAm patterns for molecular definition of cell preparations, and our epigenetic scores facilitate robust and cost-effective quality control of MSC cultures.

  8. Ovarian normal and tumor-associated fibroblasts retain in vivo stromal characteristics in a 3-D matrix-dependent manner.

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    Quiros, Roderick M; Valianou, Matthildi; Kwon, Youngjoo; Brown, Kimberly M; Godwin, Andrew K; Cukierman, Edna

    2008-07-01

    Due to a lack of experimental systems, little is known about ovarian stroma. Here, we introduce an in vivo-like 3-D system of mesenchymal stromal progression during ovarian tumorigenesis to support the study of stroma permissiveness in human ovarian neoplasias. To sort 3-D cultures into 'normal,' 'primed' and 'activated' stromagenic stages, 29 fibroblastic cell lines from 5 ovarian tumor samples (tumor ovarian fibroblasts, TOFs) and 14 cell lines from normal prophylactic oophorectomy samples (normal ovarian fibroblasts, NOFs) were harvested and characterized for their morphological, biochemical and 3-D culture features. Under 2-D conditions, cells displayed three distinct morphologies: spread, spindle, and intermediate. We found that spread and spindle cells have similar levels of alpha-SMA, a desmoplastic marker, and consistent ratios of pFAKY(397)/totalFAK. In 3-D intermediate cultures, alpha-SMA levels were virtually undetectable while pFAKY(397)/totalFAK ratios were low. In addition, we used confocal microscopy to assess in vivo-like extracellular matrix topography, nuclei morphology and alpha-SMA features in the 3-D cultures. We found that all NOFs presented 'normal' characteristics, while TOFs presented both 'primed' and 'activated' features. Moreover, immunohistochemistry analyses confirmed that the 3-D matrix-dependent characteristics are reminiscent of those observed in in vivo stromal counterparts. We conclude that primary human ovarian fibroblasts maintain in vivo-like (staged) stromal characteristics in a 3-D matrix-dependent manner. Therefore, our stromal 3-D system offers a tool that can enhance the understanding of both stromal progression and stroma-induced ovarian tumorigenesis. In the future, this system could also be used to develop ovarian stroma-targeted therapies.

  9. Gastric Schwannoma Mimicking Malignant Gastrointestinal Stromal Tumor Exhibiting Increased Fluorodeoxyglucose Uptake

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    Sung Jin Oh; Byoung Jo Suh; Jong Kwon Park

    2016-01-01

    A schwannoma is a kind of neurogenic tumor that rarely occurs in the gastrointestinal tract. Gastric schwannomas make up 0.2% of all gastric neoplasms. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors and up to 60?70% of GIST occur in the stomach. Schwannoma and GIST are similar in clinical features, so they are difficult to differentiate preoperatively. Differential diagnosis of these two submucosal tumors is important because of the malignant potential of GIST a...

  10. Preoperative predictive factors for gastrointestinal stromal tumors: analysis of 375 surgically resected gastric subepithelial tumors.

    Science.gov (United States)

    Min, Yang Won; Park, Ha Na; Min, Byung-Hoon; Choi, Dongil; Kim, Kyoung-Mee; Kim, Sung

    2015-04-01

    Gastrointestinal stromal tumors (GISTs) and non-GIST subepithelial tumors (SETs) account for about 75 and 25% of gastric hypoechoic SETs ≥2 cm, respectively. Therefore, identifying preoperative predictive factors for GISTs are required to refine surgical indications. We performed a retrospective review of 375 surgically resected gastric hypoechoic SETs ≥2 cm. Demographic data and tumor characteristics based on upper endoscopy and CT findings were compared between GIST and non-GIST SETs originating from muscularis propria layer (leiomyomas, Schwannomas, glomus tumors, and ectopic pancreas). In cardia, leiomyomas were found twice more frequently than GISTs (63.6 versus 31.8%). Perilesional lymph node enlargement (PLNE) was found only in patients with GIST or Schwannomas. Patients with GIST showed a significantly lower rate of PLNE than those with Schwannomas (3.5 versus 29.0%). In multivariate analysis, tumor site outside cardia (odds ratio, 9.157), absence of PLNE (odds ratio, 11.519), old age, large tumor size, exophytic growth pattern, and ulceration or dimpling were identified as independent preoperative predictive factors for GISTs versus non-GIST SETs. The effort for preoperative pathologic diagnosis such as endosonography-guided tissue sampling might be positively considered for SETs at cardia and SETs with PLNE where the possibility of GIST is low.

  11. Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression.

    Science.gov (United States)

    Lopes-Coelho, Filipa; Gouveia-Fernandes, Sofia; Serpa, Jacinta

    2018-02-01

    The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.

  12. Management of a Gastrobronchial Fistula Connected to the Skin in a Giant Extragastric Stromal Tumor

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    Emilio Muñoz

    2015-01-01

    Full Text Available Introduction. Gastrointestinal stromal tumors first treatment should be surgical resection, but when metastases are diagnosed or the tumor is unresectable, imatinib must be the first option. This treatment could induce some serious complications difficult to resolve. Case Report. We present a 47-year-old black man with a giant unresectable gastric stromal tumor under imatinib therapy who presented serious complications such as massive gastrointestinal bleeding and a gastrobronchial fistula connected with the skin, successfully treated by surgery and gastroscopy. Discussion. Complications due to imatinib therapy can result in life threatening. They represent a challenge for surgeons and digestologists; creative strategies are needed in order to resolve them.

  13. Good survival outcome of metastatic SDH-deficient gastrointestinal stromal tumors harboring SDHA mutations.

    Science.gov (United States)

    Pantaleo, Maria A; Lolli, Cristian; Nannini, Margherita; Astolfi, Annalisa; Indio, Valentina; Saponara, Maristella; Urbini, Milena; La Rovere, Stefano; Gill, Antony; Goldstein, David; Ceccarelli, Claudio; Santini, Donatella; Rossi, Giulio; Fiorentino, Michelangelo; Di Scioscio, Valerio; Fusaroli, Pietro; Mandrioli, Anna; Gatto, Lidia; Catena, Fausto; Basso, Umberto; Ercolani, Giorgio; Pinna, Antonio Daniele; Biasco, Guido

    2015-05-01

    A subset of patients with KIT/PDGFRA wild-type gastrointestinal stromal tumors show loss of function of succinate dehydrogenase, mostly due to germ-line mutations of succinate dehydrogenase subunits, with a predominance of succinate dehydrogenase subunit A. The clinical outcome of these patients seems favorable, as reported in small series in which patients were individually described. This work evaluates a retrospective survival analysis of a series of patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors. Sixty-nine patients with metastatic gastrointestinal stromal tumors were included in the study (11 KIT/PDGFRA wild-type, of whom 6 were succinate dehydrogenase deficient, 5 were non-succinate dehydrogenase deficient, and 58 were KIT/PDGFRA mutant). All six succinate dehydrogenase-deficient patients harbored SDHA mutations. Kaplan-Meier curves and log-rank tests were used to compare the survival of patients with succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors with that of KIT/PDGFRA wild-type patients without succinate dehydrogenase deficiency and patients with KIT/PDGFRA-mutant gastrointestinal stromal tumors. Follow-up ranged from 8.5 to 200.7 months. The difference between succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors and KIT/PDGFRA-mutant or KIT/PDGFRA wild-type non-succinate dehydrogenase deficient gastrointestinal stromal tumors was significant considering different analyses (P = 0.007 and P = 0.033, respectively, from diagnosis of gastrointestinal stromal tumor for the whole study population; P = 0.005 and P = 0.018, respectively, from diagnosis of metastatic disease for the whole study population; P = 0.007 for only patients who were metastatic at diagnosis). Patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors harboring succinate dehydrogenase subunit A mutations present an impressively

  14. A Gastrointestinal Stromal Tumor of the Stomach Demonstrating a Stepwise Progression from Low- to High-Grade Malignancy

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    Takahiko Nakajima

    2012-01-01

    Full Text Available We report a case of a gastrointestinal stromal tumor (GIST of the stomach that demonstrated a stepwise progression from low- to high-grade malignancy. The patient had been followed for a small gastric submucosal tumor that had turned malignant after 8 years of indolence, manifested by tarry stools. The tumor was enucleated, and gastric GIST was diagnosed. The most significant histological finding was that the tumor comprised two clearly demarcated areas, one with less aggressive characteristics and the other with highly aggressive characteristics. The patient exhibited multiple liver metastases 24 months after surgery. Imatinib mesylate was not administered throughout the clinical course because it was not available for clinical use at that time. The patient followed an unfavorable clinical course and died of liver dysfunction 55 months after surgery. Autopsy was performed. By comparing the immunohistochemical profiles of primary and metastatic tumors, it was established that only the tumor cells with highly aggressive characteristics had metastasized.

  15. Transition of mesenchymal stem/stromal cells to endothelial cells.

    Science.gov (United States)

    Crisan, Mihaela

    2013-08-14

    Mesenchymal stem/stromal cells (MSCs) are heterogeneous. A fraction of these cells constitute multipotent cells that can self-renew and mainly give rise to mesodermal lineage cells such as adipocytes, osteocytes and chondrocytes. The ability of MSCs to differentiate into endothelial cells remains controversial. Isolation and in vitro manipulation of MSCs before clinical application are important steps. High numbers of MSCs are needed, requiring the in vitro expansion of these clinically important cells. To this end, a well-controlled procedure for MSC isolation and maintenance in culture is necessary.

  16. Targeting Stromal-Cancer Cell Crosstalk Networks in Ovarian Cancer Treatment

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    Tsz-Lun Yeung

    2016-01-01

    Full Text Available Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment.

  17. Targeting Stromal-Cancer Cell Crosstalk Networks in Ovarian Cancer Treatment.

    Science.gov (United States)

    Yeung, Tsz-Lun; Leung, Cecilia S; Li, Fuhai; Wong, Stephen S T; Mok, Samuel C

    2016-01-06

    Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment.

  18. Ovarian tumors with functioning stroma: a clinicopathologic study with special reference to serum estrogen level, stromal morphology, and aromatase expression.

    Science.gov (United States)

    Kato, Noriko; Hayasaka, Tadashi; Takeda, Junko; Osakabe, Mitsumasa; Kurachi, Hirohisa

    2013-11-01

    Ovarian tumors with functioning stroma often show estrogenic manifestations. The range of serum estrogen level, however, has not been analyzed, nor the correlation with the stromal morphology. We reviewed the preoperative serum level of estradiol (E2) in 20 postmenopausal ovarian tumors that contained lutein- or theca-like cells in the stroma. Tumor histology included mucinous (n=7), endometrioid (n=4), clear (n=4), or Brenner tumor (n=2), carcinosarcoma (n=2), and Krukenberg tumor (n=1). Overall, the preoperative serum level of E2 ranged widely from 12.1 to 162.4 pg/mL (reference range, 10-30 pg/mL). The range of serum E2 was 24.9 to 162.4 pg/mL (mean, 58.0 pg/mL) in 7 tumors containing lutein-like cells, and 12.1 to 157.8 pg/mL (mean, 57.0 pg/mL) in 13 tumors containing theca-like cells alone. There was no significant difference in the serum E2 level between the 2 groups. To determine whether the functioning stroma is capable of final conversion of androgens to estrogens, the expression of P450 aromatase was examined immunohistochemically. P450 aromatase was exclusively expressed in the stromal cells, both lutein- and theca-like cells, in 16 tumors. In all tumors, however, it was focally or sparsely distributed, and there was no correlation between the immunoreactivity for P450 aromatase and the serum E2 level. These findings indicate that the functioning stroma, regardless of cell morphology, has a capacity for converting androgens to estrogens, but a significant amount of serum estrogens is finally qualified in the aromatase-rich peripheral tissues.

  19. TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy.

    Science.gov (United States)

    Lai, De-Wei; Lin, Keng-Hung; Sheu, Wayne Huey-Herng; Lee, Maw-Rong; Chen, Chung-Yu; Lee, Wen-Jane; Hung, Yi-Wen; Shen, Chin-Chang; Chung, Tsung-Ju; Liu, Shing-Hwa; Sheu, Meei-Ling

    2017-09-01

    Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of Nε-(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Serum Nε-(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between Nε-(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). This study demonstrates that inhibiting the Nε-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema. © 2017 American

  20. Mesenchymal Stromal Cell Therapy in Crohn's Disease.

    Science.gov (United States)

    Forbes, Geoffrey M

    2017-01-01

    Mesenchymal stromal cells (MSC) are multipotent adult stem cells with immunomodulatory properties. They uniquely express HLA class I antigen at a low level, and do not express HLA class II. Hence, for allogeneic administration, donor to recipient matching is not required; yet a prolonged chimeric state does not occur. Contrary to haematopoietic stem cell transplantation, cytotoxic drug therapy is not required to harvest, or administer, cells. Key Messages: MSC are obtained from marrow, adipose tissue or placenta. In our centre, MSC are isolated from a 10 ml donor marrow aspirate, by virtue of their adherence to plastic. They are expanded in culture, cryopreserved, and subjected to strict quality controls before release for intravenous administration. These activities occur in a dedicated, nationally accredited, laboratory. Initial observations of allogeneic MSC efficacy were in graft-versus-host disease. Both autologous and allogeneic MSC have since been evaluated in biologic refractory luminal and fistulising Crohn's disease (CD). Data from early-phase studies have suggested efficacy for luminal disease when allogeneic MSC were given intravenously and also suggested efficacy for fistulising disease when either allogeneic or autologous MSC were administered into fistulas. MSC treatment is not reported to have caused serious adverse events. Although in vitro criteria for defining MSC exist, a major challenge lies in how to define MSC for clinical use. MSC function in vivo is likely to be dependent upon donor immunological characteristics, and widely varying manufacturing processes between laboratories. MSC dose, frequency of administration, stage of disease, and presence of concomitant immunosuppression also require to be defined. MSC therapy may have future utility in CD, but considerable work is first required to determine appropriate phenotypic and functional characteristics of administered cells. © 2017 S. Karger AG, Basel.

  1. Epidemiology, survival, and costs of localized gastrointestinal stromal tumors

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    Jaime L Rubin

    2011-02-01

    Full Text Available Jaime L Rubin1, Myrlene Sanon1, Douglas CA Taylor1, John Coombs2, Vamsi Bollu2, Leonardo Sirulnik21i3 Innovus, Medford, MA, USA; 2Novartis Pharmaceuticals, East Hanover, NJ, USAPurpose: The aim of this study is to examine the epidemiologic and economic burden in surgically resected localized gastrointestinal stromal tumor (GIST patients versus age- and gender-matched controls.Method: Two data sources were used to conduct a series of complementary analyses. First, the Surveillance, Epidemiology, and End Results (SEER cancer registry was used to identify diagnosed GIST patients from 1993 to 2002 and determine incidence, prevalence, and 3-year survival. Second, using the SEER–Medicare linked database, a matched case-control analysis was conducted to determine resource utilization, GIST recurrence, and costs. Because GIST recurrence is not explicitly defined in the database, patterns in resource use were used to identify probable recurrence. Kaplan–Meier Sample Average (KMSA Estimator technique was used to estimate costs of GIST and recurrence.Results: SEER registry results show over the 10-year time horizon average annual GIST incidence was 0.32 per 100,000 persons in the United States, 15-year limited-duration prevalence was 1.62 per 100,000 persons, and 3-year survival was 73%. A total of 292 GIST patients were included in the SEER–Medicare analyses; 35 were identified with probable recurrence. GIST patients had increased risk of mortality (hazard ratio: 1.23; 95% confidence intervals: 0.94–1.61 compared to controls. Median recurrence-free and postrecurrence survival was 45 and 46 months, respectively. GIST patients incurred significantly higher medical care costs in the first year after initial resection, with $23,221 attributable to GIST. GIST recurrence costs totaled $101,700 over 5 years after initial resection.Conclusions: GIST is associated with substantial medical care costs, estimated recurrence costs more than $100

  2. A Screen for Epigenetically Silenced microRNA Genes in Gastrointestinal Stromal Tumors.

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    Mai Isosaka

    Full Text Available Dysregulation of microRNA (miRNA has been implicated in gastrointestinal stromal tumors (GISTs but the mechanism is not fully understood. In this study, we aimed to explore the involvement of epigenetic alteration of miRNA genes in GISTs.GIST-T1 cells were treated with 5-aza-2'-deoxycytidine (5-aza-dC and 4-phenylbutyric acid (PBA, after which miRNA expression profiles were analyzed using TaqMan miRNA arrays. DNA methylation was then analyzed using bisulfite pyrosequencing. The functions of miRNAs were examined using MTT assays, wound-healing assays, Boyden chamber assays and Matrigel invasion assays. Gene expression microarrays were analyzed to assess effect of ectopic miRNA expression in GIST-T1 cells.Of the 754 miRNAs analyzed, 61 were significantly upregulated in GIST-T1 cells treated with 5-aza-dC plus PBA. Among those, 21 miRNA genes were associated with an upstream CpG island (CGI, and the CGIs of miR-34a and miR-335 were frequently methylated in GIST-T1 cells and primary GIST specimens. Transfection of miR-34a or miR-335 mimic molecules into GIST-T1 cells suppressed cell proliferation, and miR-34a also inhibited migration and invasion by GIST-T1 cells. Moreover, miR-34a downregulated a number of predicted target genes, including PDGFRA. RNA interference-mediated knockdown of PDGFRA in GIST-T1 cells suppressed cell proliferation, suggesting the tumor suppressive effect of miR-34a is mediated, at least in part, through targeting PDGFRA.Our results suggest that miR-34a and miR-335 are candidate tumor suppressive miRNAs in GISTs, and that they are frequent targets of epigenetic silencing in GISTs.

  3. The expression of MDM2 in gastrointestinal stromal tumors: immunohistochemical analysis of 35 cases.

    Science.gov (United States)

    Efared, Boubacar; Atsame-Ebang, Gabrielle; Tahiri, Layla; Sidibé, Ibrahim Sory; Erregad, Fatimazahra; Hammas, Nawal; Arifi, Samia; Mellouki, Ihsane; Ousadden, Abdelmalek; Mazaz, Khalid; El Fatemi, Hinde; Chbani, Laila

    2018-01-01

    Gastrointestinal stromal tumors (GIST) are the most common primary mesenchymal tumors of the digestive system. The assessment of their biological behavior still remains a scientific challenge. To date, there are no well-established biological prognostic markers of GIST. Our aim is to study the expression of the MDM2 oncoprotein in GIST through an immunohistochemical analysis. It was a retrospective study of 35 cases of GIST diagnosed from 2009 to 2012 in the department of pathology of Hassan II university hospital, Fès, Morocco. MDM2 immunohistochemical staining was performed on archival paraffin-embedded and formalin-fixed specimens (with a threshold of nuclear positivity > 10%). Analysis of correlations between MDM2 immunoexpression and clinicopathological features of GIST has been performed. The mean age was 55.23 years (range 25-84 years) with a male predominance (sex ratio = 1.5). The stomach was the main site of GIST, with 17 cases (48.57%) followed by the small bowel (9 cases, 25.71%). The spindle cell type GIST was the most frequent morphological variant (29 cases, 82.85%). Tumor necrosis was present in 8 cases (22.85%). Two patients (5.71%) had very low risk GIST, 5 (14.28%) had low risk GIST, 7 patients (20%) had intermediate risk tumors. The remaining 21 cases (60%) had high risk GIST. At the time of diagnosis, 9 patients (25.71%) had metastatic tumors. At immunohistochemical analysis, 40% of cases (14 patients) stained positive for MDM2. Of these MDMD2-positive tumors, 11/14 (78.57%) had high risk tumors and 8/14 cases (57.14%) presented with metastatic GIST. MDM2 positivity was significantly associated with the metastatic status ( p  = 0.001). The current study suggests that MDM2 immunohistochemical expression is a negative histoprognostic factor in GIST with a statistically significant correlation with metastasis.

  4. CD117 expression in fibroblasts-like stromal cells indicates unfavorable clinical outcomes in ovarian carcinoma patients.

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    Ruixia Huang

    Full Text Available The stem cell factor (SCF receptor CD117 (c-kit, is widely used for identification of hematopoietic stem cells and cancer stem cells. Moreover, CD117 expression in carcinoma cells indicates a poor prognosis in a variety of cancers. However the potential expression in tumor microenvironment and the biological and clinical impact are currently not reported. The expression of CD117 was immunohistochemically evaluated in a serial of 242 epithelial ovarian cancer (EOC cases. Thirty-eight out of 242 cases were CD117 positive in fibroblast-like stromal cells and 22 cases were positive in EOC cells. Four cases were both positive in fibroblast-like stromal cells and EOC cells for CD117. CD117 expression in fibroblast-like stromal cells in ovarian carcinoma was closely linked to advanced FIGO stage, poor differentiation grade and histological subtype (p<0.05, and it was significantly associated with poor overall survival (OS and progression free survival (PFS (Kaplan-Meier analysis; p<0.05, log-rank test. CD117 expression in ovarian carcinoma cells was not associated with these clinicopathological variables. The CD117 positive fibroblast-like stromal cells were all positive for mesenchymal stem/stromal cell (MSC marker CD73 but negative for fibroblast markers fibroblast activation protein (FAP and α smooth muscle actin (α-SMA, indicating that the CD117+/CD73+ fibroblast-like stromal cells are a subtype of mesenchymal stem cells in tumor stroma, although further characterization of these cells are needed. It is concluded herewith that the presence of CD117+/CD73+ fibroblast-like stromal cells in ovarian carcinoma is an unfavorable clinical outcome indication.

  5. Small submucosal tumors of the stomach: differentiation of gastric schwannoma from gastrointestinal stromal tumor with CT.

    Science.gov (United States)

    Choi, Jin Wook; Choi, Dongil; Kim, Kyoung-Mee; Sohn, Tae Sung; Lee, Jun Haeng; Kim, Hee Jung; Lee, Soon Jin

    2012-01-01

    To identify the CT features that help differentiate gastric schwannomas (GS) from small (5 cm or smaller) gastrointestinal stromal tumors (GIST) and to assess the growth rates of both tumors. We included 16 small GSs and 56 GISTs located in the stomach. We evaluated the CT features including size, contour, surface pattern, margins, growth pattern, pattern and degree of contrast enhancement, and the presence of intralesional low attenuation area, hemorrhage, calcification, surface dimpling, fistula, perilesional lymph nodes (LNs), invasion to other organs, metastasis, ascites, and peritoneal seeding. We also estimated the tumor volume doubling time. Compared with GISTs, GSs more frequently demonstrated a homogeneous enhancement pattern, exophytic or mixed growth pattern, and the presence of perilesional LNs (each p < 0.05). The intralesional low attenuation area was more common in GISTs than GSs (p < 0.05). Multivariate analyses indicated that a homogeneous enhancement pattern, exophytic or mixed growth pattern, and the presence of perilesional LNs were statistically significant (p < 0.05). Tumor volume doubling times for GSs (mean, 1685.4 days) were significantly longer than that of GISTs (mean, 377.6 days) (p = 0.004). Although small GSs and GISTs show similar imaging findings, GSs more frequently show an exophytic or mixed growth pattern, homogeneous enhancement pattern, perilesional LNs and grow slower than GISTs.

  6. Small Submucosal Tumors of the Stomach: Differentiation of Gastric Schwannoma from Gastrointestinal Stromal Tumor with CT

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    Choi, Jin Wook; Choi, Dong Gil; Kim, Kyoung Mee; Sohn, Tae Sung; Lee, Jun Haeng; Kim, Hee Jung; Lee, Soon Jin [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-07-15

    To identify the CT features that help differentiate gastric schwannomas (GS) from small (5 cm or smaller) gastrointestinal stromal tumors (GIST) and to assess the growth rates of both tumors. We included 16 small GSs and 56 GISTs located in the stomach. We evaluated the CT features including size, contour, surface pattern, margins, growth pattern, pattern and degree of contrast enhancement, and the presence of intralesional low attenuation area, hemorrhage, calcification, surface dimpling, fistula, perilesional lymph nodes (LNs), invasion to other organs, metastasis, ascites, and peritoneal seeding. We also estimated the tumor volume doubling time. Compared with GISTs, GSs more frequently demonstrated a homogeneous enhancement pattern, exophytic or mixed growth pattern, and the presence of perilesional LNs (each p < 0.05). The intralesional low attenuation area was more common in GISTs than GSs (p < 0.05). Multivariate analyses indicated that a homogeneous enhancement pattern, exophytic or mixed growth pattern, and the presence of perilesional LNs were statistically significant (p < 0.05). Tumor volume doubling times for GSs (mean, 1685.4 days) were significantly longer than that of GISTs (mean, 377.6 days) (p = 0.004). Although small GSs and GISTs show similar imaging findings, GSs more frequently show an exophytic or mixed growth pattern, homogeneous enhancement pattern, perilesional LNs and grow slower than GISTs.

  7. Gastrointestinal stromal tumors mimicking gynecological masses on ultrasound: a report of two cases.

    Science.gov (United States)

    Pinto, V; Ingravallo, G; Cicinelli, E; Pintucci, A; Sambati, G S; Marinaccio, M; D'Addario, V

    2007-09-01

    Gastrointestinal stromal tumors (GISTs) are among the most common mesenchymal tumors of the gastrointestinal tract. Diagnosis of GIST on ultrasound examination can be difficult because of their similarity in appearance to gynecological neoplasms. We present two cases of GIST originating from the small bowel and the stomach, which were preoperatively misdiagnosed as a uterine leiomyoma and an ovarian tumor, respectively. The ultrasonographic differential diagnosis of these pelvic masses is discussed. Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.

  8. Intranodal Schwannoma Mimicking a Gastrointestinal Stromal Tumor of the Stomach: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Nam, Kyung Bum; Namkyoung, Sook; Kim, Heung Cheol [Dept. of Radiology, Chuncheon Scared Heart Hospital, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Kim, Hae Sung; Ryu, Byoung Yoon [Dept. of General Surgery, Chuncheon Scared Heart Hospital, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Cha, Young Hee [Dept. of Pathology, Chuncheon Scared Heart Hospital, Hallym University College of Medicine, Chuncheon (Korea, Republic of)

    2011-10-15

    A 66-year-old-woman is presented with intranodal schwannoma of the retroperitoneum. Ultrasonography (US) and computed tomography (CT) results demonstrated a large encapsulated mass with internal cystic or necrotic portions in the gastrosplenic space. The tumor abutted the greater curvature of the gastric body and slightly indented the proximal small bowel loops on a small bowel series. The observations suggested a gastrointestinal stromal tumor. The mass was surgically proven to be a retroperitoneal tumor and histopathologically intranodal ancient schwannoma.

  9. Extra-Gastrointestinal Stromal Tumor of Retroperitoneal Origin: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Seung Joon; Kim, Hyung Sik; Park, Yul Ri; Choi, Hye Young [Dept. of Radiology, Gachon Medical Center, Gachon University of Medicine and Science, Incheon (Korea, Republic of)

    2012-03-15

    Extragastrointestinal stromal tumors (EGIST) are relatively rare, and cases originating in the retroperitoneum even rarer. We report a 60-year-old woman who presented with an EGIST originating in the retroperitoneum. Computed tomography results demonstrated a soft tissue mass on the right side of the retroperitoneum. The tumor abutted the duodenum, head of the pancreas, and right kidney. The mass was surgically proven to be a retroperitoneal tumor and histopathologically proven to be a retroperitoneal EGIST.

  10. Lymphatic vascular invasion in ovarian serous tumors of low malignant potential with stromal microinvasion: a case control study.

    Science.gov (United States)

    Sangoi, Ankur R; McKenney, Jesse K; Dadras, Soheil S; Longacre, Teri A

    2008-02-01

    Stromal microinvasion in ovarian serous tumors of low malignant potential (S-LMP) stratifies patients at long-term risk for disease progression independent of stage and primary ovarian histology. Despite the histologic impression and often-quoted incidence of lymphatic vascular invasion (LVI) in S-LMP with stromal microinvasion, there has been no formal evaluation in a case control series of S-LMP. The presence and extent of (LVI) was assessed in 20 S-LMP with stromal microinvasion and 20 S-LMP case controls without stromal microinvasion and compared with a series of low-grade and high-grade serous carcinomas using D2-40 monoclonal antibody recognizing podoplanin, a novel lymphatic endothelial marker. S-LMP case controls were matched for primary ovarian histology (usual vs. micropapillary), International Federation of Gynecology and Obstetrics (FIGO) stage, and age (best possible match). The patterns of stromal microinvasion included individual eosinophilic cells and cell clusters, cribriform, simple and noncomplex branching papillae, and inverted macropapillae. Immunohistologic staining with D2-40 monoclonal antibody clearly identified intratumoral LVI in 12/20 (60%) S-LMP with stromal microinvasion and 0/20 S-LMP without stromal microinvasion. Although only 4/13 (31%) low-grade serous carcinomas and 7/20 (35%) high-grade serous carcinomas had intratumoral LVI, hilar LVI was more common in the carcinomas (15% low-grade; 69% high-grade). Intratumoral LVI in S-LMP ranged from focal (6 cases) to multifocal (6 cases, maximum of 5 discrete foci) in any 1 section and included isolated single cells, simple papillae, and in 1 case, cribriform glands. Multifocal LVI was identified in 1 study patient who was pregnant. One of the 12 S-LMP patients with LVI had an intra-abdominal recurrence with high-grade disease at 16 months; whereas all other patients with follow-up were free of disease. LVI in ovarian S-LMP was significantly associated with the presence of stromal

  11. Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

    Science.gov (United States)

    Paggetti, Jerome; Haderk, Franziska; Seiffert, Martina; Janji, Bassam; Distler, Ute; Ammerlaan, Wim; Kim, Yeoun Jin; Adam, Julien; Lichter, Peter; Solary, Eric; Berchem, Guy

    2015-01-01

    Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected α-smooth actin–positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts. PMID:26100252

  12. Correlation of Dynamic PET and Gene Array Data in Patients with Gastrointestinal Stromal Tumors

    Directory of Open Access Journals (Sweden)

    Ludwig G. Strauss

    2012-01-01

    Full Text Available Introduction. The results obtained with dynamic PET (dPET were compared to gene expression data obtained in patients with gastrointestinal stromal tumors (GIST. The primary aim was to assess the association of the dPET results and gene expression data. Material and Methods. dPET was performed following the injection of F-18-fluorodeoxyglucose (FDG in 22 patients with GIST. All patients were examined prior to surgery for staging purpose. Compartment and noncompartment models were used for the quantitative evaluation of the dPET examinations. Gene array data were based on tumor specimen obtained by surgery after the PET examinations. Results. The data analysis revealed significant correlations for the dPET parameters and the expression of zinc finger genes (znf43, znf85, znf91, znf189. Furthermore, the transport of FDG (k1 was associated with VEGF-A. The cell cycle gene cyclin-dependent kinase inhibitor 1C was correlated with the maximum tracer uptake (SUVmax in the tumors. Conclusions. The data demonstrate a dependency of the tracer kinetics on genes associated with prognosis in GIST. Furthermore, angiogenesis and cell proliferation have an impact on the tracer uptake.

  13. A Case of a Gastrointestinal Stromal Tumor with Skeinoid Fibers of the Sigmoid Colon

    Directory of Open Access Journals (Sweden)

    Tetsuo Sumi

    2014-09-01

    Full Text Available An 80-year-old man was diagnosed with rectal cancer and underwent Hartmann's procedure. Although no tumors were identified during the preoperative examination, gross examination of the resected specimen incidentally revealed a submucosal tumor that was 9 mm in diameter at the oral side and located in the proximal stump of the specimen from the sigmoid colon. We suspected a concurrent gastrointestinal stromal tumor (GIST and performed a histopathological examination. An L-shaped nodular lesion measuring 9 × 6 mm was histologically composed of a patternless proliferation of spindle cells intermingled with eosinophilic globules. Cellular atypia, prominent mitotic figures and necrotic foci were not observed in the nodule. The spindle cells were positive for CD34, CD117 and vimentin, but negative for CD56, smooth muscle actin and S-100 protein. MIB-1 positivity was estimated to be as low as approximately 1-2%. Electron microscopy showed a bundle of wool-like fibers with a periodicity of approximately 40 nm. We therefore considered the lesion to be a low-risk GIST with skeinoid fibers in the large intestine. Although numerous previous reports have reported skeinoid fibers in the stomach and small intestines, there have been only 9 cases (including the present case of skeinoid fibers in the large intestine.

  14. A Rare Case of Mesenteric Gastrointestinal Stromal Tumor ...

    African Journals Online (AJOL)

    Gastrointestinal stromal tumours (GIST) are rare tumours arising from mesenchyme of gastrointestinal tract and overexpress C-kit protein. Mainly seen in stomach and small bowel. Mesenteric GIST are rarely reported as they constitute less than 1% of total GIST. We here report such a rare case of GIST arising from ...

  15. Malignant gastrointestinal stromal tumor presenting with hemoperitoneum in puerperium: report of a case with review of the literature

    Directory of Open Access Journals (Sweden)

    Vasilakaki Thivi

    2010-11-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GISTs are mesenchymal tumors that develop in the wall of the gastrointestinal tract and their diagnosis during pregnancy or puerperium is extremely rare. Case A 28-year old patient presented with acute abdomen due to hemoperitoneum from a large mass arising of the small intestine with distended vessels on its top and a ruptured superficial vessel bleeding into the peritoneal cavity. The patient was at the tenth postpartum day of her first pregnancy. The preoperative diagnosis was a possible ovarian or uterine mass. After an emergency exploratory laparotomy a segmental bowel resection was performed, removing the tumor with a part of 3-cm of the small intestine. Histology revealed GIST with maximum diameter of 13 cm and mitotic rates more than 5 mitoses per 50 high power fields with some atypical forms, indicating a high risk malignancy. Immunohistochemical staining of the tumor tissue demonstrated strongly positive reactivity to CD 117 (c-kit and CD34 in almost all the tumor cells. The patient was treated with oral imatinib mesylate (Gleevec 400 mg daily for one year. Three years after surgery, the patient was alive without evidence of metastases or local recurrence. Conclusion Considering that only few patients with gastrointestinal stromal tumors have been reported in the obstetrical and gynecological literature, the awareness of such an entity by the obstetricians-gynecologists is necessary in order to facilitate coordinated approach with the general surgeons and oncologists for the optimal care of the patients.

  16. Circulating Tumor Cells

    National Research Council Canada - National Science Library

    Vicki Plaks; Charlotte D. Koopman; Zena Werb

    2013-01-01

    .... During successful dissemination, tumor cells invade the surrounding tissue of the primary tumor, intravasate into blood and lymphatic vessels, translocate to distant tissues, extravasate, adapt...

  17. Feto-maternal outcomes of pregnancy complicated by ovarian sex-cord stromal tumor: a systematic review of literature.

    Science.gov (United States)

    Blake, Erin A; Carter, Charelle M; Kashani, Banafsheh N; Kodama, Michiko; Mabuchi, Seiji; Yoshino, Kiyoshi; Matsuo, Koji

    2014-04-01

    Sex-cord stromal tumors (SCSTs) are rare ovarian cancers and their behavior during pregnancy is not well understood. To evaluate the maternal and fetal outcomes of pregnancy complicated by ovarian SCST, a systematic literature search was conducted in PubMed/MEDLINE using entry key words "pregnancy" and each type of ovarian SCST ("sex cord stromal tumor," "granulosa cell tumor," "thecoma," "Sertoli-Leydig cell tumor," or "gynandroblastoma") between 1955 and 2012 that identified 46 cases eligible for the analysis. Clinical characteristics, pregnancy outcome, tumor characteristics, and survival outcomes were evaluated. Serious adverse events were defined as complications related to the SCST that resulted in severe morbidity or mortality for mother, fetus, or both. The most common histology was granulosa cell tumor (22.0%), followed by thecoma (18.6%) and Sertoli-Leydig cell tumor (8.5%). Abdomino-pelvic pain (45.7%), palpable mass (30.4%), and virilization (26.1%) were the three most common symptoms. The majority were stage I (76.1%), tumor size complication (13.0%). Logistic regression test identified younger age (pregnancy was comparable to ovarian SCST not related to pregnancy (5-year rate, stages I and II-IV, 100% and 70.0%, respectively). In conclusion, although the majority of cases resulted in live birth, ovarian SCST-complicated pregnancy falls into the category of high-risk pregnancy. Risk factors for SAE identified in our study will help to guide strategic management of pregnancy complicated by ovarian SCST. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Ovarian Tumors related to Intronic Mutations in DICER1: A Report from the International Ovarian and Testicular Stromal Tumor Registry

    Science.gov (United States)

    Schultz, Kris Ann; Harris, Anne; Messinger, Yoav; Sencer, Susan; Baldinger, Shari; Dehner, Louis P.; Hill, D. Ashley

    2015-01-01

    Germline DICER1 mutations have been described in individuals with pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumor (SLCT), sarcomas, multinodular goiter, thyroid carcinoma, cystic nephroma and other neoplastic conditions. Early results from the International Ovarian and Testicular Stromal Tumor Registry show germline DICER1 mutations in 48% of girls and women with SLCT. In this report, a young woman presented with ovarian undifferentiated sarcoma. Four years later, she presented with SLCT. She was successfully treated for both malignancies. Sequence results showed a germline intronic mutation in DICER1. This mutation results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction. Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein disrupting the RNase IIIb domain. A second individual with SLCT was found to have an identical germline mutation. In each of the ovarian tumors, an additional somatic mutation in the RNase IIIb domain of DICER1 was found. In rare patients, germline intronic mutations in DICER1 that are predicted to cause incorrect splicing can also contribute to the pathogenesis of SLCT. PMID:26289771

  19. Pleiotropic effects of cancer cells' secreted factors on human stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Al-toub, Mashael; Almusa, Abdulaziz; Almajed, Mohammed

    2013-01-01

    cells' secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB-231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological characteristics of MSCs. METHODS: Morphological changes were assessed using fluorescence microscopy......, but not from MCF7 and HT-29, developed an elongated, spindle-shaped morphology with bipolar processes. In association with phenotypic changes, genome-wide gene expression and bioinformatics analysis revealed an enhanced pro-inflammatory response of those MSCs. Pharmacological inhibitions of FAK and MAPKK......INTRODUCTION: Studying cancer tumors' microenvironment may reveal a novel role in driving cancer progression and metastasis. The biological interaction between stromal (mesenchymal) stem cells (MSCs) and cancer cells remains incompletely understood. Herein, we investigated the effects of tumor...

  20. Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4.

    Science.gov (United States)

    Martinez-Outschoorn, Ubaldo E; Curry, Joseph M; Ko, Ying-Hui; Lin, Zhao; Tuluc, Madalina; Cognetti, David; Birbe, Ruth C; Pribitkin, Edmund; Bombonati, Alessandro; Pestell, Richard G; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2013-08-15

    Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken

  1. Microcystic stromal tumor of the ovary: report of 16 cases of a hitherto uncharacterized distinctive ovarian neoplasm.

    Science.gov (United States)

    Irving, Julie A; Young, Robert H

    2009-03-01

    We have encountered 16 ovarian neoplasms of probable stromal origin whose most distinctive feature is microcystic change, which is usually conspicuous. On the basis of our extensive experience with ovarian tumors, the neoplasm is unique and warrants separate categorization; we have elected to designate it "microcystic stromal tumor" because of its most striking feature. The patients ranged from 26 to 63 (mean 45) years of age and typically presented with a pelvic mass. Hormonal manifestations were possibly present in only 2. All tumors were unilateral with a mean size of 8.7 (range: 2 to 27) cm and none had evidence of extraovarian spread. The tumors were solid-cystic (11 cases), solid (3 cases), or predominantly cystic (2 cases). The solid component was usually firm and tan or white-tan, but in 1 case was yellowish; soft foci were present in 3 cases and small foci of hemorrhage, necrosis, or both, in 3. On microscopic examination the appearance of the tumors varied according to the relative prominence of their 3 fundamental components: microcysts, solid cellular regions, and fibrous stroma. Microcysts dominated in 9 cases, were roughly equal to noncystic morphology in 5 cases and were minor in 2. The microcystic pattern was characterized by small rounded to oval cystic spaces, in areas coalescing to larger irregular channels; intracytoplasmic vacuoles were also frequently present. The solid cellular areas were usually focally intersected by fibrous bands and hyaline plaques reminiscent of thecoma. The cells contained moderately conspicuous finely granular, lightly eosinophilic cytoplasm, with generally bland, round to oval or spindle-shaped nuclei with fine chromatin and small indistinct nucleoli. Foci of bizarre nuclei were, however, present in 10 cases. Mitotic rate was low in all cases, ranging from 0 to 2 mitoses/10 high-power fields. Immunohistochemical results were as follows: CD10, 16/16 cases positive; vimentin, 16/16 cases positive; inhibin, 1/16 cases

  2. Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    C.E. Henry

    2017-06-01

    Full Text Available OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n = 178. Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions.

  3. Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer.

    Science.gov (United States)

    Henry, C E; Emmanuel, C; Lambie, N; Loo, C; Kan, B; Kennedy, C J; de Fazio, A; Hacker, N F; Ford, C E

    2017-06-01

    The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n=178). Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Effects of granulosa cells on steroidogenesis, proliferation and apoptosis of stromal cells and theca cells derived from the goat ovary.

    Science.gov (United States)

    Qiu, Mingning; Quan, Fusheng; Han, Chengquan; Wu, Bin; Liu, Jun; Yang, Zhongcai; Su, Feng; Zhang, Yong

    2013-11-01

    The aim of this study was to investigate the effect of granulosa cells from small antral follicles on steroidogenesis, proliferation and apoptosis of goat ovarian stromal and theca cells in vitro. Using Transwell co-culture system, we evaluated androgen production, LH responsiveness, cell proliferation and apoptosis and some molecular expression regarding steroidogenic enzyme and apoptosis-related genes in stromal and theca cells. The results indicated that the co-culture with granulosa cells increased steroidogenesis, LH responsiveness and bcl-2 gene expression as well as decreased apoptotic bax and bad expressions in stromal and theca cells. Thus, granulosa cells had a capacity of promoting steroidogenesis in stromal cell and LH responsiveness in cortical stromal cells, maintaining steroidogenesis in theca cells, inhibiting apoptosis of cortical stromal cells and improving anti-apoptotic abilities of stromal and theca cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Adult stromal cells derived from human adipose tissue provoke pancreatic cancer cell death both in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Beatrice Cousin

    Full Text Available BACKGROUND: Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. Disrupting this homeostasis can induce aberrant cell proliferation, adhesion, function and migration that might promote malignant behavior. Indeed, aberrant stromal-epithelial interactions contribute to pancreatic ductal adenocarcinoma (PDAC spread and metastasis, and this raises the possibility that novel stroma-targeted therapies represent additional approaches for combating this malignant disease. The aim of the present study was to determine the effect of human stromal cells derived from adipose tissue (ADSC on pancreatic tumor cell proliferation. PRINCIPAL FINDINGS: Co-culturing pancreatic tumor cells with ADSC and ADSC-conditioned medium sampled from different donors inhibited cancer cell viability and proliferation. ADSC-mediated inhibitory effect was further extended to other epithelial cancer-derived cell lines (liver, colon, prostate. ADSC conditioned medium induced cancer cell necrosis following G1-phase arrest, without evidence of apoptosis. In vivo, a single intra-tumoral injection of ADSC in a model of pancreatic adenocarcinoma induced a strong and long-lasting inhibition of tumor growth. CONCLUSION: These data indicate that ADSC strongly inhibit PDAC proliferation, both in vitro and in vivo and induce tumor cell death by altering cell cycle progression. Therefore, ADSC may constitute a potential cell-based therapeutic alternative for the treatment of PDAC for which no effective cure is available.

  6. An Intra-Abdominal Desmoid Tumor, Embedded in the Pancreas, Preoperatively Diagnosed as an Extragastric Growing Gastrointestinal Stromal Tumor

    Directory of Open Access Journals (Sweden)

    Mari Mizuno

    2017-04-01

    Full Text Available A 45-year-old woman was found to have a pancreatic tumor by abdominal ultrasound performed for a medical check-up. Abdominal contrast-enhanced computed tomography showed a hypovascular tumor measuring 30 mm in diameter in the pancreatic tail. Endoscopic ultrasound-guided fine needle aspiration was performed. An extragastric growing gastrointestinal stromal tumor was thereby diagnosed preoperatively, and surgical resection was planned. Laparoscopic surgery was attempted but conversion to open surgery was necessitated by extensive adhesions, and distal pancreatectomy, splenectomy, and partial gastrectomy were performed. The histological diagnosis was an intra-abdominal desmoid tumor. A desmoid tumor is a fibrous soft tissue tumor arising in the fascia and musculoaponeurotic tissues. It usually occurs in the extremities and abdominal wall, and only rarely in the abdominal cavity. We experienced a case with an intra-abdominal desmoid tumor that was histologically diagnosed after laparotomy, which had been preoperatively diagnosed as an extragastric growing gastrointestinal stromal tumor. Although rare, desmoid tumors should be considered in the differential diagnosis of intra-abdominal tumors. Herein, we report this case with a literature review.

  7. Expression of tyrosine kinase gene in mouse thymic stromal cells

    NARCIS (Netherlands)

    Rinke de Wit, T. F.; Izon, D. J.; Revilla, C.; Oosterwegel, M.; Bakker, A. Q.; van Ewijk, W.; Kruisbeek, A. M.

    1996-01-01

    Amongst the most important signal transduction molecules involved in regulating growth and differentiation are the protein tyrosine kinases (PTK). Since T cell development is a consequence of interactions between thymic stromal cells (TSC) and thymocytes, identification of the PTK in both

  8. Endogenous collagen influences differentiation of human multipotent mesenchymal stromal cells

    NARCIS (Netherlands)

    Fernandes, H.; Mentink, A.; Bank, R.; Stoop, R.; Blitterswijk, C. van; Boer, J. de

    2010-01-01

    Human multipotent mesenchymal stromal cells (hMSCs) are multipotent cells that, in the presence of appropriate stimuli, can differentiate into different lineages such as the osteogenic, chondrogenic, and adipogenic lineages. In the presence of ascorbic acid, MSCs secrete an extracellular matrix

  9. Endogenous Collagen Influences Differentiation of Human Multipotent Mesenchymal Stromal Cells

    NARCIS (Netherlands)

    Fernandes, H.A.M.; Mentink-Leusink, Anouk; Bank, Ruud; Stoop, Reinout; van Blitterswijk, Clemens; de Boer, Jan

    2010-01-01

    Human multipotent mesenchymal stromal cells (hMSCs) are multipotent cells that, in the presence of appropriate stimuli, can differentiate into different lineages such as the osteogenic, chondrogenic, and adipogenic lineages. In the presence of ascorbic acid, MSCs secrete an extracellular matrix

  10. Endogenous Collagen Influences Differentiation of Human Multipotent Mesenchymal Stromal Cells

    NARCIS (Netherlands)

    Fernandes, Hugo; Mentink, Anouk; Bank, Ruud; Stoop, Reinout; van Blitterswijk, Clemens; de Boer, Jan

    Human multipotent mesenchymal stromal cells (hMSCs) are multipotent cells that, in the presence of appropriate stimuli, can differentiate into different lineages such as the osteogenic, chondrogenic, and adipogenic lineages. In the presence of ascorbic acid, MSCs secrete an extracellular matrix

  11. IL-33 and Thymic Stromal Lymphopoietin in mast cell functions

    NARCIS (Netherlands)

    Saluja, Rohit; Zoltowska, Anna; Ketelaar, Maria Elizabeth; Nilsson, Gunnar

    2016-01-01

    Thymic Stromal Lymphopoietin (TSLP) and Interleukin 33 (IL-33) are two cytokines released by cells that are in proximity to our environment, e.g., keratinocytes of the skin and epithelial cells of the airways. Pathogens, allergens, chemicals and other agents induce the release of TSLP and IL-33,

  12. Bone marrow stromal cell : mediated neuroprotection for spinal cord repair

    NARCIS (Netherlands)

    Ritfeld, Gaby Jane

    2014-01-01

    Currently, there is no treatment available that restores anatomy and function after spinal cord injury. This thesis explores transplantation of bone marrow-derived mesenchymal stem cells (bone marrow stromal cells; BMSCs) as a therapeutic approach for spinal cord repair. BMSCs secrete neurotrophic

  13. Stromal cell-derived factor 1α (SDF-1α)

    DEFF Research Database (Denmark)

    Li, Dana; Bjørnager, Louise; Langkilde, Anne

    2016-01-01

    OBJECTIVES: Stromal cell-derived factor 1a (SDF-1α), is a chemokine and is able to home hematopoietic progenitor cells to injured areas of heart tissue for structural repair. Previous studies have found increased levels of SDF-1α in several cardiac diseases, but only few studies have investigated...

  14. Stromal-epithelial crosstalk provides a suitable microenvironment for the progression of ovarian cancer cells in vitro.

    Science.gov (United States)

    Fu, Shilong; Dong, Lihua; Sun, Wei; Xu, Yi; Gao, Li; Miao, Yi

    2013-11-01

    The tumor microenvironment plays an important role in the progression of cancer. This study focused on carcinoma-associated fibroblasts (CAFs) and stromal-epithelial interaction between CAFs and epithelial ovarian carcinoma (EOC) cells. We isolated and established primary cultures of CAFs and co-cultured CAFs and EOC cells in vitro. The co-culture conditioned medium (CC-CM) was harvested and its influence on EOC cells was examined. Cytokine, chemokine, and growth factor levels were screened using a biotin label-based human antibody array system. We found that the stromal-epithelial crosstalk provided a suitable microenvironment for the progression of ovarian cancer cells in vitro.

  15. Tumoral pseudoangiomatous stromal hyperplasia: Radiological and pathological correlation with review of literature

    Directory of Open Access Journals (Sweden)

    Noora Rafeek

    2017-03-01

    Full Text Available Tumoral pseudoangiomatous stromal hyperplasia (PASH is rare and presents more often as a clinically apparent, well-circumscribed, solid mass. It may clinically and radiologically mimic fibroadenoma or Phyllodes tumor. In this article, our objective was to describe the clinical presentations, ultrasound and histopathological appearances of tumoral PASH in three patients. Among the three PASH tumors, all except one were palpable breast masses; and the non-palpable mass was detected on ultrasound. All patients underwent core biopsy followed by wide local excision of the mass which were histopathologically proven to be PASH.

  16. [At last, an effective therapy for non-differentiated GI sarcomas (gastro intestinal stromal tumor)].

    Science.gov (United States)

    Des Guetz, G; De Mestier, Ph; Pierga, Jean-Yves

    2002-10-01

    Gastrointestinal stromal tumors (GISTs) are non differentiated sarcoma of the gastrointestinal tract and have for a long time been confused with well differentiated tumors and classified as leiomyosarcoma. These tumors are characterized immunohistochemically by CD 117 staining. This marker represents the expression of c-kit which is a receptor for growth factor with enzymatic activity (tyrosine kinase). Recent studies have found that an inhibitor of specific tyrosine kinase is effective in the treatment of GIST with an estimated response rate of more than 60%. This new drug could significantly improve the prognosis of these aggressive chemoresistant tumors.

  17. Isolation and characterization of stromal progenitor cells from ascites of patients with epithelial ovarian adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Ho Chih-Ming

    2012-02-01

    Full Text Available Abstract Background At least one-third of epithelial ovarian cancers are associated with the development of ascites containing heterogeneous cell populations, including tumor cells, inflammatory cells, and stromal elements. The components of ascites and their effects on the tumor cell microenvironment remain poorly understood. This study aimed to isolate and characterize stromal progenitor cells from the ascites of patients with epithelial ovarian adenocarcinoma (EOA. Methods Seventeen ascitic fluid samples and 7 fresh tissue samples were collected from 16 patients with EOA. The ascites samples were then cultured in vitro in varying conditions. Flow cytometry and immunocytochemistry were used to isolate and characterize 2 cell populations with different morphologies (epithelial type and mesenchymal type deriving from the ascites samples. The in vitro cell culture model was established using conditional culture medium. Results The doubling times of the epithelial type and mesenchymal type cells were 36 h and 48 h, respectively, indicating faster growth of the epithelial type cells compared to the mesenchymal type cells. Cultured in vitro, these ascitic cells displayed the potential for self-renewal and long-term proliferation, and expressed the typical cancer stem/progenitor cell markers CD44high, CD24low, and AC133+. These cells also demonstrated high BMP-2, BMP4, TGF-β, Rex-1, and AC133 early gene expression, and expressed EGFR, integrin α2β1, CD146, and Flt-4, which are highly associated with tumorigenesis and metastasis. The epithelial type cells demonstrated higher cytokeratin 18 and E-cadherin expression than the mesenchymal type cells. The mesenchymal type cells, in contrast, demonstrated higher AC133, CD73, CD105, CD117, EGFR, integrin α2β1, and CD146 surface marker expression than the epithelial type cells. Conclusion The established culture system provides an in vitro model for the selection of drugs that target cancer

  18. Isolation and characterization of stromal progenitor cells from ascites of patients with epithelial ovarian adenocarcinoma.

    Science.gov (United States)

    Ho, Chih-Ming; Chang, Shwu-Fen; Hsiao, Chih-Chiang; Chien, Tsai-Yen; Shih, Daniel Tzu-Bi

    2012-02-14

    At least one-third of epithelial ovarian cancers are associated with the development of ascites containing heterogeneous cell populations, including tumor cells, inflammatory cells, and stromal elements. The components of ascites and their effects on the tumor cell microenvironment remain poorly understood. This study aimed to isolate and characterize stromal progenitor cells from the ascites of patients with epithelial ovarian adenocarcinoma (EOA). Seventeen ascitic fluid samples and 7 fresh tissue samples were collected from 16 patients with EOA. The ascites samples were then cultured in vitro in varying conditions. Flow cytometry and immunocytochemistry were used to isolate and characterize 2 cell populations with different morphologies (epithelial type and mesenchymal type) deriving from the ascites samples. The in vitro cell culture model was established using conditional culture medium. The doubling times of the epithelial type and mesenchymal type cells were 36 h and 48 h, respectively, indicating faster growth of the epithelial type cells compared to the mesenchymal type cells. Cultured in vitro, these ascitic cells displayed the potential for self-renewal and long-term proliferation, and expressed the typical cancer stem/progenitor cell markers CD44(high), CD24(low), and AC133(+). These cells also demonstrated high BMP-2, BMP4, TGF-β, Rex-1, and AC133 early gene expression, and expressed EGFR, integrin α2β1, CD146, and Flt-4, which are highly associated with tumorigenesis and metastasis. The epithelial type cells demonstrated higher cytokeratin 18 and E-cadherin expression than the mesenchymal type cells. The mesenchymal type cells, in contrast, demonstrated higher AC133, CD73, CD105, CD117, EGFR, integrin α2β1, and CD146 surface marker expression than the epithelial type cells. The established culture system provides an in vitro model for the selection of drugs that target cancer-associated stromal progenitor cells, and for the development of ovarian

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  11. A Duodenal SDH-Deficient Gastrointestinal Stromal Tumor in a Patient With a Germline SDHB Mutation.

    Science.gov (United States)

    Elston, Marianne S; Sehgal, Shekhar; Dray, Michael; Phillips, Elizabeth; Conaglen, John V; Clifton-Bligh, Roderick J; Gill, Anthony J

    2017-05-01

    Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract arising from the interstitial cells of Cajal. Succinate dehydrogenase (SDH)-deficient GISTs are a unique class of GIST defined by loss of immunohistochemical expression of SDHB, indicating dysfunction of the mitochondrial complex 2; lack of driver mutations in KIT and PDGFRA; and distinctive morphologic features and natural history. To date, all reported SDH-deficient GISTs have arisen in the stomach. We report an SDH-deficient GIST arising in the gastrointestinal tract outside the stomach. A 29-year-old man with a germline SDHB mutation (p.Arg90*) presented with acute upper gastrointestinal hemorrhage. Endoscopy identified a lesion in the second part of the duodenum, close to the distal common bile duct, consistent with a GIST. Endoscopic ultrasonography and magnetic resonance imaging did not demonstrate metastatic or nodal disease. Open transduodenal excision was performed to remove the tumor. Histologic evaluation confirmed the clinical diagnosis of a GIST, with positive staining for DOG1 and KIT. The mitotic count was low (1 per 50 high-power fields). Immunohistochemistry for SDHB was negative in the presence of an internal control. SDHA expression was retained. No somatic mutations were identified in KIT (exons 9, 11, 13, and 17) or PDGFRA (exons 12, 14, and 18). The germline SDHB mutation and loss of heterozygosity were confirmed on molecular testing of the tumor. We describe an SDH-deficient GIST occurring outside of the stomach. This case indicates that SDH-deficient GISTs may also arise in the small intestine.

  12. Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer.

    Science.gov (United States)

    Kuhnert, Frank; Chen, Guoying; Coetzee, Sandra; Thambi, Nithya; Hickey, Carlos; Shan, Jing; Kovalenko, Pavel; Noguera-Troise, Irene; Smith, Eric; Fairhurst, Jeanette; Andreev, Julian; Kirshner, Jessica R; Papadopoulos, Nicholas; Thurston, Gavin

    2015-10-01

    The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), a fully human IgG1 monoclonal antibody that binds human Dll4 with sub-nanomolar affinity and inhibits Notch signaling. Administering REGN421 to immunodeficient mice engineered to express human Dll4 inhibited the growth of several human tumor xenografts in association with the formation of nonfunctional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by the tumor endothelium, and Dll4 blockade by human-specific or mouse-specific Dll4 antibodies exerted potent antitumor activity, which relied entirely on targeting Dll4 expressed by tumor stromal cells but not by the tumor cells themselves. However, Dll4 blockade reduced Notch signaling in both blood vessels and tumor cells surrounding the blood vessels, suggesting that endothelial-expressed Dll4 might induce Notch signaling in adjacent ovarian tumor cells. The antitumor effects of targeting Dll4 were augmented significantly by simultaneous inhibition of VEGF signaling, whereas this combined blockade reversed normal organ vascular changes induced by Dll4 blockade alone. Overall, our findings deepen the rationale for antibody-based strategies to target Dll4 in ovarian cancers, especially in combination with VEGF blockade. ©2015 American Association for Cancer Research.

  13. Imatinib and gastrointestinal stromal tumor (GIST: a selective targeted therapy Imatinib y tumor del estroma gastrointestinal (GIST: un tratamiento selectivo frente a una diana molecular

    Directory of Open Access Journals (Sweden)

    A. Fernández

    2004-10-01

    Full Text Available Gastrointestinal stromal tumors are the most frequent mesenchymal tumors in the gastrointestinal tract. They originate from the interstitial cells of Cajal and are characterized by an anomalous receptor for a growth factor with tyrosine-kinase activity (c-kit. This anomaly causes a permanent activation of the receptor and uncontrolled cell growth. These tumors show a poor response to traditional chemotherapy drugs, and are thus associated with low survival in cases of advanced disease. Imatinib, a tyrosine kinase inhibitor, is an example of selective targeted oncologic therapy that induces improved survival in these patients. We discuss two cases of metastatic gastrointestinal stromal tumors with a good response to imatinib, and also review the pathophysiology and treatment-related outcome of this type of tumors. We include results from clinical phase-III studies.Los tumores del estroma gastrointestinal son los tumores mesenquimales más frecuentes del tracto digestivo y se originan de las células intersticiales de Cajal. Se caracterizan por presentar un receptor para el factor de crecimiento con actividad tirosin kinasa (c-kit anómalo que condiciona su activación permanente y un crecimiento celular incontrolado. Tienen una baja supervivencia en casos de enfermedad avanzada, con escasa respuesta a los agentes quimioterápicos tradicionales. El imatinib es un fármaco inhibidor de la tirosín kinasa y un ejemplo de terapia oncológica selectiva que condiciona un importante aumento en la supervivencia de estos pacientes. Se presentan 2 casos de enfermedad metastásica con buena respuesta a imatinib, así como una revisión sobre la fisiopatología y evolución en el tratamiento de este tipo de tumores, incluyendo resultados de estudios en fase III.

  14. A Spontaneously Ruptured Hepatic Metastasis From a Gastric Gastrointestinal Stromal Tumor That Presented as Hemoperitoneum

    Directory of Open Access Journals (Sweden)

    Jung-Hee Yoon

    2013-11-01

    Full Text Available Spontaneous hepatic hemorrhage is a rare condition that may be caused by an underlying hepatic tumor, most commonly hepatocellular carcinoma or hepatic adenoma. A spontaneous rupture of a hepatic metastasis from a gastric gastrointestinal stromal tumor is also extremely rare, and the majority of affected patients present with hypovolemic shock or an acute abdomen. In this article, we report the case of a 65-year-old man with a spontaneous rupture of a hepatic metastasis from a gastric gastrointestinal stromal tumor that presented as hypovolemic shock. Cross-sectional imaging studies (computed tomography or magnetic resonance imaging play a significant role in the diagnosis of this condition and guides its management.

  15. Stromal Cell Expression of Caveolin-1 Predicts Outcome in Breast Cancer

    Science.gov (United States)

    Sloan, Erica K.; Ciocca, Daniel R.; Pouliot, Normand; Natoli, Anthony; Restall, Christina; Henderson, Michael A.; Fanelli, Mariel A.; Cuello-Carrión, Fernando D.; Gago, Francisco E.; Anderson, Robin L.

    2009-01-01

    Caveolin-1 has been linked to tumor progression and clinical outcome in breast cancer, but a clear resolution of its role as a prognostic marker is lacking. We assessed caveolin-1 levels in normal breast tissue and two breast cancer cohorts for which outcome data were available. We found that caveolin-1 was not expressed in normal breast luminal epithelium but was present in the epithelial compartment of some tumors. We found no association between caveolin-1 expression in the epithelial compartment and clinical outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor, rather than within tumor cells, associated strongly with reduced metastasis and improved survival (P < 0.0001). The onset of mammary tumors driven by Her2/neu overexpression was accelerated in mice lacking caveolin-1, thereby supporting the observation that the presence of caveolin-1 in the tumor microenvironment modulates tumor development. These studies suggest that stromal caveolin-1 expression may be a potential therapeutic target and a valuable prognostic indicator of breast cancer progression. PMID:19411449

  16. Stroma Cells in Tumor Microenvironment and Breast Cancer

    Science.gov (United States)

    Mao, Yan; Keller, Evan T.; Garfield, David H.; Shen, Kunwei; Wang, Jianhua

    2015-01-01

    Cancer is a systemic disease, encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion and metastasis. In breast cancer, CAFs not only promote tumor progression, but also induce therapeutic resistances. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistances. This review summarizes the current understanding of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. The effects of other stromal components such as endothelial cells, macrophages and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to sort patients into a specific and confirmed subtype for personalized treatment. PMID:23114846

  17. A Rare Case of Mesenteric Gastrointestinal Stromal Tumor ...

    African Journals Online (AJOL)

    accounting for <1% of all gastrointestinal tumors.[2]. Most of the tumors are seen in the stomach and rarely ... A 32‑year‑old male presented to us with a history of gradual abdominal distension for 5 months and acute pain of 2 days duration. There was no history of any previous investigations or any hospital admissions.

  18. Human mesenchymal stromal cells : biological characterization and clinical application

    NARCIS (Netherlands)

    Bernardo, Maria Ester

    2010-01-01

    This thesis focuses on the characterization of the biological and functional properties of human mesenchymal stromal cells (MSCs), isolated from different tissue sources. The differentiation capacity of MSCs from fetal and adult tissues has been tested and compared. Umbilical cord blood (UCB) has

  19. Granular Cell Tumor

    African Journals Online (AJOL)

    ultrastructure and immunochemical staining. 4 strongly suggest Schwann cell derivation . hyperplasia at the edges of the tumor. Necrosis within the tumor was absent, no mitosis was. Granular cell tumors are seldom diagnosed identified in the section and the edges of the accurately clinically. The lesion in this case was.

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  8. Interleukin 7-engineered stromal cells: a new approach for hastening naive T cell recruitment.

    Science.gov (United States)

    Di Ianni, Mauro; Del Papa, Beatrice; De Ioanni, Maria; Terenzi, Adelmo; Sportoletti, Paolo; Moretti, Lorenzo; Falzetti, Franca; Gaozza, Eugenia; Zei, Tiziana; Spinozzi, Fabrizio; Bagnis, Claude; Mannoni, Patrice; Bonifacio, Elisabetta; Falini, Brunangelo; Martelli, Massimo F; Tabilio, Antonio

    2005-06-01

    In this study we determined whether human stromal cells could be engineered with a retroviral vector carrying the interleukin 7 (IL-7) gene and investigated the effects on T cells in vitro and in vivo in a murine model. Transduced mesenchymal cells strongly express CD90 (98.15%), CD105 (87.6%), and STRO-1 (86.7%). IL-7 production was 16.37 (+/-2 SD) pg/ml, which remained stable for 60 days. In vitro-immunoselected naive T cells maintained the CD45RA+ CD45RO- naive phenotype (4.2 times more than controls) after 7 days of culture with IL-7-engineered stromal cells. The apoptosis rate (4.7%) of the naive T cells cultured with transduced stromal cells overlapped with that of freshly isolated cells. Immunohistological analysis detected stromal cells in bone marrow, spleen, and thymus. Cotransplantation of IL-7-engineered stromal cells with CD34+ cells improved engraftment in terms of CD45+ cells and significantly increased the CD3+ cell count in peripheral blood, bone marrow, and spleen. These data demonstrate the following: (1) human stromal cells can be transduced, generating a normal layer; (2) transduced stromal cells in vitro maintain the naive T cell phenotype; and (3) IL-7-transduced stromal cells in vivo home to lymphoid organs and produce sufficient IL-7 in loco, supporting T cell development in a cotransplantation model. Because of their efficient cytokine production and homing, IL-7-engineered stromal cells might be an ideal vehicle to hasten immunological reconstitution in T cell-depleted hosts.

  9. Metaphyseal giant cell tumor

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, L.F.; Hemais, P.M.P.G.; Aymore, I.L.; Carmo, M.C.R. do; Cunha, M.E.P.R. da; Resende, C.M.C.

    Three cases of metaphyseal giant cell tumor are presented. A review of the literature is done, demostrating the lesion is rare and that there are few articles about it. Age incidence and characteristics of the tumor are discussed.

  10. A case-report of synchronous adenocarcinoma and gastrointestinal stromal tumor of the colon

    Directory of Open Access Journals (Sweden)

    A. O. Rasulov

    2015-01-01

    Full Text Available Synchronous colonic tumors of different morphology are rarely described in the literature and do not have a clear ethiological connection. This fact is the key to a more detailed study of the clinical and morphological and molecular genetic features of different gistotipov synchronous tumors. There is increasing publications and clinical observations of simultaneous coexistence of adenocarcinoma and gastrointestinal stromal tumor. A separate and very valuable space is given interaction surgeons oncologists and pathologists. Today, for the correct pathological diagnosis of synchronous tumors of different biological nature, it is obligatory to conduct immunohistochemical study. Data on the results of treatment of synchronous tumors must necessarily be recorded in the cancer registries. Based on that, the developed algorithms timely diagnosis and proper treatment strategy in the cohort of patients. We present a case report of a 56 year old patient with a rare synchronous epithelial and non-epithelial colon tumors

  11. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells.

    Science.gov (United States)

    Geyh, S; Oz, S; Cadeddu, R-P; Fröbel, J; Brückner, B; Kündgen, A; Fenk, R; Bruns, I; Zilkens, C; Hermsen, D; Gattermann, N; Kobbe, G; Germing, U; Lyko, F; Haas, R; Schroeder, T

    2013-09-01

    Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.

  12. The clinicopathologic observation, c-KIT gene mutation and clonal status of gastrointestinal stromal tumor in the sacrum

    Directory of Open Access Journals (Sweden)

    Gong Li

    2009-06-01

    Full Text Available Abstract Background It is very rare that gastrointestinal stromal tumor (GIST occurs in the sacrum. Only one case of GIST occuring in the sacral region, with intracranial metastasis, has been reported in the literature. Moreover, only few cases have been published in literature about its clonal origin. Case presentation In this report, we present a rare case of GIST occuring in the sacrum and describe its clinicopathologic features, c-KIT gene mutation and clonal status. Microscopically, the lesion was composed of spindle cells arranged in cords, knitted and whirlpool patterns. Trabecula of bone were found in the lesion. The cytoplasm of tumor cells were abundant, and the nuclei were fusiform. Mitotic figures were rare. Immunohistochemically, the tumor cells showed positive reactivity for CD117 and CD34. On mutation analysis, a c-KIT gene mutation was found in exon 11. The result of clonal analysis demonstrated that the GIST was monoclonal. Conclusion In summary, we showed that tumor material, phenotypically identical with GISTs was found in the sacrum. It is difficult to differentiate GISTs from other spindle cell tumors, hence the need for immunohistochemistry, the examination of c-KIT gene amplification and sequencing.

  13. The clinicopathologic observation, c-KIT gene mutation and clonal status of gastrointestinal stromal tumor in the sacrum.

    Science.gov (United States)

    Gong, Li; Li, Yan-Hong; Zhao, Hua-Dong; Zhao, Jian-Ye; Zhang, Wei

    2009-06-06

    It is very rare that gastrointestinal stromal tumor (GIST) occurs in the sacrum. Only one case of GIST occuring in the sacral region, with intracranial metastasis, has been reported in the literature. Moreover, only few cases have been published in literature about its clonal origin. In this report, we present a rare case of GIST occuring in the sacrum and describe its clinicopathologic features, c-KIT gene mutation and clonal status. Microscopically, the lesion was composed of spindle cells arranged in cords, knitted and whirlpool patterns. Trabecula of bone were found in the lesion. The cytoplasm of tumor cells were abundant, and the nuclei were fusiform. Mitotic figures were rare. Immunohistochemically, the tumor cells showed positive reactivity for CD117 and CD34. On mutation analysis, a c-KIT gene mutation was found in exon 11. The result of clonal analysis demonstrated that the GIST was monoclonal. In summary, we showed that tumor material, phenotypically identical with GISTs was found in the sacrum. It is difficult to differentiate GISTs from other spindle cell tumors, hence the need for immunohistochemistry, the examination of c-KIT gene amplification and sequencing.

  14. Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST).

    Science.gov (United States)

    Mahadevan, Daruka; Theiss, Noah; Morales, Carla; Stejskal, Amy E; Cooke, Laurence S; Zhu, Min; Kurtzman, Drew; Swart, Rachel; Ong, Evan; Qi, Wenqing

    2015-02-10

    c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance. RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting. Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 µM to IM respectively. GIST48 have an IC50 0.66 µM to IM, 0.91 µM to amuvatinib [AMU] and 0.67 µM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63). Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.

  15. Distribution of mast cells in benign odontogenic tumors.

    Science.gov (United States)

    de Assis Caldas Pereira, Francisco; Gurgel, Clarissa Araújo Silva; Ramos, Eduardo Antônio Gonçalves; Vidal, Manuela Torres Andion; Pinheiro, Antônio Luiz Barbosa; Jurisic, Vladimir; Sales, Caroline Brandi Schlaepfer; Cury, Patrícia Ramos; dos Santos, Jean Nunes

    2012-04-01

    The aim of this study was to investigate the presence of mast cells in a series of odontogenic tumors. Forty-five cases of odontogenic tumors were investigated using immunohistochemistry for mast cell triptase, and differences between groups were statistically evaluated. Mast cells were present in 96% of odontogenic tumors. Mast cells present in solid ameloblastoma were observed in the tumor stroma surrounding more solid and follicular epithelial islands, with or without squamous metaplasia. The odontogenic mixoma showed few mast cells. In odontogenic tumors with a cystic structure, the mast cells were distributed throughout all areas of the lesions, mainly in keratocystic odontogenic tumor. In addition, the total density of mast cells between all odontogenic tumors showed no significant difference (p > 0.05). A greater mast cells distribution was found in keratocystic odontogenic tumor in relation to adenomatoid odontogenic tumor (p odontogenic tumor were compared to the odontogenic myxoma (p odontogenic tumor showed a higher mean of mast cells when compared with the other tumors of the sample. Mast cells values presented by syndrome keratocystic odontogenic tumor were significantly greater than those of the sporadic keratocystic odontogenic tumor that were not associated with the syndrome (p = 0.03). Mast cells are probably one of the major components of the stromal scaffold in odontogenic tumors. We found significant differences of mast cells between syndrome nonsyndrome keratocystic odontogenic tumors, although their distribution did not seem to have any influence on the biologic behavior of benign odontogenic tumors.

  16. Delayed menopause due to granulosa cell tumor of the ovary

    Directory of Open Access Journals (Sweden)

    Bhushan Murkey

    2011-01-01

    Full Text Available A 52-year-old patient presented with complaints of menorrhagia. Endometrial biopsy revealed simple hyperplasia of the endometrium. Total abdominal hysterectomy with bilateral oophorectomy was carried out. The ovaries looked grossly normal, but histopathology reported granulosa cell tumor of the right ovary. Granulosa cell tumors belong to the sexcord stromal category and account for approximately 2% of all ovarian tumors. We review the features and treatment of granulosa cell tumors and the importance of screening for ovarian tumors in a case of endometrial hyperplasia and delayed menopause.

  17. Gastrointestinal stromal tumor complicated by Streptococcus milleri bacteremia and liver abscess.

    Science.gov (United States)

    Kwon, Yong; Dang, Ngoc-Duyen T; Elmunzer, Badih Joseph

    2009-07-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Often discovered incidentally, GISTs can present with nonspecific abdominal symptoms or more overt symptoms of bleeding, obstruction, or perforation. Despite a myriad of clinical presentations, bacteremia associated with a GIST has not been described. In this report, we present an unusual clinical case that illustrates how GISTs can become infected, and demonstrate the importance of Streptococcus milleri bacteremia as an indicator of possible underlying gastrointestinal neoplasm.

  18. Gastrointestinal stromal tumor of large size, extragastrointestinal localization and different morphological features

    Directory of Open Access Journals (Sweden)

    Shpon’ka I.S.

    2015-09-01

    Full Text Available The problems of accurate verification of the gastro¬intestinal stromal tumor are relevant today for many reasons. Thus, the histological diagnosis is complicated by the morphological similarity of other gastrointestinal tract mesenchymal neoplasms and by histologicaly different zones within the same investigation. We present the situation with the above issues: the differential diagnosis includes an analysis of morphological criteria and received immunohisto-chemical reactions. Between immunophenotypes of histologicaly different zones principal difference is not revealed.

  19. The Impact of Epithelial-Stromal Interactions on Human Breast Tumor Heterogeneity

    Science.gov (United States)

    2015-10-01

    AWARD NUMBER: W81XWH-13-1-0357 TITLE: The Impact of Epithelial-Stromal Interactions on Human Breast Tumor Heterogeneity PRINCIPAL... Heterogeneity 5b. GRANT NUMBER W81XWH-13-1-0357 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dr. Crista Thompson 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail... Heterogeneity is a key factor underlying the variability in patient response to treatment, especially in Triple-Negative (TN) breast cancer cases. In

  20. Microencapsulation of Neuroblastoma Cells and Mesenchymal Stromal Cells in Collagen Microspheres: A 3D Model for Cancer Cell Niche Study.

    Directory of Open Access Journals (Sweden)

    Pan Yeung

    Full Text Available There is a growing trend for researchers to use in vitro 3D models in cancer studies, as they can better recapitulate the complex in vivo situation. And the fact that the progression and development of tumor are closely associated to its stromal microenvironment has been increasingly recognized. The establishment of such tumor supportive niche is vital in understanding tumor progress and metastasis. The mesenchymal origin of many cells residing in the cancer niche provides the rationale to include MSCs in mimicking the niche in neuroblastoma. Here we co-encapsulate and co-culture NBCs and MSCs in a 3D in vitro model and investigate the morphology, growth kinetics and matrix remodeling in the reconstituted stromal environment. Results showed that the incorporation of MSCs in the model lead to accelerated growth of cancer cells as well as recapitulation of at least partially the tumor microenvironment in vivo. The current study therefore demonstrates the feasibility for the collagen microsphere to act as a 3D in vitro cancer model for various topics in cancer studies.

  1. Microencapsulation of Neuroblastoma Cells and Mesenchymal Stromal Cells in Collagen Microspheres: A 3D Model for Cancer Cell Niche Study.

    Science.gov (United States)

    Yeung, Pan; Sin, Hoi Shun; Chan, Shing; Chan, Godfrey Chi Fung; Chan, Barbara Pui

    2015-01-01

    There is a growing trend for researchers to use in vitro 3D models in cancer studies, as they can better recapitulate the complex in vivo situation. And the fact that the progression and development of tumor are closely associated to its stromal microenvironment has been increasingly recognized. The establishment of such tumor supportive niche is vital in understanding tumor progress and metastasis. The mesenchymal origin of many cells residing in the cancer niche provides the rationale to include MSCs in mimicking the niche in neuroblastoma. Here we co-encapsulate and co-culture NBCs and MSCs in a 3D in vitro model and investigate the morphology, growth kinetics and matrix remodeling in the reconstituted stromal environment. Results showed that the incorporation of MSCs in the model lead to accelerated growth of cancer cells as well as recapitulation of at least partially the tumor microenvironment in vivo. The current study therefore demonstrates the feasibility for the collagen microsphere to act as a 3D in vitro cancer model for various topics in cancer studies.

  2. Prenatal diagnosis of juvenile granulosa cell tumor of the testis.

    Science.gov (United States)

    Peterson, Chad; Skoog, Steven

    2008-12-01

    Juvenile granulosa cell tumor is a rare benign neoplasm of the testicular stroma that accounts for 1-5% of all prepubertal testis tumors [Metcalfe PD, Farivar-Mohseni H, Farhat W, McLorie G, Khoury A, Bagli DJ. Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery. J Urol 2003;170:2412-2416; Ross JH, Rybicki L, Kay R. Clinical behavior and a contemporary management algorithm for prepubertal testis tumors: a summary of the prepubertal testis tumor registry. J Urol 2002;168:1675-1679]. A prior case series retrospectively identified a cystic testis tumor on prenatal ultrasound images which was subsequently diagnosed as a juvenile granulosa cell tumor [Bryan DE, Cain MP, Casale AJ. Juvenile granulosa-theca cell (sex cord-stromal) tumor of the infant testis. J Urol 2003;169:1497-1498]. We report a case of a prenatally diagnosed testis tumor which was subsequently diagnosed as a juvenile granulosa cell tumor.

  3. Gastric Schwannoma mimicking malignant gastrointestinal stromal tumor and misdiagnosed by (18)F-FDG PET/CT.

    Science.gov (United States)

    Zhang, Yiqiu; Li, Beilei; Cai, Liang; Hou, Xiaoguang; Shi, Hongcheng; Hou, Jun

    2015-01-01

    Gastric Schwannoma is a rare benign mesenchymal tumor that accounts for only 0.2% of all gastric tumors. The current study presents a case of gastric Schwannoma misdiagnosed as malignant gastrointestinal stromal tumor (GIST) by esophagogastroduodenoscopy, endoscopic ultrasonography, and contrast-enhanced or not enhanced and (18)F-FDG PET/CT imaging.

  4. Stromal Cells Derived from Visceral and Obese Adipose Tissue Promote Growth of Ovarian Cancers.

    Directory of Open Access Journals (Sweden)

    Yan Zhang

    Full Text Available Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC, which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC and visceral (V-ASC white adipose tissue(WAT of lean(Le and obese(Ob mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes in vitro as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.

  5. Stromal Cells Derived from Visceral and Obese Adipose Tissue Promote Growth of Ovarian Cancers.

    Science.gov (United States)

    Zhang, Yan; Nowicka, Aleksandra; Solley, Travis N; Wei, Caimiao; Parikh, Aaroh; Court, Laurence; Burks, Jared K; Andreeff, Michael; Woodward, Wendy A; Dadbin, Ali; Kolonin, Mikhail G; Lu, Karen H; Klopp, Ann H

    2015-01-01

    Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC), which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO) changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) white adipose tissue(WAT) of lean(Le) and obese(Ob) mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes in vitro as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.

  6. Obscure Gastrointestinal Bleeding Due to a Small Intestinal Gastrointestinal Stromal Tumor in a Young Adult

    Directory of Open Access Journals (Sweden)

    Mami Yamamoto

    2016-11-01

    Full Text Available The source of most cases of gastrointestinal bleeding is the upper gastrointestinal tract. Since bleeding from the small intestine is very rare and difficult to diagnose, time is required to identify the source. Among small intestine bleeds, vascular abnormalities account for 70–80%, followed by small intestine tumors that account for 5–10%. The reported peak age of the onset of small intestinal tumors is about 50 years. Furthermore, rare small bowel tumors account for only 1–2% of all gastrointestinal tumors. We describe a 29-year-old man who presented with obscure anemia due to gastrointestinal bleeding and underwent laparotomy. Surgical findings revealed a well-circumscribed lesion measuring 45 × 40 mm in the jejunum that initially appeared similar to diverticulosis with an abscess. However, the postoperative pathological diagnosis was a gastrointestinal stromal tumor with extramural growth.

  7. Analyzing the effects of stromal cells on the recruitment of leukocytes from flow.

    Science.gov (United States)

    Munir, Hafsa; Rainger, G Ed; Nash, Gerard B; McGettrick, Helen

    2015-01-07

    Stromal cells regulate the recruitment of circulating leukocytes during inflammation through cross-talk with neighboring endothelial cells. Here we describe two in vitro "vascular" models for studying the recruitment of circulating neutrophils from flow by inflamed endothelial cells. A major advantage of these models is the ability to analyze each step in the leukocyte adhesion cascade in order, as would occur in vivo. We also describe how both models can be adapted to study the role of stromal cells, in this case mesenchymal stem cells (MSC), in regulating leukocyte recruitment. Primary endothelial cells were cultured alone or together with human MSC in direct contact on Ibidi microslides or on opposite sides of a Transwell filter for 24 hr. Cultures were stimulated with tumor necrosis factor alpha (TNFα) for 4 hr and incorporated into a flow-based adhesion assay. A bolus of neutrophils was perfused over the endothelium for 4 min. The capture of flowing neutrophils and their interactions with the endothelium was visualized by phase-contrast microscopy. In both models, cytokine-stimulation increased endothelial recruitment of flowing neutrophils in a dose-dependent manner. Analysis of the behavior of recruited neutrophils showed a dose-dependent decrease in rolling and a dose-dependent increase in transmigration through the endothelium. In co-culture, MSC suppressed neutrophil adhesion to TNFα-stimulated endothelium. Our flow based-adhesion models mimic the initial phases of leukocyte recruitment from the circulation. In addition to leukocytes, they can be used to examine the recruitment of other cell types, such as therapeutically administered MSC or circulating tumor cells. Our multi-layered co-culture models have shown that MSC communicate with endothelium to modify their response to pro-inflammatory cytokines, altering the recruitment of neutrophils. Further research using such models is required to fully understand how stromal cells from different tissues

  8. Current concepts in non-gastrointestinal stromal tumor soft tissue sarcomas: A primer for radiologists

    Energy Technology Data Exchange (ETDEWEB)

    Baheti, Akahay D. [Dept. of Radiology, Tata Memorial Centre, Mumbai (India); Tirumani, Harika [Dept. of Radiology, University of Arkansas for Medical Sciences, Little Rock (United States); O' Neill, Alibhe; Jagannathan, Jyothi P. [Dept. of Imaging, Dana-Farber Cancer Institute, Boston (United States)

    2017-01-15

    Non-gastrointestinal stromal tumor (GIST) soft tissue sarcomas (STSs) are a heterogeneous group of neoplasms whose classification and management continues to evolve with better understanding of their biologic behavior. The 2013 World Health Organization (WHO) has revised their classification based on new immunohistochemical and cytogenetic data. In this article, we will provide a brief overview of the revised WHO classification of soft tissue tumors, discuss in detail the radiology and management of the two most common adult non-GIST STS, namely liposarcoma and leiomyosarcoma, and review some of the emerging histology-driven targeted therapies in non-GIST STS, focusing on the role of the radiologist.

  9. Perivascular Epithelioid Cell Tumor in the Stomach

    Directory of Open Access Journals (Sweden)

    Sun Ah Shin

    2017-07-01

    Full Text Available Perivascular epithelioid cell tumors or PEComas can arise in any location in the body. However, a limited number of cases of gastric PEComa have been reported. We present two cases of gastric PEComas. The first case involved a 62-year-old woman who presented with a 4.2 cm gastric subepithelial mass in the prepyloric antrum, and the second case involved a 67-year-old man with a 5.0 cm mass slightly below the gastroesophageal junction. Microscopic examination revealed that both tumors were composed of perivascular epithelioid cells that were immunoreactive for melanocytic and smooth muscle markers. Prior to surgery, the clinical impression of both tumors was gastrointestinal stromal tumor (GIST, and the second case was erroneously diagnosed as GIST even after microscopic examination. Although gastric PEComa is a very rare neoplasm, it should be considered in the differential diagnosis of gastric submucosal lesions.

  10. Mesenchymal Stromal Cells: Updates and Therapeutic Outlook in Rheumatic Diseases

    Directory of Open Access Journals (Sweden)

    Christian Jorgensen

    2013-10-01

    Full Text Available Multipotent mesenchymal stromal cells or mesenchymal stem cells (MSCs are adult stem cells exhibiting functional properties that have opened the way for cell-based clinical therapies. MSCs have been reported to exhibit immunosuppressive as well as healing properties, improving angiogenesis and preventing apoptosis or fibrosis through the secretion of paracrine mediators. This review summarizes recent progress on the clinical application of stem cells therapy in some inflammatory and degenerative rheumatic diseases. To date, most of the available data have been obtained in preclinical models and clinical efficacy needs to be evaluated through controlled randomized double-blind trials.

  11. Genetic Recombination Between Stromal and Cancer Cells Results in Highly Malignant Cells Identified by Color-Coded Imaging in a Mouse Lymphoma Model.

    Science.gov (United States)

    Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kousuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

    2017-12-01

    The tumor microenvironment (TME) promotes tumor growth and metastasis. We previously established the color-coded EL4 lymphoma TME model with red fluorescent protein (RFP) expressing EL4 implanted in transgenic C57BL/6 green fluorescent protein (GFP) mice. Color-coded imaging of the lymphoma TME suggested an important role of stromal cells in lymphoma progression and metastasis. In the present study, we used color-coded imaging of RFP-lymphoma cells and GFP stromal cells to identify yellow-fluorescent genetically recombinant cells appearing only during metastasis. The EL4-RFP lymphoma cells were injected subcutaneously in C57BL/6-GFP transgenic mice and formed subcutaneous tumors 14 days after cell transplantation. The subcutaneous tumors were harvested and transplanted to the abdominal cavity of nude mice. Metastases to the liver, perigastric lymph node, ascites, bone marrow, and primary tumor were imaged. In addition to EL4-RFP cells and GFP-host cells, genetically recombinant yellow-fluorescent cells, were observed only in the ascites and bone marrow. These results indicate genetic exchange between the stromal and cancer cells. Possible mechanisms of genetic exchange are discussed as well as its ramifications for metastasis. J. Cell. Biochem. 118: 4216-4221, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  12. Metastatic ovarian sex-cord stromal tumor with annular tubules in a patient without Peutz-Jeghers syndrome.

    Science.gov (United States)

    Dart, Kimi; Schwartzenfeld, Ted; Brandes, Warren; D'Errico, Anthony; Stender, Michael

    2014-06-01

    Sex-cord stromal tumors (SCSTs) with annular tubules (SCTATs) are a small class of ovarian lesions that possess histologic features of both Sertoli and granulosa cells. Approximately one-third of patients with SCTAT also have Peutz-Jaghers syndreome, which makes these cases especially rare. Patients with non-PJS-associated SCTAT make up the remaining two-thirds; 20% of these cases have a metastatic presentation. Metastasis of these tumors to the head and neck region has only been reported in a few instances. In this article we report a case of a 25-year-old woman who presented with "a lump in her throat" and was ultimately diagnosed with SCTAT. We also discuss the current protocols in the diagnosis and treatment of this entity.

  13. A stable explant culture of HER2/neu invasive carcinoma supported by alpha-Smooth Muscle Actin expressing stromal cells to evaluate therapeutic agents

    Directory of Open Access Journals (Sweden)

    Piechocki Marie P

    2008-04-01

    Full Text Available Abstract Background To gain a better understanding of the effects of therapeutic agents on the tumor microenvironment in invasive cancers, we developed a co-culture model from an invasive lobular carcinoma. Tumor cells expressing HER2/neu organize in nests surrounded by alpha-Smooth Muscle Actin (α-SMA expressing tumor stroma to resemble the morphology of an invading tumor. This co-culture, Mammary Adenocarcinoma Model (MAM-1 maintains a 1:1 ratio of HER2/neu positive tumor cells to α-SMA-reactive stromal cells and renews this configuration for over 20 passages in vitro. Methods We characterized the cellular elements of the MAM-1 model by microarray analysis, and immunocytochemistry. We developed flow cytometric assays to evaluate the relative responses of the tumor and stroma to the tyrosine kinase inhibitor, Iressa. Results The MAM-1 gene expression profile contains clusters that represent the ErbB-2 breast cancer signature and stroma-specific clusters associated with invasive breast cancers. The stability of this model and the ability to antigenically label the tumor and stromal fractions allowed us to determine the specificity of Iressa, a receptor tyrosine kinase inhibitor, for targeting the tumor cell population. Treatment resulted in a selective dose-dependent reduction in phospho-pMEK1/2 and pp44/42MAPK in tumor cells. Within 24 h the tumor cell fraction was reduced 1.9-fold while the stromal cell fraction increased >3-fold, consistent with specific reductions in phospho-pp44/42 MAPK, MEK1/2 and PCNA in tumor cells and reciprocal increases in the stromal cells. Erosion of the tumor cell nests and augmented growth of the stromal cells resembled a fibrotic response. Conclusion This model demonstrates the specificity of Iressa for HER2/neu expressing tumor cells versus the tumor associated myofibroblasts and is appropriate for delineating effects of therapy on signal transduction in the breast tumor microenvironment and improving

  14. Synchronous Gastric Gastrointestinal Stromal Tumor and Colon Adenocarcinoma: A Case Report

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    Thivi Vasilakaki

    2014-01-01

    Full Text Available Gastrointestinal stromal tumors (GISTs represent the majority of primary mesenchymal tumors of the gastrointestinal tract. They are generally considered to be solitary tumors and therefore the synchronous occurrence with other primary malignancies of gastrointestinal track is considered a rare event. Here we present the case of a 75-year-old man admitted to our hospital with a 10-day history of gastrointestinal bleeding. Colonoscopy revealed an ulcerative mass of 4 cm in diameter in the ascending colon. Gastroscopy revealed a bulge in the gastric body measuring 1 cm in diameter with normal overlying mucosa. Surgical intervention was suggested and ileohemicolectomy with regional lymph node resection along with gastric wedge resection was performed. Pathologic examination of the ascending colon mass showed an invasive moderately differentiated adenocarcinoma stage III B (T3N1M0. Grossly resected wedge of stomach showed a well circumscribed intramural tumor which microscopically was consistent with essentially benign gastrointestinal stromal tumor (according to Miettinen criteria. The patient did not receive additional treatment. Two years later the patient showed no evidence of recurrence or metastasis.

  15. Mesenchymal stromal cells and hematopoietic stem cell transplantation.

    Science.gov (United States)

    Bernardo, Maria Ester; Fibbe, Willem E

    2015-12-01

    Mesenchymal stromal cells (MSCs) comprise a heterogeneous population of multipotent cells that can be isolated from various human tissues and culture-expanded ex vivo for clinical use. Due to their immunoregulatory properties and their ability to secrete growth factors, MSCs play a key role in the regulation of hematopoiesis and in the modulation of immune responses against allo- and autoantigens. In light of these properties, MSCs have been employed in clinical trials in the context of hematopoietic stem cell transplantation (HSCT) to facilitate engraftment of hematopoietic stem cells (HSCs) and to prevent graft failure, as well as to treat steroid-resistant acute graft-versus-host disease (GvHD). The available clinical evidence derived from these studies indicates that MSC administration is safe. Moreover, promising preliminary results in terms of efficacy have been reported in some clinical trials, especially in the treatment of acute GvHD. In this review we critically discuss recent advances in MSC therapy by reporting on the most relevant studies in the field of HSCT. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  16. Adipose-derived stromal cells inhibit prostate cancer cell proliferation inducing apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Takahara, Kiyoshi [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Ii, Masaaki, E-mail: masaii@art.osaka-med.ac.jp [Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Inamoto, Teruo; Komura, Kazumasa; Ibuki, Naokazu; Minami, Koichiro; Uehara, Hirofumi; Hirano, Hajime; Nomi, Hayahito; Kiyama, Satoshi [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Asahi, Michio [Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Azuma, Haruhito [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan)

    2014-04-18

    Highlights: • AdSC transplantation exhibits inhibitory effect on tumor progressions of PCa cells. • AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway. • High expression of the TGF-β1 gene in AdSCs. - Abstract: Mesenchymal stem cells (MSCs) have generated a great deal of interest in the field of regenerative medicine. Adipose-derived stromal cells (AdSCs) are known to exhibit extensive proliferation potential and can undergo multilineage differentiation, sharing similar characteristics to bone marrow-derived MSCs. However, as the effect of AdSCs on tumor growth has not been studied sufficiently, we assessed the degree to which AdSCs affect the proliferation of prostate cancer (PCa) cell. Human AdSCs exerted an inhibitory effect on the proliferation of androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) human PCa cells, while normal human dermal fibroblasts (NHDFs) did not, and in fact promoted PCa cell proliferation to a degree. Moreover, AdSCs induced apoptosis of LNCaP cells and PC3 cells, activating the caspase3/7 signaling pathway. cDNA microarray analysis suggested that AdSC-induced apoptosis in both LNCaP and PC3 cells was related to the TGF-β signaling pathway. Consistent with our in vitro observations, local transplantation of AdSCs delayed the growth of tumors derived from both LNCaP- and PC3-xenografts in immunodeficient mice. This is the first preclinical study to have directly demonstrated that AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway, irrespective of androgen-responsiveness. Since autologous AdSCs can be easily isolated from adipose tissue without any ethical concerns, we suggest that therapy with these cells could be a novel approach for patients with PCa.

  17. Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor.

    Science.gov (United States)

    Bosbach, Benedikt; Rossi, Ferdinand; Yozgat, Yasemin; Loo, Jennifer; Zhang, Jennifer Q; Berrozpe, Georgina; Warpinski, Katherine; Ehlers, Imke; Veach, Darren; Kwok, Andrew; Manova, Katia; Antonescu, Cristina R; DeMatteo, Ronald P; Besmer, Peter

    2017-10-03

    Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic KitV558Δ mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant KitV558Δ/+ mice, double-mutant KitV558Δ;Y567F/Y567F knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in KitV558Δ;Y719F/Y719F mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing KitV558Δ/+ mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinib-resistant KitV558Δ;T669I/+ tumors.

  18. Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid.

    Science.gov (United States)

    Hulikova, Alzbeta; Black, Nicholas; Hsia, Lin-Ting; Wilding, Jennifer; Bodmer, Walter F; Swietach, Pawel

    2016-09-06

    Proliferation and invasion of cancer cells require favorable pH, yet potentially toxic quantities of acid are produced metabolically. Membrane-bound transporters extrude acid from cancer cells, but little is known about the mechanisms that handle acid once it is released into the poorly perfused extracellular space. Here, we studied acid handling by myofibroblasts (colon cancer-derived Hs675.T, intestinal InMyoFib, embryonic colon-derived CCD-112-CoN), skin fibroblasts (NHDF-Ad), and colorectal cancer (CRC) cells (HCT116, HT29) grown in monoculture or coculture. Expression of the acid-loading transporter anion exchanger 2 (AE2) (SLC4A2 product) was detected in myofibroblasts and fibroblasts, but not in CRC cells. Compared with CRC cells, Hs675.T and InMyoFib myofibroblasts had very high capacity to absorb extracellular acid. Acid uptake into CCD-112-CoN and NHDF-Ad cells was slower and comparable to levels in CRC cells, but increased alongside SLC4A2 expression under stimulation with transforming growth factor β1 (TGFβ1), a cytokine involved in cancer-stroma interplay. Myofibroblasts and fibroblasts are connected by gap junctions formed by proteins such as connexin-43, which allows the absorbed acid load to be transmitted across the stromal syncytium. To match the stimulatory effect on acid uptake, cell-to-cell coupling in NHDF-Ad and CCD-112-CoN cells was strengthened with TGFβ1. In contrast, acid transmission was absent between CRC cells, even after treatment with TGFβ1. Thus, stromal cells have the necessary molecular apparatus for assembling an acid-venting route that can improve the flow of metabolic acid through tumors. Importantly, the activities of stromal AE2 and connexin-43 do not place an energetic burden on cancer cells, allowing resources to be diverted for other activities.

  19. Brain Metastasis from Gastrointestinal Stromal Tumor: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Hideaki Naoe

    2011-10-01

    Full Text Available Metastasis of gastrointestinal stromal tumor (GIST into the central nervous system is extremely rare. We report a patient with synchronous GIST and brain metastasis. At disease onset, there was left hemiplegia and ptosis of the right eyelids. Resection cytology of the brain tumor was reported as metastasis of GIST. After positron emission tomography examination, another tumor in the small bowel was discovered, which suggested a small bowel GIST associated with intracranial metastasis. Immunohistochemical analysis of the intestinal tumor specimen obtained by double balloon endoscopy showed a pattern similar to the brain tumor, with the tumors subsequently identified as intracranial metastases of jejunal GIST. After surgical resection of one brain tumor, the patient underwent whole brain radiation therapy followed by treatment with imatinib mesylate (Gleevec; Novartis Pharma, Basel, Switzerland. Mutational analysis of the original intestinal tumor revealed there were no gene alterations in KIT or PDGFRα. Since the results indicated the treatment had no apparent effect on either of the tumors, and because ileus developed due to an intestinal primary tumor, the patient underwent surgical resection of the intestinal lesion. However, the patient’s condition gradually worsen and she subsequently died 4 months after the initial treatment.

  20. Nanoparticle labeling identifies slow cycling human endometrial stromal cells

    Science.gov (United States)

    2014-01-01

    Introduction Evidence suggests that the human endometrium contains stem or progenitor cells that are responsible for its remarkable regenerative capability. A common property of somatic stem cells is their quiescent state. It remains unclear whether slow-cycling cells exist in the human endometrium. We hypothesized that the human endometrium contains a subset of slow-cycling cells with somatic stem cell properties. Here, we established an in vitro stem cell assay to isolate human endometrial-derived mesenchymal stem-like cells (eMSC). Methods Single-cell stromal cultures were initially labeled with fluorescent nanoparticles and a small population of fluorescent persistent cells (FPC) remained after culture of 21 days. Two populations of stromal cells, namely FPC and non-FPC were sorted. Results Quantitative analysis of functional assays demonstrated that the FPC had higher colony forming ability, underwent more rounds of self-renewal and had greater enrichment of phenotypically defined prospective eMSC markers: CD146+/CD140b+ and W5C5+ than the non-FPC. They also differentiate into multiple mesenchymal lineages and the expression of lineage specific markers was lower than that of non-FPC. The FPC exhibit low proliferation activities. A proliferation dynamics study revealed that more FPC had a prolonged G1 phase. Conclusions With this study we present an efficient method to label and isolate slow-proliferating cells obtained from human endometrial stromal cultures without genetic modifications. The FPC population could be easily maintained in vitro and are of interest for tissue-repair and engineering perspectives. In summary, nanoparticle labeling is a promising tool for the identification of putative somatic stem or progenitor cells when their surface markers are undefined. PMID:24996487

  1. Classification and biology of tumour associated stromal cells.

    Science.gov (United States)

    Raffaghello, Lizzia; Dazzi, Francesco

    2015-12-01

    Stroma is a fundamental component of the tumour microenvironment whereby it supports malignant cell growth and spreading. It consists of different entities including cells of the immune system, vascular structures and fibroblasts. Much attention has recently been paid to fibroblasts since there is compelling evidence that they orchestrate the recruitment of and educate other cells to promote cancer growth. This review proposes to discuss in detail the nomenclature, origin, and biological functions of the different stromal cells residing in tumours. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  2. Phyllodes Tumor of Anogenital Mammary-like Glands with Diffuse Pseudoangiomatous Stromal Hyperplasia

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    Nuket ELİYATKIN

    2017-05-01

    Full Text Available Anogenital mammary-like glands may give rise to various pathologic lesions identical to those known in mammary pathology. Tumor occurring in the anogenital region is extremely rare. The histogenetic origin of this tumor is controversial as it is being debated whether such lesions evolve from ectopic breast tissue and most recently, anogenital mammary-like gland. We report a 28-year-old girl who presented with a painless mass in the anogenital region, which was subsequently excised. Microscopic examination revealed morphologic pattern characteristic of benign phyllodes tumor with pseudoangiomatous stromal hyperplasia. We present this case to emphasize the importance of recognizing this uncommon lesion occurring at an extremely unusual site. We also discuss the histogenesis of phyllodes tumor and related lesions occurring in the anogenital region in light of the current literature along with a brief review of the previously reported cases of anogenital mammary-like glands.

  3. Spontaneous Rupture of Recurrent Gastrointestinal Stromal Tumor Associated with Neurofibromatosis Type 1

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    Shin-Mae Wang

    2005-11-01

    Full Text Available The incidence of gastrointestinal stromal tumor (GIST among neurofibromatosis type 1 (NF-1 patients is approximately 3.9–25%, and this relationship is generally considered to be non-coincidental. We report a patient with NF-1 who underwent laparotomy 3 times due to recurrent intra-abdominal tumor rupture with internal bleeding in the space of 13 years. The pathologic diagnoses were schwannoma, malignant peripheral nerve sheath tumor and GIST. Because of the similar histologic features of these tumors, we considered them to be of the same nature. Immunohistochemical staining can help in the differential diagnosis. We suggest that NF-1 patients with gastrointestinal symptoms receive further survey to rule out GISTs.

  4. Gastric Schwannoma Mimicking Malignant Gastrointestinal Stromal Tumor Exhibiting Increased Fluorodeoxyglucose Uptake.

    Science.gov (United States)

    Oh, Sung Jin; Suh, Byoung Jo; Park, Jong Kwon

    2016-01-01

    A schwannoma is a kind of neurogenic tumor that rarely occurs in the gastrointestinal tract. Gastric schwannomas make up 0.2% of all gastric neoplasms. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors and up to 60-70% of GIST occur in the stomach. Schwannoma and GIST are similar in clinical features, so they are difficult to differentiate preoperatively. Differential diagnosis of these two submucosal tumors is important because of the malignant potential of GIST and the relatively benign course of gastric schwannomas. We report a 49-year-old woman who was diagnosed after operation with a gastric schwannoma, which was suspected a malignant GIST by fluorine-18-fluorodeoxyglucose positron emission computed tomography imaging.

  5. Gastric Schwannoma Mimicking Malignant Gastrointestinal Stromal Tumor Exhibiting Increased Fluorodeoxyglucose Uptake

    Directory of Open Access Journals (Sweden)

    Sung Jin Oh

    2016-04-01

    Full Text Available A schwannoma is a kind of neurogenic tumor that rarely occurs in the gastrointestinal tract. Gastric schwannomas make up 0.2% of all gastric neoplasms. Gastrointestinal stromal tumors (GIST are the most common mesenchymal tumors and up to 60-70% of GIST occur in the stomach. Schwannoma and GIST are similar in clinical features, so they are difficult to differentiate preoperatively. Differential diagnosis of these two submucosal tumors is important because of the malignant potential of GIST and the relatively benign course of gastric schwannomas. We report a 49-year-old woman who was diagnosed after operation with a gastric schwannoma, which was suspected a malignant GIST by fluorine-18-fluorodeoxyglucose positron emission computed tomography imaging.

  6. In vivo fluorescence imaging reveals the promotion of mammary tumorigenesis by mesenchymal stromal cells.

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    Chien-Chih Ke

    Full Text Available Mesenchymal stromal cells (MSCs are multipotent adult stem cells which are recruited to the tumor microenvironment (TME and influence tumor progression through multiple mechanisms. In this study, we examined the effects of MSCs on the tunmorigenic capacity of 4T1 murine mammary cancer cells. It was found that MSC-conditioned medium increased the proliferation, migration, and efficiency of mammosphere formation of 4T1 cells in vitro. When co-injected with MSCs into the mouse mammary fat pad, 4T1 cells showed enhanced tumor growth and generated increased spontaneous lung metastasis. Using in vivo fluorescence color-coded imaging, the interaction between GFP-expressing MSCs and RFP-expressing 4T1 cells was monitored. As few as five 4T1 cells could give rise to tumor formation when co-injected with MSCs into the mouse mammary fat pad, but no tumor was formed when five or ten 4T1 cells were implanted alone. The elevation of tumorigenic potential was further supported by gene expression analysis, which showed that when 4T1 cells were in contact with MSCs, several oncogenes, cancer markers, and tumor promoters were upregulated. Moreover, in vivo longitudinal fluorescence imaging of tumorigenesis revealed that MSCs created a vascularized environment which enhances the ability of 4T1 cells to colonize and proliferate. In conclusion, this study demonstrates that the promotion of mammary cancer progression by MSCs was achieved through the generation of a cancer-enhancing microenvironment to increase tumorigenic potential. These findings also suggest the potential risk of enhancing tumor progression in clinical cell therapy using MSCs. Attention has to be paid to patients with high risk of breast cancer when considering cell therapy with MSCs.

  7. Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer

    NARCIS (Netherlands)

    Gorter, Arko; Zijlmans, Henry J.; van Gent, Hestia; Trimbos, J. Baptist; Fleuren, Gert J.; Jordanova, Ekaterina S.

    2010-01-01

    Cervical carcinoma is the second most frequent cancer type in women worldwide. Both inflammatory cells and stromal cells are important for tumor progression. Stromal cells produce growth factors and extracellular matrix and provide an adequate environment for angiogenesis. Versican, a member of the

  8. Bystander effect in glioma suicide gene therapy using bone marrow stromal cells.

    Science.gov (United States)

    Li, Shaoyi; Gu, Chunyu; Gao, Yun; Amano, Shinji; Koizumi, Shinichiro; Tokuyama, Tsutomu; Namba, Hiroki

    2012-11-01

    An established rat intracranial glioma was successfully treated through the tumoricidal bystander effect generated by intratumoral injection of rat bone marrow stromal cells (BMSCs) transduced with the herpes simplex virus-thymidine kinase gene (BMSCtk cells) followed by systemic ganciclovir administration. In the present study, we tested the bystander effect of this treatment strategy when using human BMSCs as the vector cells. Human BMSCtk cells were mixed with various kinds of brain tumor cell lines (human and rat glioma cells) and examined in vitro and in vivo tumoricidal bystander effects, by co-culture study and co-implantation study in the nude mouse, respectively. A significant in vitro bystander effect was observed between human BMSCtk cells and any of the tumor cells examined in the ganciclovir-containing medium. A potent in vivo bystander effect against human and rat glioma cells was also demonstrated when ganciclovir was administered. Migratory activity of the human BMSCs toward the tumor cells was enhanced by the conditioned media obtained from both human and rat glioma cells compared to the fresh media. The results of this study have demonstrated that the bystander effect generated by BMSCtk cells and ganciclovir is not cell type-specific, suggesting that the strategy would be quite feasible for clinical use. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Stromal and Epithelial Caveolin-1 Both Confer a Protective Effect Against Mammary Hyperplasia and Tumorigenesis : Caveolin-1 Antagonizes Cyclin D1 Function in Mammary Epithelial Cells

    OpenAIRE

    Williams, Terence M.; Sotgia, Federica; Lee, Hyangkyu; Hassan, Ghada; Di Vizio, Dolores; Bonuccelli, Gloria; Capozza, Franco; Mercier, Isabelle; Rui, Hallgeir; Pestell, Richard G.; Lisanti, Michael P.

    2006-01-01

    Here, we investigate the role of caveolin-1 (Cav-1) in breast cancer onset and progression, with a focus on epithelial-stromal interactions, ie, the tumor microenvironment. Cav-1 is highly expressed in adipocytes and is abundant in mammary fat pads (stroma), but it remains unknown whether loss of Cav-1 within mammary stromal cells affects the differentiated state of mammary epithelia via paracrine signaling. To address this issue, we characterized the development of the mammary ductal system ...

  10. Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer 1

    OpenAIRE

    Henry, CE; Emmanuel, C.; Lambie, N; C. Loo; Kan, B; Kennedy, CJ; de Fazio, A; Hacker, NF; Ford, CE

    2017-01-01

    OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicop...

  11. PDGFRβ Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas.

    Directory of Open Access Journals (Sweden)

    Vinay K Kartha

    Full Text Available Carcinoma associated fibroblasts (CAFs form the main constituents of tumor stroma and play an important role in tumor growth and invasion. The presence of CAFs is a strong predictor of poor prognosis of head and neck squamous cell carcinoma. Despite significant progress in determining the role of CAFs in tumor progression, the mechanisms contributing to their activation remain poorly characterized, in part due to fibroblast heterogeneity and the scarcity of reliable fibroblast surface markers. To search for such markers in oral squamous cell carcinoma (OSCC, we applied a novel approach that uses RNA-sequencing data derived from the cancer genome atlas (TCGA. Specifically, our strategy allowed for an unbiased identification of genes whose expression was closely associated with a set of bona fide stroma-specific transcripts, namely the interstitial collagens COL1A1, COL1A2, and COL3A1. Among the top hits were genes involved in cellular matrix remodeling and tumor invasion and migration, including platelet-derived growth factor receptor beta (PDGFRβ, which was found to be the highest-ranking receptor protein genome-wide. Similar analyses performed on ten additional TCGA cancer datasets revealed that other tumor types shared CAF markers with OSCC, including PDGFRβ, which was found to significantly correlate with the reference collagen expression in ten of the 11 cancer types tested. Subsequent immunostaining of OSCC specimens demonstrated that PDGFRβ was abundantly expressed in stromal fibroblasts of all tested cases (12/12, while it was absent in tumor cells, with greater specificity than other known markers such as alpha smooth muscle actin or podoplanin (3/11. Overall, this study identified PDGFRβ as a novel marker of stromal activation in OSCC, and further characterized a list of promising candidate CAF markers that may be relevant to other carcinomas. Our novel approach provides for a fast and accurate method to identify CAF markers without

  12. PDGFRβ Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas.

    Science.gov (United States)

    Kartha, Vinay K; Stawski, Lukasz; Han, Rong; Haines, Paul; Gallagher, George; Noonan, Vikki; Kukuruzinska, Maria; Monti, Stefano; Trojanowska, Maria

    2016-01-01

    Carcinoma associated fibroblasts (CAFs) form the main constituents of tumor stroma and play an important role in tumor growth and invasion. The presence of CAFs is a strong predictor of poor prognosis of head and neck squamous cell carcinoma. Despite significant progress in determining the role of CAFs in tumor progression, the mechanisms contributing to their activation remain poorly characterized, in part due to fibroblast heterogeneity and the scarcity of reliable fibroblast surface markers. To search for such markers in oral squamous cell carcinoma (OSCC), we applied a novel approach that uses RNA-sequencing data derived from the cancer genome atlas (TCGA). Specifically, our strategy allowed for an unbiased identification of genes whose expression was closely associated with a set of bona fide stroma-specific transcripts, namely the interstitial collagens COL1A1, COL1A2, and COL3A1. Among the top hits were genes involved in cellular matrix remodeling and tumor invasion and migration, including platelet-derived growth factor receptor beta (PDGFRβ), which was found to be the highest-ranking receptor protein genome-wide. Similar analyses performed on ten additional TCGA cancer datasets revealed that other tumor types shared CAF markers with OSCC, including PDGFRβ, which was found to significantly correlate with the reference collagen expression in ten of the 11 cancer types tested. Subsequent immunostaining of OSCC specimens demonstrated that PDGFRβ was abundantly expressed in stromal fibroblasts of all tested cases (12/12), while it was absent in tumor cells, with greater specificity than other known markers such as alpha smooth muscle actin or podoplanin (3/11). Overall, this study identified PDGFRβ as a novel marker of stromal activation in OSCC, and further characterized a list of promising candidate CAF markers that may be relevant to other carcinomas. Our novel approach provides for a fast and accurate method to identify CAF markers without the need for

  13. Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

    Czech Academy of Sciences Publication Activity Database

    Borghese, C.; Casagrande, N.; Pivetta, E.; Colombatti, A.; Boccellino, M.; Amler, Evžen; Normanno, N.; Caraglia, M.; de Rosa, G.; Aldinucci, D.

    2017-01-01

    Roč. 8, č. 26 (2017), s. 42926-42938 ISSN 1949-2553 Institutional support: RVO:68378041 Keywords : zoledronic acid * self-assembling nanoparticles * mesenchymal stromal cells * prostate cancer * tumor microenvironment Subject RIV: FP - Other Medical Disciplines Impact factor: 5.168, year: 2016

  14. A Color-coded Imageable Syngeneic Mouse Model of Stromal-cell Recruitment by Metastatic Lymphoma.

    Science.gov (United States)

    Matsumoto, Takuro; Suetsugu, Atsushi; Shibata, Yuhei; Nakamura, Nobuhiko; Aoki, Hitomi; Kunisada, Takahiro; Tsurumi, Hisashi; Shimizu, Masahito; Hoffman, Robert M

    2015-09-01

    A syngeneic color-coded imageable lymphoma model has been developed to visualize recruitment of host stromal cells by malignant lymphoma during metastasis. The EL4 cell line was previously derived from a lymphoma induced in a C57/BL6 mouse by 9,10-dimethyl-1,2-benzanthracene. EL4 lymphoma cells expressing red fluorescent protein (EL4-RFP) were initially established. EL4-RFP cells were subsequently injected into the tail vein of C57/BL6-GFP transgenic mice. EL4-RFP metastasis was observed in the lymph nodes of the upper mediastinum and in the liver 28 days after cell injection. Large EL4-RFP liver metastases in C57/BL6-GFP mice contained GFP-expressing stromal cells derived from the host. In addition, EL4-RFP lymphoma metastasis was formed in peri-gastric lymph nodes, which were also enriched in host GFP-expressing cells. Furthermore, EL4-RFP lymphoma cells were also observed in the peripheral blood and bone marrow of C57/BL6-GFP transgenic mice, where they were associated with GFP-expressing host cells. Lymph node, liver and bone marrow metastases were found approximately 4 weeks after transplantation and all RFP-expressing metastases were highly enriched in GFP-expressing host stromal cells. This model of malignant lymphoma can be used to study early tumor development, metastasis, and the role of the stroma, as well as for discovery and evaluation of novel therapeutics for this treatment-resistant disease. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Membrane particles generated from mesenchymal stromal cells modulate immune responses by selective targeting of pro-inflammatory monocytes

    OpenAIRE

    Gonçalves, F.D.C. (Fabiany Da C.); Luk, Franka; Korevaar, Sander; Bouzid, R. (Rachid); Paz, A.H.; López-Iglesias, C. (Carmen); Baan, Carla; Merino, Ana; Hoogduijn, Martin

    2017-01-01

    textabstractMesenchymal stromal cells (MSC) are a promising therapy for immunological disorders. However, culture expanded MSC are large and get trapped in the capillary networks of the lungs after intravenous infusion, where they have a short survival time. Hypothetically, living cells are a risk for tumor formation. To reduce risks associated with MSC infusion and improve the distribution in the body, we generated membrane particles (MP) of MSC and MSC stimulated with IFN-γ (MPγ). Tracking ...

  16. A Unique Case of Extraovarian Sex-Cord Stromal Fibrosarcoma, With Subsequent Relapse of Differentiated Sex-Cord Tumor.

    Science.gov (United States)

    Wang, Jayson; Papanastasopoulos, Panagiotis; Savage, Philip; Smith, James Richard; Fisher, Cyril; El-Bahrawy, Mona A

    2015-07-01

    Primary fibrosarcoma arising from ovarian sex-cord stroma is a very rare neoplasm, with only a few reports in the literature. These tumors have been reported to express inhibin which allows their distinction from fibrosarcomas of soft tissue. Here, we report a case of a fibrosarcoma arising in the broad ligament. Despite being totally separate from the ovary, the tumor was diagnosed as sex-cord stromal type on the basis of inhibin expression. Furthermore, this patient suffered a recurrence of her tumor in the pelvis, which showed both the fibrosarcomatous, as well as other sex-cord elements, confirming the sex-cord stromal differentiation of the sarcoma. To our knowledge, this is the first case of a sex-cord stromal fibrosarcoma arising from an extraovarian site. Furthermore, this is also the first case of a recurrent fibrosarcoma, which showed redifferentiation of the tumor into other sex-cord components.

  17. Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/β-catenin pathway

    OpenAIRE

    Chang, Po-Hao; Hwang-Verslues, Wendy W.; Chang, Yi-Cheng; Chen, Chun-Chin; Hsiao, Michael; Jeng, Yung-Ming; Chang, King-Jen; Lee, Eva Y.-H. P.; Shew, Jin-Yuh; Lee, Wen-Hwa

    2012-01-01

    Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and i...

  18. 'Big'-insulin-like growth factor-II signaling is an autocrine survival pathway in gastrointestinal stromal tumors.

    NARCIS (Netherlands)

    Rikhof, B.; Graaf, W.T.A. van der; Suurmeijer, A.J.H.; Doorn, J. van; Meersma, G.J.; Groenen, P.J.T.A.; Schuuring, E.M.; Meijer, C.; Jong, S. de

    2012-01-01

    New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor

  19. Fear of progression in patients with gastrointestinal stromal tumors (GIST): Is extended lifetime related to the Sword of Damocles?

    NARCIS (Netherlands)

    Custers, J.A.E.; Tielen, R.; Prins, J.B.; Wilt, J.H.W. de; Gielissen, M.F.M.; Graaf, W.T.A. van der

    2015-01-01

    BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare and before 2000, patients had a dismal prognosis with a median survival of less than a year after tumor metastasis. However, the median overall survival has increased to more than five years following the introduction of imatinib and other

  20. 'Big'-Insulin-Like Growth Factor-II Signaling Is an Autocrine Survival Pathway in Gastrointestinal Stromal Tumors

    NARCIS (Netherlands)

    Rikhof, Bart; van der Graaf, Winette T. A.; Suurmeijer, Albert J. H.; van Doorn, Jaap; Meersma, Gert Jan; Groenen, Patricia J. T. A.; Schuuring, Ed M. D.; Meijer, Coby; de Jong, Steven

    New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor

  1. Small Bowel Stromal Tumors: Different Clinicopathologic and Computed Tomography Features in Various Anatomic Sites.

    Directory of Open Access Journals (Sweden)

    Gu-sheng Xing

    Full Text Available Gastrointestinal stromal tumors (GISTs can present with different clinical and immunohistochemical characteristics according to different anatomic sites. The aim of this study was to compare clinicopathologic and computed tomography (CT features of small bowel stromal tumors located in the duodenum, jejunum, and ileum. In total, 197 patients (109 male, 88 female with small bowel GISTs were retrospectively reviewed. All tumors had definite anatomic sites in the small bowel tract with surgical confirmation. The clinicopathologic variables included age, sex, onset of symptoms, and tumor risk category. CT variables included tumor size, degree enhancement, enhancement pattern (region of necrosis, adjacent tissue involvement, lymphadenopathy, and distant metastasis. We assessed any possible differences according to different GIST site of origin. Based on tumor size and mitotic count, the risk categories in different anatomic sites did not differ significantly between duodenal and jejunal GISTs. However, high risk ileum GISTs accounted for 66.0% of ileal cases, which was higher than duodenum cases (36.8%, P = 0.002 and jejunum cases (43.9%, P = 0.004. The mean size of GISTs in the ileum was 9.77 cm, which was significantly larger than in the duodenum (7.41 cm, P = 0.043, and in the jejunum (8.14 cm, P = 0.027. On CT images, enhancement degree appeared to gradually increase from the duodenum to the ileum in the portal phase, and the enhancement pattern presented a tendency for heterogeneity. In Conclusions, the clinicopathologic and CT features of small bowel GISTs can differ according to different primary anatomic sites.

  2. Gastrointestinal stromal tumor masquerading as a lung neoplasm. A case presentation and literature review

    Directory of Open Access Journals (Sweden)

    Papagiannopoulos K

    2008-05-01

    Full Text Available Abstract Gastrointestinal stromal tumors (GISTs are rare neoplasms of the gastrointestinal tract. Their incidence in the esophagus is 1%–3%. Never has a GIST been documented to directly invade the lung. We report a primary esophageal GIST with direct invasion into the lung parenchyma, presenting predominantly with respiratory symptoms. We include a retrospective literature review. Although the principle 'common things are common' usually guides our everyday clinical practice, this case emphasizes that rare entities can mimic common pathologies and underlines the importance of having a clearly defined differential diagnostic list which should be meticulously scrutinized.

  3. Ileocolic intussusception secondary to gastrointestinal stromal tumor in a 61-year-old.

    Science.gov (United States)

    Gelabert, Christopher; Torradas, Jose; Nelson, Mathew

    2014-10-01

    Intussusception is a common emergency in patients age of 3 months to 5 years. In adults, the diagnosis is infrequent but must be considered in the clinical setting of abdominal pain and vomiting. We present a case of a 61-year-old woman presenting with epigastric abdominal pain and vomiting, diagnosed with intussusception secondary to gastrointestinal stromal tumor. Serial bedside ultrasound examinations uncovered the diagnosis of intussusception, confirmed by computed tomographic scan during a paroxysm of pain. Intussusception has a much higher predilection for neoplasms in adults, with a high morbidity and mortality, so early recognition is critical in improving patient outcomes.

  4. Multifocal gastrointestinal stromal tumor (GIST) of the stomach in an 11-year-old girl

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jin [University of North Carolina Hospitals, Department of Radiology, Chapel Hill, NC (United States); Rubinas, Tara C. [University of North Carolina Hospitals, Department of Pathology, Chapel Hill, NC (United States); Fordham, Lynn A. [University of North Carolina School of Medicine, Department of Radiology, Chapel Hill, NC (United States); Phillips, J.D. [University of North Carolina School of Medicine, Department of Surgery, Division of Pediatric Surgery, Chapel Hill, NC (United States)

    2006-11-15

    A previously healthy 11-year-old girl presented with an 8-month history of anemia and left upper quadrant abdominal pain. US examination demonstrated a 9-cm cystic mass with a fluid-fluid level in the left upper quadrant with unclear organ of origin. Abdominal MR imaging demonstrated a complex cystic mass, likely arising from the stomach. Additional T2 hyperintense submucosal lesions were identified in the gastric wall. Surgical excision confirmed the diagnosis of multifocal gastric gastrointestinal stromal tumor (GIST). MR imaging was helpful in suggesting a gastric origin of the primary mass and in demonstrating multifocal disease within the stomach. (orig.)

  5. Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors.

    Science.gov (United States)

    Obata, Y; Horikawa, K; Takahashi, T; Akieda, Y; Tsujimoto, M; Fletcher, J A; Esumi, H; Nishida, T; Abe, R

    2017-06-29

    Gastrointestinal stromal tumors (GISTs) are caused by gain-of-function mutations in the Kit receptor tyrosine kinase. Most primary GIST patients respond to the Kit inhibitor imatinib, but this drug often becomes ineffective because of secondary mutations in the Kit kinase domain. The characteristic intracellular accumulation of imatinib-sensitive and -resistant Kit protein is well documented, but its relationship to oncogenic signaling remains unknown. Here, we show that in cancer tissue from primary GIST patients as well as in cell lines, mutant Kit accumulates on the Golgi apparatus, whereas normal Kit localizes to the plasma membrane (PM). In imatinib-resistant GIST with a secondary Kit mutation, Kit localizes predominantly on the Golgi apparatus. Both imatinib-sensitive and imatinib-resistant Kit (Kit(mut)) become fully auto-phosphorylated only on the Golgi and only if in a complex-glycosylated form. Kit(mut) accumulates on the Golgi during the early secretory pathway, but not after endocytosis. The aberrant kinase activity of Kit(mut) prevents its export from the Golgi to the PM. Furthermore, Kit(mut) on the Golgi signals and activates the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway, signal transducer and activator of transcription 5 (STAT5), and the Mek-Erk pathway. Blocking the biosynthetic transport of Kit(mut) to the Golgi from the endoplasmic reticulum inhibits oncogenic signaling. PM localization of Kit(mut) is not required for its signaling. Activation of Src-family tyrosine kinases on the Golgi is essential for oncogenic Kit signaling. These results suggest that the Golgi apparatus serves as a platform for oncogenic Kit signaling. Our study demonstrates that Kit(mut)'s pathogenicity is related to its mis-localization, and may offer a new strategy for treating imatinib-resistant GISTs.

  6. Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia.

    Science.gov (United States)

    Geyh, S; Rodríguez-Paredes, M; Jäger, P; Khandanpour, C; Cadeddu, R-P; Gutekunst, J; Wilk, C M; Fenk, R; Zilkens, C; Hermsen, D; Germing, U; Kobbe, G; Lyko, F; Haas, R; Schroeder, T

    2016-03-01

    Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.

  7. Prognostic Value of Her2/neu Expression in Gastrointestinal Stromal Tumors: Immunohistochemical Study

    Directory of Open Access Journals (Sweden)

    Ahmed M Abd El-Aziz

    2017-02-01

    Full Text Available Background: Gastrointestinal stromal tumor (GIST is a relatively rare type of neoplasms. In Egypt, it represents 2.5% of gastrointestinal tumors and 0.3% of all malignancies. Most of the GISTs develop in the stomach. Aim: To reveal the significance of Her2/neu immunohistochemical expression in GIST and its correlation with other histopathologic parameters and tumor relapse after regular follow-up. Patients and methods: This study is a retrospective and prospective cohort. It included 32 patients with GISTs, who were resectable with no distant metastasis. Immunohistochemical staining by Her2/neu was performed after complete surgical resection of the tumors with preservation of the pseudocapsule. Results: In total, 53.1% of cases were men and 46.9% women. Tumors were classified into low-risk (25%, intermediate-risk (21.9%, and high-risk groups (53.1%. Her2/neu expression was negative in 56.3% of GISTs and positive in 43.7%. Its expression was significantly correlated with risk grade ( P = .04, tumor size ( P = .001, mitotic count ( P = .00, and increased risk of relapse ( P = .00. Furthermore, tumor relapse was significantly correlated with the tumor mitotic counts ( P = .00. Using kappa agreement test, it showed that 4 mitotic counts/50 high-power fields (HPF was the cutoff value with which the tumor might be associated more with relapse, with 83% sensitivity, 70% specificity, and P value of .003. Conclusions: Her2/neu might be used as an independent prognostic marker for tumor recurrence after complete resection of GIST, and the cutoff value of mitotic count that might predict tumor relapse is 4/50 HPF. However, more clinical studies with greater number of cases with fluorescent in situ hybridization integration are recommended.

  8. Prognostic Value of Her2/neu Expression in Gastrointestinal Stromal Tumors: Immunohistochemical Study

    Science.gov (United States)

    Abd El-Aziz, Ahmed M; Ibrahim, Eman A; Abd-Elmoghny, Ashraf; El-Bassiouny, Mohammed; Laban, Zina M; Saad El-Din, Somaia A; Shohdy, Youhanna

    2017-01-01

    Background: Gastrointestinal stromal tumor (GIST) is a relatively rare type of neoplasms. In Egypt, it represents 2.5% of gastrointestinal tumors and 0.3% of all malignancies. Most of the GISTs develop in the stomach. Aim: To reveal the significance of Her2/neu immunohistochemical expression in GIST and its correlation with other histopathologic parameters and tumor relapse after regular follow-up. Patients and methods: This study is a retrospective and prospective cohort. It included 32 patients with GISTs, who were resectable with no distant metastasis. Immunohistochemical staining by Her2/neu was performed after complete surgical resection of the tumors with preservation of the pseudocapsule. Results: In total, 53.1% of cases were men and 46.9% women. Tumors were classified into low-risk (25%), intermediate-risk (21.9%), and high-risk groups (53.1%). Her2/neu expression was negative in 56.3% of GISTs and positive in 43.7%. Its expression was significantly correlated with risk grade (P = .04), tumor size (P = .001), mitotic count (P = .00), and increased risk of relapse (P = .00). Furthermore, tumor relapse was significantly correlated with the tumor mitotic counts (P = .00). Using kappa agreement test, it showed that 4 mitotic counts/50 high-power fields (HPF) was the cutoff value with which the tumor might be associated more with relapse, with 83% sensitivity, 70% specificity, and P value of .003. Conclusions: Her2/neu might be used as an independent prognostic marker for tumor recurrence after complete resection of GIST, and the cutoff value of mitotic count that might predict tumor relapse is 4/50 HPF. However, more clinical studies with greater number of cases with fluorescent in situ hybridization integration are recommended. PMID:28469470

  9. Bystander killing effect of tymidine kinase gene-transduced adult bone marrow stromal cells with ganciclovir on malignant glioma cells.

    Science.gov (United States)

    Mori, Kentaro; Iwata, Junko; Miyazaki, Masahiro; Osada, Hideo; Tange, Yuichi; Yamamoto, Takuji; Aiko, Yasuhisa; Tamura, Masaru; Shiroishi, Toshihiko

    2010-01-01

    Transduction of the suicide gene of Herpes simplex virus thymidine kinase (Hsv-tk) into glioma cells or neural stem cells combined with pro-drug ganciclovir (GCV) treatment has been effective to treat experimental glioma in the rat through the bystander effect. Bone marrow stromal cells (MSCs) in the adult bone marrow have tropism for brain tumors and act as tumor stromal cells. Whether adult MSCs expressing Hsv-tk can also act as effector cells of the bystander killing effect on murine glioma cells was investigated. In vitro study of co-culture between 9L/LacZ (9L) glioma cells and Hsv-tk-transduced MSCs (MSCs/tk(+)) followed by GCV administration in the culture medium resulted in apparent nuclear morphological changes in the 9L glioma cells surrounding the MSCs/tk(+). 9L glioma cell survival in the presence of MSCs/tk(+) and GCV treatment was quantitatively measured and showed significant decrease of 9L glioma cell proliferation with higher MSCs/tk(+) ratio and GCV concentration. Intracerebral co-inoculation experiments in Fisher rats used 9L glioma cells and either MSCs/tk(+) or Hsv-tk-non-transduced MSCs (MSCs/tk(-)) followed by intraperitoneal injection of GCV (100 mg/kg, daily for 7 days). The animals co-inoculated with 9L glioma cells and MSCs/tk(+) showed significant retardation of tumor growth and prolongation of survival time compared with the animals with 9L glioma cells and MSCs/tk(-). Quantitative findings were established of the novel effects of adult MSCs/tk(+) as effector cells of the bystander killing effect on glioma cells.

  10. Ovarian cancer cells stimulate uPA gene expression in fibroblastic stromal cells via multiple paracrine and autocrine mechanisms.

    Science.gov (United States)

    Noskova, Vera; Ahmadi, Sara; Asander, Eleonor; Casslén, Bertil

    2009-10-01

    Expression of uPA mRNA is massively up-regulated in the stroma of poorly differentiated ovarian tumors. We hypothesized that this expression was induced by paracrine signals from the epithelial tumor cells, and established an in vitro model of ovarian cancer microenvironment to study intercellular cross-talk. ES-2 clear cell carcinoma cells were grown in tissue culture inserts in a double-chamber system with fibroblastic stromal LEP cells embedded in Matrigel. Binding-site directed antibodies were used to neutralize soluble cytokines in ES-2 conditioned medium (CM) before incubation with LEP cells. Real time PCR measured uPA mRNA in LEP cells, as well as mRNA for cytokines in both cell types. Co-culture with ES-2 cells as well as incubation with ES-2 CM induced uPA mRNA in LEP cells about two-fold. In short time (12 h) incubation of LEP cells with CM, antibodies to EGF and bFGF reduced induction of uPA mRNA, suggesting that these cytokines function as paracrine signals. EGF mRNA and bFGF mRNA were also found in ES-2 cells. At longer incubation (24 h) antibodies to bFGF, HB-EGF, HGF, IGF-1, and IL-1alpha reduced uPA mRNA induction, suggesting an autocrine function for these cytokines in LEP cells. In fact, expression of the same five cytokines was up-regulated in LEP cells exposed to CM. We identified two cytokines as paracrine signals, and five cytokines as autocrine signals in ovarian cancer cell induced up-regulation of uPA mRNA in stromal fibroblastic cells. It is crucial to understand intra-tumoral cross-talk, since it can offer new therapeutic approaches.

  11. Gene methylation of human ovarian carcinoma stromal progenitor cells promotes tumorigenesis.

    Science.gov (United States)

    Ho, Chih-Ming; Shih, Daniel Tzu-Bi; Hsiao, Chih-Chiang; Huang, Shih-Hung; Chang, Shwu-Fen; Cheng, Wen-Fang

    2015-11-23

    This study aimed to investigate whether the DNA methylation of human ovarian carcinoma stromal progenitor cells (OCSPCs) could promote the tumorigenesis of ovarian carcinoma. OCSPCs were first isolated from fresh tumor tissues and ascites of ovarian cancer patients. In vivo and in vitro experiments on the effect of the OCSPCs on tumorigenesis and the effects of DNA demethylation on the OCSPCs were then performed. The OCSPCs possessed self-renewal and multipotent differentiation capacity with elevated expressions of OCT4, NANOG, BMP2, BMP4, Rex-1, AC133 and TGF-β. The OCSPCs, when combined with tumor cells in vivo could promote tumor growth. The methylation profiles of tumor suppressor genes (TSGs) were significantly higher in the OCSPCs than in ovarian cancer cells (p cells. The expression levels of TSGs were re-expressed by 5-aza-2-dC to inhibit the self-renewal and growth of OCSPCs. OCSPCs with decreased TSG expressions in the ovarian tumor microenvironment were able to promote tumorigenesis which could be reversed by DNA demethylation. DNA demethylation reversing the expression of TSGs in OCSPCs may represent a potential therapeutic target for ovarian cancer.

  12. Cryopreservation and revival of mesenchymal stromal cells

    DEFF Research Database (Denmark)

    Haack-Sørensen, Mandana; Kastrup, Jens

    2011-01-01

    ) opens up new possibilities for cell therapy. To facilitate these applications, cryopreservation and long-term storage of MSCs becomes an absolute necessity. As a result, optimization of this cryopreservation protocol is absolutely critical. The major challenge during cellular cryopreservation...... is the lethality associated with the cooling and thawing processes. The major objective is to minimize damage to cells during low temperature freezing and storage and the use of a suitable cryoprotectant. The detrimental effects of cellular cryopreservation can be minimized by controlling the cooling rate, using...... better cryoprotective agents, maintaining appropriate storage temperatures, and controlling the cell thawing rate. As is described in this chapter, human MSCs can either be frozen in cryovials or in freezing bags together with cryopreserve solutions containing dimethyl sulfoxide (DMSO)....

  13. Multiparameter Analysis of Human Bone Marrow Stromal Cells Identifies Distinct Immunomodulatory and Differentiation-Competent Subtypes

    NARCIS (Netherlands)

    S. James (Sally); J. Fox (James); F. Afsari (Farinaz); J. Lee (Jennifer); S. Clough (Sally); C. Knight (Charlotte); J. Ashmore (James); P. Ashton (Peter); O. Preham (Olivier); M.J. Hoogduijn (Martin); R.D.A.R. Ponzoni (Raquel De Almeida Rocha); Y. Hancock; M. Coles (Mark); P.G. Genever (Paul)

    2015-01-01

    textabstractBone marrow stromal cells (BMSCs, also called bone-marrow-derived mesenchymal stromal cells) provide hematopoietic support and immunoregulation and contain a stem cell fraction capable of skeletogenic differentiation. We used immortalized human BMSC clonal lines for multi-level analysis

  14. The role of stromal cells in inflammatory bone loss.

    Science.gov (United States)

    Wehmeyer, C; Pap, T; Buckley, C D; Naylor, A J

    2017-07-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation, local and systemic bone loss and a lack of compensatory bone repair. Fibroblast-like synoviocytes (FLS) are the most abundant cells of the stroma and a key population in autoimmune diseases such as RA. An increasing body of evidence suggests that these cells play not only an important role in chronic inflammation and synovial hyperplasia, but also impact bone remodelling. Under inflammatory conditions FLS release inflammatory cytokines, regulate bone destruction and formation and communicate with immune cells to control bone homeostasis. Other stromal cells, such as osteoblasts and terminally differentiated osteoblasts, termed osteocytes, are also involved in the regulation of bone homeostasis and are dysregulated during inflammation. This review highlights our current understanding of how stromal cells influence the balance between bone formation and bone destruction. Increasing our understanding of these processes is critical to enable the development of novel therapeutic strategies with which to treat bone loss in RA. © 2017 British Society for Immunology.

  15. Anchored and soluble gangliosides contribute to myelosupportivity of stromal cells

    Energy Technology Data Exchange (ETDEWEB)

    Ziulkoski, Ana L. [Programa de Pos-Graduacao em Ciencias Biologicas: Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Departamento de Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Instituto de Ciencias da Saude, Centro Universitario Feevale, Novo Hamburgo, RS (Brazil); Santos, Aline X.S. dos; Andrade, Claudia M.B.; Trindade, Vera M.T. [Programa de Pos-Graduacao em Ciencias Biologicas: Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Departamento de Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Daniotti, Jose Luis [Departamento de Quimica Biologica, Faculdad de Ciencias Quimicas, Universidad Nacional de Cordoba, Cordoba (Argentina); Borojevic, Radovan [Departamento de Histologia e Embriologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro (Brazil); Guma, Fatima C.R., E-mail: fatima.guma@ufrgs.br [Programa de Pos-Graduacao em Ciencias Biologicas: Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Departamento de Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil)

    2009-10-09

    Stroma-mediated myelopoiesis depends upon growth factors and an appropriate intercellular microenvironment. Previous studies have demonstrated that gangliosides, produced by hepatic stromal cell types, are required for optimal myelosupportive function. Here, we compared the mielossuportive functions of a bone marrow stroma (S17) and skin fibroblasts (SF) regarding their ganglioside pattern of synthesis and shedding. The survival and proliferation of a myeloid precursor cell (FDC-P1) were used as reporter. Although the ganglioside synthesis of the two stromal cells was similar, their relative content and shedding were distinct. The ganglioside requirement for mielossuportive function was confirmed by the decreased proliferation of FDC-P1 cells in ganglioside synthesis-inhibited cultures and in presence of an antibody to GM3 ganglioside. The distinct mielossuportive activities of the S17 and SF stromata may be related to differences on plasma membrane ganglioside concentrations or to differences on the gangliosides shed and their subsequent uptake by myeloid cells, specially, GM3 ganglioside.

  16. Mesenchymal Stromal Cells as Active Regulators of Lymphocyte Recruitment to Blood Vascular Endothelial Cells.

    Science.gov (United States)

    Mcgettrick, Helen M; Ward, Lewis S C; Rainger, George Edward; Nash, Gerard B

    2017-01-01

    Methods are described for analyzing adhesion and migration of isolated lymphocytes on endothelial cell monolayers which have been cocultured with different mesenchymal stromal cells, with or without additional cytokine treatment. The different cells types are grown on opposite sides of 3.0 or 0.4 μm pore filters, depending on whether migration through the whole construct is to be analyzed, or adhesion to the endothelial cells alone. Migration away from the sub-endothelial space and through the stromal layer can also be assessed by culturing mesenchymal stromal cells within a 3-D collagen gel overlaid with endothelial cells. Assays may be "static" or the filter-based constructs can be incorporated into flow chambers so that cell behavior can be directly observed under conditions simulating those in vivo. In general, by choice of method, one can evaluate efficiency of attachment, and ability of cells to migrate across the endothelial monolayer, through the filter and through the stromal cell layer in 2-D or 3-D. Fluorescence microscopic examination of fixed filters can be used, e.g., to ascertain whether lymphocytes are retained by stromal cells. In general, static assays have the higher throughput and greatest ease of use, while the flow-based assays are more physiologically relevant and allow detailed recording of cell behavior in real time.

  17. Endoscopic en bloc resection of an exophytic gastrointestinal stromal tumor with suction excavation technique.

    Science.gov (United States)

    Choi, Hyuk Soon; Chun, Hoon Jai; Kim, Kyoung-Oh; Kim, Eun Sun; Keum, Bora; Jeen, Yoon-Tae; Lee, Hong Sik; Kim, Chang Duck

    2016-06-21

    Here, we report the first successful endoscopic resection of an exophytic gastrointestinal stromal tumor (GIST) using a novel perforation-free suction excavation technique. A 49-year-old woman presented for further management of a gastric subepithelial tumor on the lesser curvature of the lower body, originally detected via routine upper gastrointestinal endoscopy. Abdominal computed tomography and endoscopic ultrasound showed a 4-cm extraluminally protruding mass originating from the muscularis propria layer. The patient firmly refused surgical resection owing to potential cardiac problems, and informed consent was obtained for endoscopic removal. Careful dissection and suction of the tumor was repeated until successful extraction was achieved without serosal injury. We named this procedure the suction excavation technique. The tumor's dimensions were 3.5 cm × 2.8 cm × 2.5 cm. The tumor was positive for C-KIT and CD34 by immunohistochemical staining. The mitotic count was 6/50 high-power fields. The patient was followed for 5 years without tumor recurrence. This case demonstrated the use of endoscopic resection of an exophytic GIST using the suction excavation technique as a potential therapy without surgical resection.

  18. Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients.

    Science.gov (United States)

    Seiz, Lina; Dorn, Julia; Kotzsch, Matthias; Walch, Axel; Grebenchtchikov, Nicolai I; Gkazepis, Apostolos; Schmalfeldt, Barbara; Kiechle, Marion; Bayani, Jane; Diamandis, Eleftherios P; Langer, Rupert; Sweep, Fred C G J; Schmitt, Manfred; Magdolen, Viktor

    2012-04-01

    Several members of the human kallikrein-related peptidase family, including KLK6, are up-regulated in ovarian cancer. High KLK6 mRNA or protein expression, measured by quantitative polymerase chain reaction and enzyme-linked immunoassay, respectively, was previously found to be associated with a shortened overall and progression-free survival (OS and PFS, respectively). In the present study, we aimed at analyzing KLK6 protein expression in ovarian cancer tissue by immunohistochemistry. Using a newly developed monospecific polyclonal antibody, KLK6 immunoexpression was initially evaluated in normal tissues. We observed strong staining in the brain and moderate staining in the kidney, liver, and ovary, whereas the pancreas and the skeletal muscle were unreactive, which is in line with previously published results. Next, both tumor cell- and stromal cell-associated KLK6 immunoexpression were analyzed in tumor tissue specimens of 118 ovarian cancer patients. In multivariate Cox regression analysis, only stromal cell-associated expression, besides the established clinical parameters FIGO stage and residual tumor mass, was found to be statistically significant for OS and PFS [high vs. low KLK6 expression; hazard ratio (HR), 1.92; p=0.017; HR, 1.80; p=0.042, respectively]. These results indicate that KLK6 expressed by stromal cells may considerably contribute to the aggressiveness of ovarian cancer.

  19. Multiple malignant extragastrointestinal stromal tumors of the greater omentum and results of immunohistochemistry and mutation analysis: A case report

    OpenAIRE

    Kim, Jong-Han; Boo, Yoon-Jung; Jung, Cheol-Woong; Park, Sung-Soo; Kim, Seung-Joo; Mok, Young-Jae; Kim, Sang-Dae; Chae, Yang-Suk; Kim, Chong-Suk

    2007-01-01

    To report an extragastrointestinal stromal tumor (EGIST) that occurs outside the gastrointestinal tract and shows unique clinicopathologic and immunohistochemical features. In our case, we experienced multiple soft tissue tumors that originate primarily in the greater omentum, and in immunohistochemical analysis, the tumors showed features that correspond to malignant EGIST. Two large omental masses measured 15 cm x 10 cm and 5 cm × 4 cm sized and several small ovoid fragments were attached t...

  20. A subset of high Gleason grade prostate carcinomas contain a large burden of prostate cancer syndecan-1 positive stromal cells.

    Science.gov (United States)

    Sharpe, Benjamin; Alghezi, Dhafer A; Cattermole, Claire; Beresford, Mark; Bowen, Rebecca; Mitchard, John; Chalmers, Andrew D

    2017-05-01

    There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility. Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters. We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells. The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma

  1. Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/β-catenin pathway.

    Science.gov (United States)

    Chang, Po-Hao; Hwang-Verslues, Wendy W; Chang, Yi-Cheng; Chen, Chun-Chin; Hsiao, Michael; Jeng, Yung-Ming; Chang, King-Jen; Lee, Eva Y-H P; Shew, Jin-Yuh; Lee, Wen-Hwa

    2012-09-15

    Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-catenin into nucleus, leading to downregulation of c-myc and cyclin D1 via the phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in patients with breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and show that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes.

  2. Multifocal Tumorous Pseudoangiomatous Stromal Hyperplasia Presenting as Asymmetric Bilateral Breast Enlargement.

    Science.gov (United States)

    Vasconcelos, I; Perez Fernandez, C M; Günzel, S; Schoenegg, W

    2015-02-01

    PASH is a benign proliferation of stromal myofibroblasts that affects mostly premenopausal women and typically shows estrogen and progesterone receptor expression, allowing speculation regarding a hormonal cause. It usually presents as an incidental finding on a mammogram or as a palpable mass. We present a case of diffuse asymmetrical massive breast enlargement in a premenopausal woman with history of previous multiple PASH excisions for recurrent lesions, caused by multifocal tumorous PASH virtually replacing the breast parenchyma. Immunohistochemistry examination showed no hormone receptor expression. Despite its benign nature, such presentation of PASH is managed with bilateral mastectomy and immediate reconstruction with expanders for cosmetic and comfort reasons, while tumor excision or expectant management is deemed to lead to recurrence and progression. Although a hormonal origin is speculated based on hormone expression studies and typical patient profile, this case showed 0 % estrogen/progesterone expression in the final histology specimen.

  3. Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis.

    Science.gov (United States)

    Trukhacheva, Elena; Lin, Zhihong; Reierstad, Scott; Cheng, You-Hong; Milad, Magdy; Bulun, Serdar E

    2009-02-01

    Estradiol and its nuclear receptors, estrogen receptor (ER) alpha and ERbeta, play critical roles in endometrium and endometriosis. Levels of ERbeta, due to pathological hypomethylation of its promoter, are significantly higher in endometriotic vs. endometrial tissue and stromal cells, whereas ERalpha levels are lower in endometriosis. Estradiol regulates ERalpha gene expression via its alternatively used promoters A, B, and C. The aim of the study was to determine whether high levels of ERbeta in endometriotic stromal cells from ovarian endometriomas regulate ERalpha gene expression. ERbeta knockdown significantly increased ERalpha mRNA and protein levels in endometriotic stromal cells. Conversely, ERbeta overexpression in endometrial stromal cells decreased ERalpha mRNA and protein levels. ERbeta knockdown significantly decreased proliferation of endometriotic stromal cells. Chromatin immunoprecipitation assays demonstrated that estradiol enhanced ERbeta binding to nonclassical activator protein 1 and specificity protein 1 motifs in the ERalpha gene promoters A and C and a classic estrogen response element in promoter B in endometriotic stromal cells. High levels of ERbeta suppress ERalpha expression and response to estradiol in endometrial and endometriotic stromal cells via binding to classic and nonclassic DNA motifs in alternatively used ERalpha promoters. ERbeta also regulates cell cycle progression and might contribute to proliferation of endometriotic stromal cells. We speculate that a significantly increased ratio of ERbeta:ERalpha in endometriotic tissues may also suppress progesterone receptor expression and contribute to progesterone resistance. Thus, ERbeta may serve as a significant therapeutic target for endometriosis.

  4. A sclerosing stromal tumor of the ovary with masculinization in a premenarchal girl

    Directory of Open Access Journals (Sweden)

    Soo Min Park

    2011-05-01

    Full Text Available A sclerosing stromal tumor of the ovary is an extremely rare benign tumor; it usually is found during the second and third decades of life. Patients present with pelvic pain or a palpable abdominal mass. Hormonal effects such as masculinization are uncommon. Here, an 11-year old premenarchal girl presented with deepening of the voice. In addition, clitoromegaly and hirsutism with a male suprapubic hair pattern were observed. The laboratory findings showed that the testosterone level was elevated to 3.67 ng/mL, andostenedione to above 10 ng/mL, dehydroepiandrosterone-sulfate to 346 μg/dL and 17-hydroxy progesterone (17-OHP to 11.28 ng/mL. The chromosome evaluation revealed a 46,XX female karyotype. An adrenocorticotropic hormone stimulation test was performed. The 17-OHP to cortisol ratio in 30 minutes was 0.045, which suggested a heterozygote for the 21-hydroxylase deficiency. However, the CYP21A2 gene encoding steroid 21-hydroxylase showed normal. The pelvic ultrasound showed a heterogeneous mass consisting of predominantly solid tissue in the pelvic cavity. The pelvic magnetic resonance imaging revealed an 8.9× 6.2×6.6 cm mass of the left ovary. A left oophrectomy was performed and microscopic examination confirmed a sclerosing stromal tumor. Immunohistochemical studies showed that the tumor was positive for smooth muscle actin and vimentin, but negative for S-100 protein and cytokeratin. Following surgery, the hormone levels returned to the normal range and the hirsutism resolved.

  5. A malignant omental extra-gastrointestinal stromal tumor on a young man: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Almaroof Babatunde

    2008-05-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GIST are uncommon intra-abdominal tumors. These tumors tend to present with higher frequency in the stomach and small bowel. In fewer than 5% of cases, they originate primarily from the mesentery, omentum, or peritoneum. Furthermore, these extra-gastrointestinal tumors (EGIST tend to be more common in patients greater than 50 years of age. Rarely do EGIST tumors present in those younger than 40 years of age. Case presentation We report a case of a large EGIST in a 27-year-old male. An abdominal pelvic computerized tomography imaging demonstrated an intra-abdominal mass of 22 cm, without invasion of adjacent viscera or liver lesions. This mass was resected en bloc with its fused omentum and an adherent portion of sigmoid colon. Pathology results demonstrated a malignant gastrointestinal stromal tumor with positive CD117 (c-kit staining, and negative margins of resection, and no continuity of tumor with the sigmoid colon. Due to the malignant and aggressive nature of this patient's tumor, he was started on STI-571 as adjuvant chemotherapy. Conclusion Stromal tumors of an extra-gastrointestinal origin are rare. Of the reported omental and mesenteric EGISTs in four published series, a total of 99 tumors were studied. Of the 99 patients in these series only 8 were under 40 years of age, none were younger than 30 years old; and only 5 were younger than 35 years old. Our patient's age is at the lower end of the age spectrum for the reported EGISTs. Young patients who present with an extra-gastrointestinal stromal tumor (EGIST, who have complete resection with negative margins, have a good prognosis. There is little data to support the role of STI-571 in adjuvant or neoadjuvant therapy after curative resection. Given the lack of data, the use of STI-571 must be individualized.

  6. Senescence and quiescence in adipose-derived stromal cells

    DEFF Research Database (Denmark)

    Søndergaard, Rebekka Harary; Follin, Bjarke; Lund, Lisbeth Drozd

    2017-01-01

    cycle regulation and expression of cyclins, p21 and p27. hPL rejuvenates FBS-expanded ASCs with regard to cell cycle regulation and expression of cyclins, p21 and p27. This indicates a reversible arrest. Therefore, we conclude that ASCs expanded until P7 are not senescent regardless of culture......Background aims. Adipose-derived stromal cells (ASCs) are attractive sources for cell-based therapies. The hypoxic niche of ASCs in vivo implies that cells will benefit from hypoxia during in vitro expansion. Human platelet lysate (hPL) enhances ASC proliferation rates, compared with fetal bovine...... serum (FBS) at normoxia. However, the low proliferation rates of FBS-expanded ASCs could be signs of senescence or quiescence. We aimed to determine the effects of hypoxia and hPL on the expansion of ASCs and whether FBS-expanded ASCs are senescent or quiescent. Methods. ASCs expanded in FBS or h...

  7. Metastatic Ovarian Cancer Can Be Efficiently Treated by Genetically Modified Mesenchymal Stromal Cells.

    Science.gov (United States)

    Toro, Lenka; Bohovic, Roman; Matuskova, Miroslava; Smolkova, Bozena; Kucerova, Lucia

    2016-08-16

    Due to late diagnosis, often recurrence, formation of metastases and resistance to commonly used chemotherapeutics human ovarian carcinoma represents a serious disease with high mortality. Adipose tissue-derived mesenchymal stromal cells (AT-MSC) can serve as vehicles for therapeutic genes and we engineered AT-MSC to express either Herpes simplex virus thymidine kinase (HSVtk-MSC), which phosphorylates ganciclovir (GCV) to its toxic metabolites or yeast fused cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT-MSC), which converts 5-fluorocytosine (5-FC) to highly toxic 5-fluorouracil (5-FU). Here, we reported different responses of cytotoxicity mediated by CD::UPRT-MSC/5-FC treatment on human ovarian carcinoma cell lines-SKOV-3 and A2780 used in adherent or three-dimensional (3D) cell culture and we proved high potential of 3D model to predict results in our in vivo experiments. Both tumor cell lines showed similarly high chemosensitivity to the used treatment in adherent culture, but 3D model revealed severe discrepancy-only 36% of SKOV-3 cells but even 90% of A2780 cells were eliminated. This result served as a prognostic marker-we were able to achieve significantly decreased tumor volumes of subcutaneous xenografts of A2780 cells in nude mice and we prolonged tumor-free survival in 33% of animals bearing highly metastatic ovarian carcinoma after CD::UPRT-MSC/5-FC treatment.

  8. Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells

    OpenAIRE

    Burgett, M E; Lathia, J D; Roth, P.; Nowacki, A S; Galileo, D S; Pugacheva, E.; Huang, P.; Vasanji, A.; Li, M.; Byzova, T; Mikkelsen, T; Bao, S.; Rich, J N; Weller, M.; Gladson, C. L.

    2016-01-01

    The secretion of soluble pro-angiogenic factors by tumor cells and stromal cells in the perivascular niche promotes the aggressive angiogenesis that is typical of glioblastoma (GBM). Here, we show that angiogenesis also can be promoted by a direct interaction between brain tumor cells, including tumor cells with cancer stem-like properties (CSCs), and endothelial cells (ECs). As shown in vitro, this direct interaction is mediated by binding of integrin ?v?3 expressed on ECs to the RGD-peptide...

  9. Reduction of stromal fibroblast-induced mammary tumor growth, by retroviral ribozyme transgenes to hepatocyte growth factor/scatter factor and its receptor, c-MET.

    Science.gov (United States)

    Jiang, Wen G; Grimshaw, David; Martin, Tracey A; Davies, Gaynor; Parr, Christian; Watkins, Gareth; Lane, Jane; Abounader, Roger; Laterra, John; Mansel, Robert E

    2003-09-15

    Hepatocyte growth factor/scatter factor (HGF/SF) is known to increase the invasiveness and migration of cancer cells in vitro and induce angiogenesis. This study examined if inhibition of HGF/SF receptor expression by cancer cells and HGF/SF expression by stromal fibroblasts affects the growth of mammary cancer. Transgenes encoding ribozymes to specifically target human HGF/SF receptor (pLXSN-MET) or HGF/SF (pLXSN-HGF) were constructed using a pLXSN retroviral vector. Human mammary cancer cells MDA MB 231 was transduced with pLXSN-MET (MDA(+/+)). A human fibroblast cell line MRC5, which produces bioactive HGF/SF, was transduced with pLXSN-HGF (MRC5(+/+)). These cells were used in a nude mice breast tumor model. HGF receptor in MDA(+/+) cells and HGF in MRC5(+/+)cells were successfully removed with respective ribozymes as shown by reverse transcription-PCR and Western blotting, respectively. MDA(+/+) was found to have reduced invasiveness when stimulated with HGF/SF. MRC5(+/+) exhibited a significant reduction in HGF/SF production. When injected into athymic nude mice, MDA(+/+) exhibited a slower rate of growth, compared with the wild type (MDA(-/-)), and the cells transduced with control viral vector (MDA(+/-)). The growth of MDA(-/-) tumor was significantly enhanced when coimplanted with wild-type MRC5 (MRC5(-/-)), and the stimulatory effect was reduced when MRC5(+/+) cells were coimplanted instead of MRC5(-/-). The reduction of tumor growth was accompanied by reduction of angiogenesis, as demonstrated by the staining of VE-cadherin in primary tumor tissues. Retroviral ribozyme transgenes targeting HGF/SF in fibroblasts or its receptor cMET in mammary cancer cells can reduce the growth of mammary cancer and associated angiogenesis by inhibiting paracrine stromal-tumor cell interactions.

  10. PhiC31/PiggyBac modified stromal stem cells: effect of interferon γ and/or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on murine melanoma.

    Science.gov (United States)

    Bahrambeigi, Vahid; Ahmadi, Nafiseh; Moisyadi, Stefan; Urschitz, Johann; Salehi, Rasoul; Haghjooy Javanmard, Shaghayegh

    2014-11-26

    TRAIL and IFNγ are promising anti-cancer cytokines and it has been shown that IFNγ may sensitize cancer cells to TRAIL. Adipose derived mesenchymal stem cells (ADSCs) are attractive vehicles for delivering anti-cancer agents. In this study, we evaluated the therapeutic potential of PhiC31 (φC31) recombinase and/or piggyBac transposase (pBt) modified ADSCs expressing either TRAIL, IFNγ, or co-expressing TRAIL/IFNγ in mouse models of melanoma. The expression and bioactivity of mouse IFNγ and TRAIL in φC31 and pBt modified cells were confirmed. We examined the effects of modified ADSCs on signal intensity of red fluorescence protein expressed by melanoma cells in subcutaneous tumors or established lung metastases and on survival (6 mice per group). We also conducted a flow cytometric analysis of systemic CD4(+)CD25(+)FOXP3(+) T regulatory cells (Tregs) and histological analysis of melanoma tumors. Data were analyzed by Student t test, ANOVA, and log-rank tests. All statistical tests were two-sided. We demonstrated non-viral DNA-integrating vectors can be used for stable transgene expression. IFNγ inhibited melanoma cell growth in vitro probably via IFNγ-induced JAK/STAT1 signaling pathway activation. Murine TRAIL induced apoptosis in the human cell lines CAOV-4 and Ej-138, while MCF7 and B16F10 cells appeared to be insensitive to TRAIL. Treatment of melanoma cells with IFNγ did not influence their response to TRAIL. In contrast, results from in vivo studies showed that IFNγ-expressing ADSCs, engrafted into tumor stroma, inhibited tumor growth and angiogenesis, prevented systemic increase of Tregs, increased PD-L1 expression and CD8+ infiltration (but not interleukin-2+ cells), and prolonged the survival of mice (68 days, 95% confidence interval [CI] = 52 to 86 days compared to 36 days, 95% CI = 29 to 39 days for control, P < .001). For the first time, we employed DNA integrating vectors for safe and stable modification of MSCs. Our data indicate potential

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  15. Genetic engineering of mesenchymal stromal cells for cancer therapy: turning partners in crime into Trojan horses

    Directory of Open Access Journals (Sweden)

    Niess Hanno

    2016-09-01

    Full Text Available Mesenchymal stromal cells (MSCs are adult progenitor cells with a high migratory and differentiation potential, which influence a broad range of biological functions in almost every tissue of the body. Among other mechanisms, MSCs do so by the secretion of molecular cues, differentiation toward more specialized cell types, or influence on the immune system. Expanding tumors also depend on the contribution of MSCs to building a supporting stroma, but the effects of MSCs appear to go beyond the mere supply of connective tissues. MSCs show targeted “homing” toward growing tumors, which is then followed by exerting direct and indirect effects on cancer cells. Several research groups have developed novel strategies that make use of the tumor tropism of MSCs by engineering them to express a transgene that enables an attack on cancer growth. This review aims to familiarize the reader with the current knowledge about MSC biology, the existing evidence for MSC contribution to tumor growth with its underlying mechanisms, and the strategies that have been developed using MSCs to deploy an anticancer therapy.

  16. Single incision versus conventional laparoscopic resection in gastrointestinal stromal tumors: a retrospective cohort analysis at a single tertiary care center

    Directory of Open Access Journals (Sweden)

    Kong J

    2014-06-01

    Full Text Available Jing Kong, Shuo-Dong Wu, Yang Su, Ying FanChina Medical University Shengjing Hospital, Shenyang, People's Republic of ChinaBackground: Single-incision laparoscopic surgery (SILS, an advanced form of minimally invasive surgery, has recently been used for surgical management of gastrointestinal stromal tumors (GIST. The literature comparing SILS to conventional laparoscopic surgery for treatment of this disease is limited. This study aimed to evaluate the feasibility and effectiveness of SILS compared with conventional laparoscopic resection for GIST.Methods: A retrospective case-cohort study compared the benefits and outcomes of SILS and conventional laparoscopic partial gastrectomy for GIST. Between April 2008 and December 2012, 39 patients underwent laparoscopic gastrectomy for gastric stromal tumors in our department. All operations were performed by a single experienced surgeon. The medical records of these patients were reviewed retrospectively with regard to tumor size, operating time, and other clinical features.Results: SILS resection was performed on 19 patients, whereas 20 patients had conventional laparoscopic resection. Compared with the conventional laparoscopic group, the operative time for the SILS group was shorter, but the time for recovery of gastrointestinal function and postoperative hospital stay for the SILS group was similar to that of the conventional laparoscopic group. No intraoperative or postoperative complications were recorded in either group.Conclusion: Compared with the conventional laparoscopic procedure, SILS in gastric stromal tumors is as feasible and safe when performed by experienced surgeons.Keywords: gastric stromal tumor, SILS

  17. Giant Cell Tumor of Bone - an Overview

    Directory of Open Access Journals (Sweden)

    Anshul Sobti

    2016-01-01

    Full Text Available Giant Cell tumors (GCT are benign tumors with potential for aggressive behavior and capacity to metastasize. Although rarely lethal, benign bone tumors may be associated with a substantial disturbance of the local bony architecture that can be particularly troublesome in peri-articular locations. Its histogenesis remains unclear. It is characterized by a proliferation of mononuclear stromal cells and the presence of many multi- nucleated giant cells with homogenous distribution. There is no widely held consensus regarding the ideal treatment method selection. There are advocates of varying surgical techniques ranging from intra-lesional curettage to wide resection. As most giant cell tumors are benign and are located near a joint in young adults, several authors favor an intralesional approach that preserves anatomy of bone in lieu of resection. Although GCT is classified as a benign lesion, few patients develop progressive lung metastases with poor outcomes. Treatment is mainly surgical. Options of chemotherapy and radiotherapy are reserved for selected cases. Recent advances in the understanding of pathogenesis are essential to develop new treatments for this locally destructive primary bone tumor.

  18. Regenerative Potential of Mesenchymal Stromal Cells: Age-Related Changes.

    Science.gov (United States)

    Bruna, Flavia; Contador, David; Conget, Paulette; Erranz, Benjamín; Sossa, Claudia L; Arango-Rodríguez, Martha L

    2016-01-01

    Preclinical and clinical studies have shown that a therapeutic effect results from mesenchymal stromal cells (MSCs) transplant. No systematic information is currently available regarding whether donor age modifies MSC regenerative potential on cutaneous wound healing. Here, we evaluate whether donor age influences this potential. Two different doses of bone marrow MSCs (BM-MSCs) from young, adult, or old mouse donors or two doses of their acellular derivatives mesenchymal stromal cells (acd-MSCs) were intradermally injected around wounds in the midline of C57BL/6 mice. Every two days, wound healing was macroscopically assessed (wound closure) and microscopically assessed (reepithelialization, dermal-epidermal junction, skin appendage regeneration, granulation tissue, leukocyte infiltration, and density dermal collagen fibers) after 12 days from MSC transplant. Significant differences in the wound closure kinetic, quality, and healing of skin regenerated were observed in lesions which received BM-MSCs from different ages or their acd-MSCs compared to lesions which received vehicle. Nevertheless, our data shows that adult's BM-MSCs or their acd-MSCs were the most efficient for recovery of most parameters analyzed. Our data suggest that MSC efficacy was negatively affected by donor age, where the treatment with adult's BM-MSCs or their acd-MSCs in cutaneous wound promotes a better tissue repair/regeneration. This is due to their paracrine factors secretion.

  19. Regenerative Potential of Mesenchymal Stromal Cells: Age-Related Changes

    Science.gov (United States)

    Bruna, Flavia; Contador, David; Conget, Paulette; Erranz, Benjamín; Sossa, Claudia L.; Arango-Rodríguez, Martha L.

    2016-01-01

    Preclinical and clinical studies have shown that a therapeutic effect results from mesenchymal stromal cells (MSCs) transplant. No systematic information is currently available regarding whether donor age modifies MSC regenerative potential on cutaneous wound healing. Here, we evaluate whether donor age influences this potential. Two different doses of bone marrow MSCs (BM-MSCs) from young, adult, or old mouse donors or two doses of their acellular derivatives mesenchymal stromal cells (acd-MSCs) were intradermally injected around wounds in the midline of C57BL/6 mice. Every two days, wound healing was macroscopically assessed (wound closure) and microscopically assessed (reepithelialization, dermal-epidermal junction, skin appendage regeneration, granulation tissue, leukocyte infiltration, and density dermal collagen fibers) after 12 days from MSC transplant. Significant differences in the wound closure kinetic, quality, and healing of skin regenerated were observed in lesions which received BM-MSCs from different ages or their acd-MSCs compared to lesions which received vehicle. Nevertheless, our data shows that adult's BM-MSCs or their acd-MSCs were the most efficient for recovery of most parameters analyzed. Our data suggest that MSC efficacy was negatively affected by donor age, where the treatment with adult's BM-MSCs or their acd-MSCs in cutaneous wound promotes a better tissue repair/regeneration. This is due to their paracrine factors secretion. PMID:27247575

  20. Tumores del estroma gastrointestinal: Estudio retrospectivo de 43 casos Gastrointestinal stromal tumors: a retrospective study of 43 cases

    Directory of Open Access Journals (Sweden)

    S. Alberto

    2008-11-01

    Full Text Available Introducción: los tumores del estroma gastrointestinal (GIST son poco frecuentes, con una incidencia de 10 a 20 casos por millón de habitantes y año. Aparecen en todo el tubo digestivo, mesenterio o epiplón adyacente; siendo más frecuentes en el estómago (60-70%; también pueden aparecer en el intestino delgado (20-25%, colon y recto (5% y esófago (Background: gastrointestinal stromal tumors (GISTs are rare (10 to 20/million. They exist in the whole digestive system and its surroundings, and are most common in the stomach (70%, followed by the small intestine (20-25%, colon and rectum (5%, and esophagus (< 5%. Their clinical presentation varies from small, incidentally found nodules to large and aggressive tumors. Nowadays GISTs are classified according to Fletcher's classification. Objective: to review the features of our GIST population. Methods: a retrospective study of GIST patients identified by immunohistochemical criteria, from 1997 to December 2007, and classified according to Fletcher's criteria. Results: 43 patients were included (24 men, 19 women with a mean age of 62.7 years. Gastric GISTs (20 cases, 46.5%, small intestine GISTs (18 cases, 41.9%; in 5 cases metastases of occult tumors were found. Eighteen cases had no symptoms. Tumors were classified according to Fletcher's criteria as high-risk (n = 19, intermediate-risk (n = 7, low-risk (n = 12, and indeterminate-risk (n = 5. Death occurred in 10 patients, and 13 patients had metastatic disease. Conclusions: our results are in accordance with the world literature, in which a majority of cases are men with gastric tumors. The 5-year survival rate was 42%. Fletcher's criteria were easily applicable criteria and could predict tumor behavior.

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  13. MicorRNA targeting to modulate tumor microenvironment

    NARCIS (Netherlands)

    Kuninty, Praneeth Reddy; Schnittert, Jonas; Storm, Gerrit; Prakash, Jai

    2016-01-01

    Communication between stromal cells and tumor cells initiates tumor growth, angiogenesis, invasion, and metastasis. Stromal cells include cancer-associated fibroblasts, tumor-associated macrophages, pericytes, endothelial cells, and infiltrating immune cells. MicroRNAs (miRNAs) in the tumor

  14. MicroRNA targeting to modulate tumor microenvironment

    NARCIS (Netherlands)

    Kuninty, Praneeth R.; Schnittert, Jonas; Storm, G|info:eu-repo/dai/nl/073356328; Prakash, Jai

    2016-01-01

    Communication between stromal cells and tumor cells initiates tumor growth, angiogenesis, invasion, and metastasis. Stromal cells include cancer-associated fibroblasts, tumor-associated macrophages, pericytes, endothelial cells, and infiltrating immune cells. MicroRNAs (miRNAs) in the tumor

  15. Granulosa cell tumor of the ovary: a clinicopathological study of six cases

    OpenAIRE

    RC Adhikari; Jha, A; G Shayami

    2011-01-01

    Background: Ovarian granulosa cell tumors are rare malignant neoplasms that originate from the sexcord stromal cells of the ovary. The study aims to collate data of all granulosa cell tumors diagnosed in Tribhuvan University Teaching Hospital over the last 3 years and to describe the incidence, patient profile, ultrasonographic and histopathologic findings in our local context. Materials and Methods: A total of 6 (5%) granulosa cell tumors, diagnosed in Tribhuvan University Teaching Hospital ...

  16. Aspects of surgical treatment for gastro-intestinal stromal tumors; Chirurgische Therapieaspekte gastrointestinaler Stromatumoren

    Energy Technology Data Exchange (ETDEWEB)

    Hohenberger, P. [Medizinische Fakultaet Mannheim, Universitaet Heidelberg, Sektion Chirurgische Onkologie und Thoraxchirurgie, Chirurgische Universitaetsklinik, Mannheim (Germany)

    2009-12-15

    Gastro-intestinal stromal tumors (GIST) form the commonest subgroup of soft tissue sarcomas. They arise in the muscular layer of the esophagus, stomach, small intestines and rectum. Characteristic and important for the assessment of the extent of tumors is the peripheral rim vascularization of primary tumors and metastases. Indications for resection are given for tumors larger than 2 cm in size. Locally advanced GISTs can be advantageously treated with imatinib/sunitinib as neoadjuvant and it is often possible to select a low level of resection for this size of tumor and when the rim area is not hypervascularized. Even in the metastizing stage surgical treatment can be used for elimination of resistant metastases or for removal of residual tumor tissue in an attempt to counteract secondary tumor progression. The effect of this treatment is currently being tested in a randomized phase III study. (orig.) [German] Gastrointestinale Stromatumoren (GIST) stellen die haeufigste Subgruppe von Weichgewebesarkomen dar. Sie entstehen in der Muskularisschicht von Oesophagus, Magen, Duenndarm und Rektum. Charakteristisch und wichtig fuer die Einschaetzung des Tumorausmasses ist die Randvaskularisation von Primaertumoren und Metastasen. Die Indikation zur Resektion gilt fuer Tumoren ab 2 cm Groesse. Lokal fortgeschrittene GIST koennen sehr vorteilhaft mit Imatinib/Sunitinib neoadjuvant vorbehandelt werden, und es ist oft moeglich, bei der Tumorgroesse und wenn keine hypervaskularisierten Randbereiche vorliegen, ein geringeres Resektionsausmass zu waehlen. Auch im metastasierten Stadium hat die chirurgische Therapie einen Platz zur Eliminierung resistenter Metastasen bzw. zur Entfernung von Residualtumorgewebe als Versuch, einer sekundaeren Tumorprogression zu begegnen. Dieser Behandlungseffekt wird derzeit in einer randomisierten Phase-III-Studie ueberprueft. (orig.)

  17. Mutations in Exons 9 and 13 of KIT Gene Are Rare Events in Gastrointestinal Stromal Tumors

    Science.gov (United States)

    Lasota, Jerzy; Wozniak, Agnieszka; Sarlomo-Rikala, Maarit; Rys, Janusz; Kordek, Radzislaw; Nassar, Aziza; Sobin, Leslie H.; Miettinen, Markku

    2000-01-01

    Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases. PMID:11021812

  18. Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET

    Directory of Open Access Journals (Sweden)

    Fanti Stefano

    2010-12-01

    Full Text Available Abstract Background Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging. Methods Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control, imatinib (150 mg/kg b.i.d. by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d. by oral gavage, everolimus (10 mg/kg/d. + imatinib (150 mg/kg b.i.d. by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d. by oral gavage, nilotinib (75 mg/kg/d. + imatinib (150 mg/kg b.i.d by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm3. Small animal PET (GE Explore tomography was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment. Results After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm3 and the treatments began at day 38 after cell injection. Tumor volume control (cm3 after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and Conclusions As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism

  19. Crosstalk between Tumor Cells and Macrophages in Stroma Renders Tumor Cells as the Primary Source of MCP-1/CCL2 in Lewis Lung Carcinoma

    Directory of Open Access Journals (Sweden)

    Teizo eYoshimura

    2015-06-01

    Full Text Available The chemokine MCP-1/CCL2 is produced by a variety of tumors and plays an important role in cancer progression. We and others previously demonstrated that the primary source of MCP-1 in several mouse tumors, including 4T1 breast cancer, M5076 sarcoma and B16 melanoma, was stromal cells. In the present study, we identified that tumor cells were the primary source of MCP-1 in Lewis lung carcinoma (LLC, because MCP-1 mRNA was highly expressed in tumors grown in both WT and MCP-1-/- mice with elevated serum MCP-1 levels. Since LLC cells isolated from tumors expressed low levels of MCP-1 in vitro, it appeared that the tumor-stromal cell interaction in a tumor microenvironment increased MCP-1 expression in LLC cells. In fact, co-culture of LLC cells with normal mouse peritoneal macrophages or normal lung cells containing macrophages increased MCP-1 expression by LLC cells. Macrophages from TNFα-/- mice failed to activate LLC cells and anti-TNFα neutralizing antibody abolished the effect of WT macrophages on LLC cells. When LLC cells were transplanted into TNFα-/- mice, the levels of MCP-1 mRNA in tumors and serum MCP-1 levels were markedly lower as compared to WT mice, and importantly tumors grew more slowly. Taken together, our results indicate that TNFα released by tumor cell-activated macrophages is critical for increased MCP-1 production by tumors cells. Thus, disruption of tumor-stromal cell interaction may inhibit tumor progression by reducing the production of tumor-promoting proinflammatory mediators, such as MCP-1.

  20. Selenium supplementation restores the antioxidative capacity and prevents cell damage in bone marrow stromal cells in vitro

    DEFF Research Database (Denmark)

    Ebert, Regina; Ulmer, Matthias; Zeck, Sabine

    2006-01-01

    signaling, cumulative cell damage, senescence, and tumor development. Selenium-dependent (glutathione peroxidases [GPxs] and thioredoxin reductases [TrxRs]) and selenium-independent (superoxide dismutases [SODs] and catalase [CAT]) enzyme systems regulate cellular ROS steady state levels. SODs process......Bone marrow stromal cells (BMSCs) and other cell populations derived from mesenchymal precursors are developed for cell-based therapeutic strategies and undergo cellular stress during ex vivo procedures. Reactive oxygen species (ROS) of cellular and environmental origin are involved in redox...... superoxide anion to hydrogen peroxide, which is subsequently neutralized by GPx and CAT; TrxR neutralizes other ROS, such as peroxinitrite. Primary BMSCs and telomerase-immortalized human mesenchymal stem cells (hMSC-TERT) express GPx1-3, TrxR1, TrxR2, SOD1, SOD2, and CAT. We show here that in standard cell...

  1. Stromal cell-derived factor-1 stimulates cell recruitment, vascularization and osteogenic differentiation

    NARCIS (Netherlands)

    Eman, Rhandy M; Oner, F Cumhur; Kruyt, Moyo C; Dhert, Wouter J A; Alblas, Jacqueline

    The use of growth factors in osteogenic constructs to promote recruitment of bone forming endogenous cells is not clear, while the advantage of circumventing cell seeding techniques before implantation is highly recognized. Therefore, the additive effect of the chemokine stromal cell-derived

  2. CD34 defines an osteoprogenitor cell population in mouse bone marrow stromal cells

    DEFF Research Database (Denmark)

    Abdallah, Basem M; Al-Shammary, Asma; Skagen, Peter

    2015-01-01

    Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) and their progenitors have been identified based on retrospective functional criteria. CD markers are employed to define cell populations with distinct functional characteristics. However, defining and pro...

  3. Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function

    NARCIS (Netherlands)

    F. Luk (Franka); Carreras-Planella, L. (Laura); S.S. Korevaar (Sander); S.F. De Witte (Samantha Fh); F.E. Borràs (Francesc); M.G.H. Betjes (Michiel); C.C. Baan (Carla); M.J. Hoogduijn (Martin); M. Franquesa (Marcella)

    2017-01-01

    textabstractThe immunomodulatory capacity of mesenchymal stem or stromal cells (MSC) makes them a promising tool for treatment of immune disease and organ transplantation. The effects of MSC on B cells are characterized by an abrogation of plasmablast formation and induction of regulatory B cells

  4. Genomic mapping of pathways in endometrial adenocarcinoma and a gastrointestinal stromal tumor located in Meckel's diverticulum.

    Science.gov (United States)

    Englert-Golon, Monika; Budny, Bartlomiej; Burchardt, Bartosz; Wrotkowska, Elzbieta; Ziemnicka, Katarzyna; Ruchała, Marek; Sajdak, Stefan

    2016-02-01

    The present study reports the case of a 71-year-old female patient diagnosed with endometrial adenocarcinoma, which was confirmed by histopathology. In the course of performing an elective hysterectomy with adnexa removal, a solid tumor located in Meckel's diverticulum (MD) was identified and excised. Due to the unique nature of the lesion, the tumor tissue underwent broad mapping of any genomic alterations once the histopathological examination was completed. The genetic testing was conducted using a high-resolution microarray and resulted in the identification of 45 genomic abnormalities, including 4 chromosomal aneuploidies. Within those regions, alterations of 87 known cancer genes were assigned. The involvement of v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog gene alteration was noted to be a key player for triggering gastrointestinal stromal tumor transformation for this unusual case. A total of 12 genes, showing mutual interaction in different cancer types or involved in diverse cellular processes, were identified. These reported data may shed light on the carcinogenesis of a rare MD tumor.

  5. Fulminant Hepatic Failure Caused by Diffuse Liver Metastases following Gastrointestinal Stromal Tumor Resection

    Directory of Open Access Journals (Sweden)

    Abdel-Rauf Zeina

    2009-01-01

    Full Text Available Metastatic tumors to the liver resulting in fulminant hepatic failure are a rare occurrence and have not been previously described in patients with gastrointestinal stromal tumor (GIST. A 70 year-old man was referred to hospital with postprandial discomfort. On examination a 19.5 cm large epithelioid GIST of the stomach was diagnosed. The mass exhibited unfavorable prognostic features: mitotic index 18/50 high-power fields, large primary tumor size and male sex. Complete tumor resection with negative margins was achieved and metastases were not detected. The patient presented six months later with jaundice, asterixis and elevated liver enzymes. Computerized tomography showed multiple liver hypodense lesions representing metastases. Treatment with imatinib mesylate was of no avail and the patient died 3 days later as the result of hepatic failure. Massive liver metastases can, even though rarely, be responsible for fulminant hepatic failure. Clinical and radiological follow-up are crucial in patients with GIST even after surgical resection.

  6. Gastrointestinal stromal tumor (GIST coexisting with pancreatic cancer and hepatic hemangioma

    Directory of Open Access Journals (Sweden)

    M. A. Beltrán

    2014-11-01

    Full Text Available The occurrence of gastric gastrointestinal stromal tumors (GIST associated to pancreatic adenocarcinoma has been reported in 0.2% pancreatic cancers. There are no published reports on distal pancreatic adenocarcinoma associated to gastric antral GIST. Herein, we discuss a 75 years-old female patient who was admitted to our institution with upper digestive hemorrhage. The endoscopy showed large, superficial erosions over the cardias and, on the posterior wall of the antrum, a rounded sub-mucosal non-eroded lesion suspected of gastric GIST. An abdominal computed tomography scan found a hepatic hemangioma on the left hepatic lobe. In the pancreatic distal body and tail a solid exophytic lesion was identified. The surgical findings confirmed the radiologic diagnostic. The biopsy reported a hepatic hemangioma. The pancreatic tail and the proximal part of the body harbored a well-differentiated ductal adenocarcinoma measuring 3.4 cm x 3 cm x 2.5 cm with negative margins. The gastric tumor measured 4 cm x 2.5 cm x 1 cm, was positive for CD117, CD34, and DOG-1; it had a positive Ki67 in less than 2%, and 2 or less mitoses per 50 high-power fields. This uncommon case illustrates the occurrence of synchronous tumors of different cellular origins in the same patient, which were diagnosed during the study for another unrelated condition. The individual incidence of these tumors is low and if associated they probably will continue to be found incidentally.

  7. Familial Gastrointestinal Stromal Tumor with Germline KIT Mutations Accompanying Hereditary Breast and Ovarian Cancer Syndrome.

    Science.gov (United States)

    Sekido, Yuki; Ohigashi, Seiji; Takahashi, Tsuyoshi; Hayashi, Naoki; Suzuki, Koyu; Hirota, Seiichi

    2017-03-01

    Familial gastrointestinal stromal tumor (GIST) is a rare disease with germline mutations in the c-kit gene (KIT) or platelet-derived growth factor receptor alpha gene (PDGFRA). We had encountered multiple GISTs in the stomach and small intestine during a screening of ovarian cancer for a woman with hereditary breast and ovarian cancer syndrome (HBOC) with breast cancer susceptibility gene II (BRCA2) mutations. The aim of this study was to examine this case in detail. A 65-year-old woman diagnosed with HBOC harboring BRCA2 mutations was found to have multiple tumors in the stomach and small intestine by abdominal screening. All tumors were resected, and KIT gene mutations (p.Trp557Leu and p.Lys558Glu) in exon 11 were detected in all tumors and peripheral blood leukocytes. The patient was diagnosed with familial GIST. This was an extremely rare case in which familial GIST with germline KIT gene mutations co-existed with HBOC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  8. Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: four cases of rare tumors and a review of the literature.

    Science.gov (United States)

    Afşar, Ciğdem Usul; Kara, Ismail Oğuz; Kozat, Banu Kara; Demiryürek, Haluk; Duman, Berna Bozkurt; Doran, Figen

    2013-05-01

    Neurofibromatosis type 1 (NF1) is a genetic syndrome that predisposes patients to benign and malignant tumor development. Patients with NF1 develop multiple neurofibromas that can transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors. In contrast, malignant tumors unrelated to the nervous system rarely coexist with neurofibromatosis. The aim of this article was to present four cases of adult NF1 patients with malignant tumors unrelated to the nervous system as well as a bibliographic search for papers describing these tumors in NF1, focusing on osteosarcomas, gastrointestinal stromal tumors (GISTs), leiomyosarcomas and somatostatinomas and their genetic alterations in NF1. Search engines such as PubMed and MEDLINE were browsed for English-language articles since 1989 using a list of keywords, as well as references from review articles. Search terms were NF1, osteosarcoma, leiomyosarcoma, somatostatinoma and GIST. Data were summarized in a table at the end of the Results section. In our four NF1 cases, there were one osteosarcoma, one leiomyosarcoma, one somatostatinoma and GIST and one GIST. NF1 was diagnosed at an adult age when these patients were admitted to our oncology department. The results generated by the literature search yielded 75 articles about NF and GIST. We summarized the clinical characteristics of 43 patients with NF1 and somatostatinoma. Forty-five articles involving NF and osteosarcoma were found, and of these, 26 involved NF1; from these articles, we identified the clinical features of 8 patients. Twenty-five articles were found concerning NF1 and leiomyosarcoma, and of those, we summarized the clinical features of 15 patients. Here we reviewed somatostatinomas, GISTs, osteosarcomas and leiomyosarcomas occurring in NF1 patients. Patients with NF1 who present with gastrointestinal symptoms, should be carefully evaluated carefully with a high index of suspicion of potential GISTs, periampullary and duodenal tumors

  9. Good manufacturing practices production of mesenchymal stem/stromal cells.

    Science.gov (United States)

    Sensebé, Luc; Bourin, Philippe; Tarte, Karin

    2011-01-01

    Because of their multi/pluripotency and immunosuppressive properties mesenchymal stem/stromal cells (MSCs) are important tools for treating immune disorders and for tissue repair. The increasing use of MSCs has led to production processes that need to be in accordance with Good Manufacturing Practice (GMP). In cellular therapy, safety remains one of the main concerns and refers to donor validation, choice of starting material, processes, and the controls used, not only at the batch release level but also during the development of processes. The culture processes should be reproducible, robust, and efficient. Moreover, they should be adapted to closed systems that are easy to use. Implementing controls during the manufacturing of clinical-grade MSCs is essential. The controls should ensure microbiological safety but also avoid potential side effects linked to genomic instability driving transformation and senescence or decrease of cell functions (immunoregulation, differentiation potential). In this rapidly evolving field, a new approach to controls is needed.

  10. Kisspeptin-10 inhibits stromal-derived factor 1-induced invasion of human endometrial cancer cells.

    Science.gov (United States)

    Schmidt, Elena; Haase, Maike; Ziegler, Elke; Emons, Günter; Gründker, Carsten

    2014-02-01

    The cross talk between metastatic cancer cells and target sites is critical for the development and progression of metastases. Disruption of this interaction will allow to design mechanism-based effective and specific therapeutic interventions for metastases. We have established a coculture system of cells derived from different tumor entities and MG63 human osteoblastlike cells to analyze tumor cell invasion. Recently, we have shown that breast cancer cell invasion was dramatically increased when cocultured with MG63 cells.Using this model, we have now analyzed whether stromal-derived factor 1 (SDF-1) is responsible for human endometrial cancer cell invasion and whether kisspeptin-10 (KP-10) treatment affects SDF-1-induced invasion of endometrial cancer cells in vitro. Invasion was quantified by assessment of endometrial cancer cell migration rate through an artificial basement membrane in a modified Boyden chamber during coculture with MG63 cells or after treatment with SDF-1α, SDF-1β, or the combination of both SDF-1 isoforms. In addition, the role of SDF-1 in invasion of endometrial cancer cells was analyzed by blocking SDF-1 secretion during coculture with MG64 cells. Furthermore, the effects of KP-10 treatment on MG63 coculture-driven and SDF-1-induced invasion were analyzed. Endometrial cancer cell invasion was significantly increased when cocultured with MG63 cells. Treatment with KP-10 reduced the ability to invade a reconstituted basement membrane and to migrate in response to the cellular stimulus. This effect was significant in a dose window of 10(-13) to 10(-11) mol/L. During coculture, SDF-1 protein expression of MG63 cells was significantly increased. The MG63 coculture-induced increase of endometrial cancer cell invasion could be blocked by anti-SDF-1 antibodies. Treatment of endometrial cancer cells in monoculture (without MG63) with SDF-1α, SDF-1β, or the combination of both isoforms resulted in a significant increase of endometrial cancer

  11. Microarray Analysis on Gene Regulation by Estrogen, Progesterone and Tamoxifen in Human Endometrial Stromal Cells

    Directory of Open Access Journals (Sweden)

    Chun-E Ren

    2015-03-01

    Full Text Available Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies.

  12. Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells.

    Directory of Open Access Journals (Sweden)

    J Dinesh Kumar

    Full Text Available Stromal cells such as myofibroblasts influence tumor progression. The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow-derived mesenchymal stromal cells (MSCs which then colonize tumors. Using iTRAQ and LC-MS/MS we identified the adipokine, chemerin, as overexpressed in esophageal squamous cancer associated myofibroblasts (CAMs compared with adjacent tissue myofibroblasts (ATMs. The chemerin receptor, ChemR23, is expressed by MSCs. Conditioned media (CM from CAMs significantly increased MSC cell migration compared to ATM-CM; the action of CAM-CM was significantly reduced by chemerin-neutralising antibody, pretreatment of CAMs with chemerin siRNA, pretreatment of MSCs with ChemR23 siRNA, and by a ChemR23 receptor antagonist, CCX832. Stimulation of MSCs by chemerin increased phosphorylation of p42/44, p38 and JNK-II kinases and inhibitors of these kinases and PKC reversed chemerin-stimulated MSC migration. Chemerin stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor (MIF that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations. In a xenograft model consisting of OE21 esophageal cancer cells and CAMs, homing of MSCs administered i.v. was inhibited by CCX832. Thus, chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression.

  13. Comparing the immunosuppressive potency of naïve marrow stromal cells and Notch-transfected marrow stromal cells

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    Dao Mo A

    2011-10-01

    Full Text Available Abstract Background SB623 cells are expanded from marrow stromal cells (MSCs transfected with a Notch intracellular domain (NICD-expressing plasmid. In stroke-induced animals, these cells reduce infarct size and promote functional recovery. SB623 cells resemble the parental MSCs with respect to morphology and cell surface markers despite having been in extended culture. MSCs are known to have immunosuppressive properties; whether long-term culture of MSCs impact their immunomodulatory activity has not been addressed. Methods To assess the possible senescent properties of SB623 cells, we performed cell cycle related assays and beta-galactosidase staining. To assess the immunomodulatory activity of these expanded NICD-transfected MSCs, we performed co-cultures of SB623 cells or MSCs with either enriched human T cells or monocytes and assessed cytokine production by flow cytometry. In addition, we monitored the immunosuppressive activity of SB623 cells in both allogenic and xenogenic mixed lymphocyte reaction (MLR. Results Compared to MSCs, we showed that a small number of senescent-like cells appear in each lot of SB623 cells. Nevertheless, we demonstrated that these cells suppress human T cell proliferation in both the allogeneic and xenogeneic mixed lymphocyte reaction (MLR in a manner comparable to MSCs. IL-10 producing T cells were generated and monocyte-dendritic cell differentiation was dampened by co-culture with SB623 cells. Compared to the parental MSCs, SB623 cells appear to exert a greater inhibitory impact on the maturation of dendritic cells as demonstrated by a greater reduction in the surface expression of the co-stimulatory molecule, CD86. Conclusion The results demonstrated that the immunosuppressive activity of the expanded NICD-transfected MSCs is comparable to the parental MSCs, in spite of the appearance of a small number of senescent-like cells.

  14. Mixed epithelial and stromal tumor of the kidney (MEST) simulating an upper tract TCC.

    Science.gov (United States)

    Sountoulides, Petros; Koptsis, Michail; Metaxa, Linda; Theodosiou, Alexandros; Kikidakis, Dimitrios; Filintatzi, Chrysa; Paschalidis, Konstantinos

    2012-02-01

    We present a rare and interesting case of a mixed epithelial and stromal tumour (MEST) of the kidney. The case is unique as it involves a male patient with no history of hormonal therapy presenting with a filling defect in the renal collecting system and positive urine cytology. The patient was diagnosed with transitional cell carcinoma of the renal pelvis and subjected to nephroureterectomy, which revealed a solid tumour arising from the lower calyces and extending into the renal pelvis and upper ureter. Pathology revealed a MEST. The patient was disease-free at the 6-month follow-up.

  15. CTNNB1 Mutations in Ovarian Microcystic Stromal Tumors: Identification of a Novel Deletion Mutation and the Use of Pyrosequencing to Identify Reported Point Mutation.

    Science.gov (United States)

    Na, Kiyong; Kim, Eun Kyung; Jang, Wonjun; Kim, Hyun-Soo

    2017-06-01

    Microcystic stromal tumor (MCST) is a rare stromal tumor of the ovary. In this study, we describe clinicopathological characteristics and results of mutational analyses of the CTNNB1gene in two cases of ovarian MCST and we provide a thorough review of previously published cases alongside our current cases and clarify the clinicopathological characteristics of ovarian MCST. Patients' age was 33 and 31 years, respectively. One patient presented with fever and low abdominal pain, whereas a pelvic mass was incidentally detected in another patient. Grossly, the cut surface of the tumors was mixed solid and cystic. Histologically, the tumor characteristically displayed numerous microcysts, solid cellular areas, and intervening hyalinized stroma. Areas of moderate-to-severe nuclear pleomorphism with occasional multinucleated giant cells and bizarre nuclei were noted in one of the two cases. Immunohistochemically, both cases demonstrated diffuse and strong β-catenin expression in the nuclei and the cytoplasm. The tumor cells were also diffusely positive for CD10, vimentin, Wilms tumor 1, and cyclin D1. The tumor cells were consistently negative for E-cadherin, inhibin-α, calretinin, estrogen receptor, and progesterone receptor. Mutational analyses using direct sequencing and pyrosequencing methods exhibited a single nucleotide mutation in CTNNB1 exon 3 (c.122C>T) in one case. We also found a novel deletion mutation in the same exon (c.88_99delTACCTGGACTCT) in another case. We demonstrated a previously reported CTNNB1 point-mutation using pyrosequencing and a novel deletion mutation in ovarian MCSTs. The review of the literature of previously published cases in combination with our current cases clarifies the clinicopathological characteristics of ovarian MCST and the comprehensive analysis of these cases would expand our knowledge regarding ovarian MCST. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. Circulating tumor cells

    Science.gov (United States)

    Raimondi, Cristina; Nicolazzo, Chiara; Gradilone, Angela; Giannini, Giuseppe; De Falco, Elena; Chimenti, Isotta; Varriale, Elisa; Hauch, Siegfried; Plappert, Linda; Cortesi, Enrico; Gazzaniga, Paola

    2014-01-01

    The hypothesis of the “liquid biopsy” using circulating tumor cells (CTCs) emerged as a minimally invasive alternative to traditional tissue biopsy to determine cancer therapy. Discordance for biomarkers expression between primary tumor tissue and circulating tumor cells (CTCs) has been widely reported, thus rendering the biological characterization of CTCs an attractive tool for biomarkers assessment and treatment selection. Studies performed in metastatic colorectal cancer (mCRC) patients using CellSearch, the only FDA-cleared test for CTCs assessment, demonstrated a much lower yield of CTCs in this tumor type compared with breast and prostate cancer, both at baseline and during the course of treatment. Thus, although attractive, the possibility to use CTCs as therapy-related biomarker for colorectal cancer patients is still limited by a number of technical issues mainly due to the low sensitivity of the CellSearch method. In the present study we found a significant discordance between CellSearch and AdnaTest in the detection of CTCs from mCRC patients. We then investigated KRAS pathway activating mutations in CTCs and determined the degree of heterogeneity for KRAS oncogenic mutations between CTCs and tumor tissues. Whether KRAS gene amplification may represent an alternative pathway responsible for KRAS activation was further explored. KRAS gene amplification emerged as a functionally equivalent and mutually exclusive mechanism of KRAS pathway activation in CTCs, possibly related to transcriptional activation. The serial assessment of CTCs may represent an early biomarker of treatment response, able to overcome the intrinsic limit of current molecular biomarkers represented by intratumor heterogeneity. PMID:24521660

  17. B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3

    Science.gov (United States)

    Fei, Fei; Joo, Eun Ji; Tarighat, Somayeh S.; Schiffer, Isabelle; Paz, Helicia; Fabbri, Muller; Abdel-Azim, Hisham; Groffen, John; Heisterkamp, Nora

    2015-01-01

    The molecular interactions between B-cell precursor acute lymphoblastic leukemia (pre-B ALL) cells and stromal cells in the bone marrow that provide microenvironmentally-mediated protection against therapeutic drugs are not well-defined. Galectin-3 (Lgals3) is a multifunctional galactose-binding lectin with reported location in the nucleus, cytoplasm and extracellular space in different cell types. We previously reported that ALL cells co-cultured with stroma contain high levels of Galectin-3. We here establish that, in contrast to more mature B-lineage cancers, Galectin-3 detected in and on the ALL cells originates from stromal cells, which express it on their surface, secrete it as soluble protein and also in exosomes. Soluble and stromal-bound Galectin-3 is internalized by ALL cells, transported to the nucleus and stimulates transcription of endogenous LGALS3 mRNA. When human and mouse ALL cells develop tolerance to different drugs while in contact with protective stromal cells, Galectin-3 protein levels are consistently increased. This correlates with induction of Galectin-3 transcription in the ALL cells. Thus Galectin-3 sourced from stroma becomes supplemented by endogenous Galectin-3 production in the pre-B ALL cells that are under continuous stress from drug treatment. Our data suggest that stromal Galectin-3 may protect ALL cells through auto-induction of Galectin-3 mRNA and tonic NFκB pathway activation. Since endogenously synthesized Galectin-3 protects pre-B ALL cells against drug treatment, we identify Galectin-3 as one possible target to counteract the protective effects of stroma. PMID:25869099

  18. Granulosa Cell Tumor-like Variant of Endometrioid Carcinoma of the Ovary with Osseous Metaplasia: Report of a Rare Case

    OpenAIRE

    Kavita Mardi; Neelam Gupta; Shivani Sood; Manju Rao

    2015-01-01

    The sex cord-like variant of endometrioid carcinoma is a rare subtype with a close histological resemblance to the sex cord-stromal tumor of the ovaries, in particular the Sertoli cell tumor. However, very few cases of the granulosa cell tumor-like variant have been reported since it is commonly misdiagnosed as a granulose cell tumor. Immunohistochemistry is useful in the diagnosis of these tumors as they are typically negative for inhibin alpha. We herein describe the histolog...

  19. Gastrointestinal stromal tumors as an incidental finding in patients with a presumptive diagnosis of ovarian cancer.

    Science.gov (United States)

    Muñoz, Mario; Ramirez, Pedro T; Echeverri, Carolina; Alvarez, Luis Guillermo; Palomino, Maria Alejandra; Pareja, Luis René

    2012-01-01

    To report the clinical presentation and oncologic outcomes of a series of patients who presented with an abdominal or pelvic mass and were diagnosed with a gastrointestinal stromal tumor (GIST). Data were obtained on all patients who presented with an abdominal or pelvic mass between September 2007 and June 2010 and who were ultimately diagnosed with a GIST. The patients' medical records were reviewed. A literature review was also conducted. Six patients were identified who met the inclusion criteria. All six patients had a tumor in the intestinal tract arising from the small bowel. The mean tumor size was 12 cm (range, 6 to 22 cm). A complete resection was achieved in five of the six patients. There were no intraoperative complications; one patient had a postoperative complication. Two patients were treated with imatinib after surgery. The mean follow-up time was 32 months (range, 0.3 to 40 months). At the last follow-up, five of the six patients were without any evidence of disease. One patient died of an unrelated hepatic encephalopathy. The incidence in our institution is 3%. GISTs are uncommon; however, they should be considered in the differential diagnosis of patients presenting with an abdominal or pelvic mass.

  20. A Case of a Gastrointestinal Stromal Tumor Diagnosed at the Postpartum Period.

    Science.gov (United States)

    Kurt, Sefa; Canda, Aras Emre; Karadeniz, Emre; Yavuzsen, Tugba; Sagol, Ozgul; Obuz, Funda; Canda, Mehmet Serefettin

    2016-01-01

    Introduction. We discuss a rare gastrointestinal stromal tumor (GIST) case detected at the 10th postpartum week and we want to pay attention to the challenges and improvements in the diagnosis, surgery, chemotherapy, and follow-up of this rare tumor accompanied with the review of the current literature. Case Presentation. A 32-year-old multiparous woman presented with abdominal swelling 10 weeks after her second vaginal birth. Abdominal examination revealed a mass starting from the pelvic level and extending to the right upper quadrant. Radiological examinations showed a solid, multiloculated, and hypervascular mass starting from the pelvis and extending to the transverse colon. En bloc mass with a 20 cm jejunal segment resection and a left pelvic side wall peritonectomy with omentectomy was performed. The pathologic examination revealed a high-risk GIST which originated from the jejunum and disseminated to the peritoneum. The patient has been given imatinib 400 mg/day since then. She did not reveal any progression during the 15-month follow-up postoperatively. Conclusion. GIST tumors are rare and there is not sufficient information in the literature regarding its management. In this patient having high risk GIST and GIST sarcomatosis we successfully treated the patient by surgery and adjuvant imatinib chemotherapy.

  1. A Case of a Gastrointestinal Stromal Tumor Diagnosed at the Postpartum Period

    Directory of Open Access Journals (Sweden)

    Sefa Kurt

    2016-01-01

    Full Text Available Introduction. We discuss a rare gastrointestinal stromal tumor (GIST case detected at the 10th postpartum week and we want to pay attention to the challenges and improvements in the diagnosis, surgery, chemotherapy, and follow-up of this rare tumor accompanied with the review of the current literature. Case Presentation. A 32-year-old multiparous woman presented with abdominal swelling 10 weeks after her second vaginal birth. Abdominal examination revealed a mass starting from the pelvic level and extending to the right upper quadrant. Radiological examinations showed a solid, multiloculated, and hypervascular mass starting from the pelvis and extending to the transverse colon. En bloc mass with a 20 cm jejunal segment resection and a left pelvic side wall peritonectomy with omentectomy was performed. The pathologic examination revealed a high-risk GIST which originated from the jejunum and disseminated to the peritoneum. The patient has been given imatinib 400 mg/day since then. She did not reveal any progression during the 15-month follow-up postoperatively. Conclusion. GIST tumors are rare and there is not sufficient information in the literature regarding its management. In this patient having high risk GIST and GIST sarcomatosis we successfully treated the patient by surgery and adjuvant imatinib chemotherapy.

  2. Status of the Gastric Mucosa with Endoscopically Diagnosed Gastrointestinal Stromal Tumor

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    Kouichi Nonaka

    2014-01-01

    Full Text Available Background. Since gastrointestinal stromal tumor (GIST is a mesenchymal submucosal tumor, the endosonographic, CT, and MRI features of gastric GISTs have been widely investigated. However, the GIST-bearing gastric mucosa status has not been reported. Objective. To characterize the GIST-bearing gastric mucosa status in terms of the degree of inflammation and atrophy, assessed endoscopically. Subjects and Methods. The subjects were 46 patients with submucosal tumors (histologically proven gastric GISTs who had undergone upper gastrointestinal endoscopy in our hospital between April 2007 and September 2012. They were retrospectively evaluated regarding clinicopathological features, the endoscopically determined status of the entire gastric mucosa (presence or absence and degree of atrophy, presence or absence and severity of endoscopic gastritis/atrophy (A-B classification at the GIST site, and presence or absence of H. pylori infection. Results. Twenty-three patients had no mucosal atrophy, but 17 and 6 had closed- and open-type atrophy, respectively. Twenty-six, 5, 12, 1, 1, and 1 patients had grades B0, B1, B2, B3, A0, and A1 gastritis/atrophy at the lesion site, respectively, with no grade A2 gastritis/atrophy. Conclusion. The results suggest that gastric GISTs tend to arise in the stomach wall with H. pylori-negative, nonatrophic mucosa or H. pylori-positive, mildly atrophic mucosa.

  3. Differentiating gastrointestinal stromal tumors from gastric adenocarcinomas and normal mucosae using confocal Raman microspectroscopy

    Science.gov (United States)

    Hsu, Chih-Wei; Huang, Chia-Chi; Sheu, Jeng-Horng; Lin, Chia-Wen; Lin, Lien-Fu; Jin, Jong-Shiaw; Chen, Wenlung

    2016-07-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and gastric adenocarcinomas are a common cancer worldwide. To differentiate GISTs from adenocarcinomas is important because the surgical processes for both are different; the former excises the tumor with negative margins, while the latter requires radical gastrectomy with lymph node dissection. Endoscopy with biopsy is used to distinguish GISTs from adenocarcinomas; however, it may cause tumor bleeding in GISTs. We reported here the confocal Raman microspectroscopy as an effective tool to differentiate GISTs, adenocarcinomas, and normal mucosae. Of 119 patients enrolled in this study, 102 patients underwent gastrectomy (40 GISTs and 62 adenocarcinomas), and 17 patients with benign lesions were obtained as normal mucosae. Raman signals were integrated for 100 s for each spot on the specimen, and 5 to 10 spots, depending on the sample size, were chosen for each specimen. There were significant differences among those tissues as evidenced by different Raman signal responding to phospholipids and protein structures. The spectral data were further processed and analyzed by using principal component analysis. A two-dimensional plot demonstrated that GISTs, adenocarcinomas, and normal gastric mucosae could be effectively differentiated from each other.

  4. Endoscopic ultrasonographic characteristics of gastric schwannoma distinguished from gastrointestinal stromal tumor.

    Science.gov (United States)

    Park, Hyung-Chul; Son, Dong-Jun; Oh, Hyung-Hoon; Oak, Chan-Young; Kim, Mi-Young; Chung, Cho-Yun; Myung, Dae-Seong; Kim, Jong-Sun; Cho, Sung-Bum; Lee, Wan-Sik; Joo, Young-Eun

    2015-01-01

    Gastric schwannoma (GS), a rare neurogenic mesenchymal tumor, is usually benign, slow-growing, and asymptomatic. However, GS is often misdiagnosed as gastrointestinal stromal tumors (GIST) on endoscopic and radiological examinations. The purpose of this study was to evaluate EUS characteristics of GS distinguished from GIST. A total of 119 gastric subepithelial lesions, including 31 GSs and 88 GISTs, who were histologically identified and underwent EUS, were enrolled in this study. We evaluated the EUS characteristics, including location, size, gross morphology, mucosal lesion, layer of origin, border, echogenic pattern, marginal halo, and presence of an internal echoic lesion by retrospective review of the medical records. GS patients comprised nine males and 22 females, indicating female predominance. In the gross morphology according to Yamada's classification, type I was predominant in GS and type III was predominant in GIST. In location, GSs were predominantly located in the gastric body and GISTs were predominantly located in the cardia or fundus. The frequency of 4th layer origin and isoechogenicity as compared to the echogenicity of proper muscle layer was significantly more common in GS than GIST. Although not statistically significant, marginal halo was more frequent in GS than GIST. The presence of an internal echoic lesion was significantly more common in GIST than GS. The EUS characteristics, including tumor location, gross morphology, layer of origin, echogenicity in comparison with the normal muscle layer, and presence of an internal echoic lesion may be useful in distinguishing between GS and GIST.

  5. Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation, differentiation, and maintenance of hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Stopp, Sabine; Bornhäuser, Martin; Ugarte, Fernando; Wobus, Manja; Kuhn, Matthias; Brenner, Sebastian; Thieme, Sebastian

    2013-04-01

    The melanoma cell adhesion molecule defines mesenchymal stromal cells in the human bone marrow that regenerate bone and establish a hematopoietic microenvironment in vivo. The role of the melanoma cell adhesion molecule in primary human mesenchymal stromal cells and the maintenance of hematopoietic stem and progenitor cells during ex vivo culture has not yet been demonstrated. We applied RNA interference or ectopic overexpression of the melanoma cell adhesion molecule in human mesenchymal stromal cells to evaluate the effect of the melanoma cell adhesion molecule on their proliferation and differentiation as well as its influence on co-cultivated hematopoietic stem and progenitor cells. Knockdown and overexpression of the melanoma cell adhesion molecule affected several characteristics of human mesenchymal stromal cells related to osteogenic differentiation, proliferation, and migration. Furthermore, knockdown of the melanoma cell adhesion molecule in human mesenchymal stromal cells stimulated the proliferation of hematopoietic stem and progenitor cells, and strongly reduced the formation of long-term culture-initiating cells. In contrast, melanoma cell adhesion molecule-overexpressing human mesenchymal stromal cells provided a supportive microenvironment for hematopoietic stem and progenitor cells. Expression of the melanoma cell adhesion molecule increased the adhesion of hematopoietic stem and progenitor cells to human mesenchymal stromal cells and their migration beneath the monolayer of human mesenchymal stromal cells. Our results demonstrate that the expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells determines their fate and regulates the maintenance of hematopoietic stem and progenitor cells through direct cell-cell contact.

  6. A Stromal Cell Niche for Human and Mouse Type 3 Innate Lymphoid Cells.

    Science.gov (United States)

    Hoorweg, Kerim; Narang, Priyanka; Li, Zhi; Thuery, Anne; Papazian, Natalie; Withers, David R; Coles, Mark C; Cupedo, Tom

    2015-11-01

    Adaptive immunity critically depends on the functional compartmentalization of secondary lymphoid organs. Mesenchymal stromal cells create and maintain specialized niches that support survival, activation, and expansion of T and B cells, and integrated analysis of lymphocytes and their niche has been instrumental in understanding adaptive immunity. Lymphoid organs are also home to type 3 innate lymphoid cells (ILC3), innate effector cells essential for barrier immunity. However, a specialized stromal niche for ILC3 has not been identified. A novel lineage-tracing approach now identifies a subset of murine fetal lymphoid tissue organizer cells that gives rise exclusively to adult marginal reticular cells. Moreover, both cell types are conserved from mice to humans and colocalize with ILC3 in secondary lymphoid tissues throughout life. In sum, we provide evidence that fetal stromal organizers give rise to adult marginal reticular cells and form a dedicated stromal niche for innate ILC3 in adaptive lymphoid organs. Copyright © 2015 by The American Association of Immunologists, Inc.

  7. Benign notochordal cell tumors.

    Science.gov (United States)

    Martínez Gamarra, C; Bernabéu Taboada, D; Pozo Kreilinger, J J; Tapia Viñé, M

    2017-08-01

    Benign notochordal cell tumors (TBCN) are lesions with notochordal differentiation which affect the axial skeleton. They are characterized by asymptomatic or non-specific symptomatology and are radiologically unnoticed because of their small size, or because they are mistaken with other benign bone lesions, such as vertebral hemangiomas. When they are large, or symptomatic, can be differential diagnosis with metastases, primary bone tumors and chordomas. We present a case of a TBCN in a 50-year-old woman, with a sacral lesion seen in MRI. A CT-guided biopsy was scheduled to analyze the lesion, finding that the tumor was not clearly recognizable on CT, so the anatomical references of MRI were used to select the appropriate plane. The planning of the approach and the radio-pathological correlation were determinant to reach the definitive diagnosis. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Developing a Continuous Bioprocessing Approach to Stromal Cell Manufacture.

    Science.gov (United States)

    Miotto, Martina; Gouveia, Ricardo; Abidin, Fadhilah Zainal; Figueiredo, Francisco; Connon, Che J

    2017-11-29

    To this day, the concept of continuous bioprocessing has been applied mostly to the manufacture of molecular biologics such as proteins, growth factors, and secondary metabolites with biopharmaceutical uses. The present work now sets to explore the potential application of continuous bioprocess methods to source large numbers of human adherent cells with potential therapeutic value. To this purpose, we developed a smart multifunctional surface coating capable of controlling the attachment, proliferation, and subsequent self-detachment of human corneal stromal cells. This system allowed the maintenance of cell cultures under steady-state growth conditions, where self-detaching cells were continuously replenished by the proliferation of those remaining attached. This facilitated a closed, continuous bioprocessing platform with recovery of approximately 1% of the total adherent cells per hour, a yield rate that was maintained for 1 month. Moreover, both attached and self-detached cells were shown to retain their original phenotype. Together, these results represent the proof-of-concept for a new high-throughput, high-standard, and low-cost biomanufacturing strategy with multiple potentials and important downstream applications.

  9. Impaired function of bone marrow stromal cells in systemic mastocytosis

    Directory of Open Access Journals (Sweden)

    Krisztian Nemeth

    2015-07-01

    Full Text Available Patients with systemic mastocytosis (SM have a wide variety of problems, including skeletal abnormalities. The disease results from a mutation of the stem cell receptor (c-kit in mast cells and we wondered if the function of bone marrow stromal cells (BMSCs; also known as MSCs or mesenchymal stem cells might be affected by the invasion of bone marrow by mutant mast cells. As expected, BMSCs from SM patients do not have a mutation in c-kit, but they proliferate poorly. In addition, while osteogenic differentiation of the BMSCs seems to be deficient, their adipogenic potential appears to be increased. Since the hematopoietic supportive abilities of BMSCs are also important, we also studied the engraftment in NSG mice of human CD34+ hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM could not support hematopoiesis to the extent that healthy BMSCs do. Finally, we performed an expression analysis and found significant differences between healthy and SM derived BMSCs in the expression of genes with a variety of functions, including the WNT signaling, ossification, and bone remodeling. We suggest that some of the symptoms associated with SM might be driven by epigenetic changes in BMSCs caused by dysfunctional mast cells in the bone marrow of the patients.

  10. [Xenogeneic protein free cultivation of mesenchymal multipotent stromal cells].

    Science.gov (United States)

    Stehlík, D; Pytlík, R; Rychtrmocová, H; Veselá, R; Kopečný, Z; Trč, T

    2011-01-01

    The aim of this study was to compare the standard laboratory method of cultivation of mesenchymal multipotent stromal cells (MSC) and a novel technique of rapid MSC expansion focused on simple clinical use. Bone marrow mononuclear cells of donors were cultured for 14 days by the standard and the new cultivation method. The standard method (STD) was based on an alpha MEM medium supplemented with foetal calf serum (FCS). The new animal protein-free method (CLI) was based on the clinical grade medium CellgroTM, pooled human serum and human recombinant growth factors (EGF, PDGF-BB, M-CSF, FGF-2) supplemented with dexamethasone, insulin and ascorbic acid. The cell product was analyzed by flow cytometry. Furthermore, the cell products of STD and CLI methods were differentiated in vitro, and histochemical and immunohistochemical analyses, electron microscopy and elemental analysis were performed. Some cells were seeded on biodegradable scaffolds, in vivo implanted into immunodeficient mice for 6 weeks and evaluated by histological methods. Yields of the CLI method after 14 days of cultivation were 40-fold higher than those obtained by the STD technique (psystem cultivation in good manufacturing practice (GMP) conditions. It seems to be easily transferable to good clinical practice compared to other protocols and should extend the possibilities of cell therapy and tissue engineering of cartilage and bone. The new method is protected by Czech patent 301 148 and by Europian patent EP 1999250 according to Czech and international laws.

  11. Lysophosphatidic acid-induced expression of periostin in stromal cells: Prognoistic relevance of periostin expression in epithelial ovarian cancer.

    Science.gov (United States)

    Choi, Kyung Un; Yun, Jeong Sup; Lee, Il Hwan; Heo, Soon Chul; Shin, Sang Hun; Jeon, Eun Su; Choi, Yoon Ji; Suh, Dong-Soo; Yoon, Man-Soo; Kim, Jae Ho

    2011-01-15

    Lysophosphatidic acid (LPA) is a bioactive lipid crucial for the initiation and progression of ovarian cancer. Identification of LPA-induced biomarkers is necessary for predicting prognosis of ovarian cancer patients. Here we report periostin, an extracellular matrix protein, as an LPA-induced protein in stromal cells and as a prognostic marker in patients with epithelial ovarian cancer (EOC). In human EOC tissues, periostin was mainly expressed in cancer-associated stromal fibroblasts, but not in cancer cells. The expression levels of periostin highly correlated with poor survival and tumor recurrence of ovarian cancer patients. Treatment of human adipose tissue-derived stromal cells with LPA or conditioned media from human ovarian adenocarcinoma cell lines, such as SK-OV-3 and OVCAR-3, induced expression of periostin. The periostin expression induced by cancer-conditioned media was abrogated by silencing of the LPA receptor 1 expression using small hairpin RNA lentivirus. Recombinant periostin stimulated adhesion and invasion of SK-OV-3 human ovarian adenocarcinoma cells and induced expression of matrix metalloprotease-2 in the cancer cells. These results suggest that LPA is associated with the expression of periostin in cancer-associated fibroblasts of EOC. Copyright © 2010 UICC.

  12. Intraoperative scrape cytology: Adult granulosa cell tumor of ovary

    Directory of Open Access Journals (Sweden)

    Prabal Deb

    2011-01-01

    Full Text Available Adult granulosa cell tumor is often a hormonally active stromal cell neoplasm of the ovary with malignant potential. Intra-operative pathological assessment is a valuable tool in guiding optimal surgical treatment in patients. Of the various intra-operative cytological diagnostic modalities, scrape smear cytology is an effective, economical, simple, fast and reliable method with results comparable with frozen section diagnosis. We describe a case of adult granulosa cell tumor in a 30-years-old lady diagnosed on intra-operative scrape cytology, and further reconfirmed on frozen section and histopathology.

  13. Relaxin acts on stromal cells to promote epithelial and stromal proliferation and inhibit apoptosis in the mouse cervix and vagina.

    Science.gov (United States)

    Yao, LiJuan; Agoulnik, Alexander I; Cooke, Paul S; Meling, Daryl D; Sherwood, O David

    2008-05-01

    The objective of this study was to determine whether stromal and/or epithelial relaxin receptor (LGR7) is required for relaxin to promote proliferation and inhibit apoptosis of stromal and epithelial cells in the mouse cervix and vagina. Tissue recombinants were prepared with stroma (St) and epithelium (Ep) from wild-type (wt) and LGR7 knockout (ko) mice: wt-St+wt-Ep, wt-St+ko-Ep, ko-St+wt-Ep, and ko-St+ko-Ep. Tissue recombinants were grafted under the renal capsule of intact syngeneic female mice. After 3 wk of transplant growth, hosts were ovariectomized and fitted with silicon implants containing progesterone and estradiol-17beta (designated d 1 of treatment). Animals were injected sc with relaxin or relaxin vehicle PBS at 6-h intervals from 0600 h on d 8 through 0600 h on d 10 of treatment. To evaluate cell proliferation, 5-bromo-2'-deoxyuridine was injected sc 10 h before cervices and vaginas were collected at 1000 h on d 10. Terminal deoxynucleotidyl transferase-mediated deoxyuridine 5'-triphosphate nick end labeling was used to quantify apoptosis. Relaxin markedly increased proliferation and decreased apoptosis of epithelial and stromal cells in tissue recombinants containing wt stroma (P vagina, whereas epithelial LGR7 does not affect these processes.

  14. Relaxin Acts on Stromal Cells to Promote Epithelial and Stromal Proliferation and Inhibit Apoptosis in the Mouse Cervix and Vagina

    Science.gov (United States)

    Yao, LiJuan; Agoulnik, Alexander I.; Cooke, Paul S.; Meling, Daryl D.; Sherwood, O. David

    2008-01-01

    The objective of this study was to determine whether stromal and/or epithelial relaxin receptor (LGR7) is required for relaxin to promote proliferation and inhibit apoptosis of stromal and epithelial cells in the mouse cervix and vagina. Tissue recombinants were prepared with stroma (St) and epithelium (Ep) from wild-type (wt) and LGR7 knockout (ko) mice: wt-St+wt-Ep, wt-St+ko-Ep, ko-St+wt-Ep, and ko-St+ko-Ep. Tissue recombinants were grafted under the renal capsule of intact syngeneic female mice. After 3 wk of transplant growth, hosts were ovariectomized and fitted with silicon implants containing progesterone and estradiol-17β (designated d 1 of treatment). Animals were injected sc with relaxin or relaxin vehicle PBS at 6-h intervals from 0600 h on d 8 through 0600 h on d 10 of treatment. To evaluate cell proliferation, 5-bromo-2′-deoxyuridine was injected sc 10 h before cervices and vaginas were collected at 1000 h on d 10. Terminal deoxynucleotidyl transferase-mediated deoxyuridine 5′-triphosphate nick end labeling was used to quantify apoptosis. Relaxin markedly increased proliferation and decreased apoptosis of epithelial and stromal cells in tissue recombinants containing wt stroma (P vagina, whereas epithelial LGR7 does not affect these processes. PMID:18218691

  15. Ovarian Germ Cell Tumors Treatment

    Science.gov (United States)

    ... Fallopian Tube, & Primary Peritoneal Cancer Screening Research Ovarian Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Ovarian Germ Cell Tumors Go to Health Professional Version Key ...

  16. The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis.

    Science.gov (United States)

    Clarke, Cassie J; Berg, Tracy J; Birch, Joanna; Ennis, Darren; Mitchell, Louise; Cloix, Catherine; Campbell, Andrew; Sumpton, David; Nixon, Colin; Campbell, Kirsteen; Bridgeman, Victoria L; Vermeulen, Peter B; Foo, Shane; Kostaras, Eleftherios; Jones, J Louise; Haywood, Linda; Pulleine, Ellie; Yin, Huabing; Strathdee, Douglas; Sansom, Owen; Blyth, Karen; McNeish, Iain; Zanivan, Sara; Reynolds, Andrew R; Norman, Jim C

    2016-03-21

    Expression of the initiator methionine tRNA (tRNAi(Met)) is deregulated in cancer. Despite this fact, it is not currently known how tRNAi(Met) expression levels influence tumor progression. We have found that tRNAi(Met) expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAi(Met) in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAi(Met) contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAi(Met) gene (2+tRNAi(Met) mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAi(Met) mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAi(Met) mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAi(Met) significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAi(Met)-overexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAi(Met)-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNAi(Met) mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAi(Met) levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Testicular germ cell tumors.

    Science.gov (United States)

    Diamantopoulos, N; Kortsaris, A

    2010-01-01

    Testicular cancer is the most frequent solid tumor in young male adults and a disease with elusive pathogenesis. Germ cell tumors represent 95% of all testicular cancers. There was an increasing incidence of testicular germ cell tumors during the second half of the 20th century. Despite their increased incidence, mortality is lower than 10% and the cure rate has reached 95%. Epidemiology of the disease shows remarkable geographic and racial variation. Known risk factors and the increased incidence during the last 50 years have led to the development of the two prevalent theories for the pathogenesis of the disease, Henderson theory and Rajpertde Meyts and Skakkebaek theory. Appropriate diagnosis and staging of the disease are crucial for successful management. Testicular ultrasound, CT scans, histological examination and serum tumor markers should be utilized in order to stratify the patient correctly. Treatment strategy is chosen according to the patient stage and prognostic group stratification. "Fine tuning" is needed in order to find the balance between treatment, cure and toxicity. Despite progress in therapeutic management, cure rates for poor risk patients do not exceed 50%. These patients should be encouraged to participate in clinical trials. Long-term toxicity of testicular germ cell tumors' treatment is also another issue that should be kept in mind during follow-up of these patients. This disease became the model of "curable" cancer and gave hope for cure of metastatic malignant diseases in general, as only 400 patients die from this disease in USA annually. More progress will be made only through well-designed clinical trials.

  18. Infection Programs Sustained Lymphoid Stromal Cell Responses and Shapes Lymph Node Remodeling upon Secondary Challenge

    Directory of Open Access Journals (Sweden)

    Julia L. Gregory

    2017-01-01

    Full Text Available Lymph nodes (LNs are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner. Infection induced rapid transcriptional responses in LSCs. This transcriptional program was transient, returning to homeostasis within 1 month of infection, yet expanded fibroblastic reticular cell networks persisted for more than 3 months after infection, and this altered LN composition reduced the magnitude of LSC responses to subsequent heterologous infection. Our results reveal the complexity of LSC responses during infection and suggest that amplified networks of LN stromal cells support successive immune responses.

  19. Cryopreservation and Revival of Human Mesenchymal Stromal Cells.

    Science.gov (United States)

    Haack-Sørensen, Mandana; Ekblond, Annette; Kastrup, Jens

    2016-01-01

    Cell-based therapy is a promising and innovative new treatment for different degenerative and autoimmune diseases, and mesenchymal stromal cells (MSCs) from the bone marrow have demonstrated great therapeutic potential due to their immunosuppressive and regenerative capacities.The establishment of methods for large-scale expansion of clinical-grade MSCs in vitro has paved the way for their therapeutic use in clinical trials. However, the clinical application of MSCs also requires cryopreservation and banking of the cell products. To preserve autologous or allogeneic MSCs for future clinical applications, a reliable and effective cryopreservation method is required.Developing a successful cryopreservation protocol for clinical stem cell products, cryopreservation media, cryoprotectant agents (CPAs), the freezing container, the freezing temperature, and the cooling and warming rate are all aspects which should be considered.A major challenge is the selection of a suitable cryoprotectant which is able to penetrate the cells and yet has low toxicity.This chapter focuses on recent technological developments relevant for the cryopreservation of MSCs using the most commonly used cryopreservation medium containing DMSO and animal serum or human-derived products for research use and the animal protein-free cryopreservation media CryoStor (BioLife Solutions) for clinical use.

  20. The Stromal Microenvironment Modulates Mitochondrial Oxidative Phosphorylation in Chronic Lymphocytic Leukemia Cells

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    Hima V. Vangapandu

    2017-10-01

    Full Text Available Peripheral blood chronic lymphocytic leukemia (CLL cells are replicationally quiescent mature B-cells. In short-term cultures, supporting stromal cells provide a survival advantage to CLL cells by inducing transcription and translation without promoting proliferation. We hypothesized that the stromal microenvironment augments malignant B cells' metabolism to enable the cells to cope with their energy demands for transcription and translation. We used extracellular flux analysis to assess the two major energy-generating pathways, mitochondrial oxidative phosphorylation (OxPhos and glycolysis, in primary CLL cells in the presence of three different stromal cell lines. OxPhos, measured as the basal oxygen consumption rate (OCR and maximum respiration capacity, was significantly higher in 28 patients' CLL cells cocultured with bone marrow–derived NK.Tert stromal cells than in CLL cells cultured alone (P = .004 and <.0001, respectively. Similar OCR induction was observed in CLL cells cocultured with M2-10B4 and HS-5 stromal lines. In contrast, heterogeneous changes in the extracellular acidification rate (a measure of glycolysis were observed in CLL cells cocultured with stromal cells. Ingenuity Pathway Analysis of CLL cells' metabolomics profile indicated stroma-mediated stimulation of nucleotide synthesis. Quantitation of ribonucleotide pools showed a significant two-fold increase in CLL cells cocultured with stromal cells, indicating that the stroma may induce CLL cellular bioenergy and the RNA building blocks necessary for the transcriptional requirement of a prosurvival phenotype. The stroma did not impact the proliferation index (Ki-67 staining of CLL cells. Collectively, these data suggest that short-term interaction (≤24 hours with stroma increases OxPhos and bioenergy in replicationally quiescent CLL cells.

  1. A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers.

    Science.gov (United States)

    Herbert, Brittney-Shea; Chanoux, Rebecca A; Liu, Yunlong; Baenziger, Peter H; Goswami, Chirayu P; McClintick, Jeanette N; Edenberg, Howard J; Pennington, Robert E; Lipkin, Steven M; Kopelovich, Levy

    2010-10-01

    Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited "hit" in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP-31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry "one-hit" p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well.

  2. Small bud of probable gastrointestinal stromal tumor within a laparoscopically-resected gastric schwannoma.

    Science.gov (United States)

    Cho, Haruhiko; Watanabe, Takafumi; Aoyama, Toru; Hayashi, Tsutomu; Yamada, Takanobu; Ogata, Takashi; Yoshikawa, Takaki; Tsuburaya, Akira; Sekiguchi, Hironobu; Nakamura, Yoshiyasu; Sakuma, Yuji; Kameda, Yoichi; Miyagi, Yohei

    2012-06-01

    Submucosal tumors (SMTs) of the gastrointestinal (GI) tract can be potentially difficulty to diagnose pathologically. We report a case of a gastric SMT that was resected by laparoscopic partial gastrectomy. Although the initial histological and immunohistochemical examinations considered the tumor as a schwannoma, mRNA-based KIT genotyping indicated that the tumor included cells with KIT gene expression, and that a small number of cells carried a deletion mutation in exon 11. Additional histopathological investigations revealed small aggregates of enlarged spindle to epithelioid cells, which were positive for KIT, CD34 and DOG1, and negative for S-100, scattered among the S-100-positive schwannoma cells. We consider that the cells carrying the KIT gene mutation are microscopic buds of a gastrointestinal stroma tumor (GIST), and to the best of our knowledge, this is the first report of probable GIST tissues identified in a schwannoma. Our observations raised the significance of genotyping for diagnosis of GI tract SMTs.

  3. Adipose tissue mesenchymal stromal cells as therapeutic vehicles against glioblastoma

    OpenAIRE

    Krasheninnikova, Maria Alieva

    2012-01-01

    Lately adipose tissue mesenchymal stem cells (hAMSCs) have emerged as cellular vehicles for therapy of solid tumors, due to their ease of isolation and manipulation, and wound/tumor homing capacity. HAMSCs have been successfully used in suicide gene therapy, employing the prodrug activating system based on Herpes simplex virus type I thymidine kinase (HSV-TK)/ganciclovir (GCV). In the current study we demonstrate an effective model of glioblastoma therapy based on the use of genetically modif...

  4. Gold nanoparticles cellular toxicity and recovery: adipose Derived Stromal cells.

    Science.gov (United States)

    Mironava, Tatsiana; Hadjiargyrou, Michael; Simon, Marcia; Rafailovich, Miriam H

    2014-03-01

    Gold nanoparticles (AuNPs) are currently used in numerous medical applications. Herein, we describe their in vitro impact on human adipose-derived stromal cells (ADSCs) using 13 nm and 45 nm citrate-coated AuNPs. In their non-differentiated state, ADSCs were penetrated by the AuNPs and stored in vacuoles. The presence of the AuNPs in ADSCs resulted in increased population doubling times, decreased cell motility and cell-mediated collagen contraction. The degree to which the cells were impacted was a function of particle concentration, where the smaller particles required a sevenfold higher concentration to have the same effect as the larger ones. Furthermore, AuNPs reduced adipogenesis as measured by lipid droplet accumulation and adiponectin secretion. These effects correlated with transient increases in DLK1 and with relative reductions in fibronectin. Upon removal of exogenous AuNPs, cellular NP levels decreased and normal ADSC functions were restored. As adiponectin helps regulate energy metabolism, local fluctuations triggered by AuNPs can lead to systemic changes. Hence, careful choice of size, concentration and clinical application duration of AuNPs is warranted.

  5. Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells

    Energy Technology Data Exchange (ETDEWEB)

    Aanei, Carmen Mariana, E-mail: caanei@yahoo.com [Laboratoire Hematologie, CHU de Saint-Etienne, 42055, Saint-Etienne (France); Department of Immunology, Gr. T. Popa University of Medicine and Pharmacy, 700115, Iasi (Romania); Eloae, Florin Zugun [Department of Immunology, Gr. T. Popa University of Medicine and Pharmacy, 700115, Iasi (Romania); Flandrin-Gresta, Pascale [Laboratoire Hematologie, CHU de Saint-Etienne, 42055, Saint-Etienne (France); CNRS UMR 5239, Universite de Lyon, 42023, Saint-Etienne (France); Tavernier, Emmanuelle [Service Hematologie Clinique, Institut de Cancerologie de la Loire, 42270, Saint-Priest-en-Jarez (France); CNRS UMR 5239, Universite de Lyon, 42023, Saint-Etienne (France); Carasevici, Eugen [Department of Immunology, Gr. T. Popa University of Medicine and Pharmacy, 700115, Iasi (Romania); Guyotat, Denis [Service Hematologie Clinique, Institut de Cancerologie de la Loire, 42270, Saint-Priest-en-Jarez (France); CNRS UMR 5239, Universite de Lyon, 42023, Saint-Etienne (France); Campos, Lydia [Laboratoire Hematologie, CHU de Saint-Etienne, 42055, Saint-Etienne (France); CNRS UMR 5239, Universite de Lyon, 42023, Saint-Etienne (France)

    2011-11-01

    Direct cell-cell contact between haematopoietic progenitor cells (HPCs) and their cellular microenvironment is essential to maintain 'stemness'. In cancer biology, focal adhesion (FA) proteins are involved in survival signal transduction in a wide variety of human tumours. To define the role of FA proteins in the haematopoietic microenvironment of myelodysplastic syndromes (MDS), CD73-positive mesenchymal stromal cells (MSCs) were immunostained for paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} and p130CAS, and analysed for reactivity, intensity and cellular localisation. Immunofluorescence microscopy allowed us to identify qualitative and quantitative differences, and subcellular localisation analysis revealed that in pathological MSCs, paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} formed nuclear molecular complexes. Increased expression of paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} and enhanced nuclear co-localisation of these proteins correlated with a consistent proliferative advantage in MSCs from patients with refractory anaemia with excess blasts (RAEB) and negatively impacted clonogenicity of HPCs. These results suggest that signalling via FA proteins could be implicated in HPC-MSC interactions. Further, because FAK is an HSP90{alpha}/{beta} client protein, these results suggest the utility of HSP90{alpha}/{beta} inhibition as a target for adjuvant therapy for myelodysplasia.

  6. Translating Research into Clinical Scale Manufacturing of Mesenchymal Stromal Cells

    Directory of Open Access Journals (Sweden)

    Karen Bieback

    2010-01-01

    Full Text Available It sounds simple to obtain sufficient numbers of cells derived from fetal or adult human tissues, isolate and/or expand the stem cells, and then transplant an appropriate number of these cells into the patient at the correct location. However, translating basic research into routine therapies is a complex multistep process which necessitates product regulation. The challenge relates to managing the expected therapeutic benefits with the potential risks and to balance the fast move to clinical trials with time-consuming cautious risk assessment. This paper will focus on the definition of mesenchymal stromal cells (MSCs, and challenges and achievements in the manufacturing process enabling their use in clinical studies. It will allude to different cellular sources, special capacities of MSCs, but also to current regulations, with a special focus on accessory material of human or animal origin, like media supplements. As cellular integrity and purity, formulation and lot release testing of the final product, validation of all procedures, and quality assurance are of utmost necessity, these topics will be addressed.

  7. Pfetin as a Risk Factor of Recurrence in Gastrointestinal Stromal Tumors

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    Hajime Orita

    2014-01-01

    Full Text Available Background. Despite complete resection of gastrointestinal stromal tumors (GIST, recurrent and/or metastatic disease occurs, often depending on the grade of malignancy. As such, markers are needed that accurately predict patients at high risk for recurrence. Previously our group reported Pfetin as a prognostic biomarker for GIST. In order to create an approach for predicting risk of recurrence, we incorporated Pfetin expression with clinicopathological data to produce a predictive model. Object. Forty-five patients with localized primary GIST were treated with complete gross surgical resection surgically at our institution between 1995 and 2010 were included. The majority of tumors originated in the stomach (38 cases, as well as small intestine (6 cases and rectum (1 case. Method. (1 We performed retrospective analysis of the connection between Pfetin expression, clinicopathological data, and incidences of recurrence, using bivariate and multivariate analyses. (2 The reactivity of the monoclonal antibody against Pfetin was examined by immunohistochemistry. Pfetin. We have reported Pfetin, identified microarray technology, and compared between statistically different GISTs for good and poor prognoses and for prognostic marker. Results. There were 7 cases of recurrences. (1 By univariate analysis, tumor size, mitoses, exposure to abdominal cavity, and complete tumor removal predicted risk of recurrence. (2 Pfetin-negative cases were significantly related to recurrence (P = 0.002. Conclusions. This analysis demonstrates that lack of Pfetin expression is an additional predictor of recurrence in resected GIST. Further study may determine the role of this variable added to the current predictive model for selection of adjuvant therapy.

  8. Comparison between air and carbon dioxide insufflation in the endoscopic submucosal excavation of gastrointestinal stromal tumors.

    Science.gov (United States)

    Shi, Wei-Bin; Wang, Zi-Hao; Qu, Chun-Ying; Zhang, Yi; Jiang, Han; Zhou, Min; Chen, Ying; Xu, Lei-Ming

    2012-12-28

    To evaluate the safety and efficacy of CO(2) insufflation compared with air insufflation in the endoscopic submucosal excavation (ESE) of gastrointestinal stromal tumors. Sixty patients were randomized to undergo endoscopic submucosal excavation, with the CO(2) group (n = 30) and the air group (n = 30) undergoing CO(2) insufflation and air insufflation in the ESE, respectively. The end-tidal CO(2) level (pETCO(2)) was observed at 4 time points: at the beginning of ESE, at total removal of the tumors, at completed wound management, and 10 min after ESE. Additionally, the patients' experience of pain at 1, 3, 6 and 24 h after the examination was registered using a visual analog scale (VAS). Both the CO(2) group and air group were similar in mean age, sex, body mass index (all P > 0.05). There were no significant differences in PetCO(2) values before and after the procedure (P > 0.05). However, the pain scores after the ESE at different time points in the CO(2) group decreased significantly compared with the air group (1 h: 21.2 ± 3.4 vs 61.5 ± 1.7; 3 h: 8.5 ± 0.7 vs 42.9 ± 1.3; 6 h: 4.4 ± 1.6 vs 27.6 ± 1.2; 24 h: 2.3 ± 0.4 vs 21.4 ± 0.7, P < 0.05). Meanwhile, the percentage of VAS scores of 0 in the CO(2) group after 1, 3, 6 and 24 h was significantly higher than that in the air group (60.7 ± 1.4 vs 18.9 ± 1.5, 81.5 ± 2.3 vs 20.6 ± 1.2, 89.2 ± 0.7 vs 36.8 ± 0.9, 91.3 ± 0.8 vs 63.8 ± 1.3, respectively, P < 0.05). Moreover, the condition of the CO(2) group was better than that of the air group with respect to anal exsufflation. Insufflation of CO(2) in the ESE of gastrointestinal stromal tumors will not cause CO(2) retention and it may significantly reduce the level of pain, thus it is safe and effective.

  9. The Fate of the Adipose-Derived Stromal Cells during Angiogenesis and Adipogenesis after Cell-Assisted Lipotransfer.

    Science.gov (United States)

    Hong, Ki Yong; Yim, Sangjun; Kim, Hyun Jung; Jin, Ung Sik; Lim, SooA; Eo, SuRak; Chang, Hak; Minn, Kyung Won

    2018-02-01

    Cell-assisted lipotransfer is a process in which fat grafting is supplemented with autologous adipose-derived stromal cells. Since the efficacy of the technique was demonstrated, studies have focused on the mechanism by which cell-assisted lipotransfer enhances the rate of graft survival. However, the microenvironmental changes in donor and recipient tissue associated with cell-assisted lipotransfer remain unclear. The authors introduced an animal model of cell-assisted lipotransfer using two different transgenic reporter mice. Donor fat from green fluorescent protein-expressing C57BL/6J mice and donor adipose-derived stromal cells from DsRed-expressing C57BL/6J mice were co-transplanted into recipient C57BL/6J mice. During adipose remodeling after cell-assisted lipotransfer, the fate of each donor adipocyte and donor adipose-derived stromal cell was traced using immunofluorescent staining with the whole-mount method. Adipose-derived stromal cell supplementation altered inflammation and promoted angiogenesis and subsequent revascularization in recipient tissue. Tracing at postoperative week 4 revealed that surviving donor adipose-derived stromal cells participated in angiogenesis by differentiating into endothelial cells. Moreover, newly differentiated fat from donor adipose-derived stromal cells and recipient tissue integrated with surviving donor fat, leading to improved retention of the graft. Adipose-derived stromal cell supplementation resulted in a quantitative difference in angiogenesis and adipogenesis during adipose remodeling according to the concentration of adipose-derived stromal cells. The authors characterized the dynamic changes occurring in donor adipose-derived stromal cells and fat and recipient tissue by tracing these cellular components following cell-assisted lipotransfer. The authors' findings highlight the therapeutic value of cell-assisted lipotransfer in tissue transplantation.

  10. Comparison of Endoscopic and Open Resection for Small Gastric Gastrointestinal Stromal Tumor

    Directory of Open Access Journals (Sweden)

    Fan Feng

    2015-12-01

    Full Text Available The National Comprehensive Cancer Network recommends conservative follow-up for gastric gastrointestinal stromal tumors (GISTs less than 2 cm. We have previously reported that the mitotic index of 22.22% of small gastric GISTs exceeded 5 per 50 high-power fields and recommended that all small gastric GISTs should be resected once diagnosed. The aim of the present study is to compare the safety and outcomes of endoscopic and open resection of small gastric GISTs. From May 2010 to March 2014, a total of 90 small gastric GIST patients were enrolled in the present study, including 40 patients who underwent surgical resection and 50 patients who underwent endoscopic resection. The clinicopathological characteristics, resection-related factors, and clinical outcomes were recorded and analyzed. The clinicopathological characteristics were comparable between the two groups except for tumor location and DOG-1 expression. Compared with the surgical resection group, the operation time was shorter (P = .000, blood loss was less (P = .000, pain intensity was lower (P < .05, duration of first flatus and defecation was shorter (P < .05, and medical cost of hospitalization was lower (P = .027 in the endoscopic resection group. The complications and postoperative hospital stay were comparable between the two groups. No in situ recurrence or liver metastasis was observed during follow-up. Endoscopic resection of small gastric GISTs is safe and feasible compared with surgical resection, although perforation could not be totally avoided during and after resection. The clinical outcome of endoscopic resection is also favorable.

  11. Efficacy of Endoscopic Submucosal Excavation for Gastrointestinal Stromal Tumors in the Cardia.

    Science.gov (United States)

    Wang, Shanshan; Shen, Lei

    2016-12-01

    Our goal was to estimate the feasibility and efficacy of endoscopic submucosal excavation (ESE) for the treatment of gastrointestinal stromal tumors (GISTs) in the cardia. We analyzed the clinical data of 30 patients who were diagnosed with GISTs after ESE in the cardia at the Endoscopy Center of Renmin Hospital of Wuhan University (China) from June 2009 to 2015. We evaluated the operative and postoperative conditions and long-term follow-up of these patients. The success rate and the complete resection rate were both 100%. The maximum diameter of the tumor ranged from 1.0 to 3.5 cm (2.2±0.2 cm). The operation time was 20 to 120 min (50±5 min). During ESE, bleeding occurred in all cases (100%) with a mean blood loss of 50 mL, and perforation in 6 (20%), including 2 full-thickness resections. GIST was confirmed by pathology in all cases. Follow-up included endoscopy at 1, 3, and 6 months, and at 1 year. At 1 month, ulcer was detected in 23 cases (76.67%), titanium clips remained in 17 cases (56.67%), and scar tissues were observed in the remainder. No recurrence was found with gastroscopy. The cardia is a unique anatomic location for GISTs, which often requires complex surgeries prone to complications. ESE for GISTs of the cardia is a challenging, but safe and effective procedure.

  12. Development of enterohepatic fistula after embolization in ileal gastrointestinal stromal tumor: a case report.

    Science.gov (United States)

    Lee, Yun Ho; Koo, Ja Seol; Jung, Chang Ho; Chung, Sang Yoon; Lee, Jae Joong; Kim, Seung Young; Hyun, Jong Jin; Jung, Sung Woo; Choung, Rok Seon; Lee, Sang Woo; Choi, Jai Hyun

    2013-11-21

    Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor of the gastrointestinal tract that has been associated with the formation of fistulas to adjacent organs in few case reports. However, GIST with enterohepatic fistula has not been reported. Here we report the case of an enterohepatic fistula that occurred after embolization of a liver mass originating in the distal ileum. An 87-year-old woman was hospitalized for melena. On initial conventional endoscopy, a bleeding focus in the gastrointestinal tract was not found. Because of massive hematochezia, enteroscopy was performed through the anus. A protruding, ulcerative mass was found in the distal ileum that was suspected to be the source of the bleeding; a biopsy sample was taken. Electrocoagulation was not successful in controlling the bleeding; therefore, embolization was performed. After embolization, the patient developed a high fever and severe abdominal tenderness with rebound tenderness. Follow-up abdominopelvic computed tomography revealed an enterohepatic fistula between the liver and distal ileum. The fistula was treated surgically by segmental resection of the distal ileum and unlooping of the liver mass.

  13. Three cases of bone metastases in patients with gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Maurizio Zompatori

    2011-04-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. Tumor resection is the treatment of choice for localized disease. Tyrosine kinase inhibitors (imatinib, sunitinib are the standard therapy for metastatic or unresectable GISTs. GISTs usually metastasize to the liver and peritoneum. Bone metastases are uncommon. We describe three cases of bone metastases in patients with advanced GISTs: two women (82 and 54 years of age, and one man (62 years of age. Bones metastases involved the spine, pelvis and ribs in one patient, multiple vertebral bodies and pelvis in one, and the spine and iliac wings in the third case. The lesions presented a lytic pattern in all cases. Two patients presented with multiple bone metastases at the time of initial diagnosis and one patient after seven years during the follow-up period. This report describes the diagnosis and treatment of the lesions and may help clinicians to manage bones metastases in GIST patients.

  14. Meta-analysis of laparoscopic vs. open resection of gastric gastrointestinal stromal tumors.

    Science.gov (United States)

    Ye, Liangying; Wu, Xiaojing; Wu, Tongwei; Wu, Qijing; Liu, Zhao; Liu, Chuan; Li, Sen; Chen, Tao

    2017-01-01

    This meta-analysis compared laparoscopic surgery (LAP) and open resection (OPEN) for the treatment of gastric gastrointestinal stromal tumors (GISTs) with regard to feasibility and safety. We searched PubMed, Embase, and Web of Science for studies published before March 2016 comparing the LAP and OPEN procedures for GISTs. RevMan 5.1 software was used for the meta-analysis. In total, 28 studies met the inclusion criteria for the meta-analysis. The mean tumor sizes in the OPEN and LAP groups were 4.54 and 5.67 cm. Compared with the OPEN patients, the LAP patients experienced shorter surgical times (P = 0.05), less blood loss (P5 cm), the present study did not report significant differences in operation time (P = 0.93), postoperative complications (P = 0.30), or recurrence rate (P = 0.61) between the two groups, though LAP was associated with favorable results regarding blood loss (P = 0.03) and hospital stay (POPEN procedure, the LAP procedure is associated with preferable short-term postoperative outcomes and does not compromise long-term oncological outcomes. For gastric GISTs >5 cm, no significant difference was detected between LAP and OPEN if patient selection and intraoperative decisions were carefully considered.

  15. Spectral Computed Tomography Imaging of Gastric Schwannoma and Gastric Stromal Tumor.

    Science.gov (United States)

    Liu, Jianli; Chai, Yanjun; Zhou, Junlin; Dong, Chi; Zhang, Wenjuan; Liu, Bin

    Gastric schwannomas (GSs) and gastrointestinal stromal tumors (GSTs) are grossly similar submucosal neoplasms with different prognoses. We explored the value of spectral computed tomography (CT) to distinguish between them. Patients diagnosed with GS or GST at Lanzhou University Second Hospital, China, between May 2013 and June 2015 were included retrospectively. The subjects underwent spectral CT examination before surgery and had histologically confirmed diagnosis of GS or GST. Twelve patients with GS (3 men; 9 women; mean [SD] age, 47.0 [11.5] years) and 20 with GST (7 men; 13 women; mean [SD] age, 54.7 [9.9]) showed significant differences in terms of arterial phase (AP) at 70 keV (P < 0.001), portal phase (PP) at 70 keV (P = 0.002), AP iodine concentration, PP iodine concentration, AP water concentration, AP slope of spectral curve, and PP slope of spectral curve (all P < 0.001). Spectral CT may be useful for noninvasive diagnosis of submucosal tumors.

  16. Meta-analysis of laparoscopic vs. open resection of gastric gastrointestinal stromal tumors.

    Directory of Open Access Journals (Sweden)

    Liangying Ye

    Full Text Available This meta-analysis compared laparoscopic surgery (LAP and open resection (OPEN for the treatment of gastric gastrointestinal stromal tumors (GISTs with regard to feasibility and safety.We searched PubMed, Embase, and Web of Science for studies published before March 2016 comparing the LAP and OPEN procedures for GISTs. RevMan 5.1 software was used for the meta-analysis.In total, 28 studies met the inclusion criteria for the meta-analysis. The mean tumor sizes in the OPEN and LAP groups were 4.54 and 5.67 cm. Compared with the OPEN patients, the LAP patients experienced shorter surgical times (P = 0.05, less blood loss (P5 cm, the present study did not report significant differences in operation time (P = 0.93, postoperative complications (P = 0.30, or recurrence rate (P = 0.61 between the two groups, though LAP was associated with favorable results regarding blood loss (P = 0.03 and hospital stay (P5 cm, no significant difference was detected between LAP and OPEN if patient selection and intraoperative decisions were carefully considered.

  17. Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer

    DEFF Research Database (Denmark)

    Donnem, Tom; Hald, Sigurd M; Paulsen, Erna-Elise

    2015-01-01

    PURPOSE: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor-node-metastasis (TNM) classification in colorectal cancer. In non-small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor...... as an immunoscore in NSCLC. EXPERIMENTAL DESIGN: The prognostic impact of stromal CD8(+) TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I-IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts...

  18. Non-glycanated Decorin Is a Drug Target on Human Adipose Stromal Cells

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    Alexes C. Daquinag

    2017-09-01

    Full Text Available Adipose stromal cells (ASCs have been identified as a mesenchymal cell population recruited from white adipose tissue (WAT by tumors and supporting cancer progression. We have previously reported the existence of a non-glycanated decorin isoform (ngDCN marking mouse ASCs. We identified a peptide CSWKYWFGEC that binds to ngDCN and hence can serve as a vehicle for ASC-directed therapy delivery. We used hunter-killer peptides composed of CSWKYWFGEC and a pro-apoptotic moiety to deplete ASCs and suppress growth of mouse tumors. Here, we report the discovery of the human non-glycanated decorin isoform. We show that CSWKYWFGEC can be used as a probe to identify ASCs in human WAT and tumors. We demonstrate that human ngDCN is expressed on ASC surface. Finally, we validate ngDCN as a molecular target for pharmacological depletion of human ASCs with hunter-killer peptides. We propose that ngDCN-targeting agents could be developed for obesity and cancer treatment.

  19. Flotillin-1 protein is upregulated in human endometrial cancer and localization shifts from epithelial to stromal with increasing tumor grade.

    Science.gov (United States)

    Winship, Amy Louise; Rainczuk, Kate; Dimitriadis, Evdokia

    2016-01-01

    Endometrial cancer is the most common invasive gynecological malignancy. Flotillin-1 is an integral membrane protein and estrogen responsive gene. Flotillin-1 expression and localization in human endometrial cancers grades 1-3 was investigated using real-time RT-PCR and immunohistochemistry. Flotillin-1 mRNA levels were unchanged in endometrial cancer versus benign endometrium. Flotillin-1 protein was significantly reduced in the epithelial compartment with increasing tumor grade, although levels increased in the tumor stroma across grades. We have identified a novel factor in human endometrial cancer and observed a shift in epithelial to stromal localization with increasing tumor grade in women.

  20. Metastatic Cerebellar Gastrointestinal Stromal Tumor with Obstructive Hydrocephalus Arising from the Small Intestine: A Case Report and Review of the Literature

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    Kunitomo Sato

    2014-01-01

    Full Text Available Gastrointestinal stromal tumor (GIST is defined as a c-kit-positive gastrointestinal, mesenteric, or omental mesenchymal tumor that very rarely metastasizes to the brain. Metastasis to the cerebellum is particularly rare. An 80-year-old man presented with nausea and vomiting with disturbance of consciousness. Magnetic resonance imaging (MRI revealed tumor in the cerebellar vermis causing obstructive hydrocephalus. The patient subsequently underwent midline suboccipital craniotomy, and the tumor was totally removed. Immunohistochemical analysis showed tumor cells positive for c-kit and CD34, and cerebellar metastasis of GIST was diagnosed. Postoperative radiotherapy was administered. Following surgery and radiotherapy, the patient developed ileus caused by tumor in the small intestine and underwent laparotomy for tumor removal. Following abdominal surgery, left hemiparesis and consciousness disturbance were noted. Computed tomography showed recurrent large tumor with perifocal edema in the right frontal lobe of the brain. The patient died 3 months after initial craniotomy. Intracranial metastasis of GIST is extremely rare. In cases such as the present, where the condition of the patient rapidly deteriorates and features such as rising intracranial pressure and ileus prevent the use of oral agents, molecular-targeted agents administered by intravenous infusion should be utilized.

  1. GATA-4 and FOG-2 expression in pediatric ovarian sex cord-stromal tumors replicates embryonal gonadal phenotype: results from the TREP project.

    Directory of Open Access Journals (Sweden)

    Calogero Virgone

    Full Text Available AIM: GATA proteins are a family of zinc finger transcription factors regulating gene expression, differentiation and proliferation in various tissues. The expression of GATA-4 and FOG-2, one of its modulators, was studied in pediatric Sex Cord-Stromal tumors of the ovary, in order to evaluate their potential role as diagnostic markers and prognostic factors. MATERIALS AND METHODS: Clinical and histological data of 15 patients, enrolled into the TREP Project since 2000 were evaluated. When available, immunostaines for FOG-2, GATA-4, α-Inhibin, Vimentin and Pancytokeratin were also analyzed. RESULTS: In our series there were 6 Juvenile Granulosa Cell Tumors (JGCT, 6 Sertoli-Leydig Cell Tumors (SLCT, 1 Cellular Fibroma, 1 Theca Cell Tumor and 1 Stromal Sclerosing Tumor (SST. Thirteen patients obtained a complete remission (CR, 1 reached a second CR after the removal of a metachronous tumor and 1 died of disease. Inhibin was detectable in 11/15, Vimentin in 13/15, Pancytokeratin in 6/15, GATA-4 in 5/13 and FOG-2 in 11/15. FOG-2 was highly expressed in 5/6 JGCT, while GATA-4 was weakly detectable only in 1 of the cases. SLCT expressed diffusely FOG-2 (4/6 and GATA-4 (3/5. GATA-4 and FOG-2 were detected in fibroma and thecoma but not in the SST. CONCLUSIONS: Pediatric granulosa tumors appear to express a FOG-2/GATA-4 phenotype in keeping with primordial ovarian follicles. High expression of GATA-4 does not correlate with aggressive behaviour as seen in adults, but it is probably involved in cell proliferation its absence can be associated with the better outcome of JGCT. SLCTs replicate the phenotype of Sertoli cells during embryogenesis in normal testis. In this group, the lack of expression of FOG-2 in tumors in advanced stages might reveal a hypothetical role in inhibiting GATA-4 cell proliferation pathway. In fibroma/thecoma group GATA-4 and FOG-2 point out the abnormal activation of GATA pathway and might be involved in the onset of these tumors.

  2. Markers for Characterization of Bone Marrow Multipotential Stromal Cells

    Directory of Open Access Journals (Sweden)

    Sally A. Boxall

    2012-01-01

    Full Text Available Given the observed efficacy of culture-expanded multipotential stromal cells, also termed mesenchymal stem cells (MSCs, in the treatment of graft-versus host and cardiac disease, it remains surprising that purity and potency characterization of manufactured cell batches remains rather basic. In this paper, we will initially discuss surface and molecular markers that were proposed to serve as the indicators of the MSC potency, in terms of their proliferative potential or the ability to differentiate into desired lineages. The second part of this paper will be dedicated to a critical discussion of surface markers of uncultured (i.e., native bone marrow (BM MSCs. Although no formal consensus has yet been reached on which markers may be best suited for prospective BM MSC isolation, markers that cross-react with MSCs of animal models (such as CD271 and W8-B2/MSCA-1 may have the strongest translational value. Whereas small animal models are needed to discover the in vivo function on these markers, large animal models are required for safety and efficacy testing of isolated MSCs, particularly in the field of bone and cartilage tissue engineering.

  3. Tumor del estroma gastrointestinal del intestino delgado Gastrointestinal stromal tumor of small intestine

    Directory of Open Access Journals (Sweden)

    Magaly Marión Luna Gozá

    2011-12-01

    Full Text Available Los tumores del estroma gastrointestinal fueron catalogados originalmente como otros tumores (leiomioma, leiomioblastoma o leiomiosarcoma, debido a su apariencia histológica similar; sin embargo, los avances en la biología molecular y la inmunohistoquímica, han permitido diferenciarlos de otras neoplasias digestivas, y definirlos como una entidad clínica e histopatológica propia. Se presenta un paciente, de sexo femenino, de la raza negra, de 79 años de edad, con dolor abdominal de 3 días de evolución, que se había iniciado en fosa ilíaca derecha y luego se mantuvo en bajo vientre, acompañado de vómitos, fatiga y decaimiento. Se decide intervenir quirúrgicamente y se lleva al salón de operaciones con el diagnóstico de una apendicitis aguda, del muñón, tipo oclusiva en el anciano, sin descartar una oclusión por bridas. Al realizar laparotomía se encuentra sangre libre en cavidad que no coagula, y se observó tumor hemorrágico, pediculado, muy móvil, hacia íleon terminal. Se realiza exéresis de este, se resecan aproximadamente 5 cm de intestino delgado y se realiza sutura termino-terminal posteriormente. Se realizó amplia toillette de la cavidad peritoneal y el cierre habitual, con evolución satisfactoria, y con alta a los 7 días. Se mantiene asintomática al año y medio de operada, y la biopsia arrojó tumor de intestino delgado, de bajo grado de malignidad, de 5 cm de diámetro.The tumors of the gastrointestinal stroma were originally classified as other type of tumors (leiomyoma, leiomyobastoma or leiomyosarcoma due to it similar histological appearance; however, the advances in the molecular biology and the immunohistochemistry have allowed its differentiation of other digestive neoplasms and to define them as an own clinical and histopathological entity. This is the case of a black female patient aged 79 presenting with abdominal pain during 3 days of evolution started in the right iliac fossa and then it remains in

  4. Chondrogenically differentiated mesenchymal stromal cell pellets stimulate endochondral bone regeneration in critical-sized bone defects

    NARCIS (Netherlands)

    J. van der Stok (Johan); M.K.E. Koolen; H. Jahr (Holger); N. Kops (Nicole); J.H. Waarsing (Jan); H.H. Weinans (Harrie); O.P. van der Jagt (Olav)

    2014-01-01

    markdownabstractAbstract: Grafting bone defects or atrophic non-unions with mesenchymal stromal cells (MSCs)-based grafts is not yet successful. MSC-based grafts typically use undifferentiated or osteogenically differentiated MSCs and regenerate bone through intramembranous ossification.

  5. Decidual Stromal Cell Response to Paracrine Signals from the Trophoblast: Amplification of Immune and Angiogenic Modulators

    DEFF Research Database (Denmark)

    Hess, AP; Hamilton, AE; Talbi, S

    2007-01-01

    During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important fo...

  6. Reducing macrophages to improve bone marrow stromal cell survival in the contused spinal cord.

    NARCIS (Netherlands)

    Ritfeld, G.J.; Nandoe, R.D.S.; Rahiem, S.T.; Hurtado, A.; Roos, R.A.; Grotenhuis, A.; Oudega, M.

    2010-01-01

    We tested whether reducing macrophage infiltration would improve the survival of allogeneic bone marrow stromal cells (BMSC) transplanted in the contused adult rat thoracic spinal cord. Treatment with cyclosporine, minocycline, or methylprednisolone all resulted in a significant decrease in

  7. Simvastatin Modulates Mesenchymal Stromal Cell Proliferation and Gene Expression

    Science.gov (United States)

    Zanette, Dalila Lucíola; Lorenzi, Julio Cesar Cetrulo; Panepucci, Rodrigo Alexandre; Palma, Patricia Vianna Bonini; dos Santos, Daiane Fernanda; Prata, Karen Lima; Silva, Wilson Araújo

    2015-01-01

    Statins are widely used hypocholesterolemic drugs that block the mevalonate pathway, responsible for the biosysnthesis of cholesterol. However, statins also have pleiotropic effects that interfere with several signaling pathways. Mesenchymal stromal cells (MSC) are a heterogeneous mixture of cells that can be isolated from a variety of tissues and are identified by the expression of a panel of surface markers and by their ability to differentiate in vitro into osteocytes, adipocytes and chondrocytes. MSC were isolated from amniotic membranes and bone marrows and characterized based on ISCT (International Society for Cell Therapy) minimal criteria. Simvastatin-treated cells and controls were directly assayed by CFSE (Carboxyfluorescein diacetate succinimidyl ester) staining to assess their cell proliferation and their RNA was used for microarray analyses and quantitative PCR (qPCR). These MSC were also evaluated for their ability to inhibit PBMC (peripheral blood mononuclear cells) proliferation. We show here that simvastatin negatively modulates MSC proliferation in a dose-dependent way and regulates the expression of proliferation-related genes. Importantly, we observed that simvastatin increased the percentage of a subset of smaller MSC, which also were actively proliferating. The association of MSC decreased size with increased pluripotency and the accumulating evidence that statins may prevent cellular senescence led us to hypothesize that simvastatin induces a smaller subpopulation that may have increased ability to maintain the entire pool of MSC and also to protect them from cellular senescence induced by long-term cultures/passages in vitro. These results may be important to better understand the pleiotropic effects of statins and its effects on the biology of cells with regenerative potential. PMID:25874574

  8. Radiation rescue: mesenchymal stromal cells protect from lethal irradiation.

    Directory of Open Access Journals (Sweden)

    Claudia Lange

    Full Text Available BACKGROUND: Successful treatment of acute radiation syndromes relies on immediate supportive care. In patients with limited hematopoietic recovery potential, hematopoietic stem cell (HSC transplantation is the only curative treatment option. Because of time consuming donor search and uncertain outcome we propose MSC treatment as an alternative treatment for severely radiation-affected individuals. METHODS AND FINDINGS: Mouse mesenchymal stromal cells (mMSCs were expanded from bone marrow, retrovirally labeled with eGFP (bulk cultures and cloned. Bulk and five selected clonal mMSCs populations were characterized in vitro for their multilineage differentiation potential and phenotype showing no contamination with hematopoietic cells. Lethally irradiated recipients were i.v. transplanted with bulk or clonal mMSCs. We found a long-term survival of recipients with fast hematopoietic recovery after the transplantation of MSCs exclusively without support by HSCs. Quantitative PCR based chimerism analysis detected eGFP-positive donor cells in peripheral blood immediately after injection and in lungs within 24 hours. However, no donor cells in any investigated tissue remained long-term. Despite the rapidly disappearing donor cells, microarray and quantitative RT-PCR gene expression analysis in the bone marrow of MSC-transplanted animals displayed enhanced regenerative features characterized by (i decreased proinflammatory, ECM formation and adhesion properties and (ii boosted anti-inflammation, detoxification, cell cycle and anti-oxidative stress control as compared to HSC-transplanted animals. CONCLUSIONS: Our data revealed that systemically administered MSCs provoke a protective mechanism counteracting the inflammatory events and also supporting detoxification and stress management after radiation exposure. Further our results suggest that MSCs, their release of trophic factors and their HSC-niche modulating activity rescue endogenous hematopoiesis

  9. Radiation rescue: mesenchymal stromal cells protect from lethal irradiation.

    Science.gov (United States)

    Lange, Claudia; Brunswig-Spickenheier, Bärbel; Cappallo-Obermann, Heike; Eggert, Katharina; Gehling, Ursula M; Rudolph, Cornelia; Schlegelberger, Brigitte; Cornils, Kerstin; Zustin, Jozef; Spiess, Andrej-Nikolai; Zander, Axel R

    2011-01-05

    Successful treatment of acute radiation syndromes relies on immediate supportive care. In patients with limited hematopoietic recovery potential, hematopoietic stem cell (HSC) transplantation is the only curative treatment option. Because of time consuming donor search and uncertain outcome we propose MSC treatment as an alternative treatment for severely radiation-affected individuals. Mouse mesenchymal stromal cells (mMSCs) were expanded from bone marrow, retrovirally labeled with eGFP (bulk cultures) and cloned. Bulk and five selected clonal mMSCs populations were characterized in vitro for their multilineage differentiation potential and phenotype showing no contamination with hematopoietic cells. Lethally irradiated recipients were i.v. transplanted with bulk or clonal mMSCs. We found a long-term survival of recipients with fast hematopoietic recovery after the transplantation of MSCs exclusively without support by HSCs. Quantitative PCR based chimerism analysis detected eGFP-positive donor cells in peripheral blood immediately after injection and in lungs within 24 hours. However, no donor cells in any investigated tissue remained long-term. Despite the rapidly disappearing donor cells, microarray and quantitative RT-PCR gene expression analysis in the bone marrow of MSC-transplanted animals displayed enhanced regenerative features characterized by (i) decreased proinflammatory, ECM formation and adhesion properties and (ii) boosted anti-inflammation, detoxification, cell cycle and anti-oxidative stress control as compared to HSC-transplanted animals. Our data revealed that systemically administered MSCs provoke a protective mechanism counteracting the inflammatory events and also supporting detoxification and stress management after radiation exposure. Further our results suggest that MSCs, their release of trophic factors and their HSC-niche modulating activity rescue endogenous hematopoiesis thereby serving as fast and effective first-line treatment to

  10. Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

    Science.gov (United States)

    Clavreul, Anne; Pourbaghi-Masouleh, Milad; Roger, Emilie; Lautram, Nolwenn; Montero-Menei, Claudia N; Menei, Philippe

    2017-09-29

    Glioblastoma (GB) is the most malignant brain tumor in adults. It is characterized by angiogenesis and a high proliferative and invasive capacity. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) is of limited efficacy. Innovative anticancer drugs targeting both tumor cells and angiogenesis are urgently required, together with effective systems for their delivery to the brain. We assessed the ability of human mesenchymal stromal cells (MSCs) to uptake the multikinase inhibitor, sorafenib (SFN), and to carry this drug to a brain tumor following intranasal administration. MSCs were primed with SFN and drug content and release were quantified by analytical chemistry techniques. The ability of SFN-primed MSCs to inhibit the survival of the human U87MG GB cell line and endothelial cells was assessed in in vitro assays. These cells were then administered intranasally to nude mice bearing intracerebral U87MG xenografts. Their effect on tumor growth and angiogenesis was evaluated by magnetic resonance imaging and immunofluorescence analyses, and was compared with the intranasal administration of unprimed MSCs or SFN alone. MSCs took up about 9 pg SFN per cell, with no effect on viability, and were able to release 60% of the primed drug. The cytostatic activity of the released SFN was entirely conserved, resulting in a significant inhibition of U87MG and endothelial cell survival in vitro. Two intranasal administrations of SFN-primed MSCs in U87MG-bearing mice resulted in lower levels of tumor angiogenesis than the injection of unprimed MSCs or SFN alone, but had no effect on tumor volume. We also observed an increase in the proportion of small intratumoral vessels in animals treated with unprimed MSCs; this effect being abolished if the MSCs were primed with SFN. We show the potential of MSCs to carry SFN to brain tumors following an intranasal administration. However, the therapeutic effect is modest probably due to the pro

  11. The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis.

    Science.gov (United States)

    Kobayashi, Hiroharu; Yamashita, Yoriko; Iwase, Akira; Yoshikawa, Yutaka; Yasui, Hiroyuki; Kawai, Yoshichika; Uchida, Koji; Uno, Nozomi; Akatsuka, Shinya; Takahashi, Takashi; Kikkawa, Fumitaka; Toyokuni, Shinya

    2012-08-01

    To understand the role of ectopic endometriotic stromal cells in ovarian endometriosis (OEM) and the associated risks for infertility and carcinogenesis. Analyses of secreted proteins and gene expression using immortalized eutopic/ectopic endometrial(-otic) stromal cells from OEM. University. Women with and without OEM. Samples of endometrial(-otic) tissue from women with or without OEM. Immunohistochemical analysis of oxidative stress in OEM, gene expression profiles, and the identification of secreted proteins by mass spectrometry in immortalized endometrial(-otic) stromal cells. 4-Hydroxy-2-nonenal-modified proteins and carboxymethyllysine were abundant in the stroma, rather than epithelia, of OEM patients, indicating the presence of oxidative stress. Immortalized ectopic endometriotic stromal cells exhibited high IRP1/IRP2/HIF-1β expression and contained lower amounts of iron and copper than their eutopic counterparts. Expression profiles, in combination with protein identification, revealed that complement component 3 (C3) and pentraxin-3 (PTX3) are the major proteins secreted from immortalized ectopic endometriotic stromal cells. Complement-3/PTX3 promoted the secretion of various cytokines by THP1 macrophage cells and thus supported M1 differentiation. Immortalized ectopic endometriotic stromal cells in OEM predominantly secrete C3 and PTX3 and exhibit a differential regulation of iron metabolism. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  12. Growth and hormonal responsiveness of human endometrial stromal cells in culture.

    Science.gov (United States)

    Holinka, C F

    1988-06-01

    The present review describes and discusses published results on growth and hormonal responsiveness of human endometrial stromal cells in culture. The proliferative potential of serially subcultured cells, that is, the number of cell doublings before cells enter mitotic senescence and cease to divide, was unusually high in stromal cells from several endometrial specimens, a property that may reflect the unique proliferative capacity of human endometrium when compared to other adult tissues. Fluorescent visualization of microfilaments revealed distinct age-related changes in the distribution of cytoskeletal fibers. Addition of ovarian steroids to the culture medium of stromal cells resulted in significant morphologic changes. From comparative studies using different culture media it became evident that medium components remarkably influenced cell morphology during early culture periods in an irreversible manner. Cultured stromal cells yielded interesting results in experiments designed to define the role of polyamines in growth regulation. Proliferation was greatly inhibited when polyamine levels were reduced by specific inhibition of ornithine decarboxylase, the first and rate limiting enzyme in polyamine synthesis which produces putrescine by catalytic conversion from ornithine. The antiproliferative effects were reversed by addition of putrescine to the culture medium. These results clearly establish a causal link between polyamine depletion and growth deficiencies and reveal an essential function of polyamines in stromal cell proliferation. Hormonally regulated parameters in cultured stromal cells include aromatase activity, pregnancy-associated plasma protein-A, 51K secreted protein, prolactin and laminin. The hormonally regulated production of prolactin and laminin, both considered markers of decidualization, together with morphologic changes of stromal cells to decidual-like cells, strongly suggest that human endometrial stromal cells, when subjected to

  13. Pericytes limit tumor cell metastasis

    DEFF Research Database (Denmark)

    Xian, Xiaojie; Håkansson, Joakim; Ståhlberg, Anders

    2006-01-01

    Previously we observed that neural cell adhesion molecule (NCAM) deficiency in beta tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient beta cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions...... the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied beta cell tumorigenesis in primary pericyte-deficient Pdgfb(ret/ret) mice. This resulted in beta tumor cell metastases in distant organs and local lymph nodes, demonstrating a role...... and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing...

  14. Diet-induced obesity regulates adipose-resident stromal cell quantity and extracellular matrix gene expression

    OpenAIRE

    Pincu, Yair; Huntsman, Heather D.; Zou, Kai; De Lisio, Michael; Ziad S. Mahmassani; Michael R. Munroe; Garg, Koyal; Jensen, Tor; Boppart, Marni D.

    2016-01-01

    Adipose tissue expansion during periods of excess nutrient intake requires significant turnover of the extracellular matrix (ECM) to allow for maximal lipid filling. Recent data suggest that stromal cells may be a primary contributor to ECM modifications in visceral adipose. The purpose of this study was to investigate the capacity for high fat diet (HFD)-induced obesity to alter adipose-derived stromal cell (ADSC) relative quantity and ECM gene expression, and determine the extent to which e...

  15. AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

    OpenAIRE

    Collino, Federica; Bruno, Stefania; Incarnato, Danny; Dettori, Daniela; Neri, Francesco; Provero, Paolo; Pomatto, Margherita; Oliviero, Salvatore; Tetta, Ciro; Quesenberry, Peter J.; Camussi, Giovanni

    2015-01-01

    Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cell–promoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stroma...

  16. Downsizing treatment with tyrosine kinase inhibitors in patients with advanced gastrointestinal stromal tumors improved resectability.

    Science.gov (United States)

    Sjölund, Katarina; Andersson, Anna; Nilsson, Erik; Nilsson, Ola; Ahlman, Håkan; Nilsson, Bengt

    2010-09-01

    Gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase KIT. Most GISTs have mutations in the KIT or PDGFRA gene, causing activation of tyrosine kinase. Imatinib, a tyrosine kinase inhibitor (TKI), is the first-line palliative treatment for advanced GISTs. Sunitinib was introduced for patients with mutations not responsive to imatinib. The aim was to compare the survival of patients with high-risk resected GISTs treated with TKI prior to surgery with historical controls and to determine if organ-preserving surgery was facilitated. Ten high-risk GIST-patients had downsizing/adjuvant TKI treatment: nine with imatinib and one with sunitinib. The patients were matched with historical controls (n = 89) treated with surgery alone, from our population-based series (n = 259). Mutational analysis of KIT and PDGFRA was performed in all cases. The progression-free survival was calculated. The primary tumors decreased in mean diameter from 20.4 cm to 10.5 cm on downsizing imatinib. Four patients with R0 resection and a period of adjuvant imatinib had no recurrences versus 67% in the historical control group. Four patients with residual liver metastases have stable disease on continuous imatinib treatment after surgery. One patient has undergone reoperation with liver resection. The downsizing treatment led to organ-preserving surgery in nine patients and improved preoperative nutritional status in one patient. Downsizing TKI is recommended for patients with bulky tumors with invasion of adjacent organs. Sunitinib can be used for patients in case of imatinib resistance (e.g., wild-type GISTs), underlining the importance of mutational analysis for optimal surgical planning.

  17. The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST after imatinib failure - one institution study

    Directory of Open Access Journals (Sweden)

    Rutkowski Piotr

    2012-03-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GIST mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM or sunitinib (SU. Arterial hypertension (AH is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+ GIST patients after IM failure. Methods We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment. Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs of VEGFA and VEGFR2 genes. Results One year progression-free survival (PFS; calculated from the start of SU rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks in 55 patients with AH vs. 22% (median 17 weeks in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively. We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism

  18. Sex cord-stromal tumours of the ovary: a comprehensive update review

    OpenAIRE

    Horta, Mariana; Cunha, Teresa Margarida

    2015-01-01

    Ovarian sex cord-stromal tumors are infrequent and represent approximately 7% of all primary ovarian tumors. This histopathologic ovarian tumor group differs considerably from the more prevalent epithelial ovarian tumors. Although sex cord-stromal tumors present in a broad age group, the majority tend to present as a low-grade disease that usually follows a nonaggressive clinical course in younger patients. Furthermore, because the constituent cells of these tumors are engaged in ...

  19. AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs.

    Science.gov (United States)

    Collino, Federica; Bruno, Stefania; Incarnato, Danny; Dettori, Daniela; Neri, Francesco; Provero, Paolo; Pomatto, Margherita; Oliviero, Salvatore; Tetta, Ciro; Quesenberry, Peter J; Camussi, Giovanni

    2015-10-01

    Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cell-promoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI. Copyright © 2015 by the American Society of Nephrology.

  20. Pro-B cells propagated in stromal cell-free cultures reconstitute functional B-cell compartments in immunodeficient mice.

    Science.gov (United States)

    von Muenchow, Lilly; Tsapogas, Panagiotis; Albertí-Servera, Llucia; Capoferri, Giuseppina; Doelz, Marianne; Rolink, Hannie; Bosco, Nabil; Ceredig, Rhodri; Rolink, Antonius G

    2017-02-01

    Up to now long-term in vitro growth of pro-B cells was thought to require stromal cells. However, here we show that fetal liver (FL) and bone marrow (BM) derived pro-B cells can be propagated long-term in stromal cell-free cultures supplemented with IL-7, stem cell factor and FLT3 ligand. Within a week, most cells expressed surface CD19, CD79A, λ5, and VpreB antigens and had rearranged immunoglobulin D-J heavy chain genes. Both FL and BM pro-B cells reconstituted the B-cell compartments of immuno-incompetent Rag2-deficient mice, with FL pro-B cells generating follicular, marginal zone (MZB) and B1a B cells, and BM pro-B cells giving rise mainly to MZB cells. Reconstituted Rag2-deficient mice generated significant levels of IgM and IgG antibodies to a type II T-independent antigen; mice reconstituted with FL pro-B cells generated surprisingly high IgG1 titers. Finally, we show for the first time that mice reconstituted with mixtures of pro-B and pro-T cells propagated in stromal cell-free in vitro cultures mounted a T-cell-dependent antibody response. This novel stromal cell-free culture system facilitates our understanding of B-cell development and might be applied clinically. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Ethanol impairs differentiation of human adipocyte stromal cells in culture.

    Science.gov (United States)

    Crabb, David W; Zeng, Yan; Liangpunsakul, Suthat; Jones, Rosemarie; Considine, Robert

    2011-09-01

    Bioinformatic resources suggest that adipose tissue expresses mRNAs for alcohol dehydrogenases (ADHs) and ALDH2, and epidemiological studies indicate that heavy alcohol use reduces adipose tissue mass. We therefore characterized the expression of alcohol metabolizing enzymes in human, rat and mouse adipose tissue, preadipocytes, and adipocytes, the ability of adipocytes to metabolize ethanol, and the effects of ethanol on differentiation of human adipose stromal cells (hASCs). Adipose tissue, preadipocytes, and adipocytes were collected from rodents or from humans undergoing bariatric surgery. hASCs were differentiated in vitro using standard methods. Gene expression and cellular differentiation were analyzed by Western blotting, RT-PCR, and microscopy. Class I ADH was expressed in human > mouse > rat adipose tissue, whereas ALDH2 was high in all samples. ADH, catalase, and ALDH2 were induced during differentiation of hASCs. The presence of 50 mM ethanol markedly reduced the differentiation of hASCs; this effect was associated with inhibition of expression of transcription factors required for differentiation, but did not depend on the ability of the cells to metabolize ethanol. Human adipose tissue expresses alcohol oxidizing enzymes. The presence of ethanol at physiologically relevant concentrations inhibits differentiation of hASCs. Ethanol could alter adipose tissue biology, inducing a form of acquired lipodystrophy, which is consistent with epidemiological studies. 2011 by the Research Society on Alcoholism.

  2. Management of Fibrosis: The Mesenchymal Stromal Cells Breakthrough

    Directory of Open Access Journals (Sweden)

    Benoît Usunier

    2014-01-01

    Full Text Available Fibrosis is the endpoint of many chronic inflammatory diseases and is defined by an abnormal accumulation of extracellular matrix components. Despite its slow progression, it leads to organ malfunction. Fibrosis can affect almost any tissue. Due to its high frequency, in particular in the heart, lungs, liver, and kidneys, many studies have been conducted to find satisfactory treatments. Despite these efforts, current fibrosis management therapies either are insufficiently effective or induce severe adverse effects. In the light of these facts, innovative experimental therapies are being investigated. Among these, cell therapy is regarded as one of the best candidates. In particular, mesenchymal stromal cells (MSCs have great potential in the treatment of inflammatory diseases. The value of their immunomodulatory effects and their ability to act on profibrotic factors such as oxidative stress, hypoxia, and the transforming growth factor-β1 pathway has already been highlighted in preclinical and clinical studies. Furthermore, their propensity to act depending on the microenvironment surrounding them enhances their curative properties. In this paper, we review a large range of studies addressing the use of MSCs in the treatment of fibrotic diseases. The results reported here suggest that MSCs have antifibrotic potential for several organs.

  3. Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia.

    Science.gov (United States)

    Pitarresi, Jason R; Liu, Xin; Sharma, Sudarshana M; Cuitiño, Maria C; Kladney, Raleigh D; Mace, Thomas A; Donohue, Sydney; Nayak, Sunayana G; Qu, Chunjing; Lee, James; Woelke, Sarah A; Trela, Stefan; LaPak, Kyle; Yu, Lianbo; McElroy, Joseph; Rosol, Thomas J; Shakya, Reena; Ludwig, Thomas; Lesinski, Gregory B; Fernandez, Soledad A; Konieczny, Stephen F; Leone, Gustavo; Wu, Jinghai; Ostrowski, Michael C

    2016-09-01

    Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls. LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) mice showed that ETS2 expression initially increased in fibroblasts during ADM and remained elevated through progression to PDAC. Conditional ablation of Ets-2 in pancreatic fibroblasts in a Kras(G12D)-driven mouse ADM model decreased the amount of ADM events. ADMs from fibroblast Ets-2-deleted animals had reduced epithelial cell proliferation and increased apoptosis. Surprisingly, fibroblast Ets-2 deletion significantly altered immune cell infiltration into the stroma, with an increased CD8+ T-cell population, and decreased presence of regulatory T cells (Tregs), myeloid-derived suppressor cells, and mature macrophages. The mechanism involved ETS2-dependent chemokine ligand production in fibroblasts. ETS2 directly bound to regulatory sequences for Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10, a group of chemokines that act as potent mediators of immune cell recruitment. These results suggest an unappreciated role for ETS2 in fibroblasts in establishing an immune-suppressive microenvironment in response to oncogenic Kras(G12D) signaling during the initial stages of tumor development. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Mesenchymal stromal cell therapy in COPD: from bench to bedside

    Directory of Open Access Journals (Sweden)

    Antunes MA

    2017-10-01

    Full Text Available Mariana A Antunes,1,2 José Roberto Lapa e Silva,3 Patricia RM Rocco1,2 1Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro (UFRJ, RJ, Brazil; 2National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, RJ, Brazil; 3Institute of Thoracic Medicine, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro (UFRJ, Rio de Janeiro, RJ, Brazil Abstract: COPD is the most frequent chronic respiratory disease and a leading cause of morbidity and mortality. The major risk factor for COPD development is cigarette smoke, and the most efficient treatment for COPD is smoking cessation. However, even after smoking cessation, inflammation, apoptosis, and oxidative stress may persist and continue contributing to disease progression. Although current therapies for COPD (primarily based on anti-inflammatory agents contribute to the reduction of airway obstruction and minimize COPD exacerbations, none can avoid disease progression or reduce mortality. Within this context, recent advances in mesenchymal stromal cell (MSC therapy have made this approach a strong candidate for clinical use in the treatment of several pulmonary diseases. MSCs can be readily harvested from diverse tissues and expanded with high efficiency, and have strong immunosuppressive properties. Preclinical studies have demonstrated encouraging outcomes of MSCs therapy for lung disorders, including emphysema. These findings instigated research groups to assess the impact of MSCs in human COPD/emphysema, but clinical results have fallen short of expectations. However, MSCs have demonstrated a good adjuvant role in the clinical scenario. Trials that used MSCs combined with another, primary treatment (eg, endobronchial valves found that patients derived greater benefit in pulmonary function tests and/or quality of life reports, as well as reductions in systemic

  5. Influence of stromal cells on lymphocyte adhesion and migration on endothelial cells

    Science.gov (United States)

    McGettrick, Helen M.; Buckley, Chris D.; Rainger, G. Ed; Nash, Gerard B.

    2011-01-01

    Methods are described for analysing adhesion and migration of isolated lymphocytes on endothelial cell monolayers which have been co-cultured with different stromal cells, with or without additional cytokine treatment. The different cells types are grown on opposite sides of 3.0 or 0.4μm pore filters, depending on whether migration through the whole construct is to be analysed, or adhesion to the endothelial cells alone. Assays may be ‘static’ or filters can be incorporated into flow chambers so that cell behaviour can be directly observed under conditions simulating those in vivo. In general, by choice of method, one can evaluate efficiency of attachment, and ability of cells to migrate across the endothelial monolayer, through the filter and through the stromal cell layer. Fluorescence microscopic examination of fixed filters can be used e.g., to ascertain whether lymphocytes are retained by stromal cells. In general, static assays have the higher throughput and greatest ease of use, while the flow-based assays are more physiologically-relevant and allow detailed recording of cell behaviour in real time. PMID:20379868

  6. Isolation of Mesenchymal Stromal Cells (MSCs from Human Adenoid Tissue

    Directory of Open Access Journals (Sweden)

    Yoon Se Lee

    2013-04-01

    Full Text Available Background: Mesenchymal stromal cells (MSCs are multipotent progenitor cells that originally derived from bone marrow. Clinical use of bone marrow-derived MSC is difficult due to morbidity and low MSC abundance and isolation efficiency. Recently, MSCs have been isolated from various adult tissues. Here we report the isolation of adenoid tissue-derived MSCs (A-MSCs and their characteristics. Methods: We compared the surface markers, morphologies, and differentiation and proliferation capacities of previously established tonsil-derived MSCs (T-MSCs and bone marrow-derived MSCs (BM-MSCs with cells isolated from adenoid tissue. The immunophenotype of A-MSCs was investigated upon interferon (IFN-γ stimulation. Results: A-MSCs, T-MSCs, and BM-MSCs showed negative CD45, CD31 HLA-DR, CD34, CD14, CD19 and positive CD 90, CD44, CD73, CD105 expression. A-MSCs were fibroblast-like, spindle-shaped non-adherent cells, similar to T-MSCs and BM-MSCs. Adipogenesis was observed in A-MSCs by the formation of lipid droplets after Oil Red O staining. Osteogenesis was observed by the formation of the matrix mineralization in Alizarin Red staining. Chondrogenesis was observed by the accumulation of sulfated glycosaminoglycan-rich matrix in collagen type II staining. These data were similar to those of T-MSCs and BM-MSCs. Expression of marker genes (i.e., adipogenesis; lipoprotein lipase, proliferator-activator receptor-gamma, osteogenesis; osteocalcin, alkaline phasphatase, chondrogenesis; aggrecan, collagen type II α1 in A-MSCs were not different from those in T-MSCs and BM-MSCs. Conclusions: A-MSCs possess the characteristics of MSCs in terms of morphology, multipotent differentiation capacity, cell surface markers, and immunogeneity. Therefore, A-MSCs fulfill the definition of MSCs and represent an alternate source of MSCs.

  7. The clinicopathologic observation, c-KIT gene mutation and clonal status of gastrointestinal stromal tumor in the sacrum

    OpenAIRE

    Gong, Li; Li, Yan-Hong; Zhao, Hua-Dong; Zhao, Jian-Ye; Zhang, Wei

    2009-01-01

    Abstract Background It is very rare that gastrointestinal stromal tumor (GIST) occurs in the sacrum. Only one case of GIST occuring in the sacral region, with intracranial metastasis, has been reported in the literature. Moreover, only few cases have been published in literature about its clonal origin. Case presentation In this report, we present a rare case of GIST occuring in the sacrum and describe its clinicopathologic features, c-KIT gene mutation and clonal status. Microscopically, the...

  8. Massive Intra-Abdominal Imatinib-Resistant Gastrointestinal Stromal Tumor in a 21-Year-Old Male

    OpenAIRE

    Ann Falor; Arrington, Amanda K; Carrie Luu; Schoellhammer, Hans F; Michelle Ko; Warren Chow; Massimo D'Apuzzo; Jinha Park; Joseph Kim

    2013-01-01

    Gastrointestinal stromal tumors (GISTs) in adolescence are far less common than adult GISTs and have varied GIST genotypes that present diagnostic and therapeutic challenges. Here, we discuss a 21-year-old male with diagnosis of unresectable, imatinib-resistant GIST. At initial evaluation, a neoadjuvant treatment approach was recommended. As such, the patient received imatinib over the course of one year. Unfortunately, the GIST increased in size, and a subsequent attempt at surgical resectio...

  9. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells

    DEFF Research Database (Denmark)

    Simonsen, Janne Lytoft; Rosada, Cecilia; Serakinci, Nedime

    2002-01-01

    . The transduced cells have now undergone more than 260 population doublings (PD) and continue to proliferate, whereas control cells underwent senescence-associated proliferation arrest after 26 PD. The cells maintained production of osteoblastic markers and differentiation potential during continuous subculturing......, did not form tumors, and had a normal karyotype. When implanted subcutaneously in immunodeficient mice, the transduced cells formed more bone than did normal cells. These results suggest that ectopic expression of telomerase in hMSCs prevents senescence-associated impairment of osteoblast functions.......Human bone marrow stromal cells (hMSCs) were stably transduced by a retroviral vector containing the gene for the catalytic subunit of human telomerase (hTERT). Transduced cells (hMSC-TERTs) had telomerase activity, and the mean telomere length was increased as compared with that of control cells...

  10. Alternate mucoid and hyalinized stroma in clear cell carcinoma of the ovary: manifestation of serial stromal remodeling.

    Science.gov (United States)

    Kato, Noriko; Takeda, Junko; Fukase, Masayuki; Motoyama, Teiichi

    2010-06-01

    The stroma in ovarian clear cell carcinoma often shows alternate mucoid and hyalinized change. The hyalinized stroma is recognized to be an aberrant deposition of basement membrane material produced by tumor cells. The mucoid stroma, however, has drawn far less attention, and its significance remains unclear. We examined 60 ovarian clear cell carcinomas for the distribution and nature of the mucoid stroma. For comparison, 125 other surface epithelial ovarian tumors were examined. Twenty-nine of 60 (48%) clear cell carcinomas showed a mucoid stroma, either focally (21 cases) or diffusely (8 cases). The mucoid stroma in clear cell carcinomas was distinct from that in other surface epithelial tumors as follows: it showed a compact spherule-like appearance, commonly occupying the cores of small papillae. It also exhibited a cribriform pattern, resembling that of adenoid cystic carcinoma. It was rarely associated with stromal cells, despite the presence of abundant glycosaminoglycan including hyaluronan. Alternatively, it was strongly associated with hyalinized stroma. Among 40 clear cell carcinomas that had at least one type of stroma, 26 (65%) had both, either concomitantly or separately. The mucoid stroma tended to attenuate if the hyalinized stroma developed. In vitro, a clear cell carcinoma cell line, HAC-2, formed a spherule-like structure containing hyaluronan in the center, and a significant amount of hyaluronan was detected by latex agglutination immunoturbidimetry, indicating that HAC-2 itself has the potential to produce hyaluronan. All of these facts indicate that the spherule-like mucoid stroma and hyalinized stroma represent different phases of the stromal remodeling process, which is promoted by the deposition of different extracellular matrices produced by clear cell carcinoma cells. The spherule-like mucoid stroma and hyalinized stroma are considered complementary diagnostic signatures of ovarian clear cell carcinoma.

  11. Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles.

    Science.gov (United States)

    Sansone, Pasquale; Berishaj, Marjan; Rajasekhar, Vinagolu K; Ceccarelli, Claudio; Chang, Qing; Strillacci, Antonio; Savini, Claudia; Shapiro, Lauren; Bowman, Robert L; Mastroleo, Chiara; De Carolis, Sabrina; Daly, Laura; Benito-Martin, Alberto; Perna, Fabiana; Fabbri, Nicola; Healey, John H; Spisni, Enzo; Cricca, Monica; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

    2017-04-15

    The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with h