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  1. Application of hyperthermia in addition to ionizing irradiation fosters necrotic cell death and HMGB1 release of colorectal tumor cells

    SciTech Connect

    Schildkopf, Petra; Frey, Benjamin; Mantel, Frederick; Ott, Oliver J.; Weiss, Eva-Maria; Sieber, Renate; Janko, Christina; Sauer, Rolf; Fietkau, Rainer; Gaipl, Udo S.

    2010-01-01

    Colorectal cancer is the second leading cause of death in developed countries. Tumor therapies should on the one hand aim to stop the proliferation of tumor cells and to kill them, and on the other hand stimulate a specific immune response against residual cancer cells. Dying cells are modulators of the immune system contributing to anti-inflammatory or pro-inflammatory responses, depending on the respective cell death form. The positive therapeutic effects of temperature-controlled hyperthermia (HT), when combined with ionizing irradiation (X-ray), were the origin to examine whether combinations of X-ray with HT can induce immune activating tumor cell death forms, also characterized by the release of the danger signal HMGB1. Human colorectal tumor cells with differing radiosensitivities were treated with combinations of HT (41.5 {sup o}C for 1 h) and X-ray (5 or 10 Gy). Necrotic cell death was prominent after X-ray and could be further increased by HT. Apoptosis remained quite low in HCT 15 and SW480 cells. X-ray and combinations with HT arrested the tumor cells in the radiosensitive G2 cell cycle phase. The amount of released HMGB1 protein was significantly enhanced after combinatorial treatments in comparison to single ones. We conclude that combining X-ray with HT may induce anti-tumor immunity as a result of the predominant induction of inflammatory necrotic tumor cells and the release of HMGB1.

  2. Pancreatic islet cell tumor

    MedlinePlus

    Islet cell tumors; Islet of Langerhans tumor; Neuroendocrine tumors ... In the healthy pancreas, cells called islet cells produce hormones that regulate a several bodily functions. These include blood sugar level and the production of ...

  3. Tumor heterogeneity and circulating tumor cells.

    PubMed

    Zhang, Chufeng; Guan, Yan; Sun, Yulan; Ai, Dan; Guo, Qisen

    2016-05-01

    In patients with cancer, individualized treatment strategies are generally guided by an analysis of molecular biomarkers. However, genetic instability allows tumor cells to lose monoclonality and acquire genetic heterogeneity, an important characteristic of tumors, during disease progression. Researchers have found that there is tumor heterogeneity between the primary tumor and metastatic lesions, between different metastatic lesions, and even within a single tumor (either primary or metastatic). Tumor heterogeneity is associated with heterogeneous protein functions, which lowers diagnostic precision and consequently becomes an obstacle to determining the appropriate therapeutic strategies for individual cancer patients. With the development of novel testing technologies, an increasing number of studies have attempted to explore tumor heterogeneity by examining circulating tumor cells (CTCs), with the expectation that CTCs may comprehensively represent the full spectrum of mutations and/or protein expression alterations present in the cancer. In addition, this strategy represents a minimally invasive approach compared to traditional tissue biopsies that can be used to dynamically monitor tumor evolution. The present article reviews the potential efficacy of using CTCs to identify both spatial and temporal tumor heterogeneity. This review also highlights current issues in this field and provides an outlook toward future applications of CTCs. PMID:26902424

  4. Tumor cell intravasation.

    PubMed

    Chiang, Serena P H; Cabrera, Ramon M; Segall, Jeffrey E

    2016-07-01

    The process of entering the bloodstream, intravasation, is a necessary step in the development of distant metastases. The focus of this review is on the pathways and molecules that have been identified as being important based on current in vitro and in vivo assays for intravasation. Properties of the vasculature which are important for intravasation include microvessel density and also diameter of the vasculature, with increased intravasation correlating with increased vessel diameter in some tumors. TGFB signaling can enhance intravasation at least in part through induction of EMT, and we discuss other TGFB target genes that are important for intravasation. In addition to TGFB signaling, a number of studies have demonstrated that activation of EGF receptor family members stimulates intravasation, with downstream signaling through PI3K, N-WASP, RhoA, and WASP to induce invadopodia. With respect to proteases, there is strong evidence for contributions by uPA/uPAR, while the roles of MMPs in intravasation may be more tumor specific. Other cells including macrophages, fibroblasts, neutrophils, and platelets can also play a role in enhancing tumor cell intravasation. The technology is now available to interrogate the expression patterns of circulating tumor cells, which will provide an important reality check for the model systems being used. With a better understanding of the mechanisms underlying intravasation, the goal is to provide new opportunities for improving prognosis as well as potentially developing new treatments. PMID:27076614

  5. Deformability of Tumor Cells versus Blood Cells.

    PubMed

    Shaw Bagnall, Josephine; Byun, Sangwon; Begum, Shahinoor; Miyamoto, David T; Hecht, Vivian C; Maheswaran, Shyamala; Stott, Shannon L; Toner, Mehmet; Hynes, Richard O; Manalis, Scott R

    2015-01-01

    The potential for circulating tumor cells (CTCs) to elucidate the process of cancer metastasis and inform clinical decision-making has made their isolation of great importance. However, CTCs are rare in the blood, and universal properties with which to identify them remain elusive. As technological advancements have made single-cell deformability measurements increasingly routine, the assessment of physical distinctions between tumor cells and blood cells may provide insight into the feasibility of deformability-based methods for identifying CTCs in patient blood. To this end, we present an initial study assessing deformability differences between tumor cells and blood cells, indicated by the length of time required for them to pass through a microfluidic constriction. Here, we demonstrate that deformability changes in tumor cells that have undergone phenotypic shifts are small compared to differences between tumor cell lines and blood cells. Additionally, in a syngeneic mouse tumor model, cells that are able to exit a tumor and enter circulation are not required to be more deformable than the cells that were first injected into the mouse. However, a limited study of metastatic prostate cancer patients provides evidence that some CTCs may be more mechanically similar to blood cells than to typical tumor cell lines. PMID:26679988

  6. Deformability of Tumor Cells versus Blood Cells

    PubMed Central

    Shaw Bagnall, Josephine; Byun, Sangwon; Begum, Shahinoor; Miyamoto, David T.; Hecht, Vivian C.; Maheswaran, Shyamala; Stott, Shannon L.; Toner, Mehmet; Hynes, Richard O.; Manalis, Scott R.

    2015-01-01

    The potential for circulating tumor cells (CTCs) to elucidate the process of cancer metastasis and inform clinical decision-making has made their isolation of great importance. However, CTCs are rare in the blood, and universal properties with which to identify them remain elusive. As technological advancements have made single-cell deformability measurements increasingly routine, the assessment of physical distinctions between tumor cells and blood cells may provide insight into the feasibility of deformability-based methods for identifying CTCs in patient blood. To this end, we present an initial study assessing deformability differences between tumor cells and blood cells, indicated by the length of time required for them to pass through a microfluidic constriction. Here, we demonstrate that deformability changes in tumor cells that have undergone phenotypic shifts are small compared to differences between tumor cell lines and blood cells. Additionally, in a syngeneic mouse tumor model, cells that are able to exit a tumor and enter circulation are not required to be more deformable than the cells that were first injected into the mouse. However, a limited study of metastatic prostate cancer patients provides evidence that some CTCs may be more mechanically similar to blood cells than to typical tumor cell lines. PMID:26679988

  7. Canine mast cell tumors.

    PubMed

    Macy, D W

    1985-07-01

    Despite the fact that the mast cell tumor is a common neoplasm of the dog, we still have only a meager understanding of its etiology and biologic behavior. Many of the published recommendations for treatment are based on opinion rather than facts derived from careful studies and should be viewed with some skepticism. Because of the infrequent occurrence of this tumor in man, only a limited amount of help can be expected from human oncologists; therefore, burden of responsibility for progress in predicting behavior and developing treatment effective for canine mast cell tumors must fall on the shoulders of the veterinary profession. PMID:3929444

  8. Brain tumor stem cells.

    PubMed

    Palm, Thomas; Schwamborn, Jens C

    2010-06-01

    Since the end of the 'no-new-neuron' theory, emerging evidence from multiple studies has supported the existence of stem cells in neurogenic areas of the adult brain. Along with this discovery, neural stem cells became candidate cells being at the origin of brain tumors. In fact, it has been demonstrated that molecular mechanisms controlling self-renewal and differentiation are shared between brain tumor stem cells and neural stem cells and that corruption of genes implicated in these pathways can direct tumor growth. In this regard, future anticancer approaches could be inspired by uncovering such redundancies and setting up treatments leading to exhaustion of the cancer stem cell pool. However, deleterious effects on (normal) neural stem cells should be minimized. Such therapeutic models underline the importance to study the cellular mechanisms implicated in fate decisions of neural stem cells and the oncogenic derivation of adult brain cells. In this review, we discuss the putative origins of brain tumor stem cells and their possible implications on future therapies. PMID:20370314

  9. Testicular germ cell tumors.

    PubMed

    Looijenga, Leendert H J

    2014-02-01

    Human germ cell tumors are of interest because of their epidemiology, clinical behavior and pathobiology. Histologically, they are subdivided into various elements, with similarities to embryogenesis. Recent insights resulted in a division of five types of human germ cell tumors. In the context of male germ cells, three are relevant; Type I: teratomas and yolk sac tumors of neonates and infants; Type II: seminomas and nonseminomas of (predominantly) adolescents and adults; and Type III: spermatocytic seminomas of the elderly. Recent studies led to significant increases in understanding of the parameters involved in the earliest pathogenetic steps of human germ cells tumors, in particularly the seminomas and nonseminomas (Type II). In case of a disturbed gonadal physiology, either due to the germ cell itself, or the micro-environment, embryonic germ cells during a specific window of sensitization can be blocked in their maturation, resulting in carcinoma in situ or gonadoblastoma, the precursors of seminomas and nonseminomas. The level of testicularization of the gonad determines the histological composition of the precursor. These insights will allow better definition of individuals at risk to develop a germ cell malignancy, with putative preventive measurements, and allow better selection of scientific approaches to elucidate the pathogenesis. PMID:24683949

  10. Altered glycosylation in tumor cells

    SciTech Connect

    Reading, C.L. ); Hakomori, S. ); Marcus, D.M. )

    1988-01-01

    This book contains the proceeding on the following: Glycoconjugates of normal and tumor cells; Glycosyltransferases in normal and neoplastic cells; Mammalian lectins of normal tissues and tumor cells; and Immune recognition of carbohydrates and clinical applications.

  11. [Mediastinal germ cell tumors].

    PubMed

    Bremmer, F; Ströbel, P

    2016-09-01

    The mediastinum is among the most frequent anatomic region in which germ cell tumors (GCT) arise, second only to the gonads. Mediastinal GCT (mGCT) account for 16 % of all mediastinal neoplasms. Although the morphology and (according to all available data) the molecular genetics of mediastinal and gonadal GCT are identical, a number of unique aspects exist. There is a highly relevant bi-modal age distribution. In pre-pubertal children of both sexes, mGCT consist exclusively of teratomas and yolk sac tumors. The prognosis is generally favorable with modern treatment. In post-pubertal adults, virtually all patients with malignant mGCT are males; the prognosis is more guarded and depends (among other factors) on the histological GCT components and is similar to GCT in other organs. So-called somatic type malignancies (i. e. clonally related, non-germ cell neoplasias arising in a GCT) are much more frequent in mGCT than in other organs, and the association between mediastinal yolk sac tumors and hematological malignancies, such as myelodysplasias and leukemias, is unique to mediastinal tumors. The prognosis of GCT with somatic type malignancies is generally dismal. PMID:27491549

  12. Dentinogenic ghost cell tumor

    PubMed Central

    Bafna, Sweety Sagarmal; Joy, Tabita; Tupkari, Jagdish Vishnu; Landge, Jayant Shivaji

    2016-01-01

    Dentinogenic ghost cell tumor (DGCT) is a rare, odontogenic neoplasm which is considered to be a solid variant of calcifying odontogenic cyst (COC) with locally aggressive behavior. It accounts for only 2–14% of all COCs. To the best of our knowledge, only 88 cases of DGCT have been reported in the literature from 1968 to 2014. Herewith, we report a case of DGCT in a 68-year-old male patient with clinical presentation as a soft tissue growth over alveolar ridge and histopathologically characterized by ameloblastomatous epithelium, abundance of eosinophilic material and ghost cells. PMID:27194885

  13. Imaging Tumor Cell Movement In Vivo

    PubMed Central

    Entenberg, David; Kedrin, Dmitriy; Wyckoff, Jeffrey; Sahai, Erik; Condeelis, John; Segall, Jeffrey E.

    2013-01-01

    This unit describes the methods that we have been developing for analyzing tumor cell motility in mouse and rat models of breast cancer metastasis. Rodents are commonly used both to provide a mammalian system for studying human tumor cells (as xenografts in immunocompromised mice) as well as for following the development of tumors from a specific tissue type in transgenic lines. The Basic Protocol in this unit describes the standard methods used for generation of mammary tumors and imaging them. Additional protocols for labeling macrophages, blood vessel imaging, and image analysis are also included. PMID:23456602

  14. General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)

    MedlinePlus

    ... Islet Cell Tumors) Treatment (PDQ®)–Patient Version General Information About Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Go ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  15. Recurrent Giant Cell Tumor of Skull Combined with Multiple Aneurysms

    PubMed Central

    Kim, Dae Hwan

    2016-01-01

    Giant cell tumors are benign but locally invasive and frequently recur. Giant cell tumors of the skull are extremely rare. A patient underwent a surgery to remove a tumor, but the tumor recurred. Additionally, the patient developed multiple aneurysms. The patient underwent total tumor resection and trapping for the aneurysms, followed by radiotherapy. We report this rare case and suggest some possibilities for treating tumor growth combined with aneurysm development. PMID:27195256

  16. Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization.

    PubMed

    Small, Donna M; Burden, Roberta E; Jaworski, Jakub; Hegarty, Shauna M; Spence, Shaun; Burrows, James F; McFarlane, Cheryl; Kissenpfennig, Adrien; McCarthy, Helen O; Johnston, James A; Walker, Brian; Scott, Christopher J

    2013-11-01

    Recent murine studies have demonstrated that tumor-associated macrophages in the tumor microenvironment are a key source of the pro-tumorigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumor and tumor-associated cells contribute cathepsin S to promote neovascularization and tumor growth. Cathepsin S depleted and control colorectal MC38 tumor cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumor, tumor-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-associated cell derived cathepsin S. The most significant impact on tumor development was obtained when the protease was depleted from both sources. Further characterization revealed that the loss of cathepsin S led to impaired tumor vascularization, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumor growth. Analysis of cell types showed that in addition to the tumor cells, tumor-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumor-associated cells can positively contribute to developing tumors and highlight cathepsin S as a therapeutic target in cancer. PMID:23629809

  17. Detection of Circulating Tumor Cells

    PubMed Central

    Terstappen, Leon W. M. M.

    2014-01-01

    The increasing number of treatment options for patients with metastatic carcinomas has created an accompanying need for methods to determine if the tumor will be responsive to the intended therapy and to monitor its effectiveness. Ideally, these methods would be noninvasive and provide quantitative real-time analysis of tumor activity in a variety of carcinomas. Assessment of circulating tumor cells shed into the blood during metastasis may satisfy this need. Here we review the CellSearch technology used for the detection of circulating tumor cells and discuss potential future directions for improvements. PMID:25133014

  18. Addition of 10-Day Decitabine to Fludarabine/Total Body Irradiation Conditioning is Feasible and Induces Tumor-Associated Antigen-Specific T Cell Responses.

    PubMed

    Cruijsen, Marjan; Hobo, Willemijn; van der Velden, Walter J F M; Bremmers, Manita E J; Woestenenk, Rob; Bär, Brigitte; Falkenburg, J H Frederik; Kester, Michel; Schaap, Nicolaas P M; Jansen, Joop; Blijlevens, Nicole N M; Dolstra, Harry; Huls, Gerwin

    2016-06-01

    Allogeneic hematopoietic cell transplantation (HCT) offers the possibility of curative therapy for patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics and in patients who cannot tolerate consolidation chemotherapy (eg, due to previous toxicity). We assessed the toxicity and efficacy of 10-day decitabine (Dec), fludarabine (Flu), and 2 Gy total body irradiation (TBI) as a new conditioning regimen for allogeneic HCT in patients with MDS, CMML, or AML. Thirty patients were enrolled, including 11 with MDS, 2 with CMML, and 17 with AML. Patients received 20 mg/m(2)/day Dec on days -11 to -2, 30 mg/m(2)/day Flu on days -4 to -2, and 2 Gy TBI on day -1, followed by infusion of a donor stem cell graft on day 0. Postgrafting immunosuppression consisted of cyclosporin A and mycophenolate mofetil. At a median follow-up of 443 days, the overall survival was 53%, relapse incidence was 27%, and nonrelapse mortality was 27%. The incidence of severe acute (grade III/IV) graft-versus-host disease (GVHD) was 27%, and that of (predominantly mild) chronic GVHD was 60%. Immunomonitoring studies revealed that specific CD8(+) T cell responses against epigenetically silenced tumor-associated antigens (TAAs), including cancer-testis antigens (MAGE-A1/A2/A3 and PRAME) and RHAMM, occurred more frequently in patients who had received Dec/Flu/TBI conditioning (8 of 11 patients) compared with a control group of patients who had received only Flu/TBI conditioning (2 of 9 patients). In summary, Dec/Flu/TBI conditioning proved feasible and effective and enhanced the induction of TAA-reactive CD8(+) T cell responses in vivo, which may contribute to disease control post-transplantation. PMID:26860635

  19. Tumor-Associated Endothelial Cells Promote Tumor Metastasis by Chaperoning Circulating Tumor Cells and Protecting Them from Anoikis.

    PubMed

    Yadav, Arti; Kumar, Bhavna; Yu, Jun-Ge; Old, Matthew; Teknos, Theodoros N; Kumar, Pawan

    2015-01-01

    Tumor metastasis is a highly inefficient biological process as millions of tumor cells are released in circulation each day and only a few of them are able to successfully form distal metastatic nodules. This could be due to the fact that most of the epithelial origin cancer cells are anchorage-dependent and undergo rapid anoikis in harsh circulating conditions. A number of studies have shown that in addition to tumor cells, activated endothelial cells are also released into the blood circulation from the primary tumors. However, the precise role of these activated circulating endothelial cells (CECs) in tumor metastasis process is not known. Therefore, we performed a series of experiments to examine if CECs promoted tumor metastasis by chaperoning the tumor cells to distal sites. Our results demonstrate that blood samples from head and neck cancer patients contain significantly higher Bcl-2-positive CECs as compared to healthy volunteers. Technically, it is challenging to know the origin of CECs in patient blood samples, therefore we used an orthotopic SCID mouse model and co-implanted GFP-labeled endothelial cells along with tumor cells. Our results suggest that activated CECs (Bcl-2-positive) were released from primary tumors and they co-migrated with tumor cells to distal sites. Bcl-2 overexpression in endothelial cells (EC-Bcl-2) significantly enhanced adhesion molecule expression and tumor cell binding that was predominantly mediated by E-selectin. In addition, tumor cells bound to EC-Bcl-2 showed a significantly higher anoikis resistance via the activation of Src-FAK pathway. In our in vivo experiments, we observed significantly higher lung metastasis when tumor cells were co-injected with EC-Bcl-2 as compared to EC-VC. E-selectin knockdown in EC-Bcl-2 cells or FAK/FUT3 knockdown in tumor cells significantly reversed EC-Bcl-2-mediated tumor metastasis. Taken together, our results suggest a novel role for CECs in protecting the tumor cells in circulation and

  20. Targeting regulatory T cells in tumors.

    PubMed

    Liu, Chang; Workman, Creg J; Vignali, Dario A A

    2016-07-01

    Regulatory T (Treg ) cells play a crucial role in maintaining peripheral tolerance and preventing autoimmunity. However, they also represent a major barrier to effective antitumor immunity and immunotherapy. Consequently, there has been considerable interest in developing approaches that can selectively or preferentially target Treg cells in tumors, while not impacting their capacity to maintain peripheral immune homeostasis. In this review, we describe our current understanding of the mechanisms underlying the recruitment, expansion, and suppressive activity of tumor-associated Treg cells, and discuss the approaches used and the challenges encountered in the immunotherapeutic targeting of Treg cells. In addition, we summarize the primary clinical targets and some emerging data on exciting new potential Treg cell-restricted targets. We propose that discovering and understanding mechanisms that are preferentially used by Treg cells within the tumor microenvironment will lead to strategies that selectively target Treg cell-mediated suppression of antitumor immunity while maintaining peripheral immune tolerance. PMID:26787424

  1. Tumor angiogenesis--characteristics of tumor endothelial cells.

    PubMed

    Hida, Kyoko; Maishi, Nako; Torii, Chisaho; Hida, Yasuhiro

    2016-04-01

    Tumor blood vessels provide nutrition and oxygen to the tumor, resulting in tumor progression. They also act as gatekeepers, inducing tumor metastasis. Thus, targeting tumor blood vessels is an important strategy in cancer therapy. Tumor endothelial cells (TECs), which line the inner layer of blood vessels of the tumor stromal tissue, are the main targets of anti-angiogenic therapy. Because new tumor blood vessels generally sprout from pre-existing vasculature, they have been considered to be the same as normal blood vessels. However, tumor blood vessels demonstrate a markedly abnormal phenotype that includes several important morphological changes. The degree of angiogenesis is determined by the balance between the angiogenic stimulators and inhibitors released by the tumor and host cells. Recent studies have revealed that TECs also exhibit altered characteristics which depend on the tumor microenvironment. Here, we review recent studies on TEC abnormalities and heterogeneity with respect to tumor progression and consider their therapeutic implications. PMID:26879652

  2. [Ovarian germ cell tumors in girls].

    PubMed

    Nechushkina, I V; Karseladze, A I

    2015-01-01

    Morphological structure of tumor influences on the clinical course of the disease in children with germ cell tumors. Patients with ovarian dysgerminoma at the time of diagnosis are significantly older than patients with immature teratoma and yolk sac tumor. Immature teratoma and mixed germ cell tumors are significantly larger compared to other germ cell tumors. Yolk sac tumor and embryonal carcinoma are the most common cause of emergency surgical interventions and are accompanied by rupture of tumor capsule. PMID:26087605

  3. Tumor cell response to bevacizumab single agent therapy in vitro

    PubMed Central

    2013-01-01

    Background Angiogenesis represents a highly multi-factorial and multi-cellular complex (patho-) physiologic event involving endothelial cells, tumor cells in malignant conditions, as well as bone marrow derived cells and stromal cells. One main driver is vascular endothelial growth factor (VEGFA), which is known to interact with endothelial cells as a survival and mitogenic signal. The role of VEGFA on tumor cells and /or tumor stromal cell interaction is less clear. Condition specific (e.g. hypoxia) or tumor specific expression of VEGFA, VEGF receptors and co-receptors on tumor cells has been reported, in addition to the expression on the endothelium. This suggests a potential paracrine/autocrine loop that could affect changes specific to tumor cells. Methods We used the monoclonal antibody against VEGFA, bevacizumab, in various in vitro experiments using cell lines derived from different tumor entities (non small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC) and renal cell carcinoma (RCC)) in order to determine if potential VEGFA signaling could be blocked in tumor cells. The experiments were done under hypoxia, a major inducer of VEGFA and angiogenesis, in an attempt to mimic the physiological tumor condition. Known VEGFA induced endothelial biological responses such as proliferation, migration, survival and gene expression changes were evaluated. Results Our study was able to demonstrate expression of VEGF receptors on tumor cells as well as hypoxia regulated angiogenic gene expression. In addition, there was a cell line specific effect in tumor cells by VEGFA blockade with bevacizumab in terms of proliferation; however overall, there was a limited measurable consequence of bevacizumab therapy detected by migration and survival. Conclusion The present study showed in a variety of in vitro experiments with several tumor cell lines from different tumor origins, that by blocking VEGFA with bevacizumab, there was a limited autocrine or cell

  4. Tumor-associated stromal cells as key contributors to the tumor microenvironment.

    PubMed

    Bussard, Karen M; Mutkus, Lysette; Stumpf, Kristina; Gomez-Manzano, Candelaria; Marini, Frank C

    2016-01-01

    The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells. PMID:27515302

  5. Ceramide Kinase Promotes Tumor Cell Survival and Mammary Tumor Recurrence

    PubMed Central

    Payne, Ania W.; Pant, Dhruv K.; Pan, Tien-chi; Chodosh, Lewis A.

    2014-01-01

    Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTCs) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that Ceramide Kinase (Cerk) is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously up-regulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. We find that Cerk is rapidly up-regulated in tumor cells following HER2/neu down-regulation or treatment with Adriamycin and that Cerk is required for tumor cell survival following HER2/neu down-regulation. Consistent with our observations in mouse models, analysis of gene expression profiles from over 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with breast cancer. Additionally, although CERK expression is associated with aggressive subtypes of breast cancer, including those that are ER–, HER2+, basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathological variables. Together, our findings identify a functional role for Cerk in breast cancer recurrence and suggest the clinical utility of agents targeted against this pro-survival pathway. PMID:25164007

  6. Apoptin: specific killer of tumor cells?

    PubMed

    Tavassoli, M; Guelen, L; Luxon, B A; Gäken, J

    2005-08-01

    In the early 1990s it was discovered that the VP3/Apoptin protein encoded by the Chicken Anemia virus (CAV) possesses an inherent ability to specifically kill cancer cells. Apoptin was found to be located in the cytoplasm of normal cells while in tumor cells it was localized mainly in the nucleus.(1) These differences in the localization pattern were suggested to be the main mechanism by which normal cells show resistance to Apoptin-mediated cell killing. Although the mechanism of action of Apoptin is presently unknown, it seems to function by the induction of programmed cell death (PCD) after translocation from the cytoplasm to the nucleus and arresting the cell cycle at G2/M, possibly by interfering with the cyclosome.(2) In addition, cancer specific phosphorylation of Threonine residue 108 has been suggested to be important for Apoptin's function to kill tumor cells.(3) In contrast to the large number of publications reporting that nuclear localization, induction of PCD and phosphorylation of Apoptin is restricted to cancer cells, several recent studies have shown that Apoptin has the ability to migrate to the nucleus and induce PCD in some of the normal cell lines tested. There is evidence that high protein expression levels as well as the cellular growth rate may influence Apoptin's ability to specifically kill tumor cells. Thus far both in vitro and in vivo studies indicate that Apoptin is a powerful apoptosis inducing protein with a promising prospective utility in cancer therapy. However, here we show that several recent findings contradict some of the earlier results on the tumor specificity of Apoptin, thus creating some controversy in the field. The aim of this article is to review the available data, some published and some unpublished, which either agree or contradict the reported "black and white" tumor cell specificity of Apoptin. Understanding what factors appear to influence its function should help to develop Apoptin into a potent anti

  7. Apoptin: Specific killer of tumor cells?

    PubMed Central

    Tavassoli, M.; Guelen, L.; Luxon, B. A.; Gäken, J.

    2010-01-01

    In the early 1990s it was discovered that the VP3/Apoptin protein encoded by the Chicken Anemia virus (CAV) possesses an inherent ability to specifically kill cancer cells. Apoptin was found to be located in the cytoplasm of normal cells while in tumor cells it was localized mainly in the nucleus.1 These differences in the localization pattern were suggested to be the main mechanism by which normal cells show resistance to Apoptin-mediated cell killing. Although the mechanism of action of Apoptin is presently unknown, it seems to function by the induction of programmed cell death (PCD) after translocation from the cytoplasm to the nucleus and arresting the cell cycle at g2/M, possibly by interfering with the cyclosome.2 In addition, cancer specific phosphorylation of Threonine residue 108 has been suggested to be important for Apoptin’s function to kill tumor cells.3 In contrast to the large number of publications reporting that nuclear localization, induction of PCD and phosphorylation of Apoptin is restricted to cancer cells, several recent studies have shown that Apoptin has the ability to migrate to the nucleus and induce PCD in some of the normal cell lines tested. There is evidence that high protein expression levels as well as the cellular growth rate may influence Apoptin’s ability to specifically kill tumor cells. Thus far both in vitro and in vivo studies indicate that Apoptin is a powerful apoptosis inducing protein with a promising prospective utility in cancer therapy. However, here we show that several recent findings contradict some of the earlier results on the tumor specificity of Apoptin, thus creating some controversy in the field. The aim of this article is to review the available data, some published and some unpublished, which either agree or contradict the reported “black and white” tumor cell specificity of Apoptin. Understanding what factors appear to influence its function should help to develop Apoptin into a potent anti

  8. Interaction of MSC with tumor cells.

    PubMed

    Melzer, Catharina; Yang, Yuanyuan; Hass, Ralf

    2016-01-01

    Tumor development and tumor progression is not only determined by the corresponding tumor cells but also by the tumor microenvironment. This includes an orchestrated network of interacting cell types (e.g. immune cells, endothelial cells, fibroblasts, and mesenchymal stroma/stem cells (MSC)) via the extracellular matrix and soluble factors such as cytokines, chemokines, growth factors and various metabolites. Cell populations of the tumor microenvironment can interact directly and indirectly with cancer cells by mutually altering properties and functions of the involved partners. Particularly, mesenchymal stroma/stem cells (MSC) play an important role during carcinogenesis exhibiting different types of intercellular communication. Accordingly, this work focusses on diverse mechanisms of interaction between MSC and cancer cells. Moreover, some functional changes and consequences for both cell types are summarized which can eventually result in the establishment of a carcinoma stem cell niche (CSCN) or the generation of new tumor cell populations by MSC-tumor cell fusion. PMID:27608835

  9. Palifosfamide in Treating Patients With Recurrent Germ Cell Tumors

    ClinicalTrials.gov

    2015-06-11

    Adult Central Nervous System Germ Cell Tumor; Adult Teratoma; Malignant Extragonadal Germ Cell Tumor; Malignant Extragonadal Non-Seminomatous Germ Cell Tumor; Extragonadal Seminoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor; Stage IV Extragonadal Seminoma; Stage IV Ovarian Germ Cell Tumor

  10. Expression of Hyaluronidase by Tumor Cells Induces Angiogenesis in vivo

    NASA Astrophysics Data System (ADS)

    Liu, Dacai; Pearlman, Eric; Diaconu, Eugenia; Guo, Kun; Mori, Hiroshi; Haqqi, Tariq; Markowitz, Sanford; Willson, James; Sy, Man-Sun

    1996-07-01

    Hyaluronic acid is a proteoglycan present in the extracellular matrix and is important for the maintenance of tissue architecture. Depolymerization of hyaluronic acid may facilitate tumor invasion. In addition, oligosaccharides of hyaluronic acid have been reported to induce angiogenesis. We report here that a hyaluronidase similar to the one on human sperm is expressed by metastatic human melanoma, colon carcinoma, and glioblastoma cell lines and by tumor biopsies from patients with colorectal carcinomas, but not by tissues from normal colon. Moreover, angiogenesis is induced by hyaluronidase+ tumor cells but not hyaluronidase- tumor cells and can be blocked by an inhibitor of hyaluronidase. Tumor cells thus use hyaluronidase as one of the ``molecular saboteurs'' to depolymerize hyaluronic acid to facilitate invasion. As a consequence, breakdown products of hyaluronic acid can further promote tumor establishment by inducing angiogenesis. Hyaluronidase on tumor cells may provide a target for anti-neoplastic drugs.

  11. General Information about Extragonadal Germ Cell Tumors

    MedlinePlus

    ... Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Extragonadal Germ Cell Tumors Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  12. General Information about Ovarian Germ Cell Tumors

    MedlinePlus

    ... Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Ovarian Germ Cell Tumors Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  13. Patient-Derived Antibody Targets Tumor Cells

    Cancer.gov

    An NCI Cancer Currents blog on an antibody derived from patients that killed tumor cells in cell lines of several cancer types and slowed tumor growth in mouse models of brain and lung cancer without evidence of side effects.

  14. Tumor-associated macrophages promote tumor cell proliferation in nasopharyngeal NK/T-cell lymphoma

    PubMed Central

    Liu, Yixiong; Fan, Linni; Wang, Yingmei; Li, Peifeng; Zhu, Jin; Wang, Lu; Zhang, Weichen; Zhang, Yuehua; Huang, Gaosheng

    2014-01-01

    Objective: To explore the relationship between the number of tumor-associated macrophages (TAMs) and proliferative activity of tumor cells and the relationship between two macrophage biomarkers CD68 and CD163 in nasopharyngeal NK/T-cell lymphoma. Methods: Immunohistochemistry was used to reconfirm the diagnosis of nasal NK/T-cell lymphoma and detect the numbers of TAMs and the ki-67 label index of the tumor cells in all 31 cases. In addition, 12 cases of inflammatory cases were collected as controls, for which the immunostaining of CD68 and CD163 were done as well. Then staining results were analyzed with Pearson correlation and t test. Results: The number of TAMs was positively correlated with tumor proliferative activity (P = 0.024) in nasopharyngeal NK/T-cell lymphoma. The expression of CD68 and CD163 was closely related (P = 0.009), and the positive rate of CD68 was generally higher than CD163, however there is no statistical significance. Conclusion: The increase in numbers of TAMs in nasopharyngeal NK/T-cell lymphoma is related to higher proliferative index, indicating the TAMs play an important role in tumor proliferation. Meanwhile both CD68 and CD163 might be the markers for TAMs but CD163 would be the better one. PMID:25337185

  15. Experimental Adaptation of Rotaviruses to Tumor Cell Lines

    PubMed Central

    Guerrero, Carlos A.; Guerrero, Rafael A.; Silva, Elver; Acosta, Orlando; Barreto, Emiliano

    2016-01-01

    A number of viruses show a naturally extended tropism for tumor cells whereas other viruses have been genetically modified or adapted to infect tumor cells. Oncolytic viruses have become a promising tool for treating some cancers by inducing cell lysis or immune response to tumor cells. In the present work, rotavirus strains TRF-41 (G5) (porcine), RRV (G3) (simian), UK (G6-P5) (bovine), Ym (G11-P9) (porcine), ECwt (murine), Wa (G1-P8), Wi61 (G9) and M69 (G8) (human), and five wild-type human rotavirus isolates were passaged multiple times in different human tumor cell lines and then combined in five different ways before additional multiple passages in tumor cell lines. Cell death caused by the tumor cell-adapted isolates was characterized using Hoechst, propidium iodide, 7-AAD, Annexin V, TUNEL, and anti-poly-(ADP ribose) polymerase (PARP) and -phospho-histone H2A.X antibodies. Multiple passages of the combined rotaviruses in tumor cell lines led to a successful infection of these cells, suggesting a gain-of-function by the acquisition of greater infectious capacity as compared with that of the parental rotaviruses. The electropherotype profiles suggest that unique tumor cell-adapted isolates were derived from reassortment of parental rotaviruses. Infection produced by such rotavirus isolates induced chromatin modifications compatible with apoptotic cell death. PMID:26828934

  16. Treatment Option Overview (Extragonadal Germ Cell Tumors)

    MedlinePlus

    ... hCG and LDH may be at any level. Poor prognosis A nonseminoma extragonadal germ cell tumor is in the poor prognosis group if: the tumor is in the ... extragonadal germ cell tumor does not have a poor prognosis group. Treatment Option Overview Key Points There ...

  17. Juxtaglomerular cell tumor: A case report

    PubMed Central

    YANG, HONGYUAN; WANG, ZUFEI; JI, JIANSONG

    2016-01-01

    The current study reports the case of a 29-year-old female with a long-standing history of hypertension and headaches who presented to the Outpatient Clinic of The Central Hospital of Lishui (Lishui, Zhejiang, China). Abdominal ultrasound and contrast-enhanced computed tomography were performed, which showed a left renal neoplasm, prompting a diagnosis of renal angiomyolipoma or renal cell carcinoma. After a laparoscopic partial nephrectomy was performed, a number of different diagnoses were suggested by several pathologists from eight hospitals. Considering the patient's gender, age, medical history, histopathological features and immunohistochemistry, a final diagnosis of a juxtaglomerular cell tumor (JGCT) was established. The present study therefore indicates that the possibility of a JGCT should be considered when young adults present with renal parenchymatous tumors and high blood pressure. In addition, pathologists must take clinical information into account to form a precise diagnosis. PMID:26893753

  18. Interaction of tumor cells with the microenvironment

    PubMed Central

    2011-01-01

    Recent advances in tumor biology have revealed that a detailed analysis of the complex interactions of tumor cells with their adjacent microenvironment (tumor stroma) is mandatory in order to understand the various mechanisms involved in tumor growth and the development of metastasis. The mutual interactions between tumor cells and cellular and non-cellular components (extracellular matrix = ECM) of the tumor microenvironment will eventually lead to a loss of tissue homeostasis and promote tumor development and progression. Thus, interactions of genetically altered tumor cells and the ECM on the one hand and reactive non-neoplastic cells on the other hand essentially control most aspects of tumorigenesis such as epithelial-mesenchymal-transition (EMT), migration, invasion (i.e. migration through connective tissue), metastasis formation, neovascularisation, apoptosis and chemotherapeutic drug resistance. In this mini-review we will focus on these issues that were recently raised by two review articles in CCS. PMID:21914164

  19. Granular Cell Tumor: An Uncommon Benign Neoplasm

    PubMed Central

    Gayen, Tirthankar; Das, Anupam; Shome, Kaushik; Bandyopadhyay, Debabrata; Das, Dipti; Saha, Abanti

    2015-01-01

    Granular cell tumor is a distinctly rare neoplasm of neural sheath origin. It mainly presents as a solitary asymptomatic swelling in the oral cavity, skin, and rarely internal organs in the middle age. Histopathology is characteristic, showing polyhedral cells containing numerous fine eosinophilic granules with indistinct cell margins. We present a case of granular cell tumor on the back of a 48-year-old woman which was painful, mimicking an adnexal tumor. PMID:26120181

  20. Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells

    PubMed Central

    Yang, Xuguang; Li, Bingji; Liu, Jie; He, Rui

    2016-01-01

    Thymic stromal lymphopoietin (TSLP) has recently been suggested in several epithelial cancers, either pro-tumor or anti-tumor. However, the role of TSLP in colon cancer remains unknown. We here found significantly decreased TSLP levels in tumor tissues compared with tumor-surrounding tissues of patients with colon cancer and TSLP levels negatively correlated with the clinical staging score of colon cancer. TSLPR, the receptor of TSLP, was expressed in all three colon cancer cell lines investigated and colon tumor tissues. The addition of TSLP significantly enhanced apoptosis of colon cancer cells in a TSLPR-dependent manner. Interestingly, TSLP selectively induced the apoptosis of colon cancer cells, but not normal colonic epithelial cells. Furthermore, we demonstrated that TSLP induced JNK and p38 activation and initiated apoptosis mainly through the extrinsic pathway, as caspase-8 inhibitor significantly reversed the apoptosis-promoting effect of TSLP. Finally, using a xenograft mouse model, we demonstrated that peritumoral administration of TSLP greatly reduced tumor growth accompanied with extensive tumor apoptotic response, which was abolished by tumor cell-specific knockdown of TSLPR. Collectively, our study reveals a novel anti-tumor effect of TSLP via direct promotion of the apoptosis of colon cancer cells, and suggests that TSLP could be of value in treating colon cancer. PMID:26919238

  1. Ovarian Tumor Cells Studied Aboard the International Space Station (ISS)

    NASA Technical Reports Server (NTRS)

    2001-01-01

    In August 2001, principal investigator Jeanne Becker sent human ovarian tumor cells to the International Space Station (ISS) aboard the STS-105 mission. The tumor cells were cultured in microgravity for a 14 day growth period and were analyzed for changes in the rate of cell growth and synthesis of associated proteins. In addition, they were evaluated for the expression of several proteins that are the products of oncogenes, which cause the transformation of normal cells into cancer cells. This photo, which was taken by astronaut Frank Culbertson who conducted the experiment for Dr. Becker, shows two cell culture bags containing LN1 ovarian carcinoma cell cultures.

  2. NK Cells and γδ T Cells Mediate Resistance to Polyomavirus–Induced Tumors

    PubMed Central

    Mishra, Rabinarayan; Chen, Alex T.; Welsh, Raymond M.; Szomolanyi-Tsuda, Eva

    2010-01-01

    NK and γδ T cells can eliminate tumor cells in many experimental models, but their effect on the development of tumors caused by virus infections in vivo is not known. Polyomavirus (PyV) induces tumors in neonatally infected mice of susceptible strains and in adult mice with certain immune deficiencies, and CD8+ αβ T cells are regarded as the main effectors in anti-tumor immunity. Here we report that adult TCRβ knockout (KO) mice that lack αβ but have γδ T cells remain tumor-free after PyV infection, whereas TCRβ×δ KO mice that lack all T cells develop tumors. In addition, E26 mice, which lack NK and T cells, develop the tumors earlier than TCRβ×δ KO mice. These observations implicate γδ T and NK cells in the resistance to PyV-induced tumors. Cell lines established from PyV-induced tumors activate NK and γδ T cells both in culture and in vivo and express Rae-1, an NKG2D ligand. Moreover, these PyV tumor cells are killed by NK cells in vitro, and this cytotoxicity is prevented by treatment with NKG2D-blocking antibodies. Our findings demonstrate a protective role for NK and γδ T cells against naturally occurring virus-induced tumors and suggest the involvement of NKG2D-mediated mechanisms. PMID:20523894

  3. Tumor initiating cells in malignant gliomas

    PubMed Central

    Hadjipanayis, Costas G.; Van Meir, Erwin G.

    2009-01-01

    A rare subpopulation of cells within malignant gliomas, which shares canonical properties with neural stem cells (NSCs), may be integral to glial tumor development and perpetuation. These cells, also known as tumor initiating cells (TICs), have the ability to self-renew, develop into any cell in the overall tumor population (multipotency), and proliferate. A defining property of TICs is their ability to initiate new tumors in immunocompromised mice with high efficiency. Mounting evidence suggests that TICs originate from the transformation of NSCs and their progenitors. New findings show that TICs may be more resistant to chemotherapy and radiation than the bulk of tumor cells, thereby permitting recurrent tumor formation and accounting for the failure of conventional therapies. The development of new therapeutic strategies selectively targeting TICs while sparing NSCs may provide for more effective treatment of malignant gliomas. PMID:19189072

  4. Circulating Tumor Cells in Breast Cancer Patients.

    PubMed

    Hall, Carolyn; Valad, Lily; Lucci, Anthony

    2016-01-01

    Breast cancer is the most commonly diagnosed cancer among women, resulting in an estimated 40,000 deaths in 2014.1 Metastasis, a complex, multi-step process, remains the primary cause of death for these patients. Although the mechanisms involved in metastasis have not been fully elucidated, considerable evidence suggests that metastatic spread is mediated by rare cells within the heterogeneous primary tumor that acquire the ability to invade into the bloodstream. In the bloodstream, they can travel to distant sites, sometimes remaining undetected and in a quiescent state for an extended period of time before they establish distant metastases in the bone, lung, liver, or brain. These occult micrometastatic cells (circulating tumor cells, CTCs) are rare, yet their prognostic significance has been demonstrated in both metastatic and non-metastatic breast cancer patients. Because repeated tumor tissue collection is typically not feasible and peripheral blood draws are minimally invasive, serial CTC enumeration might provide "real-time liquid biopsy" snapshots that could be used to identify early-stage breast cancer patients with micrometastatic disease who are at risk for disease progression and monitor treatment response in patients with advanced disease. In addition, characterizing CTCs might aid in the development of novel, personalized therapies aimed at eliminating micrometastases. This review describes current CTC isolation, detection, and characterization strategies in operable breast cancer. PMID:27481009

  5. Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

    NASA Astrophysics Data System (ADS)

    Deng, Senyi; Wu, Qinjie; Zhao, Yuwei; Zheng, Xin; Wu, Ni; Pang, Jing; Li, Xuejing; Bi, Cheng; Liu, Xinyu; Yang, Li; Liu, Lei; Su, Weijun; Wei, Yuquan; Gong, Changyang

    2015-03-01

    Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti-tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti-tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy.

  6. Cell Fusion Connects Oncogenesis with Tumor Evolution

    PubMed Central

    Zhou, Xiaofeng; Merchak, Kevin; Lee, Woojin; Grande, Joseph P.; Cascalho, Marilia; Platt, Jeffrey L.

    2016-01-01

    Cell fusion likely drives tumor evolution by undermining chromosomal and DNA stability and/or by generating phenotypic diversity; however, whether a cell fusion event can initiate malignancy and direct tumor evolution is unknown. We report that a fusion event involving normal, nontransformed, cytogenetically stable epithelial cells can initiate chromosomal instability, DNA damage, cell transformation, and malignancy. Clonal analysis of fused cells reveals that the karyotypic and phenotypic potential of tumors formed by cell fusion is established immediately or within a few cell divisions after the fusion event, without further ongoing genetic and phenotypic plasticity, and that subsequent evolution of such tumors reflects selection from the initial diverse population rather than ongoing plasticity of the progeny. Thus, one cell fusion event can both initiate malignancy and fuel evolution of the tumor that ensues. PMID:26066710

  7. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

    PubMed Central

    Tape, Christopher J.; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M.; Worboys, Jonathan D.; Leong, Hui Sun; Norrie, Ida C.; Miller, Crispin J.; Poulogiannis, George; Lauffenburger, Douglas A.; Jørgensen, Claus

    2016-01-01

    Summary Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. Video Abstract PMID:27087446

  8. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.

    PubMed

    Tape, Christopher J; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M; Worboys, Jonathan D; Leong, Hui Sun; Norrie, Ida C; Miller, Crispin J; Poulogiannis, George; Lauffenburger, Douglas A; Jørgensen, Claus

    2016-05-01

    Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRAS(G12D)) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRAS(G12D) signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRAS(G12D) engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRAS(G12D). Consequently, reciprocal KRAS(G12D) produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRAS(G12D) alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. VIDEO ABSTRACT. PMID:27087446

  9. Engineered three-dimensional microfluidic device for interrogating cell-cell interactions in the tumor microenvironment

    PubMed Central

    Hockemeyer, K.; Janetopoulos, C.; Terekhov, A.; Hofmeister, W.; Vilgelm, A.; Costa, Lino; Wikswo, J. P.; Richmond, A.

    2014-01-01

    Stromal cells in the tumor microenvironment play a key role in the metastatic properties of a tumor. It is recognized that cancer-associated fibroblasts (CAFs) and endothelial cells secrete factors capable of influencing tumor cell migration into the blood or lymphatic vessels. We developed a microfluidic device that can be used to image the interactions between stromal cells and tumor cell spheroids in a three dimensional (3D) microenvironment while enabling external control of interstitial flow at an interface, which supports endothelial cells. The apparatus couples a 200-μm channel with a semicircular well to mimic the interface of a blood vessel with the stroma, and the design allows for visualization of the interactions of interstitial flow, endothelial cells, leukocytes, and fibroblasts with the tumor cells. We observed that normal tissue-associated fibroblasts (NAFs) contribute to the “single file” pattern of migration of tumor cells from the spheroid in the 3D microenvironment. In contrast, CAFs induce a rapid dispersion of tumor cells out of the spheroid with migration into the 3D matrix. Moreover, treatment of tumor spheroid cultures with the chemokine CXCL12 mimics the effect of the CAFs, resulting in similar patterns of dispersal of the tumor cells from the spheroid. Conversely, addition of CXCL12 to co-cultures of NAFs with tumor spheroids did not mimic the effects observed with CAF co-cultures, suggesting that NAFs produce factors that stabilize the tumor spheroids to reduce their migration in response to CXCL12. PMID:25379090

  10. Engineered three-dimensional microfluidic device for interrogating cell-cell interactions in the tumor microenvironment.

    PubMed

    Hockemeyer, K; Janetopoulos, C; Terekhov, A; Hofmeister, W; Vilgelm, A; Costa, Lino; Wikswo, J P; Richmond, A

    2014-07-01

    Stromal cells in the tumor microenvironment play a key role in the metastatic properties of a tumor. It is recognized that cancer-associated fibroblasts (CAFs) and endothelial cells secrete factors capable of influencing tumor cell migration into the blood or lymphatic vessels. We developed a microfluidic device that can be used to image the interactions between stromal cells and tumor cell spheroids in a three dimensional (3D) microenvironment while enabling external control of interstitial flow at an interface, which supports endothelial cells. The apparatus couples a 200-μm channel with a semicircular well to mimic the interface of a blood vessel with the stroma, and the design allows for visualization of the interactions of interstitial flow, endothelial cells, leukocytes, and fibroblasts with the tumor cells. We observed that normal tissue-associated fibroblasts (NAFs) contribute to the "single file" pattern of migration of tumor cells from the spheroid in the 3D microenvironment. In contrast, CAFs induce a rapid dispersion of tumor cells out of the spheroid with migration into the 3D matrix. Moreover, treatment of tumor spheroid cultures with the chemokine CXCL12 mimics the effect of the CAFs, resulting in similar patterns of dispersal of the tumor cells from the spheroid. Conversely, addition of CXCL12 to co-cultures of NAFs with tumor spheroids did not mimic the effects observed with CAF co-cultures, suggesting that NAFs produce factors that stabilize the tumor spheroids to reduce their migration in response to CXCL12. PMID:25379090

  11. Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

    ClinicalTrials.gov

    2015-12-01

    Desmoplastic Small Round Cell Tumor; Ewing Sarcoma of Bone or Soft Tissue; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

  12. The Metastasis-Promoting Roles of Tumor-Associated Immune Cells

    PubMed Central

    Smith, Heath A.; Kang, Yibin

    2013-01-01

    Tumor metastasis is driven not only by the accumulation of intrinsic alterations in malignant cells, but also by the interactions of cancer cells with various stromal cell components of the tumor microenvironment. In particular, inflammation and infiltration of the tumor tissue by host immune cells, such as tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells have been shown to support tumor growth in addition to invasion and metastasis. Each step of tumor development, from initiation through metastatic spread, is promoted by communication between tumor and immune cells via the secretion of cytokines, growth factors and proteases that remodel the tumor microenvironment. Invasion and metastasis requires neovascularization, breakdown of the basement membrane, and remodeling of the extracellular matrix for tumor cell invasion and extravasation into the blood and lymphatic vessels. The subsequent dissemination of tumor cells to distant organ sites necessitates a treacherous journey through the vasculature, which is fostered by close association with platelets and macrophages. Additionally, the establishment of the pre-metastatic niche and specific metastasis organ tropism is fostered by neutrophils and bone marrow-derived hematopoietic immune progenitor cells and other inflammatory cytokines derived from tumor and immune cells, which alter the local environment of the tissue to promote adhesion of circulating tumor cells. This review focuses on the interactions between tumor cells and immune cells recruited to the tumor microenvironment, and examines the factors allowing these cells to promote each stage of metastasis. PMID:23515621

  13. Thoracic Presentations of Small Round Blue Cell Tumors

    PubMed Central

    Chang, Annalice; Pfeifer, Kyle; Chen, Peter; Kalra, Vivek; Shin, Myung Soo

    2016-01-01

    The term “small round blue cell” is frequently used as a cursory radiologic pathological correlation of aggressive tumors throughout the body. We present a pictorial essay of common and uncommon subtypes of small round blue cell tumors in the chest illustrating the characteristic radiologic findings of each lesion. In addition, we review the pathologic findings of each tumor subtype with characteristic hematoxylin- and eosin-stained photomicrographs and immunohistochemical and molecular studies. Represented tumors include small cell carcinoma, Ewing sarcoma, extranodal marginal zone B-cell lymphoma, embryonal rhabdomyosarcoma, desmoplastic small round cell tumor, and posttransplant lymphoproliferative disorder. Understanding and ability to recognize these lesions are essential to broaden the radiologist's differential diagnosis and help guide patient care. PMID:27403403

  14. Electric Field Analysis of Breast Tumor Cells

    PubMed Central

    Sree, V. Gowri; Udayakumar, K.; Sundararajan, R.

    2011-01-01

    An attractive alternative treatment for malignant tumors that are refractive to conventional therapies, such as surgery, radiation, and chemotherapy, is electrical-pulse-mediated drug delivery. Electric field distribution of tissue/tumor is important for effective treatment of tissues. This paper deals with the electric field distribution study of a tissue model using MAXWELL 3D Simulator. Our results indicate that tumor tissue had lower electric field strength compared to normal cells, which makes them susceptible to electrical-pulse-mediated drug delivery. This difference could be due to the altered properties of tumor cells compared to normal cells, and our results corroborate this. PMID:22295214

  15. SYNOVIAL GIANT CELL TUMOR OF THE KNEE

    PubMed Central

    Abdalla, Rene Jorge; Cohen, Moisés; Nóbrega, Jezimar; Forgas, Andrea

    2015-01-01

    Synovial giant cell tumor is a benign neoplasm, rarely reported in the form of malignant metastasis. Synovial giant cell tumor most frequently occurs on the hand, and, most uncommon, on the ankle and knee. In the present study, the authors describe a rare case of synovial giant cell tumor on the knee as well as the treatment approach. Arthroscopy has been shown, in this case, to be the optimal method for treating this kind of lesion, once it allowed a less aggressive approach, while providing good visualization of all compartments of knee joint and full tumor resection. PMID:27004193

  16. Immune Cells in Blood Recognize Tumors

    Cancer.gov

    NCI scientists have developed a novel strategy for identifying immune cells circulating in the blood that recognize specific proteins on tumor cells, a finding they believe may have potential implications for immune-based therapies.

  17. CD44 enhances tumor aggressiveness by promoting tumor cell plasticity.

    PubMed

    Paulis, Yvette W J; Huijbers, Elisabeth J M; van der Schaft, Daisy W J; Soetekouw, Patricia M M B; Pauwels, Patrick; Tjan-Heijnen, Vivianne C G; Griffioen, Arjan W

    2015-08-14

    Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry. PMID:26189059

  18. Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

    PubMed Central

    Justus, Calvin R.; Sanderlin, Edward J.; Yang, Li V.

    2015-01-01

    Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention. PMID:25988385

  19. Circulating tumor cells in germ cell tumors: are those biomarkers of real prognostic value? A review

    PubMed Central

    CEBOTARU, CRISTINA LIGIA; OLTEANU, ELENA DIANA; ANTONE, NICOLETA ZENOVIA; BUIGA, RARES; NAGY, VIORICA

    2016-01-01

    Analysis of circulating tumor cells from patients with different types of cancer is nowadays a fascinating new tool of research and their number is proven to be useful as a prognostic factor in metastatic breast, colon and prostate cancer patients. Studies are going beyond enumeration, exploring the circulating tumor cells to better understand the mechanisms of tumorigenesis, invasion and metastasis and their value for characterization, prognosis and tailoring of treatment. Few studies investigated the prognostic significance of circulating tumor cells in germ cell tumors. In this review, we examine the possible significance of the detection of circulating tumor cells in this setting. PMID:27152069

  20. Activity of nintedanib in germ cell tumors.

    PubMed

    Steinemann, Gustav; Jacobsen, Christine; Gerwing, Mirjam; Hauschild, Jessica; von Amsberg, Gunhild; Höpfner, Michael; Nitzsche, Bianca; Honecker, Friedemann

    2016-02-01

    Germ cell tumors (GCTs) are the most frequent malignancy in male patients between 15 and 45 years of age. Cisplatin-based chemotherapy shows excellent cure rates, but patients with cisplatin-resistant GCTs have a poor prognosis. Nintedanib (BIBF 1120, Vargatef) inhibits the receptor classes vascular endothelial growth factor receptor, platelet derived growth factor receptor, and fibroblast growth factor receptor, and has shown activity against many tumors, as well as in idiopathic lung fibrosis and bleomycin-induced lung injury. Here, we investigated the antineoplastic and antiangiogenic properties of nintedanib in cisplatin-resistant and cisplatin-sensitive GCT cells, both alone and in combination with classical cytotoxic agents such as cisplatin, etoposide, and bleomycin. The half-maximal inhibitory concentration (IC50) of nintedanib was 4.5 ± 0.43 μmol/l, 3.1 ± 0.45 μmol/l, and 3.6 ± 0.33 μmol/l in cisplatin-sensitive NTERA2, 2102Ep, and NCCIT cells, whereas the IC50 doses of the cisplatin-resistant counterparts were 6.6 ± 0.37 μmol/l (NTERA2-R), 4.5 ± 0.83 μmol/l (2102Ep-R), and 6.1 ± 0.41 μmol/l (NCCIT-R), respectively. Single treatment with nintedanib induced apoptosis and resulted in a sustained reduction in the capacity of colony formation in both cisplatin-sensitive and cisplatin-resistant GCT cells. Cell cycle analysis showed that nintedanib induced a strong G0/G1-phase arrest in all investigated cell lines. Combination treatment with cisplatin did not result in additive, synergistic, or antagonistic effects. The in-vivo activity was studied using the chorioallantoic membrane assay and indicated the antiangiogenic potency of nintedanib with markedly reduced microvessel density. Topical treatment of inoculated tumor plaques resulted in a significant reduction of the tumor size. This indicates that nintedanib might be a promising substance in the treatment of GCT. PMID:26479145

  1. Targeting tumor cell motility to prevent metastasis

    PubMed Central

    Palmer, Trenis D.; Ashby, William J.; Lewis, John D.; Zijlstra, Andries

    2011-01-01

    Mortality and morbidity in patients with solid tumors invariably results from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities. PMID:21664937

  2. Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses

    PubMed Central

    Matsuzaki, Junko; Tsuji, Takemasa; Luescher, Immanuel F.; Shiku, Hiroshi; Mineno, Junichi; Okamoto, Sachiko; Old, Lloyd J.; Shrikant, Protul; Gnjatic, Sacha; Odunsi, Kunle

    2015-01-01

    Tumor antigen-specific CD4+ T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4+ T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4+ helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4+ T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8+ T cells by enhancing cytotoxic activity, and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8+ T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients. PMID:26447332

  3. Safety of targeting tumor endothelial cell antigens.

    PubMed

    Wagner, Samuel C; Riordan, Neil H; Ichim, Thomas E; Szymanski, Julia; Ma, Hong; Perez, Jesus A; Lopez, Javier; Plata-Munoz, Juan J; Silva, Francisco; Patel, Amit N; Kesari, Santosh

    2016-01-01

    The mechanisms underlying discrimination between "self" and "non-self", a central immunological principle, require careful consideration in immune oncology therapeutics where eliciting anti-cancer immunity must be weighed against the risk of autoimmunity due to the self origin of tumors. Whole cell vaccines are one promising immunotherapeutic avenue whereby a myriad of tumor antigens are introduced in an immunogenic context with the aim of eliciting tumor rejection. Despite the possibility collateral damage to healthy tissues, cancer immunotherapy can be designed such that off target autoimmunity remains limited in scope and severity or completely non-existent. Here we provide an immunological basis for reconciling the safety of cancer vaccines, focusing on tumor endothelial cell vaccines, by discussing the following topics: (a) Antigenic differences between neoplastic and healthy tissues that can be leveraged in cancer vaccine design; (b) The layers of tolerance that control T cell responses directed against antigens expressed in healthy tissues and tumors; and, (c) The hierarchy of antigenic epitope selection and display in response to whole cell vaccines, and how antigen processing and presentation can afford a degree of selectivity against tumors. We conclude with an example of early clinical data utilizing ValloVax™, an immunogenic placental endothelial cell vaccine that is being advanced to target the tumor endothelium of diverse cancers, and we report on the safety and efficacy of ValloVax™ for inducing immunity against tumor endothelial antigens. PMID:27071457

  4. DNA Tumor Viruses and Cell Metabolism

    PubMed Central

    Mushtaq, Muhammad; Darekar, Suhas

    2016-01-01

    Viruses play an important role in cancerogenesis. It is estimated that approximately 20% of all cancers are linked to infectious agents. The viral genes modulate the physiological machinery of infected cells that lead to cell transformation and development of cancer. One of the important adoptive responses by the cancer cells is their metabolic change to cope up with continuous requirement of cell survival and proliferation. In this review we will focus on how DNA viruses alter the glucose metabolism of transformed cells. Tumor DNA viruses enhance “aerobic” glycolysis upon virus-induced cell transformation, supporting rapid cell proliferation and showing the Warburg effect. Moreover, viral proteins enhance glucose uptake and controls tumor microenvironment, promoting metastasizing of the tumor cells. PMID:27034740

  5. Tumor-associated macrophages (not tumor cells) are the determinants of photosensitizer tumor localization

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Krosl, Gorazd

    1995-03-01

    The distribution of Photofrin and several other photosensitizers among major cellular populations contained in solid mouse tumors was examined using flow cytometry. Seven tumor models were included in the analysis: sarcomas EMT6, KHT, RIF, FsaR and FsaN, Lewis lung carcinoma and squamous cell carcinoma SCCVII. In all these tumors, the highest photosensitizer levels were found in a subpopulation of tumor associated macrophages consisting of activated cells (as suggested by their increased size, granularity, and the number of interleukin 2 receptors). There was no evidence of selective photosensitizer accumulation in malignant tumor cells. Results consistent with these observations were also obtained with the carcinogen induced squamous cell carcinoma growing in hamster cheek pouch.

  6. LOXL2 in epithelial cell plasticity and tumor progression.

    PubMed

    Cano, Amparo; Santamaría, Patricia G; Moreno-Bueno, Gema

    2012-09-01

    Several members of the lysyl oxidase family have recently emerged as important regulators of tumor progression. Among them, LOXL2 has been shown to be involved in tumor progression and metastasis of several tumor types, including breast carcinomas. Secreted LOXL2 participates in the remodeling of the extracellular matrix of the tumor microenvironment, in a similar fashion to prototypical lysyl oxidase. In addition, new intracellular functions of LOXL2 have been described, such as its involvement in the regulation of the epithelial-to-mesenchymal transition, epithelial cell polarity and differentiation mediated by transcriptional repression mechanisms. Importantly, intracellular (perinuclear) expression of LOXL2 is associated with poor prognosis and distant metastasis of specific tumor types, such as larynx squamous cell carcinoma and basal breast carcinomas. These recent findings open new avenues for the therapeutic utility of LOXL2. PMID:23030485

  7. Characterization of cell suspensions from solid tumors

    SciTech Connect

    Pallavicini, M.

    1985-07-10

    The desirable features of cells in suspension will necessarily be dependent upon the use for which the cells were prepared. Adequate cell yield or recovery is defined by the measurement to be performed. Retention of cellular morphology is important for microscopic identification of cell types in a heterogenous cell suspension, and may be used to determine whether the cells in suspension are representative of those in the tumor in situ. Different dispersal protocols may yield cells with different degrees of clonogenicity, as well as altered biochemical features, such as loss of cellular proteins, surface antigens, nucleotide pools, etc. The quality of the cell suspension can be judged by the degree of cell clumping and level of cellular debris, both of which impact on flow cytometric measurements and studies in which the number of cells be known accurately. Finally, if the data measured on the cells in suspension are to be extrapolated to phenomena occurring in the tumor in situ, it is desirable that the cells in suspension are representative of those in the solid tumor in vivo. This report compares characteristics of tumor cell suspensions obtained by different types of selected disaggregation methods. 33 refs., 2 figs., 4 tabs.

  8. Improved Methods to Generate Spheroid Cultures from Tumor Cells, Tumor Cells & Fibroblasts or Tumor-Fragments: Microenvironment, Microvesicles and MiRNA

    PubMed Central

    Lao, Zheng; Kelly, Catherine J.; Yang, Xiang-Yang; Jenkins, W. Timothy; Toorens, Erik; Ganguly, Tapan; Evans, Sydney M.; Koch, Cameron J.

    2015-01-01

    Diagnostic and prognostic indicators are key components to achieve the goal of personalized cancer therapy. Two distinct approaches to this goal include predicting response by genetic analysis and direct testing of possible therapies using cultures derived from biopsy specimens. Optimally, the latter method requires a rapid assessment, but growing xenograft tumors or developing patient-derived cell lines can involve a great deal of time and expense. Furthermore, tumor cells have much different responses when grown in 2D versus 3D tissue environments. Using a modification of existing methods, we show that it is possible to make tumor-fragment (TF) spheroids in only 2–3 days. TF spheroids appear to closely model characteristics of the original tumor and may be used to assess critical therapy-modulating features of the microenvironment such as hypoxia. A similar method allows the reproducible development of spheroids from mixed tumor cells and fibroblasts (mixed-cell spheroids). Prior literature reports have shown highly variable development and properties of mixed-cell spheroids and this has hampered the detailed study of how individual tumor-cell components interact. In this study, we illustrate this approach and describe similarities and differences using two tumor models (U87 glioma and SQ20B squamous-cell carcinoma) with supporting data from additional cell lines. We show that U87 and SQ20B spheroids predict a key microenvironmental factor in tumors (hypoxia) and that SQ20B cells and spheroids generate similar numbers of microvesicles. We also present pilot data for miRNA expression under conditions of cells, tumors, and TF spheroids. PMID:26208323

  9. Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells

    PubMed Central

    Perdicchio, Maurizio; Cornelissen, Lenneke A. M.; Streng-Ouwehand, Ingeborg; Engels, Steef; Verstege, Marleen I.; Boon, Louis; Geerts, Dirk

    2016-01-01

    The increased presence of sialylated glycans on the tumor surface has been linked to poor prognosis, yet the effects on tumor-specific T cell immunity are hardly studied. We here show that hypersialylation of B16 melanoma substantially influences tumor growth by preventing the formation of effector T cells and facilitating the presence of high regulatory T cell (Treg) frequencies. Knock-down of the sialic acid transporter created “sialic acid low” tumors, that grew slower in-vivo than hypersialylated tumors, altered the Treg/Teffector balance, favoring immunological tumor control. The enhanced effector T cell response in developing “sialic acid low” tumors was preceded by and dependent on an increased influx and activity of Natural Killer (NK) cells. Thus, tumor hypersialylation orchestrates immune escape at the level of NK and Teff/Treg balance within the tumor microenvironment, herewith dampening tumor-specific T cell control. Reducing sialylation provides a therapeutic option to render tumors permissive to immune attack. PMID:26741508

  10. Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells.

    PubMed

    Perdicchio, Maurizio; Cornelissen, Lenneke A M; Streng-Ouwehand, Ingeborg; Engels, Steef; Verstege, Marleen I; Boon, Louis; Geerts, Dirk; van Kooyk, Yvette; Unger, Wendy W J

    2016-02-23

    The increased presence of sialylated glycans on the tumor surface has been linked to poor prognosis, yet the effects on tumor-specific T cell immunity are hardly studied. We here show that hypersialylation of B16 melanoma substantially influences tumor growth by preventing the formation of effector T cells and facilitating the presence of high regulatory T cell (Treg) frequencies. Knock-down of the sialic acid transporter created "sialic acid low" tumors, that grew slower in-vivo than hypersialylated tumors, altered the Treg/Teffector balance, favoring immunological tumor control. The enhanced effector T cell response in developing "sialic acid low" tumors was preceded by and dependent on an increased influx and activity of Natural Killer (NK) cells. Thus, tumor hypersialylation orchestrates immune escape at the level of NK and Teff/Treg balance within the tumor microenvironment, herewith dampening tumor-specific T cell control. Reducing sialylation provides a therapeutic option to render tumors permissive to immune attack. PMID:26741508

  11. [Benign and malignant granular cell tumors. An immunohistochemical classification of tumor cells].

    PubMed

    Kuhn, A; Mahrle, G; Steigleder, G K

    1987-06-15

    Eight benign and three malignant granular cell tumors were characterized by means of antibodies and antisera against keratin, desmin, epithelial membrane antigen, factor VIII-related protein, lysozyme, myelin basic protein, myoglobin, neurone-specific enolase, S 100 protein, myelin-associated protein (Leu 7), glial fibrillary acidic protein, vimentin, and neurofilament. All benign granular cell tumours showed positive staining of the tumor cells to antibodies against vimentin, S 100 protein, and neurone-specific enolase; myelin-associated protein (Leu 7), in contrast, was only detectable in a few tumor sections. Histogenetically the granular cells may be classified as Schwann's cells which lost their expression of laminin. The three malignant granular cell tumors showed a staining pattern significantly different from that of the benign tumours. Thus, only neurone-specific enolase was detectable in all the tumors, whereas S 100 protein and vimentin could not be demonstrated but in one and two, resp., out of three tumors. PMID:3303714

  12. Sertoli cell tumor causing precocious puberty in a girl with Peutz-Jeghers syndrome.

    PubMed

    Zung, A; Shoham, Z; Open, M; Altman, Y; Dgani, R; Zadik, Z

    1998-09-01

    Distinctive ovarian and cervical tumors are associated with Peutz-Jeghers syndrome (PJS). The most common gynecological tumors in this syndrome are adenoma malignum of the uterine cervix and ovarian sex cord tumor, particularly sex cord tumor with annular tubules (SCTAT). Other kinds of ovarian tumors have been rarely reported in association of PJS, including Sertoli cell tumors. We report a case of a 4.5-year-old girl with PJS who presented with isosexual precocious puberty (IPP) due to ovarian lipid-rich Sertoli cell tumor. In addition to estrinizing effect of the tumor, the patient had decidual reaction secondary to tumor-derived progesterone secretion. The literature on gonadal tumors in PJS is reviewed, including one previous report of ovarian lipid-rich Sertoli cell tumor associated with this syndrome. PMID:9790799

  13. IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts

    PubMed Central

    Hamilton, Kathryn E.; Noubissi, Felicite K.; Rustgi, Anil K.

    2013-01-01

    Igf2 mRNA binding protein 1 (IMP1, CRD-BP, ZBP-1) is a messenger RNA binding protein that we have shown previously to regulate colorectal cancer (CRC) cell growth in vitro. Furthermore, increased IMP1 expression correlates with enhanced metastasis and poor prognosis in CRC patients. In the current study, we sought to elucidate IMP1-mediated functions in CRC pathogenesis in vivo. Using CRC cell xenografts, we demonstrate that IMP1 overexpression promotes xenograft tumor growth and dissemination into the blood. Furthermore, intestine-specific knockdown of Imp1 dramatically reduces tumor number in the Apc Min/+ mouse model of intestinal tumorigenesis. In addition, IMP1 knockdown xenografts exhibit a reduced number of tumor cells entering the circulation, suggesting that IMP1 may directly modulate this early metastatic event. We further demonstrate that IMP1 overexpression decreases E-cadherin expression, promotes survival of single tumor cell-derived colonospheres and promotes enrichment and maintenance of a population of CD24+CD44+ cells, signifying that IMP1 overexpressing cells display evidence of loss of epithelial identity and enhancement of a tumor-initiating cell phenotype. Taken together, these findings implicate IMP1 as a modulator of tumor growth and provide evidence for a novel role of IMP1 in early events in CRC metastasis. PMID:23764754

  14. Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses

    PubMed Central

    Chiba, Shiho; Ikushima, Hiroaki; Ueki, Hiroshi; Yanai, Hideyuki; Kimura, Yoshitaka; Hangai, Sho; Nishio, Junko; Negishi, Hideo; Tamura, Tomohiko; Saijo, Shinobu; Iwakura, Yoichiro; Taniguchi, Tadatsugu

    2014-01-01

    The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications. DOI: http://dx.doi.org/10.7554/eLife.04177.001 PMID:25149452

  15. Vasculogenesis and angiogenesis in nonseminomatous testicular germ cell tumors.

    PubMed

    Silván, Unai; Díez-Torre, Alejandro; Bonilla, Zuriñe; Moreno, Pablo; Díaz-Núñez, María; Aréchaga, Juan

    2015-06-01

    Testicular germ cell tumors (TGCTs) comprise the vast majority of all testicular malignancies and are the most common type of cancer among young male adults. The nonseminomatous variant of TGCTs is characterized by the presence of embryonic and extraembryonic tissues together with a population of pluripotent cancer stem cells, the so-called embryonal carcinoma. One of the main causes of the resistance of these tumors to therapy is their ability to invade adjacent tissues and metastasize into distant sites of the body. Both of these tumor processes are highly favored by the neovascularization of the malignant tissue. New vessels can be generated by means of angiogenesis or vasculogenesis, and both have been observed to occur during tumor vascularization. Nevertheless, the precise contribution of each process to the neoplastic vascular bed of TGCTs remains unknown. In addition, another process known as tumor-derived vasculogenesis, in which malignant cells give rise to endothelial cells, has also been reported to occur in a number of tumor types, including experimental TGCTs. The participation and cross talk of these 3 processes in tumor vascularization is of particular interest, given the embryonic origin of teratocarcinomas. Thus, in the present review, we discuss the importance of all 3 vascularization processes in the growth, invasion, and metastasis of testicular teratocarcinomas and summarize the current state of knowledge of the TGCT microenvironment and its relationship with vascularization. Finally, we discuss the importance of vascularization as a therapeutic target for this type of malignancy. PMID:25772688

  16. Energy and Redox Homeostasis in Tumor Cells

    PubMed Central

    de Oliveira, Marcus Fernandes; Amoêdo, Nívea Dias; Rumjanek, Franklin David

    2012-01-01

    Cancer cells display abnormal morphology, chromosomes, and metabolism. This review will focus on the metabolism of tumor cells integrating the available data by way of a functional approach. The first part contains a comprehensive introduction to bioenergetics, mitochondria, and the mechanisms of production and degradation of reactive oxygen species. This will be followed by a discussion on the oxidative metabolism of tumor cells including the morphology, biogenesis, and networking of mitochondria. Tumor cells overexpress proteins that favor fission, such as GTPase dynamin-related protein 1 (Drp1). The interplay between proapoptotic members of the Bcl-2 family that promotes Drp 1-dependent mitochondrial fragmentation and fusogenic antiapoptotic proteins such as Opa-1 will be presented. It will be argued that contrary to the widespread belief that in cancer cells, aerobic glycolysis completely replaces oxidative metabolism, a misrepresentation of Warburg's original results, mitochondria of tumor cells are fully viable and functional. Cancer cells also carry out oxidative metabolism and generally conform to the orthodox model of ATP production maintaining as well an intact electron transport system. Finally, data will be presented indicating that the key to tumor cell survival in an ROS rich environment depends on the overexpression of antioxidant enzymes and high levels of the nonenzymatic antioxidant scavengers. PMID:22693511

  17. Effects of Charged Particles on Human Tumor Cells

    PubMed Central

    Held, Kathryn D.; Kawamura, Hidemasa; Kaminuma, Takuya; Paz, Athena Evalour S.; Yoshida, Yukari; Liu, Qi; Willers, Henning; Takahashi, Akihisa

    2016-01-01

    The use of charged particle therapy in cancer treatment is growing rapidly, in large part because the exquisite dose localization of charged particles allows for higher radiation doses to be given to tumor tissue while normal tissues are exposed to lower doses and decreased volumes of normal tissues are irradiated. In addition, charged particles heavier than protons have substantial potential clinical advantages because of their additional biological effects, including greater cell killing effectiveness, decreased radiation resistance of hypoxic cells in tumors, and reduced cell cycle dependence of radiation response. These biological advantages depend on many factors, such as endpoint, cell or tissue type, dose, dose rate or fractionation, charged particle type and energy, and oxygen concentration. This review summarizes the unique biological advantages of charged particle therapy and highlights recent research and areas of particular research needs, such as quantification of relative biological effectiveness (RBE) for various tumor types and radiation qualities, role of genetic background of tumor cells in determining response to charged particles, sensitivity of cancer stem-like cells to charged particles, role of charged particles in tumors with hypoxic fractions, and importance of fractionation, including use of hypofractionation, with charged particles. PMID:26904502

  18. Osteoclastic giant cell tumor of the pancreas☆

    PubMed Central

    Temesgen, Wudneh M.; Wachtel, Mitchell; Dissanaike, Sharmila

    2014-01-01

    INTRODUCTION Pancreatic giant cell tumors are rare, with an incidence of less than 1% of all pancreatic tumors. Osteoclastic giant cell tumor (OGCT) of the pancreas is one of the three types of PGCT, which are now classified as undifferentiated carcinoma with osteoclast-like giant cells. PRESENTATION OF CASE The patient is a 57 year old woman who presented with a 3 week history of epigastric pain and a palpable abdominal mass. Imaging studies revealed an 18 cm × 15 cm soft tissue mass with cystic components which involved the pancreas, stomach and spleen. Exploratory laparotomy with distal pancreatectomy, partial gastrectomy and splenectomy was performed. Histology revealed undifferentiated pancreatic carcinoma with osteoclast-like giant cells with production of osteoid and glandular elements. DISCUSSION OGCT of the pancreas resembles benign-appearing giant cell tumors of bone, and contain osteoclastic-like multinucleated cells and mononuclear cells. OGCTs display a less aggressive course with slow metastasis and lymph node spread compared to pancreatic adenocarcinoma. Due to the rarity of the cancer, there is a lack of prospective studies on treatment options. Surgical en-bloc resection is currently considered first line treatment. The role of adjuvant therapy with radiotherapy or chemotherapy has not been established. CONCLUSION Pancreatic giant cell tumors are rare pancreatic neoplasms with unique clinical and pathological characteristics. Osteoclastic giant cell tumors are the most favorable sub-type. Surgical en bloc resection is the first line treatment. Long-term follow-up of patients with these tumors is essential to compile a body of literature to help guide treatment. PMID:24631915

  19. The metabolic advantage of tumor cells

    PubMed Central

    2011-01-01

    1- Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases. 2- Experiments on pancreatectomized animals; treated with pure insulin or total pancreatic extracts, showed that choline in the extract, preserved them from hepatomas. Since choline is a methyle donor, and since methylation regulates PP2A, the choline protection may result from PP2A methylation, which then attenuates kinases. 3- Moreover, kinases activated by the boosted signaling pathway inactivate pyruvate kinase and pyruvate dehydrogenase. In addition, demethylated PP2A would no longer dephosphorylate these enzymes. A "bottleneck" between glycolysis and the oxidative-citrate cycle interrupts the glycolytic pyruvate supply now provided via proteolysis and alanine transamination. This pyruvate forms lactate (Warburg effect) and NAD+ for glycolysis. Lipolysis and fatty acids provide acetyl CoA; the citrate condensation increases, unusual oxaloacetate sources are available. ATP citrate lyase follows, supporting aberrant transaminations with glutaminolysis and tumor lipogenesis. Truncated urea cycles, increased polyamine synthesis, consume the methyl donor SAM favoring carcinogenesis. 4- The decrease of butyrate, a histone deacetylase inhibitor, elicits epigenic changes (PETEN, P53, IGFBP decrease; hexokinase, fetal-genes-M2, increase) 5- IGFBP stops binding the IGF - IGFR complex, it is perhaps no longer inherited by a single mitotic daughter cell; leading to two daughter cells with a mitotic capability. 6- An excess of IGF induces a decrease of the major histocompatibility complex MHC1, Natural killer lymphocytes should eliminate such cells that start the tumor, unless the fever prostaglandin PGE2 or inflammation, inhibit them... PMID:21649891

  20. Giant Cell Tumor of Tendon Sheath

    PubMed Central

    Briët, Jan Paul; Becker, Stéphanie JE; Oosterhoff, Thijs CH; Ring, David

    2015-01-01

    Background: Giant cell tumor of tendon sheath (GCTTS) is often thought of as a volar finger mass. We hypothesized that GCTTS are equally common on the dorsal and volar aspects of the hand. In addition, we hypothesized that there are no factors associated with the location (volar versus dorsal) and largest measured dimension of a GCTTS. Methods: A total of 126 patients with a pathological diagnosis of a GCTTS of the hand or finger were reviewed. Basic demographic and GCTTS specific information was obtained. Bivariable analyses were used to assess predicting factors for location (volar or dorsal side) and largest measured diameter of a GCTTS. Results: Seventy-two tumors (57%) were on the volar side of the hand, 47 (37%) were dorsal, 6 (4.8%) were both dorsal and volar, and one was midaxial (0.79%). The most common site of a GCTTS was the index finger (30%). There were no factors significantly associated with the location (volar or dorsal, n=119) of the GCTTS. There were also no factors significantly associated with a larger diameter of a GCTTS. Conclusions: A GCTTS was more frequently seen on the volar aspect of the hand. No significant factors associated with the location or an increased size of a GCTTS were found in this study. PMID:25692164

  1. Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles.

    PubMed

    Ma, Jingwei; Zhang, Yi; Tang, Ke; Zhang, Huafeng; Yin, Xiaonan; Li, Yong; Xu, Pingwei; Sun, Yanling; Ma, Ruihua; Ji, Tiantian; Chen, Junwei; Zhang, Shuang; Zhang, Tianzhen; Luo, Shunqun; Jin, Yang; Luo, Xiuli; Li, Chengyin; Gong, Hongwei; Long, Zhixiong; Lu, Jinzhi; Hu, Zhuowei; Cao, Xuetao; Wang, Ning; Yang, Xiangliang; Huang, Bo

    2016-06-01

    Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications. PMID:27167569

  2. An overview of therapeutic approaches to brain tumor stem cells

    PubMed Central

    2012-01-01

    Primary and secondary malignant central nervous system (CNS) tumors are devastating invasive tumors able to give rise to many kinds of differentiated tumor cells. Glioblastoma multiform (GBM), is the most malignant brain tumor, in which its growth and persistence depend on cancer stem cells with enhanced DNA damage repair program that also induces recurrence and resists current chemo- and radiotherapies. Unlike non-tumor stem cells, tumor stem cells lack the normal mechanisms that regulate proliferation and differentiation, resulting in uncontrolled production and incomplete differentiation of tumor cells. In current paper recent developments and new researches in the field of brain tumor stem cells have been reviewed. PMID:23483074

  3. The chemosensitivity of testicular germ cell tumors.

    PubMed

    Voutsadakis, Ioannis A

    2014-04-01

    Although rare cancers overall, testicular germ cell tumors (TGCTs) are the most common type of cancer in young males below 40 years of age. Both subtypes of TGCTs, i.e., seminomas and non-seminomas, are highly curable and the majority of even metastatic patients may expect to be cured. These high cure rates are not due to the indolent nature of these cancers, but rather to their sensitivity to chemotherapy (and for seminomas to radiotherapy). The delineation of the cause of chemosensitivity at the molecular level is of paramount importance, because it may provide insights into the minority of TGCTs that are chemo-resistant and, thereby, provide opportunities for specific therapeutic interventions aimed at reverting them to chemosensitivity. In addition, delineation of the molecular basis of TGCT chemo-sensitivity may be informative for the cause of chemo-resistance of other more common types of cancer and, thus, may create new therapeutic leads. p53, a frequently mutated tumor suppressor in cancers in general, is not mutated in TGCTs, a fact that has implications for their chemo-sensitivity. Oct4, an embryonic transcription factor, is uniformly expressed in the seminoma and embryonic carcinoma components of non-seminomas, and its interplay with p53 may be important in the chemotherapy response of these tumors. This interplay, together with other features of TGCTs such as the gain of genetic material from the short arm of chromosome 12 and the association with disorders of testicular development, will be discussed in this paper and integrated in a unifying hypothesis that may explain their chemo-sensitivity. PMID:24692098

  4. One cell, multiple roles: contribution of mesenchymal stem cells to tumor development in tumor microenvironment

    PubMed Central

    2013-01-01

    The discovery of tissue reparative and immunosuppressive abilities of mesenchymal stem cells (MSCs) has drawn more attention to tumor microenvironment and its role in providing the soil for the tumor cell growth. MSCs are recruited to tumor which is referred as the never healing wound and altered by the inflammation environment, thereby helping to construct the tumor microenvironment. The environment orchestrated by MSCs and other factors can be associated with angiogenesis, immunosuppression, inhibition of apoptosis, epithelial-mesenchymal transition (EMT), survival of cancer stem cells, which all contribute to tumor growth and progression. In this review, we will discuss how MSCs are recruited to the tumor microenvironment and what effects they have on tumor progression. PMID:23336752

  5. Whole tumor antigen vaccination using dendritic cells: comparison of RNA electroporation and pulsing with UV-irradiated tumor cells.

    PubMed

    Benencia, Fabian; Courrèges, Maria C; Coukos, George

    2008-01-01

    Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC) based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV) B radiation using a convenient tumor model expressing human papilloma virus (HPV) E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions. PMID:18445282

  6. Tumor-Infiltrating Immune Cells Promoting Tumor Invasion and Metastasis: Existing Theories

    PubMed Central

    Man, Yan-gao; Stojadinovic, Alexander; Mason, Jeffrey; Avital, Itzhak; Bilchik, Anton; Bruecher, Bjoern; Protic, Mladjan; Nissan, Aviram; Izadjoo, Mina; Zhang, Xichen; Jewett, Anahid

    2013-01-01

    It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destructions of the tumor cells, reduction of the tumor burden, and improved clinical prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. This mini-review presents several existing hypotheses and models that favor the promoting impact of tumor-infiltrating immune cells on tumor invasion and metastasis, and also analyzes their strength and weakness. PMID:23386907

  7. Molecular biology of testicular germ cell tumors.

    PubMed

    Gonzalez-Exposito, R; Merino, M; Aguayo, C

    2016-06-01

    Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men. They constitute a unique pathology because of their embryonic and germ origin and their special behavior. Genetic predisposition, environmental factors involved in their development and genetic aberrations have been under study in many works throughout the last years trying to explain the susceptibility and the transformation mechanism of TGCTs. Despite the high rate of cure in this type of tumors because its particular sensitivity to cisplatin, there are tumors resistant to chemotherapy for which it is needed to find new therapies. In the present work, it has been carried out a literature review on the most important molecular aspects involved in the onset and development of such tumors, as well as a review of the major developments regarding prognostic factors, new prognostic biomarkers and the possibility of new targeted therapies. PMID:26482724

  8. Reactive Oxygen Species in Normal and Tumor Stem Cells

    PubMed Central

    Zhou, Daohong; Shao, Lijian; Spitz, Douglas R.

    2014-01-01

    Reactive oxygen species (ROS) play an important role in determining the fate of normal stem cells. Low levels of ROS are required for stem cells to maintain quiescence and self-renewal. Increases in ROS production cause stem cell proliferation/differentiation, senescence, and apoptosis in a dose-dependent manner, leading to their exhaustion. Therefore, the production of ROS in stem cells is tightly regulated to ensure that they have the ability to maintain tissue homeostasis and repair damaged tissues for the life span of an organism. In this chapter, we discuss how the production of ROS in normal stem cells is regulated by various intrinsic and extrinsic factors and how the fate of these cells is altered by the dysregulation of ROS production under various pathological conditions. In addition, the implications of the aberrant production of ROS by tumor stem cells for tumor progression and treatment are also discussed. PMID:24974178

  9. Enhanced delivery of liposomes to lung tumor through targeting interleukin-4 receptor on both tumor cells and tumor endothelial cells.

    PubMed

    Chi, Lianhua; Na, Moon-Hee; Jung, Hyun-Kyung; Vadevoo, Sri Murugan Poongkavithai; Kim, Cheong-Wun; Padmanaban, Guruprasath; Park, Tae-In; Park, Jae-Yong; Hwang, Ilseon; Park, Keon Uk; Liang, Frank; Lu, Maggie; Park, Jiho; Kim, In-San; Lee, Byung-Heon

    2015-07-10

    A growing body of evidence suggests that pathological lesions express tissue-specific molecular targets or biomarkers within the tissue. Interleukin-4 receptor (IL-4R) is overexpressed in many types of cancer cells, including lung cancer. Here we investigated the properties of IL-4R-binding peptide-1 (IL4RPep-1), a CRKRLDRNC peptide, and its ability to target the delivery of liposomes to lung tumor. IL4RPep-1 preferentially bound to H226 lung tumor cells which express higher levers of IL-4R compared to H460 lung tumor cells which express less IL-4R. Mutational analysis revealed that C1, R2, and R4 residues of IL4RPep-1 were the key binding determinants. IL4RPep-1-labeled liposomes containing doxorubicin were more efficiently internalized in H226 cells and effectively delivered doxorubicin into the cells compared to unlabeled liposomes. In vivo fluorescence imaging of nude mice subcutaneously xenotransplanted with H226 tumor cells indicated that IL4RPep-1-labeled liposomes accumulate more efficiently in the tumor and inhibit tumor growth more effectively compared to unlabeled liposomes. Interestingly, expression of IL-4R was high in vascular endothelial cells of tumor, while little was detected in vascular endothelial cells of control organs including the liver. IL-4R expression in cultured human vascular endothelial cells was also up-regulated when activated by a pro-inflammatory cytokine tumor necrosis factor-α. Moreover, the up-regulation of IL-4R expression was observed in primary human lung cancer tissues. These results indicate that IL-4R-targeting nanocarriers may be a useful strategy to enhance drug delivery through the recognition of IL-4R in both tumor cells and tumor endothelial cells. PMID:25979323

  10. Revisiting autophagy addiction of tumor cells

    PubMed Central

    Nyfeler, Beat; Eng, Christina H.

    2016-01-01

    ABSTRACT Inhibition of autophagy has been widely explored as a potential therapeutic intervention for cancer. Different factors such as tumor origin, tumor stage and genetic background can define a tumor's response to autophagy modulation. Notably, tumors with oncogenic mutations in KRAS were reported to depend on macroautophagy in order to cope with oncogene-induced metabolic stress. Our recent report details the unexpected finding that autophagy is dispensable for KRAS-driven tumor growth in vitro and in vivo. Additionally, we clarify that the antitumorigenic effects of chloroquine, a frequently used nonspecific inhibitor of autophagy, are not connected to the inhibition of macroautophagy. Our data suggest that caution should be exercised when using chloroquine and its analogs to decipher the roles of autophagy in cancer. PMID:27097231

  11. Surgery and Combination Chemotherapy in Treating Children With Extracranial Germ Cell Tumors

    ClinicalTrials.gov

    2016-05-06

    Childhood Embryonal Tumor; Childhood Extracranial Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Childhood Teratoma; Ovarian Embryonal Carcinoma; Ovarian Yolk Sac Tumor; Stage II Malignant Testicular Germ Cell Tumor; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Ovarian Germ Cell Tumor; Stage III Malignant Testicular Germ Cell Tumor; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Germ Cell Tumor; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma

  12. Computing tumor trees from single cells.

    PubMed

    Davis, Alexander; Navin, Nicholas E

    2016-01-01

    Computational methods have been developed to reconstruct evolutionary lineages from tumors using single-cell genomic data. The resulting tumor trees have important applications in cancer research and clinical oncology.Please see related Research articles: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0929-9 and http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0936-x . PMID:27230879

  13. Immunomagnetic separation can enrich fixed solid tumors for epithelial cells.

    PubMed Central

    Yaremko, M. L.; Kelemen, P. R.; Kutza, C.; Barker, D.; Westbrook, C. A.

    1996-01-01

    Immunomagnetic separation is a highly specific technique for the enrichment or isolation of cells from a variety of fresh tissues and microorganisms or molecules from suspensions. Because new techniques for molecular analysis of solid tumors are now applicable to fixed tissue but sometimes require or benefit from enrichment for tumor cells, we tested the efficacy of immunomagnetic separation for enriching fixed solid tumors for malignant epithelial cells. We applied it to two different tumors and fixation methods to separate neoplastic from non-neoplastic cells in primary colorectal cancers and metastatic breast cancers, and were able to enrich to a high degree of purity. Immunomagnetic separation was effective in unembedded fixed tissue as well as fixed paraffin-embedded tissue. The magnetically separated cells were amenable to fluorescence in situ hybridization and polymerase chain reaction amplification of their DNA with minimal additional manipulation. The high degree of enrichment achieved before amplification contributed to interpretation of loss of heterozygosity in metastatic breast cancers, and simplified fluorescence in situ hybridization analysis because only neoplastic cells were hybridized and counted. Immunomagnetic separation is effective for the enrichment of fixed solid tumors, can be performed with widely available commercial antibodies, and requires little specialized instrumentation. It can contribute to interpretation of results in situations where enrichment by other methods is difficult or not possible. Images Figure 1 Figure 2 Figure 3 PMID:8546231

  14. Nexavar/Stivarga and viagra interact to kill tumor cells.

    PubMed

    Tavallai, Mehrad; Hamed, Hossein A; Roberts, Jane L; Cruickshanks, Nichola; Chuckalovcak, John; Poklepovic, Andrew; Booth, Laurence; Dent, Paul

    2015-09-01

    We determined whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over-expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK-1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re-expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by 'rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti-tumor therapy for solid tumor patients. PMID:25704960

  15. Nexavar/Stivarga and Viagra Interact to Kill Tumor Cells

    PubMed Central

    TAVALLAI, MEHRAD; HAMED, HOSSEIN A.; ROBERTS, JANE L.; CRUICKSHANKS, NICHOLA; CHUCKALOVCAK, JOHN; POKLEPOVIC, ANDREW; BOOTH, LAURENCE; DENT, PAUL

    2016-01-01

    We determined whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over-expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK-1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re-expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by ‘rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti-tumor therapy for solid tumor patients. PMID:25704960

  16. Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

    PubMed Central

    Ford, Catriona A.; Petrova, Sofia; Pound, John D.; Voss, Jorine J.L.P.; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L.; Gallimore, Awen M.; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E.; Dunbar, Donald R.; Murray, Paul G.; Ruckerl, Dominik; Allen, Judith E.; Hume, David A.; van Rooijen, Nico; Goodlad, John R.; Freeman, Tom C.; Gregory, Christopher D.

    2015-01-01

    Summary Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. PMID:25702581

  17. IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells.

    PubMed

    Parihar, Robin; Dierksheide, Julie; Hu, Yan; Carson, William E

    2002-10-01

    The anti-tumor activity of recombinant mAb's directed against tumor cell growth receptors has generally been considered to result from direct antiproliferative effects, the induction of apoptosis, or possibly Ab-dependent cellular cytotoxicity mediated against tumor targets. However, it remains unclear to what degree these mechanisms actually aid in the clearance of Ab-coated tumor cells in vivo. We show here that NK cells secrete a distinct profile of potent immunostimulatory cytokines in response to dual stimulation with Ab-coated tumor cells and IL-12. This response could not be duplicated by costimulation with other ILs and was significantly enhanced in the presence of monocytes. Cytokine production was dependent upon synergistic signals mediated by the activating receptor for the Fc portion of IgG (FcgammaRIII) and the IL-12 receptor expressed on NK cells. Coadministration of Ab-coated tumor cells and IL-12 to BALB/c mice resulted in enhanced circulating levels of NK cell-derived cytokines with the capacity to augment anti-tumor immunity. These findings suggest that, in addition to mediating cellular cytotoxicity and apoptosis, the anti-tumor activity of mAb's might also result from activation of a potent cytokine secretion program within immune effectors capable of recognizing mAb-coated targets. PMID:12370276

  18. Immunosuppressive cells in tumor immune escape and metastasis.

    PubMed

    Liu, Yang; Cao, Xuetao

    2016-05-01

    Tumor immune escape and the initiation of metastasis are critical steps in malignant progression of tumors and have been implicated in the failure of some clinical cancer immunotherapy. Tumors develop numerous strategies to escape immune surveillance or metastasize: Tumors not only modulate the recruitment and expansion of immunosuppressive cell populations to develop the tumor microenvironment or pre-metastatic niche but also switch the phenotype and function of normal immune cells from a potentially tumor-reactive state to a tumor-promoting state. Immunosuppressive cells facilitate tumor immune escape by inhibiting antitumor immune responses and furthermore promote tumor metastasis by inducing immunosuppression, promoting tumor cell invasion and intravasation, establishing a pre-metastatic niche, facilitating epithelial-mesenchymal transition, and inducing angiogenesis at primary tumor or metastatic sites. Numerous translational studies indicate that it is possible to inhibit tumor immune escape and prevent tumor metastasis by blocking immunosuppressive cells and eliminating immunosuppressive mechanisms that are induced by either immunosuppressive cells or tumor cells. Furthermore, many clinical trials targeting immunosuppressive cells have also achieved good outcome. In this review, we focus on the underlying mechanisms of immunosuppressive cells in promoting tumor immune escape and metastasis, discuss our current understanding of the interactions between immunosuppressive cells and tumor cells in the tumor microenvironment, and suggest future research directions as well as potential clinical strategies in cancer immunotherapy. PMID:26689709

  19. High-Dose Thiotepa Plus Peripheral Stem Cell Transplantation in Treating Patients With Refractory Solid Tumors

    ClinicalTrials.gov

    2013-03-06

    Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Ovarian Cancer; Retinoblastoma; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  20. Addition of Propolis to Irinotecan Therapy Prolongs Survival in Ehrlich Ascites Tumor-Bearing Mice

    PubMed Central

    Lisičić, Duje; Đikić, Domagoj; Blažević, Ana Sofia; Mihaljević, Josipa; Oršolić, Nada; Knežević, Anica Horvat

    2014-01-01

    Abstract We investigated possible synergistic action of anticancer drug Irinotecan (IRI) combined with ethanolic (EEP) and water-soluble (WSDP) derivate of propolis on Swiss albino mice injected with Ehrlich ascites tumor (EAT). For survival analysis mice were administered WSDP and EEP (100 mg/kg) daily for 3 consecutive days, beginning on 3rd day after EAT cell (1×106) injection. IRI was administered at a dose of 50 mg/kg on days 1, 13, and 19. We simultaneously studied peripheral white blood cell count, cell types washed from the peritoneal cavity, functional activity of macrophages from peritoneal cavity, and the level of primary DNA damage in leukocytes, kidney, and liver cells using the alkaline comet assay. Three out of 9 mice per group survived the entire duration of the experiment (90 days) in groups treated with IRI combined with WSDP and EEP. All test components increased survival of mice by 7.53% to 231.54%. Combined treatment with IRI and/or WSDP and EEP significantly decreased percentage of tumor cells in the peritoneal cavity as compared to nontreated EAT-injected mice. All treated animals had significantly higher percentage of neutrophils in the peritoneal cavity in comparison to nontreated EAT-injected mice. We observed significantly higher value of DNA damage in leukocytes of mice treated with IRI and combination of IRI and/or WSDP and EEP as compared to nontreated EAT-injected mice, while the same treatment decreased DNA damage in kidney. Our results showed that addition of propolis to IRI treatment enhanced antitumor activity of IRI and prolongs survival in EAT-bearing mice, which definitely deserve further studies to clarify the possible mechanisms of antitumor actions of combined herb–drug treatments. PMID:24383762

  1. Do cell-autonomous and non-cell-autonomous effects drive the structure of tumor ecosystems?

    PubMed

    Tissot, Tazzio; Ujvari, Beata; Solary, Eric; Lassus, Patrice; Roche, Benjamin; Thomas, Frédéric

    2016-04-01

    By definition, a driver mutation confers a growth advantage to the cancer cell in which it occurs, while a passenger mutation does not: the former is usually considered as the engine of cancer progression, while the latter is not. Actually, the effects of a given mutation depend on the genetic background of the cell in which it appears, thus can differ in the subclones that form a tumor. In addition to cell-autonomous effects generated by the mutations, non-cell-autonomous effects shape the phenotype of a cancer cell. Here, we review the evidence that a network of biological interactions between subclones drives cancer cell adaptation and amplifies intra-tumor heterogeneity. Integrating the role of mutations in tumor ecosystems generates innovative strategies targeting the tumor ecosystem's weaknesses to improve cancer treatment. PMID:26845682

  2. Giant Cell Tumor of Bone - An Overview

    PubMed Central

    Sobti, Anshul; Agrawal, Pranshu; Agarwala, Sanjay; Agarwal, Manish

    2016-01-01

    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. PMID:26894211

  3. Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering

    NASA Astrophysics Data System (ADS)

    Kumar, Sandeep; Kulkarni, Rahul; Sen, Shamik

    2016-06-01

    Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs.

  4. Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering.

    PubMed

    Kumar, Sandeep; Kulkarni, Rahul; Sen, Shamik

    2016-01-01

    Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs. PMID:27125980

  5. Lipid tethering of breast tumor cells enables real-time imaging of free-floating cell dynamics and drug response

    PubMed Central

    Whipple, Rebecca A.; Zhang, Peipei; Sooklal, Elisabeth L.; Martin, Stuart S.; Jewell, Christopher M.

    2016-01-01

    Free-floating tumor cells located in the blood of cancer patients, known as circulating tumor cells (CTCs), have become key targets for studying metastasis. However, effective strategies to study the free-floating behavior of tumor cells in vitro have been a major barrier limiting the understanding of the functional properties of CTCs. Upon extracellular-matrix (ECM) detachment, breast tumor cells form tubulin-based protrusions known as microtentacles (McTNs) that play a role in the aggregation and re-attachment of tumor cells to increase their metastatic efficiency. In this study, we have designed a strategy to spatially immobilize ECM-detached tumor cells while maintaining their free-floating character. We use polyelectrolyte multilayers deposited on microfluidic substrates to prevent tumor cell adhesion and the addition of lipid moieties to tether tumor cells to these surfaces through interactions with the cell membranes. This coating remains optically clear, allowing capture of high-resolution images and videos of McTNs on viable free-floating cells. In addition, we show that tethering allows for the real-time analysis of McTN dynamics on individual tumor cells and in response to tubulin-targeting drugs. The ability to image detached tumor cells can vastly enhance our understanding of CTCs under conditions that better recapitulate the microenvironments they encounter during metastasis. PMID:26871289

  6. Kinetic studies of porphyrin distribution in suspensions of tumor cells

    NASA Astrophysics Data System (ADS)

    Zorin, Vladimir P.; Mel'nov, Sergey B.; Savitsky, Valery P.; Zorina, Tatyana E.

    1996-12-01

    Using a fluorescence activated cell sorting, we investigated the dynamics of porphyrins in suspensions of tumor cells. In addition to direct studies of the incorporation and output of several porphyrins (hematoporphyrin, hematoporphyrin dimethyl ester, chlorin e6 and its mono-, di-, trimethyl esters) from cells, their transfer between cells was investigated. It was shown that the rate of pigment accumulation by cells correlated with the rate of porphyrin penetration across the plasma membrane. As a result, apolar chlorins and HpDME displayed enhanced staining capacity which was independent on the integrity of plasma membrane of cells. To estimate the rate of pigment redistribution between cells, the suspension of tumor cells loaded with porphyrin had been mixed with unloaded cells and the distribution of all cells according to porphyrin fluorescence was determined in different intervals of time. It was obtained that the highest rate of the pigment transfer between cells was exhibited in the case of moderately apolar pigment. Porphyrins with dominantly hydrophobic and hydrophilic properties had a decreased capacity to intercellular migration. The results of this study indicate that, depending on the photosensitizer used, the processes of its distribution in the bulk of tumor tissue mediated by intercellular exchange may occur with a different rate.

  7. Granular cell tumor of the esophagus.

    PubMed

    Patel, R M; DeSota-LaPaix, F; Sika, J V; Mallaiah, L R; Purow, E

    1981-12-01

    Two cases of granular cell tumor of the esophagus are reported and the main features of the previously reported cases are summarized. Dysphagia and substernal discomfort or pain are the most common symptoms seen and are likely to occur with lesions greater than 1 cm. in diameter. The diagnosis should be considered in adult females with an intramural mass of the esophagus. The cell of origin is still disputed. The treatment of choice, when the patient is symptomatic or the lesion greater than 1 cm. in size, is local resection. The tumor, when incidentally discovered in an asymptomatic patient, may safely be followed endoscopically. PMID:6277183

  8. Tumor cohesion and glioblastoma cell dispersal

    PubMed Central

    Foty, Ramsey A

    2013-01-01

    Patients with glioblastoma typically present when tumors are at an advanced stage. Surgical resection, radiotherapy and adjuvant chemotherapy are currently the standard of care for glioblastoma. However, due to the infiltrative and dispersive nature of the tumor, recurrence rate remains high and typically results in very poor prognosis. Efforts to treat the primary tumor are, therefore, palliative rather than curative. From a practical perspective, controlling growth and dispersal of the recurrence may have a greater impact on disease-free survival, In order for cells to disperse, they must first detach from the mass. Preventing detachment may keep tumors that recur more localized and perhaps more amenable to therapy. Here we introduce a new perspective in which a quantifiable mechanical property, namely tissue surface tension, can provide novel information on tumor behavior. The overall theme of the discussion will attempt to integrate how adhesion molecules can alter a tumor’s mechanical properties and how, in turn, these properties can be modified to prevent tumor cell detachment and dispersal. PMID:23902244

  9. Tumoral NKG2D alters cell cycle of acute myeloid leukemic cells and reduces NK cell-mediated immune surveillance.

    PubMed

    Tang, Mingying; Acheampong, Desmond Omane; Wang, Youfu; Xie, Wei; Wang, Min; Zhang, Juan

    2016-06-01

    The stimulatory natural killer group 2 member D (NKG2D) lymphocyte receptor, initially discovered and expressed mostly on natural killer (NK) cells, T cells and natural killer T cells, can promote tumor immune surveillance. However, with increasing tumor grade, tumors themselves express NKG2D to self-stimulate oncogenic pathways. To confirm that cancer cells themselves express NKG2D, we have now investigated the role of the tumoral NKG2D in NK cell-mediated immune surveillance. Both anti-NKG2D and shRNA to that down-regulated tumoral NKG2D increased the number of cells in G1 phase and S phase, increased the expression of cyclin E-CDK2 and decreased P21. In addition, CD107a, IFN-γ and TNF-α increased when the cells were treated with anti-NKG2D which suggests that blocking tumoral NKG2D could augment tumor surveillance of NK cells. Altogether, tumoral NKG2D stimulates cell propagation and immune escape in acute myeloid leukemia cells. PMID:26740330

  10. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model

    PubMed Central

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D.; Shetake, Neena; Balla, Murali M. S.; Kumar, Amit; Ray, Pritha; Ghosh, Anu

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  11. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model.

    PubMed

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D; Shetake, Neena; Balla, Murali M S; Kumar, Amit; Ray, Pritha; Ghosh, Anu; Pandey, B N

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  12. Circulating Tumor Cell Composition in Renal Cell Carcinoma

    PubMed Central

    Bublitz, Kira; Lazaridis, Lazaros; Goergens, André; Giebel, Bernd; Schuler, Martin; Hoffmann, Andreas-Claudius

    2016-01-01

    Purpose Due to their minimal-invasive yet potentially current character circulating tumor cells (CTC) might be useful as a “liquid biopsy” in solid tumors. However, successful application in metastatic renal cell carcinoma (mRCC) has been very limited so far. High plasticity and heterogeneity of CTC morphology challenges currently available enrichment and detection techniques with EpCAM as the usual surface marker being underrepresented in mRCC. We recently described a method that enables us to identify and characterize non-hematopoietic cells in the peripheral blood stream with varying characteristics and define CTC subgroups that distinctly associate to clinical parameters. With this pilot study we wanted to scrutinize feasibility of this approach and its potential usage in clinical studies. Experimental Design Peripheral blood was drawn from 14 consecutive mRCC patients at the West German Cancer Center and CTC profiles were analyzed by Multi-Parameter Immunofluorescence Microscopy (MPIM). Additionally angiogenesis-related genes were measured by quantitative RT-PCR analysis. Results We detected CTC with epithelial, mesenchymal, stem cell-like or mixed-cell characteristics at different time-points during anti-angiogenic therapy. The presence and quantity of N-cadherin-positive or CD133-positive CTC was associated with inferior PFS. There was an inverse correlation between high expression of HIF1A, VEGFA, VEGFR and FGFR and the presence of N-cadherin-positive and CD133-positive CTC. Conclusions Patients with mRCC exhibit distinct CTC profiles that may implicate differences in therapeutic outcome. Prospective evaluation of phenotypic and genetic CTC profiling as prognostic and predictive biomarker in mRCC is warranted. PMID:27101285

  13. Sertoli-Leydig cell tumor

    MedlinePlus

    ... the testes, release a male sex hormone called testosterone . These cells are also found in a woman's ... the levels of female and male hormones, including testosterone . An ultrasound or another imaging test will likely ...

  14. Chemotherapy of WAP-T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination.

    PubMed

    Jannasch, Katharina; Wegwitz, Florian; Lenfert, Eva; Maenz, Claudia; Deppert, Wolfgang; Alves, Frauke

    2015-07-01

    In this study, the effects of the standard chemotherapy, cyclophosphamide/adriamycin/5-fluorouracil (CAF) on tumor growth, dissemination and recurrence after orthotopic implantation of murine G-2 cells were analyzed in the syngeneic immunocompetent whey acidic protein-T mouse model (Wegwitz et al., PLoS One 2010; 5:e12103; Schulze-Garg et al., Oncogene 2000; 19:1028-37). Single-dose CAF treatment reduced tumor size significantly, but was not able to eradicate all tumor cells, as recurrent tumor growth was observed 4 weeks after CAF treatment. Nine days after CAF treatment, residual tumors showed features of regressive alterations and were composed of mesenchymal-like tumor cells, infiltrating immune cells and some tumor-associated fibroblasts with an intense deposition of collagen. Recurrent tumors were characterized by coagulative necrosis and less tumor cell differentiation compared with untreated tumors, suggesting a more aggressive tumor phenotype. In support, tumor cell dissemination was strongly enhanced in mice that had developed recurrent tumors in comparison with untreated controls, although only few disseminated tumor cells could be detected in various organs 9 days after CAF application. In vitro experiments revealed that CAF treatment of G-2 cells eliminates the vast majority of epithelial tumor cells, whereas tumor cells with a mesenchymal phenotype survive. These results together with the in vivo findings suggest that tumor cells that underwent epithelial-mesenchymal transition and/or exhibit stem-cell-like properties are difficult to eliminate using one round of CAF chemotherapy. The model system described here provides a valuable tool for the characterization of the effects of chemotherapeutic regimens on recurrent tumor growth and on tumor cell dissemination, thereby enabling the development and preclinical evaluation of novel therapeutic strategies to target mammary carcinomas. PMID:25449528

  15. CDC20 maintains tumor initiating cells

    PubMed Central

    Xie, Qi; Wu, Qiulian; Mack, Stephen C.; Yang, Kailin; Kim, Leo; Hubert, Christopher G.; Flavahan, William A.; Chu, Chengwei; Bao, Shideng; Rich, Jeremy N.

    2015-01-01

    Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor. Glioblastoma displays hierarchical arrangement with a population of self-renewing and tumorigenic glioma tumor initiating cells (TICs), or cancer stem cells. While non-neoplastic neural stem cells are generally quiescent, glioblastoma TICs are often proliferative with mitotic control offering a potential point of fragility. Here, we interrogate the role of cell-division cycle protein 20 (CDC20), an essential activator of anaphase-promoting complex (APC) E3 ubiquitination ligase, in the maintenance of TICs. By chromatin analysis and immunoblotting, CDC20 was preferentially expressed in TICs relative to matched non-TICs. Targeting CDC20 expression by RNA interference attenuated TIC proliferation, self-renewal and in vivo tumor growth. CDC20 disruption mediated its effects through induction of apoptosis and inhibition of cell cycle progression. CDC20 maintains TICs through degradation of p21CIP1/WAF1, a critical negative regulator of TICs. Inhibiting CDC20 stabilized p21CIP1/WAF1, resulting in repression of several genes critical to tumor growth and survival, including CDC25C, c-Myc and Survivin. Transcriptional control of CDC20 is mediated by FOXM1, a central transcription factor in TICs. These results suggest CDC20 is a critical regulator of TIC proliferation and survival, linking two key TIC nodes – FOXM1 and p21CIP1/WAF1 — elucidating a potential point for therapeutic intervention. PMID:25938542

  16. Clustering of brain tumor cells: a first step for understanding tumor recurrence

    NASA Astrophysics Data System (ADS)

    Khain, Evgeniy; Nowicki, M. O.; Chiocca, E. A.; Lawler, S. E.; Schneider-Mizell, C. M.; Sander, L. M.

    2012-02-01

    Glioblastoma tumors are highly invasive; therefore the overall prognosis of patients remains poor, despite major improvements in treatment techniques. Cancer cells detach from the inner tumor core and actively migrate away [1]; eventually these invasive cells might form clusters, which can develop to recurrent tumors. In vitro experiments in collagen gel [1] followed the clustering dynamics of different glioma cell lines. Based on the experimental data, we formulated a stochastic model for cell dynamics, which identified two mechanisms of clustering. First, there is a critical value of the strength of adhesion; above the threshold, large clusters grow from a homogeneous suspension of cells; below it, the system remains homogeneous, similarly to the ordinary phase separation. Second, when cells form a cluster, there is evidence that their proliferation rate increases. We confirmed the theoretical predictions in a separate cell migration experiment on a substrate and found that both mechanisms are crucial for cluster formation and growth [2]. In addition to their medical importance, these phenomena present exciting examples of pattern formation and collective cell behavior in intrinsically non-equilibrium systems [3]. [4pt] [1] A. M. Stein et al, Biophys. J., 92, 356 (2007). [0pt] [2] E. Khain et al, EPL 88, 28006 (2009). [0pt] [3] E. Khain et al, Phys. Rev. E. 83, 031920 (2011).

  17. Functional Alteration of Tumor-infiltrating Myeloid Cells in RNA Adjuvant Therapy.

    PubMed

    Seya, Tsukasa; Shime, Hiroaki; Matsumoto, Misako

    2015-08-01

    Macrophages, as well as dendritic cells (DCs), are derived from myeloid progenitor cells. Recent evidence suggests that tumor-infiltrating macrophages differ in many aspects from conventional tissue macrophages, including nature, function and markers. Tumors usually contain various myeloid lineage cells in their non-parenchymal environment. In immunotherapy for cancer, tumor cells and non-parenchymal cells are exposed to tumor-associated antigens (TAA) and tumor-cell-derived nucleic acids. In addition, a dsRNA mimic, polyinosinic:polycytidylic acid (polyI:C), exhibits strong adjuvant activity, which acts both on the immune system and tumor constituents. Herein we discuss the RNA recognition system and unique cellular output in tumor-associated myeloid cells in response to immunotherapy. We especially focus on the mechanism by which RNA adjuvant alters the tumor-supportive nature of tumor-infiltrated myeloid cells to those with tumoricidal activity. We discuss how RNA administration makes tumor cells collapse and its significance of evoking cell death signals in tumor cells and macrophages. This knowledge will be applicable to the development of an alternative immunotherapy for cancer. PMID:26168476

  18. Combination Chemotherapy in Treating Young Patients With Recurrent or Resistant Malignant Germ Cell Tumors

    ClinicalTrials.gov

    2016-04-12

    Childhood Extracranial Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Ovarian Choriocarcinoma; Ovarian Embryonal Carcinoma; Ovarian Yolk Sac Tumor; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Testicular Choriocarcinoma; Testicular Choriocarcinoma and Embryonal Carcinoma; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma; Testicular Embryonal Carcinoma and Yolk Sac Tumor; Testicular Yolk Sac Tumor

  19. Perspectives on Reprograming Cancer-Associated Dendritic Cells for Anti-Tumor Therapies

    PubMed Central

    Benencia, Fabian; Muccioli, Maria; Alnaeeli, Mawadda

    2014-01-01

    In recent years, the relevance of the tumor microenvironment (TME) in the progression of cancer has gained considerable attention. It has been shown that the TME is capable of inactivating various components of the immune system responsible for tumor clearance, thus favoring cancer cell growth and tumor metastasis. In particular, effects of the TME on antigen-presenting cells, such as dendritic cells (DCs) include rendering these cells unable to promote specific immune responses or transform them into suppressive cells capable of inducing regulatory T cells. In addition, under the influence of the TME, DCs can produce growth factors that induce neovascularization, therefore further contributing to tumor development. Interestingly, cancer-associated DCs harbor tumor antigens and thus have the potential to become anti-tumor vaccines in situ if properly reactivated. This perspective article provides an overview of the scientific background and experimental basis for reprograming cancer-associated DCs in situ to generate anti-tumor immune responses. PMID:24778991

  20. Tumor cell differentiation by label-free microscopy

    NASA Astrophysics Data System (ADS)

    Schneckenburger, Herbert; Weber, Petra; Wagner, Michael

    2013-05-01

    Autofluorescence and Raman measurements of U251-MG glioblastoma cells prior and subsequent to activation of tumor suppressor genes are compared. While phase contrast images and fluorescence intensity patterns of the tumor (control) cells and the less malignant cells are similar, differences can be deduced from fluorescence spectra and nanosecond decay times. In particular, upon excitation around 375nm, the fluorescence ratio of the protein bound and the free coenzyme NADH depends on the state of malignancy and reflects different cytoplasmic (including lysosomal) and mitochondrial contributions. Slight differences are also observed in the Raman spectra of these cell lines, mainly originating from small granules (lysosomes) surrounding the cell nucleus. While larger numbers of fluorescence and Raman spectra are evaluated by multivariate statistical methods, additional information is obtained from spectral images and fluorescence lifetime images (FLIM).

  1. Circulating tumor cells: utopia or reality?

    PubMed

    Conteduca, Vincenza; Zamarchi, Rita; Rossi, Elisabetta; Condelli, Valentina; Troiani, Laura; Aieta, Michele

    2013-09-01

    Circulating tumor cells (CTCs) could be considered a sign of tumor aggressiveness, but highly sensitive and specific methods of CTC detection are necessary owing to the rarity and heterogeneity of CTCs in peripheral blood. This review summarizes recent studies on tumor biology, with particular attention to the metastatic cascade, and the molecular characterization and clinical significance of CTCs. Recent technological approaches to enrich and detect these cells and challenges of CTCs for individualized cancer treatment are also discussed. This review also provides an insight into the positive and negative features of the future potential applications of CTC detection, which sometimes remains still a 'utopia', but its actual utility remains among the fastest growing research fields in oncology. PMID:23980681

  2. Transcapillary Trafficking of Clustered Circulating Tumor Cells

    NASA Astrophysics Data System (ADS)

    Storey, Brian; Au, Sam; Chen, Yeng-Long; Sarioglu, Fatih; Javaid, Sarah; Haber, Daniel; Maheswaran, Shyamala; Stott, Shannon; Toner, Mehmet

    2015-11-01

    Aggregates of circulating tumor cells (CTC-clusters) are known to be more metastatic than equal numbers of singlet circulating tumor cells. Yet the mechanisms responsible for CTC-cluster dissemination and tumor seeding are still largely unknown. Without direct experimental evidence, it was assumed that because of their size, CTC-clusters would occlude and rupture capillaries. In this work, we have challenged this assumption by investigating the transit of CTC-clusters through microfluidic capillary constrictions under physiological pressures. Remarkably, cancer cell aggregates containing 2-20 cells were observed to successfully traverse constrictions 5-10 microns with over 90% efficiency. Clusters rapidly and reversibly reorganized into chain-like geometries to pass through constrictions in single file. This observation was verified by computational simulation of clusters modeled with physiological cell-cell interaction energies. Hydrodynamic analysis suggested that CTC-clusters were able to pass narrow constrictions by acting as individual cells in series, not as cohesive units. Upon exiting constrictions, clusters remained viable, proliferative and rapidly returned to `typical' cluster morphologies.

  3. Sphingosine Kinase Activity Is Not Required for Tumor Cell Viability

    PubMed Central

    Brown, Matthew L.; Carlson, Timothy; Coxon, Angela; Fajardo, Flordeliza; Frank, Brendon; Gustin, Darin; Kamb, Alexander; Kassner, Paul D.; Li, Shyun; Li, Yihong; Morgenstern, Kurt; Plant, Matthew; Quon, Kim; Ruefli-Brasse, Astrid; Schmidt, Joanna; Swearingen, Elissa; Walker, Nigel; Wang, Zhulun; Watson, J. E. Vivienne; Wickramasinghe, Dineli; Wong, Mariwil; Xu, Guifen; Wesche, Holger

    2013-01-01

    Sphingosine kinases (SPHKs) are enzymes that phosphorylate the lipid sphingosine, leading to the formation of sphingosine-1-phosphate (S1P). In addition to the well established role of extracellular S1P as a mitogen and potent chemoattractant, SPHK activity has been postulated to be an important intracellular regulator of apoptosis. According to the proposed rheostat theory, SPHK activity shifts the intracellular balance from the pro-apoptotic sphingolipids ceramide and sphingosine to the mitogenic S1P, thereby determining the susceptibility of a cell to apoptotic stress. Despite numerous publications with supporting evidence, a clear experimental confirmation of the impact of this mechanism on tumor cell viability in vitro and in vivo has been hampered by the lack of suitable tool reagents. Utilizing a structure based design approach, we developed potent and specific SPHK1/2 inhibitors. These compounds completely inhibited intracellular S1P production in human cells and attenuated vascular permeability in mice, but did not lead to reduced tumor cell growth in vitro or in vivo. In addition, siRNA experiments targeting either SPHK1 or SPHK2 in a large panel of cell lines failed to demonstrate any statistically significant effects on cell viability. These results show that the SPHK rheostat does not play a major role in tumor cell viability, and that SPHKs might not be attractive targets for pharmacological intervention in the area of oncology. PMID:23861887

  4. Molecular Culprits Generating Brain Tumor Stem Cells

    PubMed Central

    Oh, Se-Yeong

    2013-01-01

    Despite current advances in multimodality therapies, such as surgery, radiotherapy, and chemotherapy, the outcome for patients with high-grade glioma remains fatal. Understanding how glioma cells resist various therapies may provide opportunities for developing new therapies. Accumulating evidence suggests that the main obstacle for successfully treating high-grade glioma is the existence of brain tumor stem cells (BTSCs), which share a number of cellular properties with adult stem cells, such as self-renewal and multipotent differentiation capabilities. Owing to their resistance to standard therapy coupled with their infiltrative nature, BTSCs are a primary cause of tumor recurrence post-therapy. Therefore, BTSCs are thought to be the main glioma cells representing a novel therapeutic target and should be eliminated to obtain successful treatment outcomes. PMID:24904883

  5. Tissue-Specific Stem Cells in the Myometrium and Tumor-Initiating Cells in Leiomyoma1

    PubMed Central

    Ono, Masanori; Bulun, Serdar E.; Maruyama, Tetsuo

    2014-01-01

    ABSTRACT Tissue-specific (or somatic) stem cells constitute a subset of cells residing in normal adult tissues. By undergoing asymmetric division, they retain their ability to self-renew while producing daughter cells that go on to differentiate and play a role in tissue regeneration and repair. The human uterus consists primarily of endometrium and myometrium (the smooth muscle layer) that rapidly enlarges through its tremendous regenerative and remodeling capacity to accommodate the developing fetus. Such uterine enlargement and remodeling can take place repeatedly and cyclically over the course of a woman's reproductive life. These unique properties of the uterus suggest the existence of endometrial and myometrial stem cell systems. In addition, like somatic cells, tumor stem cells or tumor-initiating cells, a subset of cells within a tumor, retain the ability to reconstitute tumors. Uterine smooth muscle cells are thought to be the origin of leiomyomas that are the most common type of gynecologic tumor. Recent work has identified, isolated, and characterized putative stem/progenitor cells in the myometrium and in leiomyomas. Here, we review current studies of myometrial and leiomyoma stem/progenitor cells and provide a new paradigm for understanding myometrial physiology and pathology and how these cells might contribute to uterine remodeling during pregnancy and the formation of leiomyomas. The role of the WNT/CTNNB1 pathway in the pathogenesis of leiomyoma is also discussed. PMID:25376230

  6. Cutaneous mast cell tumor (Mastocytoma): Cyto- histopathological and haematological investigations

    PubMed Central

    2014-01-01

    Cutaneous mast cell tumours (MCTs) are the most common skin tumours in dogs. Due to the prevalence of canine MCTs and the variable biologic behavior of this disease, accurate prognostication and a thorough understanding of MCT biology are critical for the treatment of this disease. A cytologic diagnosis of mast cell tumor with evidence of prior hemorrhage was made, and the masses were surgically removed. Cytological evaluation of fine-needle aspirates from the cutaneous mass from the axillary comprised many well-differentiated, highly granulated mast cells with moderate numbers of eosinophils. Nuclei were varied in size and shape with high nuclear’to’cytoplasmic ratio, prominent nucleoli, marked atypical and mitotic figures. Microscopically, mass consisted of sheets of neoplastic round cells that formed nonencapsulated nodules in the dermis and infiltrated into the adjacent dermal collagen, and also there was diffuse subcutis invasion of round to pleomorphic tumor cells. Tumor cells had moderate to abundant cytoplasm, round to ovoid nuclei with scattered chromatin, and mitotic figures. In this tumor, cytoplasmic granules showed atypical metachromasia. In addition, eosinophils were scattered among the mast cells at the periphery of the nodules. The presence of eosinophils and the observation, at high magnification, of cells with cytoplasmic metachromatic granules. Invasion of the deep subcutaneous fat or cutaneous muscles were a common feature of grade III tumour. Finally, a diagnosis of grade III cutaneous mast cell tumor was made. Virtual slides The virtual slide(s) of this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4755249151157024. PMID:24444100

  7. Establishment of human colon cancer cell lines from fresh tumors versus xenografts: comparison of success rate and cell line features.

    PubMed

    Dangles-Marie, Virginie; Pocard, Marc; Richon, Sophie; Weiswald, Louis-Bastien; Assayag, Franck; Saulnier, Patrick; Judde, Jean-Gabriel; Janneau, Jean-Louis; Auger, Nathalie; Validire, Pierre; Dutrillaux, Bernard; Praz, Françoise; Bellet, Dominique; Poupon, Marie-France

    2007-01-01

    Obtaining representative human colon cancer cell lines from fresh tumors is technically difficult. Using 32 tumor fragments from patients with colon cancer, the present study shows that prior xenograft leads to more efficient cell line establishment compared with direct establishment from fresh tumors (P < 0.05). From 26 tumor specimens, we successfully established 20 tumor xenografts in nude mice (77%); among 19 of these xenografts, 9 (47%) led to cell lines, including four from liver metastases. Only 3 of 31 tumor specimens (9.7%) grew immediately in vitro, and all were derived from primary tumors. To compare major phenotypic and genotypic characteristics of human colon cancer cell lines derived from the same tumor fragment using two protocols, the two pairs of cell lines obtained from 2 of 32 tumor fragments were extensively studied. They displayed similar morphology and were able to form compact spheroids. Chemosensitivity to 5-fluorouracil, CPT11, and L-OHP differed between cell lines obtained from patient tumors and those derived from xenografts. Matched cell lines shared a common core of karyotype alterations and distinctive additional chromosomal aberrations. Expression levels of genes selected for their role in oncogenesis evaluated by real-time quantitative PCR were found to be statistically correlated whatever the in vitro culture model used. In conclusion, xenotransplantation in mice of tumor fragments before establishment of cell lines enables generation of more novel human cancer cell lines for investigation of colon cancer cell biology, opening up the opportunity of reproducing the diversity of this disease. PMID:17210723

  8. Cell-free circulating tumor DNA in cancer.

    PubMed

    Qin, Zhen; Ljubimov, Vladimir A; Zhou, Cuiqi; Tong, Yunguang; Liang, Jimin

    2016-01-01

    Cancer is a common cause of death worldwide. Despite significant advances in cancer treatments, the morbidity and mortality are still enormous. Tumor heterogeneity, especially intratumoral heterogeneity, is a significant reason underlying difficulties in tumor treatment and failure of a number of current therapeutic modalities, even of molecularly targeted therapies. The development of a virtually noninvasive "liquid biopsy" from the blood has been attempted to characterize tumor heterogeneity. This review focuses on cell-free circulating tumor DNA (ctDNA) in the bloodstream as a versatile biomarker. ctDNA analysis is an evolving field with many new methods being developed and optimized to be able to successfully extract and analyze ctDNA, which has vast clinical applications. ctDNA has the potential to accurately genotype the tumor and identify personalized genetic and epigenetic alterations of the entire tumor. In addition, ctDNA has the potential to accurately monitor tumor burden and treatment response, while also being able to monitor minimal residual disease, reducing the need for harmful adjuvant chemotherapy and allowing more rapid detection of relapse. There are still many challenges that need to be overcome prior to this biomarker getting wide adoption in the clinical world, including optimization, standardization, and large multicenter trials. PMID:27056366

  9. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior.

    PubMed

    Roudsari, Laila C; Jeffs, Sydney E; Witt, Amber S; Gill, Bartley J; West, Jennifer L

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm(2), circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization. PMID:27596933

  10. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    PubMed Central

    Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization. PMID:27596933

  11. The biology of circulating tumor cells.

    PubMed

    Pantel, K; Speicher, M R

    2016-03-10

    Metastasis is a biologically complex process consisting of numerous stochastic events which may tremendously differ across various cancer types. Circulating tumor cells (CTCs) are cells that are shed from primary tumors and metastatic deposits into the blood stream. CTCs bear a tremendous potential to improve our understanding of steps involved in the metastatic cascade, starting from intravasation of tumor cells into the circulation until the formation of clinically detectable metastasis. These efforts were propelled by novel high-resolution approaches to dissect the genomes and transcriptomes of CTCs. Furthermore, capturing of viable CTCs has paved the way for innovative culturing technologies to study fundamental characteristics of CTCs such as invasiveness, their kinetics and responses to selection barriers, such as given therapies. Hence the study of CTCs is not only instrumental as a basic research tool, but also allows the serial monitoring of tumor genotypes and may therefore provide predictive and prognostic biomarkers for clinicians. Here, we review how CTCs have contributed to significant insights into the metastatic process and how they may be utilized in clinical practice. PMID:26050619

  12. Non-MHC-dependent redirected T cells against tumor cells.

    PubMed

    Almåsbak, Hilde; Lundby, Marianne; Rasmussen, Anne-Marie

    2010-01-01

    Adoptive transfer of T cells with restricted tumor specificity provides a promising approach to immunotherapy of cancers. However, the isolation of autologous cytotoxic T cells that recognize tumor-associated antigens is time consuming and fails in many instances. Alternatively, gene modification with tumor antigen-specific T-cell receptors (TCR) or chimeric antigen receptors (CARs) can be used to redirect the specificity of large numbers of immune cells toward the malignant cells. Chimeric antigen receptors are composed of the single-chain variable fragment (scFv) of a tumor-recognizing antibody cloned in frame with human T-cell signaling domains (e.g., CD3zeta, CD28, OX40, 4-1BB), thus combining the specificity of antibodies with the effector functions of cytotoxic T cells. Upon antigen binding, the intracellular signaling domains of the CAR initiate cellular activation mechanisms including cytokine secretion and cytolysis of the antigen-positive target cell.In this chapter, we provide detailed protocols for large-scale ex vivo expansion of T cells and manufacturing of medium-scale batches of CAR-expressing T cells for translational research by mRNA electroporation. An anti-CD19 chimeric receptor for the targeting of leukemias and lymphomas was used as a model system. We are currently scaling up the protocols to adapt them to cGMP production of a large number of redirected T cells for clinical applications. PMID:20387166

  13. Tumor cell differentiation by label-free fluorescence microscopy

    NASA Astrophysics Data System (ADS)

    Weber, Petra; Wagner, Michael; Kioschis, Petra; Kessler, Waltraud; Schneckenburger, Herbert

    2012-10-01

    Autofluorescence spectra, images, and decay kinetics of U251-MG glioblastoma cells prior and subsequent to activation of tumor suppressor genes are compared. While phase contrast images and fluorescence intensity patterns of tumor (control) cells and less malignant cells are similar, differences can be deduced from autofluorescence spectra and decay kinetics. In particular, upon near UV excitation, the fluorescence ratio of the free and protein-bound coenzyme nicotinamid adenine dinucleotide depends on the state of malignancy and reflects different cytoplasmic (including lysosomal) and mitochondrial contributions. While larger numbers of fluorescence spectra are evaluated by principal component analysis, a multivariate data analysis method, additional information on cell metabolism is obtained from spectral imaging and fluorescence lifetime imaging microscopy.

  14. Tumor cell differentiation by marker free fluorescence microscopy

    NASA Astrophysics Data System (ADS)

    Schneckenburger, Herbert; Weber, Petra; Wagner, Michael; Brantsch, Marco; Biller, Philipp; Kioschis, Petra; Kessler, Waltraud

    2011-02-01

    Autofluorescence and Raman spectra, images and decay kinetics of U251-MG glioblastoma cells prior and after activation of tumor suppressor genes are compared. While phase contrast images and fluorescence patterns of the tumor (control) cells and the less malignant cells are similar, differences can be deduced from autofluorescence spectra and decay times. In particular, upon excitation around 375nm, the fluorescence ratio of the protein bound and the free coenzyme NADH depends on the state of malignancy. Slight differences are also observed in Raman spectra of these cell lines, in particular at wave numbers around 970 cm-1. While larger numbers of fluorescence and Raman spectra are evaluated by the method of multivariate data analysis, additional information is obtained from spectral images and fluorescence lifetime images (FLIM).

  15. NMR exposure sensitizes tumor cells to apoptosis.

    PubMed

    Ghibelli, L; Cerella, C; Cordisco, S; Clavarino, G; Marazzi, S; De Nicola, M; Nuccitelli, S; D'Alessio, M; Magrini, A; Bergamaschi, A; Guerrisi, V; Porfiri, L M

    2006-03-01

    NMR technology has dramatically contributed to the revolution of image diagnostic. NMR apparatuses use combinations of microwaves over a homogeneous strong (1 Tesla) static magnetic field. We had previously shown that low intensity (0.3-66 mT) static magnetic fields deeply affect apoptosis in a Ca2+ dependent fashion (Fanelli et al., 1999 FASEBJ., 13;95-102). The rationale of the present study is to examine whether exposure to the static magnetic fields of NMR can affect apoptosis induced on reporter tumor cells of haematopoietic origin. The impressive result was the strong increase (1.8-2.5 fold) of damage-induced apoptosis by NMR. This potentiation is due to cytosolic Ca2+ overload consequent to NMR-promoted Ca2+ influx, since it is prevented by intracellular (BAPTA-AM) and extracellular (EGTA) Ca2+ chelation or by inhibition of plasma membrane L-type Ca2+ channels. Three-days follow up of treated cultures shows that NMR decrease long term cell survival, thus increasing the efficiency of cytocidal treatments. Importantly, mononuclear white blood cells are not sensitised to apoptosis by NMR, showing that NMR may increase the differential cytotoxicity of antitumor drugs on tumor vs normal cells. This strong, differential potentiating effect of NMR on tumor cell apoptosis may have important implications, being in fact a possible adjuvant for antitumor therapies. PMID:16528477

  16. Select forms of tumor cell apoptosis induce dendritic cell maturation.

    PubMed

    Demaria, Sandra; Santori, Fabio R; Ng, Bruce; Liebes, Leonard; Formenti, Silvia C; Vukmanovic, Stanislav

    2005-03-01

    Dendritic cells (DC) play a crucial role in initiating immune responses to tumors. DC can efficiently present antigens from apoptotic tumor cells, but apoptotic cells are thought to lack the inflammatory signals required to induce DC maturation. Here, we show that apoptosis of 67NR mouse carcinoma cells via the Fas (CD95) pathway or induced by the anticancer drug bortezomib (PS-341) but not by ultraviolet irradiation is associated with the production of maturation signals for DC. These data have important implications for the effects of chemotherapy on antitumor immunity in solid and hematologic malignancies. PMID:15569694

  17. Influence of Cancer-Associated Endometrial Stromal Cells on Hormone-Driven Endometrial Tumor Growth

    PubMed Central

    Pineda, M. J.; Lu, Z.; Cao, D.

    2016-01-01

    Cancer-associated fibroblasts have been shown to inhibit or stimulate tumor growth depending on stage, grade, and tumor type. It remains unclear, however, the effect of endometrial-cancer-associated fibroblasts on hormone-driven responses in endometrial cancer. In this study, we investigated the effect of normal and cancer-associated stromal cells from patients with and without endometrial cancer on endometrial tumor growth in response to estradiol (E2) and progesterone (P4). Compared to benign endometrial stromal cells, the low-grade and high-grade cancer-associated stromal cells exhibited a blunted hormone response for proliferation as well as IGFBP1 secretion. Additional analysis of the influence of stromal cells on hormone-driven tumor growth was done by mixing stromal cells from benign, low-grade, or high-grade tumors, with Ishikawa cells for subcutaneous tumor formation. The presence of both benign and high-grade cancer-associated stromal cells increased estradiol-driven xenografted tumor growth compared to Ishikawa cells alone. Low-grade cancer-associated stromal cells did not significantly influence hormone-regulated tumor growth. Addition of P4 attenuated tumor growth in Ishikawa + benign or high-grade stromal cells, but not in Ishikawa cells alone or with low-grade stromal cells. Using an angiogenesis focused real-time array TGFA, TGFB2 and TGFBR1 and VEGFC were identified as potential candidates for hormone-influenced growth regulation of tumors in the presence of benign and high-grade stromal cells. In summary, endometrial-cancer-associated cells responded differently to in vitro hormone treatment compared to benign endometrial stromal cells. Additionally, presence of stromal cells differentially influenced hormone-driven xenograft growth in vivo depending on the disease status of the stromal cells. PMID:25976290

  18. Isolated tumor endothelial cells maintain specific character during long-term culture

    SciTech Connect

    Matsuda, Kohei; Ohga, Noritaka; Hida, Yasuhiro; Muraki, Chikara; Tsuchiya, Kunihiko; Kurosu, Takuro; Akino, Tomoshige; Shih, Shou-Ching; and others

    2010-04-16

    Tumor angiogenesis is necessary for solid tumor progression and metastasis. Increasing evidence indicates that tumor endothelial cells (TECs) are more relevant to the study of tumor angiogenesis than normal endothelial cells (NECs) because their morphologies and gene expression are different from NECs. However, it is challenging to isolate and culture large numbers of pure ECs from tumor tissue since the percentage of ECs is only about 1-2% and tumor cells and fibroblasts easily overgrow them. In addition, there has been concern that isolated TECs may lose their special phenotype once they are dissociated from tumor cells. In this study, we have successfully purified murine TECs from four different human tumor xenografts and NECs from murine dermal tissue. Isolated ECs expressed endothelial markers, such as CD31, VE-cadherin (CD144), and endoglin (CD105), for more than 3 months after isolation. TECs maintained tumor endothelial-specific markers, such as tumor endothelial marker 8 (TEM8) and aminopeptidase N (APN), as in tumor blood vessels in vivo. In addition, TECs were more proliferative and motile than NECs. TECs showed a higher response to VEGF and higher expression of VEGF receptors-1 and -2 than NECs did. Stem cell antigen-1 was up-regulated in all four TECs, suggesting that they have a kind of stemness. Cultured TECs maintain distinct biological differences from NECs as in vivo. In conclusion, it was suggested that TECs are relevant material for tumor angiogenesis research.

  19. Primary brain tumors, neural stem cell, and brain tumor cancer cells: where is the link?

    PubMed Central

    Germano, Isabelle; Swiss, Victoria; Casaccia, Patrizia

    2010-01-01

    The discovery of brain tumor-derived cells (BTSC) with the properties of stem cells has led to the formulation of the hypothesis that neural stem cells could be the cell of origin of primary brain tumors (PBT). In this review we present the most common molecular changes in PBT, define the criteria of identification of BTSC and discuss the similarities between the characteristics of these cells and those of the endogenous population of neural stem cells (NPCs) residing in germinal areas of the adult brain. Finally, we propose possible mechanisms of cancer initiation and progression and suggest a model of tumor initiation that includes intrinsic changes of resident NSC and potential changes in the microenvironment defining the niche where the NSC reside. PMID:20045420

  20. [Cancer stemness and circulating tumor cells].

    PubMed

    Saito, Tomoko; Mimori, Koshi

    2015-05-01

    The principle concept of cancer stem cells (CSCs) giving rise to the carcinogenesis, relapse or metastasis of malignancy is broadly recognized. On the other hand, circulating tumor cells (CTCs) also plays important roles in relapse or metastasis of malignancy, and there has been much focused on the association between CSCs and CTCs in cancer cases. The technical innovations for detection of CTCs enabled us to unveil the nature of CTCs. We now realize that CTCs isolated by cell surface antibodies, such as DCLK1, LGR5 indicated CSC properties, and CTCs with epitherial-mesenchymal transition(EMT) phenotype showed characteristics of CSCs. PMID:25985635

  1. Multifunctional Nucleic Acids for Tumor Cell Treatment

    PubMed Central

    Pofahl, Monika; Wengel, Jesper

    2014-01-01

    We report on a multifunctional nucleic acid, termed AptamiR, composed of an aptamer domain and an antimiR domain. This composition mediates cell specific delivery of antimiR molecules for silencing of endogenous micro RNA. The introduced multifunctional molecule preserves cell targeting, anti-proliferative and antimiR function in one 37-nucleotide nucleic acid molecule. It inhibits cancer cell growth and induces gene expression that is pathologically damped by an oncomir. These findings will have a strong impact on future developments regarding aptamer- and antimiR-related applications for tumor targeting and treatment. PMID:24494617

  2. General Information about Childhood Extracranial Germ Cell Tumors

    MedlinePlus

    ... Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Childhood Extracranial Germ Cell Tumors Go to ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  3. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors

    PubMed Central

    Beury, Daniel W.; Parker, Katherine H.; Nyandjo, Maeva; Sinha, Pratima; Carter, Kayla A.; Ostrand-Rosenberg, Suzanne

    2014-01-01

    MDSC and macrophages are present in most solid tumors and are important drivers of immune suppression and inflammation. It is established that cross-talk between MDSC and macrophages impacts anti-tumor immunity; however, interactions between tumor cells and MDSC or macrophages are less well studied. To examine potential interactions between these cells, we studied the impact of MDSC, macrophages, and four murine tumor cell lines on each other, both in vitro and in vivo. We focused on IL-6, IL-10, IL-12, TNF-α, and NO, as these molecules are produced by macrophages, MDSC, and many tumor cells; are present in most solid tumors; and regulate inflammation. In vitro studies demonstrated that MDSC-produced IL-10 decreased macrophage IL-6 and TNF-α and increased NO. IL-6 indirectly regulated MDSC IL-10. Tumor cells increased MDSC IL-6 and vice versa. Tumor cells also increased macrophage IL-6 and NO and decreased macrophage TNF-α. Tumor cell-driven macrophage IL-6 was reduced by MDSC, and tumor cells and MDSC enhanced macrophage NO. In vivo analysis of solid tumors identified IL-6 and IL-10 as the dominant cytokines and demonstrated that these molecules were produced predominantly by stromal cells. These results suggest that inflammation within solid tumors is regulated by the ratio of tumor cells to MDSC and macrophages and that interactions of these cells have the potential to alter significantly the inflammatory milieu within the tumor microenvironment. PMID:25170116

  4. Circulating Tumor Cells Measurements in Hepatocellular Carcinoma

    PubMed Central

    Chiappini, Franck

    2012-01-01

    Liver cancer is the fifth most common cancer in men and the seventh in women. During the past 20 years, the incidence of HCC has tripled while the 5-year survival rate has remained below 12%. The presence of circulating tumor cells (CTC) reflects the aggressiveness nature of a tumor. Many attempts have been made to develop assays that reliably detect and enumerate the CTC during the development of the HCC. In this case, the challenges are (1) there are few markers specific to the HCC (tumor cells versus nontumor cells) and (2) they can be used to quantify the number of CTC in the bloodstream. Another technical challenge consists of finding few CTC mixed with million leukocytes and billion erythrocytes. CTC detection and identification can be used to estimate prognosis and may serve as an early marker to assess antitumor activity of treatment. CTC can also be used to predict progression-free survival and overall survival. CTC are an interesting source of biological information in order to understand dissemination, drug resistance, and treatment-induced cell death. Our aim is to review and analyze the different new methods existing to detect, enumerate, and characterize the CTC in the peripheral circulation of patients with HCC. PMID:22690340

  5. Blood-Based Analyses of Cancer: Circulating Tumor Cells and Circulating Tumor DNA

    PubMed Central

    Haber, Daniel A.; Velculescu, Victor E.

    2015-01-01

    The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell–derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments. Significance Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis. PMID:24801577

  6. Pediatric germ cell tumors presenting beyond childhood?

    PubMed

    Oosterhuis, J W; Stoop, J A; Rijlaarsdam, M A; Biermann, K; Smit, V T H B M; Hersmus, R; Looijenga, L H J

    2015-01-01

    Four cases are reported meeting the criteria of a pediatric (i.e., Type I) testicular germ cell tumor (TGCT), apart from the age of presentation, which is beyond childhood. The tumors encompass the full spectrum of histologies of pediatric TGCT: teratoma, yolk sac tumor, and various combinations of the two, and lack intratubular germ cell neoplasia/carcinoma in situ in the adjacent parenchyma. The neoplasms are (near)diploid, and lack gain of 12p, typical for seminomas and non-seminomas of the testis of adolescents and adults (i.e., Type II). It is proposed that these neoplasms are therefore late appearing pediatric (Type I) TGCT. The present report broadens the concept of earlier reported benign teratomas of the post-pubertal testis to the full spectrum of pediatric TGCT. The possible wide age range of pediatric TGCT, demonstrated in this study, lends credence to the concept that TGCT should according to their pathogenesis be classified into the previously proposed types. This classification is clinically relevant, because Type I mature teratomas are benign tumors, which are candidates for testis conserving surgery, as opposed to Type II mature teratomas, which have to be treated as Type II (malignant) non-seminomas. PMID:25427839

  7. Diagnostic immunohistochemistry of canine round cell tumors.

    PubMed

    Sandusky, G E; Carlton, W W; Wightman, K A

    1987-11-01

    Sixty-five canine skin neoplasms studied using immunocytochemistry, included 22 histiocytomas, 18 amelanotic melanomas, 14 cutaneous lymphosarcomas, six mast cell tumors, and five transmissible venereal tumors. Formalin-fixed, paraffin-embedded sections were stained using the avidin-biotin-peroxidase complex (ABC) immunoperoxidase technique for reactivity with S-100 protein, kappa and lambda immunoglobulin light chains, alpha-1-antitrypsin, alpha-1-antichymotrypsin, leukocyte common antigen (LCA), neuron-specific enolase, keratin, cytokeratin, muramidase, and vimentin. Detection of S-100, kappa and lambda light chains, neuron-specific enolase, and vimentin were most useful for screening these neoplasms. None of the markers examined was consistent in staining histiocytomas. While reactivity of S-100 (ten cases) and neuron-specific enolase (ten cases) was detected in some amelanotic melanomas, lambda light chain immunoglobulin (eight cases) was relatively consistent in cutaneous lymphomas. Mast cell neoplasms reacted with avidin and, therefore, were positive, even on negative control sections. Vimentin reacted strongly on all amelanotic melanomas and transmissible venereal tumors examined. These antibodies are helpful adjuncts in the differential diagnosis of canine skin tumors. PMID:3137715

  8. T cell- but not tumor cell-produced TGF-β1 promotes the development of spontaneous mammary cancer

    PubMed Central

    Sarkar, Abira; Donkor, Moses K.; Li, Ming O.

    2011-01-01

    During their development, tumors acquire multiple capabilities that enable them to proliferate, disseminate and evade immunosurveillance. A putative mechanism is through the production of the cytokine TGF-β1. We showed in our recent studies that T cell-produced TGF-β1 inhibits antitumor T cell responses to foster tumor growth raising the question of the precise function of TGF-β1 produced by tumor cells in tumor development. Here, using a transgenic model of mammary cancer, we report that deletion of TGF-β1 from tumor cells did not protect mice from tumor development. However, ablation of TGF-β1 from T cells significantly inhibited mammary tumor growth. Additionally, absence of TGF-β1 in T cells prevented tumors from advancing to higher pathological grades and further suppressed secondary tumor development in the lungs. These findings reveal T cells but not tumor cells as a critical source of TGF-β1 that promotes tumor development. PMID:22248703

  9. NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

    PubMed Central

    Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina

    2016-01-01

    Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue. PMID:27294158

  10. Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.

    PubMed

    Osada, Takuya; Nagaoka, Koji; Takahara, Masashi; Yang, Xiao Yi; Liu, Cong-Xiao; Guo, Hongtao; Roy Choudhury, Kingshuk; Hobeika, Amy; Hartman, Zachary; Morse, Michael A; Lyerly, H Kim

    2015-05-01

    Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy. PMID:25839441

  11. Single-cell analyses of circulating tumor cells

    PubMed Central

    Chen, Xi-Xi; Bai, Fan

    2015-01-01

    Circulating tumor cells (CTCs) are a population of tumor cells mediating metastasis, which results in most of the cancer related deaths. The number of CTCs in the peripheral blood of patients is rare, and many platforms have been launched for detection and enrichment of CTCs. Enumeration of CTCs has already been used as a prognosis marker predicting the survival rate of cancer patients. Yet CTCs should be more potential. Studies on CTCs at single cell level may help revealing the underlying mechanism of tumorigenesis and metastasis. Though far from developed, this area of study holds much promise in providing new clinical application and deep understanding towards metastasis and cancer development. PMID:26487963

  12. Increased Risk of Additional Cancers Among Patients with Gastrointestinal Stromal Tumors: A Population-Based Study

    PubMed Central

    Murphy, James D.; Ma, Grace L.; Baumgartner, Joel M.; Madlensky, Lisa; Burgoyne, Adam M.; Tang, Chih-Min; Martinez, Maria Elena; Sicklick, Jason K.

    2015-01-01

    Purpose Most gastrointestinal stromal tumors (GIST) are considered non-hereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies with increased frequencies. We hypothesized that we could gain greater insight into possible associations between GIST and other malignancies using a national cancer database inquiry. Methods Patients diagnosed with GIST (2001–2011) in the Surveillance, Epidemiology, and End Results database were included. Standardized prevalence ratios (SPRs) and standardized incidence ratios (SIRs) were used to quantify cancer risks incurred by GIST patients before and after GIST diagnoses, respectively, when compared with the general U.S. population. Results Of 6,112 GIST patients, 1,047 (17.1%) had additional cancers. There were significant increases in overall cancer rates: 44% (SPR=1.44) before diagnosis and 66% (SIR=1.66) after GIST diagnoses. Malignancies with significantly increased occurrence both before/after diagnoses included other sarcomas (SPR=5.24/SIR=4.02), neuroendocrine-carcinoid tumors (SPR=3.56/SIR=4.79), non-Hodgkin’s lymphoma (SPR=1.69/SIR=1.76), and colorectal adenocarcinoma (SPR=1.51/SIR=2.16). Esophageal adenocarcinoma (SPR=12.0), bladder adenocarcinoma (SPR=7.51), melanoma (SPR=1.46), and prostate adenocarcinoma (SPR=1.20) were significantly more common only before GIST. Ovarian carcinoma (SIR=8.72), small intestine adenocarcinoma (SIR=5.89), papillary thyroid cancer (SIR=5.16), renal cell carcinoma (SIR=4.46), hepatobiliary adenocarcinomas (SIR=3.10), gastric adenocarcinoma (SIR=2.70), pancreatic adenocarcinoma (SIR=2.03), uterine adenocarcinoma (SIR=1.96), non-small cell lung cancer (SIR=1.74), and transitional cell carcinoma of the bladder (SIR=1.65) were significantly more common only after GIST. Conclusion This is the first population-based study to characterize the associations and temporal relationships between GIST and other cancers, both by site and

  13. IL17 Promotes Mammary Tumor Progression by Changing the Behavior of Tumor Cells and Eliciting Tumorigenic Neutrophils Recruitment.

    PubMed

    Benevides, Luciana; da Fonseca, Denise Morais; Donate, Paula Barbim; Tiezzi, Daniel Guimarães; De Carvalho, Daniel D; de Andrade, Jurandyr M; Martins, Gislaine A; Silva, João S

    2015-09-15

    The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL17 levels. Studying the role of IL17 in invasive breast tumor pathogenesis, we found that metastatic primary tumor-infiltrating T lymphocytes produced elevated levels of IL17, whereas IL17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, producing CXCL1, MMP9, VEGF, and TNFα, and their depletion suppressed tumor growth. IL17A also induced IL6 and CCL20 production in metastatic tumor cells, favoring the recruitment and differentiation of Th17. In addition, IL17A changed the gene-expression profile and the behavior of nonmetastatic tumor cells, causing tumor growth in vivo, confirming the protumor role of IL17. Furthermore, high IL17 expression was associated with lower disease-free survival and worse prognosis in IDC patients. Thus, IL17 blockade represents an attractive approach for the control of invasive breast tumors. PMID:26208902

  14. Curcumin and cancer cells: how many ways can curry kill tumor cells selectively?

    PubMed

    Ravindran, Jayaraj; Prasad, Sahdeo; Aggarwal, Bharat B

    2009-09-01

    Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail. PMID:19590964

  15. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses

    PubMed Central

    Joshi, Nikhil S.; Akama-Garren, Elliot H.; Lu, Yisi; Lee, Da-Yae; Chang, Gregory P.; Li, Amy; DuPage, Michel; Tammela, Tuomas; Kerper, Natanya R.; Farago, Anna F.; Robbins, Rebecca; Crowley, Denise M.; Bronson, Roderick T.; Jacks, Tyler

    2016-01-01

    SUMMARY Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically-engineered mouse lung adenocarcinoma model and found Treg cells suppress anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLS). TA-TLS have been described in human lung cancers, but their function remains to be determined. TLS in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLS upon Treg cell depletion, leading to tumor destruction. Thus, we propose Treg cells in TA-TLS can inhibit endogenous immune responses against tumors, and targeting these cells may provide therapeutic benefit for cancer patients. PMID:26341400

  16. Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid cells at the tumor site.

    PubMed

    Thoreau, Maxime; Penny, HweiXian Leong; Tan, KarWai; Regnier, Fabienne; Weiss, Julia Miriam; Lee, Bernett; Johannes, Ludger; Dransart, Estelle; Le Bon, Agnès; Abastado, Jean-Pierre; Tartour, Eric; Trautmann, Alain; Bercovici, Nadège

    2015-09-29

    Most cancer immunotherapies under present investigation are based on the belief that cytotoxic T cells are the most important anti-tumoral immune cells, whereas intra-tumoral macrophages would rather play a pro-tumoral role. We have challenged this antagonistic point of view and searched for collaborative contributions by tumor-infiltrating T cells and macrophages, reminiscent of those observed in anti-infectious responses. We demonstrate that, in a model of therapeutic vaccination, cooperation between myeloid cells and T cells is indeed required for tumor rejection. Vaccination elicited an early rise of CD11b+ myeloid cells that preceded and conditioned the intra-tumoral accumulation of CD8+ T cells. Conversely, CD8+ T cells and IFNγ production activated myeloid cells were required for tumor regression. A 4-fold reduction of CD8+ T cell infiltrate in CXCR3KO mice did not prevent tumor regression, whereas a reduction of tumor-infiltrating myeloid cells significantly interfered with vaccine efficiency. We show that macrophages from regressing tumors can kill tumor cells in two ways: phagocytosis and TNFα release. Altogether, our data suggest new strategies to improve the efficiency of cancer immunotherapies, by promoting intra-tumoral cooperation between macrophages and T cells. PMID:26337837

  17. Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid cells at the tumor site

    PubMed Central

    Thoreau, Maxime; Penny, HweiXian Leong; Tan, KarWai; Regnier, Fabienne; Weiss, Julia Miriam; Lee, Bernett; Johannes, Ludger; Dransart, Estelle; Le Bon, Agnès; Abastado, Jean-Pierre; Tartour, Eric

    2015-01-01

    Most cancer immunotherapies under present investigation are based on the belief that cytotoxic T cells are the most important anti-tumoral immune cells, whereas intra-tumoral macrophages would rather play a pro-tumoral role. We have challenged this antagonistic point of view and searched for collaborative contributions by tumor-infiltrating T cells and macrophages, reminiscent of those observed in anti-infectious responses. We demonstrate that, in a model of therapeutic vaccination, cooperation between myeloid cells and T cells is indeed required for tumor rejection. Vaccination elicited an early rise of CD11b+ myeloid cells that preceded and conditioned the intra-tumoral accumulation of CD8+ T cells. Conversely, CD8+ T cells and IFNγ production activated myeloid cells were required for tumor regression. A 4-fold reduction of CD8+ T cell infiltrate in CXCR3KO mice did not prevent tumor regression, whereas a reduction of tumor-infiltrating myeloid cells significantly interfered with vaccine efficiency. We show that macrophages from regressing tumors can kill tumor cells in two ways: phagocytosis and TNFα release. Altogether, our data suggest new strategies to improve the efficiency of cancer immunotherapies, by promoting intra-tumoral cooperation between macrophages and T cells. PMID:26337837

  18. The p75{sup NTR} tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells

    SciTech Connect

    Khwaja, Fatima; Tabassum, Arshia; Allen, Jeff; Djakiew, Daniel . E-mail: djakiewd@georgetown.edu

    2006-03-24

    The p75 neurotrophin receptor (p75{sup NTR}) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75{sup NTR} retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted ({delta}DD) dominant-negative antagonist of p75{sup NTR} showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75{sup NTR}-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75{sup NTR} expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75{sup NTR} rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75{sup NTR} was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75{sup NTR}-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75{sup NTR} expressing prostate cancer cells.

  19. Lymphatic endothelial cells support tumor growth in breast cancer

    PubMed Central

    Lee, Esak; Pandey, Niranjan B.; Popel, Aleksander S.

    2014-01-01

    Tumor lymphatic vessels (LV) serve as a conduit of tumor cell dissemination, due to their leaky nature and secretion of tumor-recruiting factors. Though lymphatic endothelial cells (LEC) lining the LV express distinct factors (also called lymphangiocrine factors), these factors and their roles in the tumor microenvironment are not well understood. Here we employ LEC, microvascular endothelial cells (MEC), and human umbilical vein endothelial cells (HUVEC) cultured in triple-negative MDA-MB-231 tumor-conditioned media (TCM) to determine the factors that may be secreted by various EC in the MDA-MB-231 breast tumor. These factors will serve as endothelium derived signaling molecules in the tumor microenvironment. We co-injected these EC with MDA-MB-231 breast cancer cells into animals and showed that LEC support tumor growth, HUVEC have no significant effect on tumor growth, whereas MEC suppress it. Focusing on LEC-mediated tumor growth, we discovered that TCM-treated LEC (‘tumor-educated LEC') secrete high amounts of EGF and PDGF-BB, compared to normal LEC. LEC-secreted EGF promotes tumor cell proliferation. LEC-secreted PDGF-BB induces pericyte infiltration and angiogenesis. These lymphangiocrine factors may support tumor growth in the tumor microenvironment. This study shows that LV serve a novel role in the tumor microenvironment apart from their classical role as conduits of metastasis. PMID:25068296

  20. Inhibition of vacuolar ATPase subunit in tumor cells delays tumor growth by decreasing the essential macrophage population in the tumor microenvironment.

    PubMed

    Katara, G K; Kulshrestha, A; Jaiswal, M K; Pamarthy, S; Gilman-Sachs, A; Beaman, K D

    2016-02-25

    In cancer cells, vacuolar ATPase (V-ATPase), a multi-subunit enzyme, is expressed on the plasma as well as vesicular membranes and critically influences metastatic behavior. The soluble, cleaved N-terminal domain of V-ATPase a2 isoform is associated with in vitro induction of tumorigenic characteristics in macrophages. This activity led us to further investigate its in vivo role in cancer progression by inhibition of a2 isoform (a2V) in tumor cells and the concomitant effect on tumor microenvironment in the mouse 4T-1 breast cancer model. Results showed that macrophages cocultivated with a2V knockdown (sh-a2) 4T-1 cells produce lower amounts of tumorigenic factors in vitro and have reduced ability to suppress T-cell activation and proliferation compared with control 4T-1 cells. Data analysis showed a delayed mammary tumor growth in Balb/c mice inoculated with sh-a2 4T-1 cells compared with control. The purified CD11b(+) macrophages from sh-a2 tumors showed a reduced expression of mannose receptor-1 (CD206), interleukin-10, transforming growth factor-β, arginase-1, matrix metalloproteinase and vascular endothelial growth factor. Flow cytometric analysis of tumor-infiltrated macrophages showed a significantly low number of F4/80(+)CD11c(+)CD206(+) macrophages in sh-a2 tumors compared with control. In sh-a2 tumors, most of the macrophages were F4/80(+)CD11c(+) (antitumor M1 macrophages) suggesting it to be the reason behind delayed tumor growth. Additionally, tumor-infiltrating macrophages from sh-a2 tumors showed a reduced expression of CD206 compared with control whereas CD11c expression was unaffected. These findings demonstrate that in the absence of a2V in tumor cells, the resident macrophage population in the tumor microenvironment is altered which affects in vivo tumor growth. We suggest that by involving the host immune system, tumor growth can be controlled through targeting of a2V on tumor cells. PMID:25961933

  1. Mast cells: potential positive and negative roles in tumor biology.

    PubMed

    Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

    2013-11-01

    Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. PMID:24777963

  2. Effusion cytomorphology of small round cell tumors

    PubMed Central

    Ikeda, Katsuhide; Tsuta, Koji

    2016-01-01

    Background: Small round cell tumors (SRCTs) are a group of tumors composed of small, round, and uniform cells with high nuclear/cytoplasmic (N/C) ratios. The appearance of SRCT neoplastic cells in the effusion fluid is very rare. We reported the cytomorphological findings of SRCTs in effusion cytology, and performed statistical and mathematical analyses for a purpose to distinguish SRCTs. Materials and Methods: We analyzed the cytologic findings of effusion samples from 40 SRCT cases and measured the lengths of the nuclei, cytoplasms, and the cell cluster areas. The SRCT cases included 14 Ewing sarcoma (EWS)/primitive neuroectodermal tumor cases, 5 synovial sarcoma cases, 6 rhabdomyosarcoma cases, 9 small cell lung carcinoma (SCLC) cases, and 6 diffuse large B-cell lymphoma (DLBL) cases. Results: Morphologically, there were no significant differences in the nuclear and cytoplasmic lengths in cases of EWS, synovial sarcoma, and rhabdomyosarcoma. The cytoplasmic lengths in cases of SCLC and DLBL were smaller than those of EWS, synovial sarcoma, and rhabdomyosarcoma. The nuclear density of the cluster in SCLC was higher than that in other SRCTs, and cases of DLBL showed a lack of anisokaryosis and anisocytosis. Conclusion: We believe that it might be possible to diagnose DLBL and SCLC from cytologic analysis of effusion samples but it is very difficult to use this method to distinguish EWS, synovial sarcoma, and rhabdomyosarcoma. Statistical and mathematical analyses indicated that nuclear density and dispersion of nuclear and cytoplasmic sizes are useful adjuncts to conventional cytologic diagnostic criteria, which are acquired from experience. PMID:27279684

  3. Immune response to UV-induced tumors: mediation of progressor tumor rejection by natural killer cells

    SciTech Connect

    Streeter, P.R.; Fortner, G.W.

    1986-03-01

    Skin tumors induced in mice by chronic ultraviolet (UV) irradiation are highly antigenic and can induce a state of transplantation immunity in syngeneic animals. In the present study, the authors compared the in vitro cytolytic activity of splenic lymphocytes from mice immunized with either regressor or progressor UV-tumors. The results of this comparison implicated tumor-specific cytolytic T (Tc) lymphocytes in rejection of regressor UV-tumors, and revealed that immunization with the progressor UV-tumor 2237 failed to elicit detectable levels of progressor tumor-specific Tc cells even as the tumors rejected. Following in vitro resensitization of spleen cells from either regressor or progressor tumor immune animals, the authors found NK-like lymphocytes with anti-tumor activity. As the authors had not detected cells with this activity in splenic lymphocyte preparations prior to in vitro resensitization, the authors examined lymphocytes from the local tumor environment during the course of progressor tumor rejection for this activity. This analysis revealed NK lymphocytes exhibiting significant levels of cytolytic activity against UV-tumors. These results implicate NK cells as potential effector cells in the rejection of progressor UV-tumors by immune animals, and suggests that these cells may be regulated by T lymphocytes.

  4. Marijuana use and testicular germ cell tumors

    PubMed Central

    Trabert, Britton; Sigurdson, Alice J.; Sweeney, Anne M.; Strom, Sara S.; McGlynn, Katherine A.

    2010-01-01

    Background Since the early 1970's the incidence of testicular germ cell tumors (TGCT) in the U.S. has been increasing, however, potential environmental exposures accounting for this rise have not been identified. A prior study reported a significant association among frequent and long-term current users of marijuana and TGCT risk. We aimed to evaluate the relationship of marijuana use and TGCT in a hospital-based case-control study conducted at The University of Texas M. D. Anderson Cancer Center. Methods TGCT cases diagnosed between January 1990 and October 1996 (n=187) and male friend controls (n=148) were enrolled in the study. All participants were between the ages of 18 and 50 at the time of cases' diagnosis and resided in Texas, Louisiana, Arkansas, or Oklahoma. Associations of marijuana use and TGCT were estimated using unconditional logistic regression, adjusting for age, race, prior cryptorchidism, cigarette smoking and alcohol intake. Results Overall, TGCT cases were more likely to be frequent marijuana users (daily or greater) than were controls [OR: 2.2, 95% CI: 1.0, 5.1]. In the histologic-specific analyses nonseminoma cases were significantly more likely than controls to be frequent users [OR: 3.1, 95% CI: 1.2, 8.2] and long-term users (10+ years) [OR: 2.4, 95% CI: 1.0, 6.1]. Discussion Our finding of an association between frequent marijuana use and TGCT, particularly among men with nonseminoma, is consistent with the findings of a previous report. Additional studies of marijuana use and TGCT are warranted, especially studies evaluating the role of endocannabinoid signaling and cannabinoid receptors in TGCT. PMID:20925043

  5. Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture

    PubMed Central

    Pollmann, Mary-Ann; Shao, Qing; Laird, Dale W; Sandig, Martin

    2005-01-01

    Introduction Metastasis involves the emigration of tumor cells through the vascular endothelium, a process also known as diapedesis. The molecular mechanisms regulating tumor cell diapedesis are poorly understood, but may involve heterocellular gap junctional intercellular communication (GJIC) between tumor cells and endothelial cells. Method To test this hypothesis we expressed connexin 43 (Cx43) in GJIC-deficient mammary epithelial tumor cells (HBL100) and examined their ability to form gap junctions, establish heterocellular GJIC and migrate through monolayers of human microvascular endothelial cells (HMVEC) grown on matrigel-coated coverslips. Results HBL100 cells expressing Cx43 formed functional heterocellular gap junctions with HMVEC monolayers within 30 minutes. In addition, immunocytochemistry revealed Cx43 localized to contact sites between Cx43 expressing tumor cells and endothelial cells. Quantitative analysis of diapedesis revealed a two-fold increase in diapedesis of Cx43 expressing cells compared to empty vector control cells. The expression of a functionally inactive Cx43 chimeric protein in HBL100 cells failed to increase migration efficiency, suggesting that the observed up-regulation of diapedesis in Cx43 expressing cells required heterocellular GJIC. This finding is further supported by the observation that blocking homocellular and heterocellular GJIC with carbenoxolone in co-cultures also reduced diapedesis of Cx43 expressing HBL100 tumor cells. Conclusion Collectively, our results suggest that heterocellular GJIC between breast tumor cells and endothelial cells may be an important regulatory step during metastasis. PMID:15987459

  6. Cell culture of small round cell tumor originating in the thoracopulmonary region. Evidence for derivation from a primitive pluripotent cell.

    PubMed

    Fujii, Y; Hongo, T; Nakagawa, Y; Nasuda, K; Mizuno, Y; Igarashi, Y; Naito, Y; Maeda, M

    1989-07-01

    The authors describe a 14-year-old girl with small round cell tumor originating in the chest wall analyzed by the extensive studies including light and electron microscopic examination, histochemical study, immunochemical study, cytogenetics, and gene analysis. A cell line producing carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) has been established from pleural effusion of the pulmonary metastatic tumor. Cytogenetic analysis disclosed a reciprocal translocation (11;22)(q24;q12). Additionally, immunocytochemical studies demonstrated that CEA, NSE, vimentin, cytokeratin, and epithelial membrane antigens are positive, but desmin and S-100 protein are negative. Although neurofilament was negative in the pulmonary metastatic tumor cells, it became positive in cell line in vitro. These results suggest that this tumor may be derived from the primitive and pluripotential cells, differentiating into mesenchymal, epithelial, and neural features in variable proportions. PMID:2731119

  7. Colon tumor cells grown in NASA Bioreactor

    NASA Technical Reports Server (NTRS)

    2001-01-01

    These photos compare the results of colon carcinoma cells grown in a NASA Bioreactor flown on the STS-70 Space Shuttle in 1995 flight and ground control experiments. The cells grown in microgravity (left) have aggregated to form masses that are larger and more similar to tissue found in the body than the cells cultured on the ground (right). The principal investigator is Milburn Jessup of the University of Texas M. D. Anderson Cancer Center. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Cell constructs grown in a rotating bioreactor on Earth (left) eventually become too large to stay suspended in the nutrient media. In the microgravity of orbit, the cells stay suspended. Rotation then is needed for gentle stirring to replenish the media around the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). Credit: NASA and University of Texas M. D. Anderson Cancer Center.

  8. Mast cell tumor destruction by deionized water.

    PubMed

    Grier, R L; Di Guardo, G; Schaffer, C B; Pedrosa, B; Myers, R; Merkley, D F; Thouvenelle, M

    1990-07-01

    In a controlled study, malignant murine P815 mastocytoma cells exposed in vitro to distilled and deionized water died as a result of progressive swelling, degranulation, and membrane rupture. A 90% mean cell death occurred when cells obtained directly from culture were exposed to deionized water for 2 minutes. Of 6 cryopreserved malignant murine cell lines, which included Cloudman S91 melanoma, CMT-93 rectum carcinoma, MMT-06052 mammary carcinoma, and S-180 Sarcoma, only P815 mastocytoma and YAC-1 lymphoma were significantly (P less than 0.05) affected by hypotonic shock; Cloudman S91 melanoma cells were the most resistant. Mastocytoma cells were selectively killed by hypotonic solution, and lymphoma cells were also killed by isotonic saline solution. Local mast cell tumor (MCT) recurrence and percentage survival were evaluated in 12 cats (21 MCT) and 54 dogs (85 MCT) subjected to surgery alone or local infiltration of deionized water as an adjunct to surgery. Of all 16 incompletely excised MCT in cats, there was no local recurrence following injection. Four mast cell tumors (2 cats) regressed after being injected in situ. In dogs with clinical stage-I MCT, local recurrence was detected in 50% (5/10), but with injection after incomplete excision, local MCT recurrence was significantly (P less than 0.05) less (6.6%, 1/15). Percentage recurrence was significantly (P less than 0.05) less and survival significantly greater when incompletely excised grade-II MCT were injected. Mean follow-up period after surgery in cats and dogs was 35 and 23.4 months, respectively. PMID:2117868

  9. Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways

    PubMed Central

    Nölting, Svenja; Maurer, Julian; Spöttl, Gerald; Aristizabal Prada, Elke Tatjana; Reuther, Clemens; Young, Karen; Korbonits, Márta; Göke, Burkhard; Grossman, Ashley; Auernhammer, Christoph J.

    2015-01-01

    Background The mTORC1-inhibitor everolimus shows limited efficacy in treating patients with gastro-entero-pancreatic or pulmonary neuroendocrine tumors (NETs), and poor outcome in patients with malignant pheochromocytoma or hepatic carcinoma. We speculated that any effect may be enhanced by antogonising other signaling pathways. Methods Therefore, we tested the effect of lovastatin—known to inhibit both ERK and AKT signaling—and everolimus, separately and in combination, on cell viability and signaling pathways in human midgut (GOT), pancreatic (BON1), and pulmonary (H727) NET, hepatocellular carcinoma (HepG2, Huh7), and mouse pheochromocytoma (MPC, MTT) cell lines. Results Lovastatin and everolimus separately significantly reduced cell viability in H727, HepG2, Huh7, MPC and MTT cells at clinically relevant doses (P ≤ 0.05). However, high doses of lovastatin were necessary to affect GOT or BON1 cell viability. Clinically relevant doses of both drugs showed additive anti-tumor effects in H727, HepG2, Huh7, MPC and MTT cells (P ≤ 0.05), but not in BON1 or GOT cells. In all cell lines investigated, lovastatin inhibited EGFR and AKT signaling. Subsequently, combination treatment more strongly inhibited EGFR and AKT signaling than everolimus alone, or at least attenuated everolimus-induced EGFR or AKT activation. Vice versa, everolimus constantly decreased pp70S6K and combination treatment more strongly decreased pp70S6K than lovastatin alone, or attenuated lovastatin-induced p70S6K activation: in BON1 cells lovastatin-induced EGFR inhibition was least pronounced, possibly explaining the low efficacy and consequent absent additive effect. Conclusion In summary, clinically relevant doses of lovastatin and everolimus were effective separately and showed additive effects in 5 out of 7 cell lines. Our findings emphasize the importance of targeting several interacting signaling pathways simultaneously when attempting to attenuate tumor growth. However, the variable

  10. Giant Cell Tumors of the Axial Skeleton

    PubMed Central

    Balke, Maurice; Henrichs, Marcel P.; Gosheger, Georg; Ahrens, Helmut; Streitbuerger, Arne; Koehler, Michael; Bullmann, Viola; Hardes, Jendrik

    2012-01-01

    Background. We report on 19 cases of giant cell tumor of bone (GCT) affecting the spine or sacrum and evaluate the outcome of different treatment modalities. Methods. Nineteen patients with GCT of the spine (n = 6) or sacrum (n = 13) have been included in this study. The mean followup was 51.6 months. Ten sacral GCT were treated by intralesional procedures of which 4 also received embolization, and 3 with irradiation only. All spinal GCT were surgically treated. Results. Two (15.4%) patients with sacral and 4 (66.7%) with spinal tumors had a local recurrence, two of the letter developed pulmonary metastases. One local recurrence of the spine was successfully treated by serial arterial embolization, a procedure previously described only for sacral tumors. At last followup, 9 patients had no evidence of disease, 8 had stable disease, 1 had progressive disease, 1 died due to disease. Six patients had neurological deficits. Conclusions. GCT of the axial skeleton have a high local recurrence rate. Neurological deficits are common. En-bloc spondylectomy combined with embolization is the treatment of choice. In case of inoperability, serial arterial embolization seems to be an alternative not only for sacral but also for spinal tumors. PMID:22448122

  11. Giant cell tumor of the spine.

    PubMed

    Ozaki, Toshifumi; Liljenqvist, Ulf; Halm, Henry; Hillmann, Axel; Gosheger, Georg; Winkelmann, Winfried

    2002-08-01

    Six patients with giant cell tumor of the spine had surgery between 1981 and 1995. Three lesions were located in the scrum, two lesions were in the thoracic spine, and one lesion was in the lumbar spine. Preoperatively, all patients had local pain and neurologic symptoms. Two patients had cement implanted after curettage or intralesional excision of the sacral tumor; one patient had a local relapse. After the second curettage and cement implantation, the tumor was controlled. One patient with a sacral lesion had marginal excision and spondylodesis; no relapse developed. Two patients with thoracic lesions had planned marginal excision and spondylodesis; the margins finally became intralesional, but no relapse developed. One patient with a lumbar lesion had incomplete removal of the tumor and received postoperative irradiation. At the final followup (median, 69 months), five of six patients were disease-free and one patient died of disease progression. Two of the five surviving patients had pain after standing or neurologic problems. Although some contamination occurred, planning a marginal excision of the lesion seems beneficial for vertebral lesions above the sacrum. Total sacrectomy of a sacral lesion seems to be too invasive when cement implantation can control the lesion. PMID:12151896

  12. Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment.

    PubMed

    Lee, J; Fenton, B M; Koch, C J; Frelinger, J G; Lord, E M

    1998-04-01

    Microenvironmental conditions within solid tumors can have marked effects on the growth of the tumors and their response to therapies. The disorganized growth of tumors and their attendant vascular systems tends to result in areas of the tumors that are deficient in oxygen (hypoxic). Cells within these hypoxic areas are more resistant to conventional therapies such as radiation and chemotherapy. Here, we examine the hypoxic state of EMT6 mouse mammary tumors and the location of host cells within the different areas of the tumors to determine whether such microenvironmental conditions might also affect their ability to be recognized by the immune system. Hypoxia within tumors was quantified by flow cytometry and visualized by immunohistochemistry using a monoclonal antibody (ELK3-51) against cellular adducts of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetam ide (EF5), a nitroimidazole compound that binds selectively to hypoxic cells. Thy-1+ cells, quantified using a monoclonal antibody, were found only in the well-oxygenated areas. The location of these Thy-1+ cells was also examined in EMT6 tumors that had been transfected with the gene for interleukin-2 (IL-2) because these tumors contain greatly increased numbers of host cells. Surprisingly, we found that IL-2-transfected tumors had significantly decreased hypoxia compared to parental tumors. Furthermore, using the fluorescent dye Hoechst 33342, an in vivo marker of perfused vessels, combined with immunochemical staining of PECAM-1 (CD31) as a marker of tumor vasculature, we found increased vascularization in the IL-2-transfected tumors. Thus, expression of IL-2 at the site of tumor growth may enhance tumor immunity not only by inducing the generation of tumor-reactive CTLs but also by allowing increased infiltration of activated T cells into the tumors. PMID:9537251

  13. Comparison of tumor curettage and resection for treatment of giant cell tumor of the bone around the knee joint

    PubMed Central

    Zhang, Sheng; Zhang, Jianhua; Wang, Xin

    2016-01-01

    Objective: To analyze the efficacies of tumor curettage and resection for treatment of giant cell tumor of the bone (GCTB) around the knee joint (KJ). Methods: A total of 126 KJ-GCTB cases were treated at our department from August 2011 to February 2015. These cases were divided into two groups (A and B) according to treatment methods. Group A underwent tumor curettage, while group B underwent tumor resection. Results: The relapse rates did not differ significantly between the groups (P>0.05), while the complication rate in group A was significantly lower than that in group B (P<0.05). In addition, the Enneking score for group A was significantly higher than that for group B (P<0.05); in addition, postoperative local recurrence, histopathological grading according to Jaffe, and radiographic imaging-based Campanacci’s staging positively correlated (P<0.05). Conclusion: Tumor curettage was the preferred surgical approach for patients with KJ-GCTB.

  14. An Unusually Large Granular Cell Tumor of the Pharynx: A Case Report and Literature Review

    PubMed Central

    Li, Xiaoxian; Parke, Robert B.; Rushton, Jennifer R.; Sienko, Anna; Zhai, Qihui “Jim”

    2009-01-01

    We report a granular cell tumor of the pharynx in a 53 year-old woman who presented with a large retropharyngeal mass. Surgical excision revealed a 5.5 cm tan rubbery unencapsulated but circumscribed mass. Histologically, the tumor is composed of diffusely arranged oval and spindle cells with abundant eosinophilic granular cytoplasm and mildly pleomorphic nuclei without necrosis or mitoses. Immunostains show the tumor cells to be positive for S-100, vimentin, non-specific esterase and focally positive for inhibin. In addition to its unusual location, this tumor is extremely large while most granular cell tumors are small (<2 cm). This case represents a unique example of a large granular cell tumor at a rare location: the pharynx. PMID:19079624

  15. Microvesicles released from tumor cells disrupt epithelial cell morphology and contractility.

    PubMed

    Bordeleau, Francois; Chan, Bryan; Antonyak, Marc A; Lampi, Marsha C; Cerione, Richard A; Reinhart-King, Cynthia A

    2016-05-24

    During tumor progression, cancer cells interact and communicate with non-malignant cells within their local microenvironment. Microvesicles (MV) derived from human cancer cells play an important role in mediating this communication. Another critical aspect of cancer progression involves widespread ECM remodeling, which occur both at the primary and metastatic sites. ECM remodeling and reorganization within the tumor microenvironment is generally attributed to fibroblasts. Here, using MCF10a cells, a well-characterized breast epithelial cell line that exhibits a non-malignant epithelial phenotype, and MVs shed by aggressive MDA-MB-231 carcinoma cells, we show that non-malignant epithelial cells can participate in ECM reorganization of 3D collagen matrices following their treatment with cancer cell-derived MVs. In addition, MVs trigger several changes in epithelial cells under 3D culture conditions. Furthermore, we show that this ECM reorganization is associated with an increase in cellular traction force following MV treatment, higher acto-myosin contractility, and higher FAK activity. Overall, our findings suggest that MVs derived from tumor cells can contribute to ECM reorganization occurring within the tumor microenvironment by enhancing the contractility of non-malignant epithelial cells. PMID:26477404

  16. Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients.

    PubMed

    Madic, Jordan; Kiialainen, Anna; Bidard, Francois-Clement; Birzele, Fabian; Ramey, Guillemette; Leroy, Quentin; Rio Frio, Thomas; Vaucher, Isabelle; Raynal, Virginie; Bernard, Virginie; Lermine, Alban; Clausen, Inga; Giroud, Nicolas; Schmucki, Roland; Milder, Maud; Horn, Carsten; Spleiss, Olivia; Lantz, Olivier; Stern, Marc-Henri; Pierga, Jean-Yves; Weisser, Martin; Lebofsky, Ronald

    2015-05-01

    Circulating tumor DNA (ctDNA) is a new circulating tumor biomarker which might be used as a prognostic biomarker in a way similar to circulating tumor cells (CTCs). Here, we used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTC detection rates and prognostic value in metastatic TNBC patients. Forty patients were enrolled before starting a new line of treatment. TP53 mutations were characterized in archived tumor tissues and in plasma DNA using two next generation sequencing (NGS) platforms in parallel. Archived tumor tissue was sequenced successfully for 31/40 patients. TP53 mutations were found in 26/31 (84%) of tumor samples. The same mutation was detected in the matched plasma of 21/26 (81%) patients with an additional mutation found only in the plasma for one patient. Mutated allele fractions ranged from 2 to 70% (median 5%). The observed correlation between the two NGS approaches (R(2) = 0.903) suggested that ctDNA levels data were quantitative. Among the 27 patients with TP53 mutations, CTC count was ≥1 in 19 patients (70%) and ≥5 in 14 patients (52%). ctDNA levels had no prognostic impact on time to progression (TTP) or overall survival (OS), whereas CTC numbers were correlated with OS (p = 0.04) and marginally with TTP (p = 0.06). Performance status and elevated LDH also had significant prognostic impact. Here, absence of prognostic impact of baseline ctDNA level suggests that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumor burden, biological features that do not dramatically affect patient outcome. PMID:25307450

  17. Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors

    ClinicalTrials.gov

    2016-07-26

    Germ Cell Tumor; Teratoma; Choriocarcinoma; Germinoma; Mixed Germ Cell Tumor; Yolk Sac Tumor; Childhood Teratoma; Malignant Germ Cell Neoplasm; Extragonadal Seminoma; Non-seminomatous Germ Cell Tumor; Seminoma

  18. Assessment of tumor characteristic gene expression in cell lines using a tissue similarity index (TSI)

    PubMed Central

    Sandberg, Rickard; Ernberg, Ingemar

    2005-01-01

    The gene expression profiles of 60 cell lines, derived from nine different tissues, were compared with their corresponding in vivo tumors and tissues. Cell lines expressed few tissue-specific (2%) or tumor-specific (5%) genes when analyzed group-wise. A tissue similarity index (TSI) was designed based upon singular value decomposition that measured in vivo tumor characteristic gene expression in each cell line independently. Only 34 of the 60 cell lines received the highest TSI toward its tumor of origin. In addition, we identified the most appropriate cell lines to be used as model systems for different in vivo tumors. Seven cell lines were identified as being of another origin than the originally presumed one. The proposed TSI will likely become an important tool for the selection of the most appropriate cell lines in pharmaceutical screening programs and experimental and biomedical research. PMID:15671165

  19. Endothelial cell Ca2+ increases upon tumor cell contact and modulates cell-cell adhesion.

    PubMed Central

    Pili, R; Corda, S; Passaniti, A; Ziegelstein, R C; Heldman, A W; Capogrossi, M C

    1993-01-01

    The signal transduction mechanisms involved in tumor cell adhesion to endothelial cells are still largely undefined. The effect of metastatic murine melanoma cell and human prostate carcinoma cell contact on cytosolic [Ca2+] of bovine artery endothelial cells was examined in indo-1-loaded endothelial cell monolayers. A rapid increase in endothelial cell [Ca2+] occurred on contact with tumor cells, but not on contact with 8-microns inert beads. A similar increase in endothelial cell [Ca2+] was observed with human neutrophils or monocyte-like lymphoma cells, but not with endothelial cells, red blood cells, and melanoma cell-conditioned medium. The increase in endothelial cell [Ca2+] was not inhibited by extracellular Ca2+ removal. In contrast, endothelial cell pretreatment with thapsigargin, which releases endoplasmic reticulum Ca2+ into the cytosol and depletes this Ca2+ store site, abolished the cytosolic [Ca2+] rise upon melanoma cell contact. Endothelial cell pretreatment with the membrane-permeant form of the Ca2+ chelator bis-(O-aminophenoxyl)ethane-N,N,N',N'-tetraacetic acid blocked the increase in cytosolic [Ca2+]. Under static and dynamic flow conditions (0.46 dyn/cm2) bis-(O-aminophenoxyl)ethane-N,N,N',N'-tetraacetic acid pretreatment of bovine pulmonary artery endothelial cell monolayers inhibited melanoma cell adhesion to the endothelial cells. Thus, tumor cell contact with endothelial cells induces a rapid Ca2+ release from endothelial intracellular stores, which has a functional role in enhancing cell-cell adhesion. Images PMID:8254056

  20. Medulloblastoma/Primitive neuroectodermal tumor and germ cell tumors: the uncommon but potentially curable primary brain tumors.

    PubMed

    Samkari, Ayman; Hwang, Eugene; Packer, Roger J

    2012-08-01

    This article presents an overview of medulloblastomas, central nervous system primitive neuroectodermal tumors, and germ cell tumors for the practicing oncologist. Discussion includes the definition of these tumors, histopathologic findings, molecular and genetic characteristics, prognoses, and evolution of treatment. PMID:22794288

  1. Granular cell tumor presenting as a large leg mass.

    PubMed

    Andalib, Ali; Heidary, Mohsen; Sajadieh-Khajouei, Sahar

    2014-10-01

    Granular cell tumor is a rare benign neoplasm most commonly appears in the head and neck region, especially in the tongue, cheek mucosa, and palate. Occurrence in limbs is even rarer. These tumors account for approximately 0.5% of all soft tissue tumors. Granular cell tumor can also affect other organs including skin, breast, and lungs. Local recurrence and metastasis is potentially higher in malignant forms with poor prognosis in respect to the benign counterparts. The average diameter of the tumor is usually about 2-3 cm. We report a granular cell tumor in the leg with an unusual size. PMID:25692157

  2. Isolation of Cancer Epithelial Cells from Mouse Mammary Tumors

    PubMed Central

    Johnson, Sara; Chen, Hexin; Lo, Pang-Kuo

    2016-01-01

    The isolation of cancer epithelial cells from mouse mammary tumor is accomplished by digestion of the solid tumor. Red blood cells and other contaminates are removed using several washing techniques such that primary epithelial cells can further enriched. This procedure yields primary tumor cells that can be used for in vitro tissue culture, fluorescence-activated cell sorting (FACS) and a wide variety of other experiments (Lo et al., 2012).

  3. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting.

    PubMed

    Chaudhary, Belal; Elkord, Eyad

    2016-01-01

    Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits. PMID:27509527

  4. Tumor-associated macrophages are involved in tumor progression in papillary renal cell carcinoma.

    PubMed

    Behnes, Carl Ludwig; Bremmer, Felix; Hemmerlein, Bernhard; Strauss, Arne; Ströbel, Philipp; Radzun, Heinz-Joachim

    2014-02-01

    Tumor-associated macrophages (TAMs) play a key role in cancer development. Especially, the immunosuppressive M2 phenotype is associated with increased tumor growth, invasiveness and metastasis. The differentiation of macrophages to the alternative phenotype M2 is mediated, inter alia, by macrophage colony-stimulating factor (M-CSF). Papillary renal cell carcinoma (RCC) represents a rare tumor type which, based upon histological criteria, can be subdivided into two subtypes (I and II), of which type II is associated with poor prognosis. In both subtypes, typically, a dense infiltrate of macrophages is found. In the present study, the expression of CD68, CD163, M-CSF, Ki-67, and CD31 was examined in 30 type I and 30 type II papillary RCCs (n = 60). Both types of papillary RCCs contained an equally dense infiltrate of CD68-positive macrophages. Nearly all macrophages in papillary RCC type II expressed CD163, a characteristic for M2 macrophages. In type I papillary RCC, less than 30 % of macrophages expressed CD163. Furthermore, tumor cells in type II papillary RCC expressed significantly more M-CSF and showed increased (Ki-67 expression defined) proliferative activity in comparison with type I papillary RCC. In addition, the (CD31 defined) capillary density was higher in type II than in type I papillary RCC. A dense infiltrate of M2 phenotype TAM and high M-CSF expression in tumor cells are key features of type II papillary RCC. These findings might explain why the prognosis of papillary RCC type II is worse than that of type I. PMID:24327306

  5. B cell regulation of anti-tumor immune response.

    PubMed

    Zhang, Yu; Morgan, Richard; Podack, Eckhard R; Rosenblatt, Joseph

    2013-12-01

    Our laboratory has been investigating the role of B cells on tumor immunity. We have studied the immune response in mice that are genetically lacking in B cells (BCDM) using a variety of syngeneic mouse tumors and compared immune responses in BCDM with those seen in wild type (WT) immunocompetent mice (ICM). A variety of murine tumors are rejected or inhibited in their growth in BCDM, compared with ICM, including the EL4 thymoma, and the MC38 colon carcinoma in C57BL/6 mice, as well as the EMT-6 breast carcinoma in BALB/c mice. In all three murine models, tumors show reduced growth in BCDM which is accompanied by increased T cell and NK cell infiltration, and a more vigorous Th1 cytokine response, and increased cytolytic T cell response in the absence of B cells. Reconstitution of the mice with B cells results in augmented tumor growth due to a diminished anti-tumor immune response and in reduction in CD8+ T cell and NK cell infiltration. Studies involving BCR transgenic mice indicated that B cells inhibit anti-tumor T cell responses through antigen non-specific mechanisms. More recent studies using the EMT-6 model demonstrated that both the number and function of Treg cells in ICM was increased relative to that seen in BCDM. Increased expansion of Treg cells was evident following EMT-6 implantation in ICM relative to that seen in non-tumor-bearing mice or BCDM. The percentage and number of Tregs in spleen, tumor draining lymph nodes, and the tumor bed are increased in ICM compared with BCDM. Treg functional capacity as measured by suppression assays appears to be reduced in BCDM compared with ICM. In contrast to other described types of B regulatory activity, adoptive transfer of B cells can rescue tumor growth independently of the ability of B cells to secrete IL-10, and also independently of MHC-II expression. In experiments using the MC38 adenocarcinoma model, BCDM reconstituted with WT B cells support tumor growth while tumor growth continues to be inhibited

  6. Isolation of Circulating Tumor Cells by Dielectrophoresis

    PubMed Central

    Gascoyne, Peter R. C.; Shim, Sangjo

    2014-01-01

    Dielectrophoresis (DEP) is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs) from blood. DEP-isolation of CTCs is independent of cell surface markers. Furthermore, isolated CTCs are viable and can be maintained in culture, suggesting that DEP methods should be more generally applicable than antibody-based approaches. The aim of this article is to review and synthesize for both oncologists and biomedical engineers interested in CTC isolation the pertinent characteristics of DEP and CTCs. The aim is to promote an understanding of the factors involved in realizing DEP-based instruments having both sufficient discrimination and throughput to allow routine analysis of CTCs in clinical practice. The article brings together: (a) the principles of DEP; (b) the biological basis for the dielectric differences between CTCs and blood cells; (c) why such differences are expected to be present for all types of tumors; and (d) instrumentation requirements to process 10 mL blood specimens in less than 1 h to enable routine clinical analysis. The force equilibrium method of dielectrophoretic field-flow fractionation (DEP-FFF) is shown to offer higher discrimination and throughput than earlier DEP trapping methods and to be applicable to clinical studies. PMID:24662940

  7. Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro.

    PubMed

    Maier, Gerhard; Fiebig, Heinz-Herbert

    2002-04-01

    Extracts of Viscum album (mistletoe) are widely used as complementary cancer therapies in Europe. The mistletoe lectins have been identified as the main active principle of mistletoe extracts. They have been shown to exhibit cytotoxic effects as well as immunomodulatory activities. The latter is exemplified by induction of cytokine secretion and increased activity of natural killer cells. Recent reports, however, indicated possible tumor growth stimulation by mistletoe extracts. Therefore, the three aqueous mistletoe extracts (Iscador M special, Iscador Qu special and Iscador P) were evaluated for antiproliferative and/or stimulatory effects in a panel of 16 human tumor cell lines in vitro using a cellular proliferation assay. The results show no evidence of stimulation of tumor growth by any of the three Iscador preparations, comprising central nervous system, gastric, non-small cell lung, mammary, prostate, renal and uterine cancer cell lines, as well as cell lines from hematological malignancies and melanomas. On the contrary, Iscador preparations containing a high lectin concentration (Iscador M special and Iscador Qu special) showed antitumor activity in the mammary cancer cell line MAXF 401NL at the 15 microg/ml dose level with a more than 70% growth inhibition compared to untreated control cells. In addition, a slight antitumor activity (growth inhibition 30-70%) was found in three tumor cell lines for Iscador M special and in seven tumor cell lines for Iscador Qu special, respectively. Iscador P, which contains no mistletoe lectin I, showed no antiproliferative activity. PMID:11984083

  8. Role of cell surface oligosaccharides of mouse mammary tumor cell lines in cancer metastasis.

    PubMed

    Zhao, Yunxue; Li, Jing; Wang, Jingjian; Xing, Yanli; Geng, Meiyu

    2007-06-01

    Malignant transformation is associated with changes in the glycosylation of cell surface proteins and lipids. In tumor cells, alterations in cellular glycosylation may play a key role in their metastatic behaviour. In the present study, we have assessed the relationship between cell surface oligosaccharides and the metastasis ability of mouse mammary tumor cell lines 67NR and 4TO7. The cell surface oligosaccharides have been analyzed using specific binding assays with some plant lectins and the metastasis ability has been studied using transwell migration and invasion assays. In addition, we investigated the role of terminal sialic acids in the metastatic potential (cell adhesion on fibronectin, cell migration and invasion) in the 4TO7 cells on treatment with neuraminidase. The cell lines used in study have different metastasis abilities in vivo - the 67NR form primary tumors, but no tumor cells are detectable in any distant tissues, while cells of the 4TO7 line are able to spread to lung. In vitro metastasis experiments have revealed higher ability of adhesion, cell migration and invasion in the 4TO7 cells than the 67NR cells. Specific lectins binding assays show that the 4TO7 cells expressed more high-mannose type, multi-antennary complex-type N-glycans, beta-1,6-GlcNAc-branching, alpha-2,6-linked sialic acids, N-acetylgalactosamine and galactosyl(beta-1,3)-N-acetylgalactosamine. Removal of sialic acids on treatment with neuraminidase decreases adhesion, but increases the migration and has shown no significant change in the invasion ability of the 4TO7 cells. The study suggests that the sialic acids are not crucial for the cell migration and invasion in the 4TO7 cells. The findings provide the new insights in understanding the role of cell surface oligosaccharides in cancer metastasis. PMID:17650582

  9. Purification of Immune Cell Populations from Freshly Isolated Murine Tumors and Organs by Consecutive Magnetic Cell Sorting and Multi-parameter Flow Cytometry-Based Sorting.

    PubMed

    Salvagno, Camilla; de Visser, Karin E

    2016-01-01

    It is well established that tumors evolve together with nonmalignant cells, such as fibroblasts, endothelial cells, and immune cells. These cells constantly entangle and interact with each other creating the tumor microenvironment. Immune cells can exert both tumor-promoting and tumor-protective functions. Detailed phenotypic and functional characterization of intra-tumoral immune cell subsets has become increasingly important in the field of cancer biology and cancer immunology. In this chapter, we describe a method for isolation of viable and pure immune cell subsets from freshly isolated murine solid tumors and organs. First, we describe a protocol for the generation of single-cell suspensions from tumors and organs using mechanical and enzymatic strategies. In addition, we describe how immune cell subsets can be purified by consecutive magnetic cell sorting and multi-parameter flow cytometry-based cell sorting. PMID:27581019

  10. Risk of tumor cell seeding through biopsy and aspiration cytology

    PubMed Central

    Shyamala, K.; Girish, H. C.; Murgod, Sanjay

    2014-01-01

    Cancer cells, besides reproducing uncontrollably, lose cohesiveness and orderliness of normal tissue, invade and get detached from the primary tumor to travel and set up colonies elsewhere. Dislodging neoplastically altered cells from a tumor during biopsy or surgical intervention or during simple procedure like needle aspiration is a possibility because they lack cohesiveness, and they attain the capacity to migrate and colonize. Considering the fact that, every tumor cell, is bathed in interstitial fluid, which drains into the lymphatic system and has an individualized arterial blood supply and venous drainage like any other normal cell in our body, inserting a needle or a knife into a tumor, there is a jeopardy of dislodging a loose tumor cell into either the circulation or into the tissue fluid. Tumor cells are easier to dislodge due to lower cell-to-cell adhesion. This theory with the possibility of seeding of tumor cells is supported by several case studies that have shown that after diagnostic biopsy of a tumor, many patients developed cancer at multiple sites and showed the presence of circulating cancer cells in the blood stream on examination. In this review, we evaluate the risk of exposure to seeding of tumor cells by biopsy and aspiration cytology and provide some suggested practices to prevent tumor cell seeding. PMID:24818087

  11. Antigen loading of dendritic cells with whole tumor cell preparations.

    PubMed

    Thumann, Peter; Moc, Isabelle; Humrich, Jens; Berger, Thomas G; Schultz, Erwin S; Schuler, Gerold; Jenne, Lars

    2003-06-01

    Dendritic cells (DC) based vaccinations have been widely used for the induction of anti-tumoral immunity in clinical studies. Antigen loading of DC with whole tumor cell preparations is an attractive method whenever tumor cell material is available. In order to determine parameters for the loading procedure, we performed dose finding and timing experiments. We found that apoptotic and necrotic melanoma cells up to a ratio of one-to-one, equivalent to 1mg/ml protein per 1 x 10(6) DC, can be added to monocyte derived DC without effecting DC recovery extensively. Using the isolated protein content of tumor cells (lysate) as a parameter, up to 5 mg/ml protein per 1 x 10(6) DC can be added. To achieve significant protein uptake at least 1 mg/ml of protein have to be added for more than 24 h as tested with FITC-labelled ovalbumin. Maturation inducing cytokines can be added simultaneously with the tumor cell preparations to immature DC without affecting the uptake. Furthermore, we tested the feasibility of cryopreservation of loaded and matured DC to facilitate the generation of ready to use aliquots. DC were cryopreserved in a mix of human serum albumin, DMSO and 5% glucose. After thawing, surface expression of molecules indicating the mature status (CD83, costimulatory and MHC molecules), was found to be unaltered. Furthermore, cryopreserved DC kept the capability to stimulate allogenic T-cell proliferation in mixed leukocyte reactions at full level. Loaded and matured DC pulsed with influenza matrix peptide (IMP) retained the capacity to induce the generation of IMP-specific cytotoxic T-lymphocytes after cryopreservation as measured by ELISPOT and tetramer staining. The expression of the chemokine receptor CXCR-4 and CCR-7 remained unaltered during cryopreservation and the migratory responsiveness towards MIP-3beta was unaltered as measured in a migration assay. Thus we conclude that the large scale loading and maturation of DC with whole tumor cell preparations can be

  12. Multiple Tumor Types May Originate from Bone Marrow-Derived Cells1*

    PubMed Central

    Liu, Chunfang; Chen, Zhongwei; Chen, Zhihong; Zhang, Tao; Lu, Yuan

    2006-01-01

    Abstract It was believed that tumors originated from the transformation of their tissue-specific stem cells. However, bone marrow-derived cells (BMDCs), which possess an unexpected degree of plasticity and often reside in other tissues, might also represent a potential source of malignancy. To study whether BMDCs play a role in the source of other tumors, BMDCs from mice were treated with 3-methycholanthrene until malignant transformation was achieved. Here we show that transformed BMDCs could form many tumor types, including epithelial tumors, neural tumors, muscular tumors, tumors of fibroblasts, blood vessel endothelial tumors, and tumors of poor differentiation in vivo. Moreover, a single transformed BMDC has the ability to self-renew, differentiate spontaneously into various types of tumor cells in vitro, express markers associated with multipotency, and form teratoma in vivo. These data suggest that multipotent cancer stem cells seemed to originate from transformed BMDCs. Conclusively, these findings reveal that BMDCs might be a source of many tumor types, even teratoma. In addition, multipotent cancer stem cells might originate from malignant transformed BMDCs. PMID:16984729

  13. Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors.

    PubMed

    García-Castro, Javier; Martínez-Palacio, Jesús; Lillo, Rosa; García-Sánchez, Félix; Alemany, Ramón; Madero, Luis; Bueren, Juan A; Ramírez, Manuel

    2005-04-01

    A long-pursued goal in cancer treatment is to deliver a therapy specifically to metastases. As a result of the disseminated nature of the metastatic disease, carrying the therapeutic agent to the sites of tumor growth represents a major step for success. We hypothesized that tumor cells injected intravenously (i.v.) into an animal with metastases would respond to many of the factors driving the metastatic process, and would target metastases. Using a model of spontaneous metastases, we report here that i.v. injected tumor cells localized on metastatic lesions. Based on this fact, we used genetically transduced tumor cells for tumor targeting of anticancer agents such as a suicide gene or an oncolytic virus, with evident antitumoral effect and negligible systemic toxicity. Therefore, autologous tumor cells may be used as cellular vehicles for systemic delivery of anticancer therapies to metastatic tumors. PMID:15650763

  14. Risk assessment of thyroid follicular cell tumors.

    PubMed Central

    Hill, R N; Crisp, T M; Hurley, P M; Rosenthal, S L; Singh, D V

    1998-01-01

    Thyroid follicular cell tumors arise in rodents from mutations, perturbations of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by thyroid-stimulating hormone (TSH), or a combination of the two. The only known human thyroid carcinogen is ionizing radiation. It is not known for certain whether chemicals that affect thyroid cell growth lead to human thyroid cancer. The U.S. Environmental Protection Agency applies the following science policy positions: 1) chemically induced rodent thyroid tumors are presumed to be relevant to humans; 2) when interspecies information is lacking, the default is to assume comparable carcinogenic sensitivity in rodents and humans; 3) adverse rodent noncancer thyroid effects due to chemically induced thyroid-pituitary disruption are presumed to be relevant to humans; 4) linear dose-response considerations are applied to thyroid cancer induced by chemical substances that either do not disrupt thyroid functioning or lack mode of action information; 5) nonlinear thyroid cancer dose-response considerations are applied to chemicals that reduce thyroid hormone levels, increase TSH and thyroid cell division, and are judged to lack mutagenic activity; and 6) nonlinear considerations may be applied in thyroid cancer dose-response assessments on a case-by-case basis for chemicals that disrupt thyroid-pituitary functioning and demonstrate some mutagenic activity. Required data for risk assessment purposes is mode of action information on mutagenicity, increases in follicular cell growth (cell size and number) and thyroid gland weight, thyroid-pituitary hormones, site of action, correlations between doses producing thyroid effects and cancer, and reversibility of effects when dosing ceases. Images Figure 1 Figure 2 Figure 3 PMID:9681971

  15. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells

    NASA Astrophysics Data System (ADS)

    Dhodapkar, Madhav V.; Krasovsky, Joseph; Olson, Kara

    2002-10-01

    Most untreated cancer patients develop progressive tumors. We tested the capacity of T lymphocytes from patients with clinically progressive, multiple myeloma to develop killer function against fresh autologous tumor. In this malignancy, it is feasible to reproducibly evaluate freshly isolated tumor cells and T cells from the marrow tumor environment. When we did this with seven consecutive patients, with all clinical stages of disease, we did not detect reactivity to autologous cancer cells. However, both cytolytic and IFN--producing responses to autologous myeloma were generated in six of seven patients after stimulation ex vivo with dendritic cells that had processed autologous tumor cells. The antitumor effectors recognized fresh autologous tumor but not nontumor cells in the bone marrow, myeloma cell lines, dendritic cells loaded with tumor-derived Ig, or allogeneic tumor. Importantly, these CD8+ effectors developed with similar efficiency by using T cells from both the blood and the bone marrow tumor environment. Therefore, even in the setting of clinical tumor progression, the tumor bed of myeloma patients contains T cells that can be activated readily by dendritic cells to kill primary autologous tumor.

  16. Late Relapse of Testicular Germ Cell Tumors.

    PubMed

    O'Shaughnessy, Matthew J; Feldman, Darren R; Carver, Brett S; Sheinfeld, Joel

    2015-08-01

    Germ cell tumors of the testis have an overall survival rate greater than 90% as a result of a successful multidisciplinary approach to management. Late relapse affects a subset of patients however, and tends to be chemorefractory and the overall prognosis is poor. Surgery is the mainstay in management of late relapse but salvage chemotherapy can be successful. In this review, the clinical presentation and detection of late relapse, clinical outcomes, and predictors of survival in late relapse and the importance of a multidisciplinary treatment approach for successful management of late relapse are discussed. PMID:26216823

  17. IL-17A promotes migration and tumor killing capability of B cells in esophageal squamous cell carcinoma

    PubMed Central

    Lu, Lin; Weng, Chengyin; Mao, Haibo; Fang, Xisheng; Liu, Xia; Wu, Yong; Cao, Xiaofei; Li, Baoxiu; Chen, Xiaojun; Gan, Qinquan; Xia, Jianchuan; Liu, Guolong

    2016-01-01

    We have previously reported that the accumulation of IL-17-producing cells could mediate tumor protective immunity by promoting the migration of NK cells, T cells and dendritic cells in esophageal squamous cell carcinoma (ESCC) patients. However, there were no reports concerning the effect of IL-17A on tumor infiltrating B cells. In this study, we investigated the accumulation of CD20+ B cells in the ESCC tumor nests and further addressed the effect of IL-17A on the migration and cytotoxicity of B cells. There was positive correlation between the levels of CD20+ B cells and IL-17+ cells. IL-17A could promote the ESCC tumor cells to produce more chemokines CCL2, CCL20 and CXCL13, which were associated with the migration of B cells. In addition, IL-17A enhanced the IgG-mediated antibody and complement mediated cytotoxicity of B cells against tumor cells. IL-17A-stimulated B cells gained more effective direct killing capability through enhanced expression of Granzyme B and FasL. The effect of IL-17A on the migration and cytotoxicity of B cells was IL-17A pathway dependent, which could be inhibited by IL-17A inhibitor. This study provides further understanding of the roles of IL-17A in humoral response, which may contribute to the development of novel tumor immunotherapy strategy. PMID:26942702

  18. Myeloid cell-driven angiogenesis and immune regulation in tumors

    PubMed Central

    Rivera, Lee B.; Bergers, Gabriele

    2015-01-01

    Angiogenesis is a hallmark of cancer as its induction is indispensable to fuel an expanding tumor. The tumor microenvironment contributes to tumor vessel growth, and distinct myeloid cells recruited by the tumor have been shown to not only support angiogenesis but to foster an immune suppressive environment that supports tumor expansion and progression. Recent findings suggest that the intertwined regulation of angiogenesis and immune modulation can offer therapeutic opportunities for the treatment of cancer. Here we review the mechanisms by which distinct myeloid cell populations contribute to tumor angiogenesis, discuss current approaches in the clinic that are targeting both angiogenic and immune suppressive pathways, and highlight important areas of future research. PMID:25770923

  19. Tumor and Endothelial Cell-Derived Microvesicles Carry Distinct CEACAMs and Influence T-Cell Behavior

    PubMed Central

    Muturi, Harrison T.; Dreesen, Janine D.; Nilewski, Elena; Jastrow, Holger; Giebel, Bernd; Ergun, Suleyman; Singer, Bernhard B.

    2013-01-01

    Normal and malignant cells release a variety of different vesicles into their extracellular environment. The most prominent vesicles are the microvesicles (MVs, 100-1 000 nm in diameter), which are shed of the plasma membrane, and the exosomes (70-120 nm in diameter), derivates of the endosomal system. MVs have been associated with intercellular communication processes and transport numerous proteins, lipids and RNAs. As essential component of immune-escape mechanisms tumor-derived MVs suppress immune responses. Additionally, tumor-derived MVs have been found to promote metastasis, tumor-stroma interactions and angiogenesis. Since members of the carcinoembryonic antigen related cell adhesion molecule (CEACAM)-family have been associated with similar processes, we studied the distribution and function of CEACAMs in MV fractions of different human epithelial tumor cells and of human and murine endothelial cells. Here we demonstrate that in association to their cell surface phenotype, MVs released from different human epithelial tumor cells contain CEACAM1, CEACAM5 and CEACAM6, while human and murine endothelial cells were positive for CEACAM1 only. Furthermore, MVs derived from CEACAM1 transfected CHO cells carried CEACAM1. In terms of their secretion kinetics, we show that MVs are permanently released in low doses, which are extensively increased upon cellular starvation stress. Although CEACAM1 did not transmit signals into MVs it served as ligand for CEACAM expressing cell types. We gained evidence that CEACAM1-positive MVs significantly increase the CD3 and CD3/CD28-induced T-cell proliferation. All together, our data demonstrate that MV-bound forms of CEACAMs play important roles in intercellular communication processes, which can modulate immune response, tumor progression, metastasis and angiogenesis. PMID:24040308

  20. Thrombospondin-1 Modulates Actin Filament Remodeling and Cell Motility in Mouse Mammary Tumor cells in Vitro

    PubMed Central

    Ndishabandi, Dorothy; Duquette, Cameron; Billah, Ghita El-Moatassim; Reyes, Millys; Duquette, Mark; Lawler, Jack; Kazerounian, Shideh

    2015-01-01

    It is well established that the secretion of thrombospondin-1 (TSP-1) by activated stromal cells and its accumulation in the tumor microenvironment during dysplasia inhibits primary tumor growth through inhibition of angiogenesis. This inhibitory function of TSP-1 is actuated either by inhibiting MMP9 activation and the release of VEGF from extracellular matrix or by an interaction with CD36 on the surface of endothelial cells resulting in an increase in apoptosis. In contrast, several published articles have also shown that as tumor cells become more invasive and enter the early stage of carcinoma, they up-regulate TSP-1 expression, which may promote invasion and migration. In our in vivo studies using the polyoma middle T antigen (PyT) transgenic mouse model of breast cancer, we observed that the absence of TSP-1 significantly increased the growth of primary tumors, but delayed metastasis to the lungs. In this study, we propose a mechanism for the promigratory function of TSP-1 in mouse mammary tumor cells in vitro. We demonstrate the correlations between expression of TSP-1 and its receptor integrin α3β1, which is considered a promigratory protein in cancer cells. In addition we propose that binding of TSP-1 to integrin α3β1 is important for mediating actin filament polymerization and therefore, cell motility. These findings can help explain the dual functionality of TSP-1 in cancer progression. PMID:26273699

  1. Single Unpurified Breast Tumor-Initiating Cells from Multiple Mouse Models Efficiently Elicit Tumors in Immune-Competent Hosts

    PubMed Central

    Kurpios, Natasza A.; Girgis-Gabardo, Adele; Hallett, Robin M.; Rogers, Stephen; Gludish, David W.; Kockeritz, Lisa; Woodgett, James; Cardiff, Robert; Hassell, John A.

    2013-01-01

    The tumor-initiating cell (TIC) frequency of bulk tumor cell populations is one of the criteria used to distinguish malignancies that follow the cancer stem cell model from those that do not. However, tumor-initiating cell frequencies may be influenced by experimental conditions and the extent to which tumors have progressed, parameters that are not always addressed in studies of these cells. We employed limiting dilution cell transplantation of minimally manipulated tumor cells from mammary tumors of several transgenic mouse models to determine their tumor-initiating cell frequency. We determined whether the tumors that formed following tumor cell transplantation phenocopied the primary tumors from which they were isolated and whether they could be serially transplanted. Finally we investigated whether propagating primary tumor cells in different tissue culture conditions affected their resident tumor-initiating cell frequency. We found that tumor-initiating cells comprised between 15% and 50% of the bulk tumor cell population in multiple independent mammary tumors from three different transgenic mouse models of breast cancer. Culture of primary mammary tumor cells in chemically-defined, serum-free medium as non-adherent tumorspheres preserved TIC frequency to levels similar to that of the primary tumors from which they were established. By contrast, propagating the primary tumor cells in serum-containing medium as adherent populations resulted in a several thousand-fold reduction in their tumor-initiating cell fraction. Our findings suggest that experimental conditions, including the sensitivity of the transplantation assay, can dramatically affect estimates of tumor initiating cell frequency. Moreover, conditional on cell culture conditions, the tumor-initiating cell fraction of bulk mouse mammary tumor cell preparations can either be maintained at high or low frequency in vitro thus permitting comparative studies of tumorigenic and non-tumorigenic cancer cells

  2. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.

    PubMed

    Gao, Xin; Wang, Xuefeng; Yang, Qianting; Zhao, Xin; Wen, Wen; Li, Gang; Lu, Junfeng; Qin, Wenxin; Qi, Yuan; Xie, Fang; Jiang, Jingting; Wu, Changping; Zhang, Xueguang; Chen, Xinchun; Turnquist, Heth; Zhu, Yibei; Lu, Binfeng

    2015-01-01

    Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. IL-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a "danger" signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8(+) T cells. In this study, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFN-γ production by CD8(+) T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor Ag-specific CD8(+) T cells. Furthermore, both NK and CD8(+) T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells worked synergistically with IL-33 expression for tumor elimination. Our studies established "alarmin" IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses. PMID:25429071

  3. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells

    PubMed Central

    Gao, Xin; Wang, Xuefeng; Yang, Qianting; Zhao, Xin; Wen, Wen; Li, Gang; Lu, Junfeng; Qin, Wenxin; Qi, Yuan; Xie, Fang; Jiang, Jingting; Wu, Changping; Zhang, Xueguang; Chen, Xinchun; Turnquist, Heth; Zhu, Yibei; Lu, Binfeng

    2014-01-01

    Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. Interleukin-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a “danger” signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8+ T cells. Here, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFNγ production by CD8+ T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor-antigen-specific CD8+ T cells. Furthermore, both NK and CD8+ T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells (Treg) worked synergistically with IL-33 expression for tumor elimination. Our studies established “alarmin” IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses. PMID:25429071

  4. Gastrointestinal tract spindle cell tumors with interstitial cells of Cajal: Prevalence excluding gastrointestinal stromal tumors

    PubMed Central

    Lee, So Jung; Hwang, Chung Su; Kim, Ahrong; Kim, Kyungbin; Choi, Kyung Un

    2016-01-01

    Leiomyomas and schwannomas of the gastrointestinal tract (GIT) are mainly comprised of spindle-shaped tumor cells and should always be differentiated from gastrointestinal stromal tumors (GISTs). Mast/stem cell growth factor receptor Kit (KIT) and discovered on GIST-1 (DOG1) are well-known diagnostic markers for the detection of a GIST by immunohistochemical staining. The aim of the present study was to assess the prevalence and significance of spindle cell tumors of the GIT with KIT- or DOG1-positive spindle-shaped cells, presumed to be interstitial cells of Cajal (ICCs), other than GISTs. A total of 71 leiomyomas and 35 schwannomas were examined and clinicopathological information was obtained. KIT and DOG1 immunostaining was performed to determine the proportions of positive cells. Mutation screening of KIT exons 9, 11, 13 and 17, and platelet-derived growth factor receptor α (PDGFRA) exons 12 and 18 was performed in cases with a relatively high proportion of either KIT- or DOG1-positive cells. The frequency of leiomyomas and schwannomas with KIT- and DOG1-positive ICCs was 35.2% (25/71 cases) and 5.7% (2/35 cases), respectively. Among the esophageal leiomyomas with KIT- and DOG-positive ICCs (14/25; 56.0%), 5 leiomyomas involved the muscularis mucosa and 9 leiomyomas involved the muscularis propria. All gastric leiomyomas with KIT- and DOG1-positive ICCs (11/25; 44%) involved the muscularis propria. All schwannomas with an increased proportion of KIT- or DOG1-positive ICCs were of gastric origin. No KIT or PDGFRA mutations were detected in 7 leiomyomas and 2 schwannomas. In conclusion, the majority of leiomyomas and the minority of schwannomas in the GIT had a significant portion of KIT- and DOG1-positive cells. All of the tumors were located in the upper GIT, and could be present in the muscularis propria or muscularis mucosa. The tumors represented a non-neoplastic proliferation of KIT- and DOG1-positive cells in the GIT. Careful evaluation of KIT- or DOG1

  5. Endoscopic resection of colorectal granular cell tumors

    PubMed Central

    Take, Iri; Shi, Qiang; Qi, Zhi-Peng; Cai, Shi-Lun; Yao, Li-Qing; Zhou, Ping-Hong; Zhong, Yun-Shi

    2015-01-01

    AIM: To determine the feasibility and effectiveness of endoscopic resection for the treatment of colorectal granular cell tumors (GCTs). METHODS: This was a retrospective study performed at a single institution. From January 2008 to April 2015, we examined a total of 11 lesions in 11 patients who were treated by an endoscopic procedure for colorectal GCTs in the Endoscopy Center, Zhongshan Hospital of Fudan University, Shanghai, China. Either endoscopic mucosal resection or endoscopic submucosal dissection (ESD) was performed by three surgeons with expertise in endoscopic treatment. The pre- and post-operative condition and follow-up of these patients were evaluated by colonoscopy and endoscopic ultrasonography (EUS). RESULTS: Of these 11 lesions, 2 were located in the cecum, 3 were in the ileocecal junction, 5 were in the ascending colon, and 1 was in the rectum. The median maximum diameter of the tumors was 0.81 cm (range 0.4-1.2 cm). The en bloc rate was 100%, and the complete resection rate was 90.9% (10/11). Post-operative pathology in one patient showed a tumor at the cauterization margin. However, during ESD, this lesion was removed en bloc, and no tumor tissue was seen in the wound. No perforations or delayed perforations were observed and emergency surgery was not required for complications. All patients were followed up to May 2015, and none had recurrence, metastasis, or complaints of discomfort. CONCLUSION: Endoscopic treatment performed by endoscopists with sufficient experience appears to be feasible and effective for colorectal GCTs. PMID:26730166

  6. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis.

    PubMed

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M

    2014-08-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  7. A Think Tank of TINK/TANKs: Tumor-Infiltrating/Tumor-Associated Natural Killer Cells in Tumor Progression and Angiogenesis

    PubMed Central

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M.

    2014-01-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This “polarization” has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as “TINKs”) and tumor-associated NK (altered peripheral NK cells, which here we call “TANKs”) are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  8. Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling.

    PubMed

    Yang, Fei; Wei, Yinxiang; Cai, Zhijian; Yu, Lei; Jiang, Lingling; Zhang, Chengyan; Yan, Huanmiao; Wang, Qingqing; Cao, Xuetao; Liang, Tingbo; Wang, Jianli

    2015-01-01

    The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8(+) T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling. PMID:24769795

  9. Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

    PubMed Central

    Yang, Fei; Wei, Yinxiang; Cai, Zhijian; Yu, Lei; Jiang, Lingling; Zhang, Chengyan; Yan, Huanmiao; Wang, Qingqing; Cao, Xuetao; Liang, Tingbo; Wang, Jianli

    2015-01-01

    The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8+ T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling. PMID:24769795

  10. ULTRASONOGRAPHIC FEATURES OF CANINE GASTROINTESTINAL STROMAL TUMORS COMPARED TO OTHER GASTROINTESTINAL SPINDLE CELL TUMORS.

    PubMed

    Hobbs, Joshua; Sutherland-Smith, James; Penninck, Dominique; Jennings, Samuel; Barber, Lisa; Barton, Bruce

    2015-01-01

    Canine gastrointestinal stromal tumors (GISTs) are a recent subtype of gastrointestinal spindle cell tumor recognized with the increasing use of immunohistochemistry. To our knowledge, no imaging features have been described in immunostochemically confirmed canine GISTs. The objective of this retrospective, cross-sectional study was to describe ultrasonographic features of canine GISTs compared with other spindle cell tumors. Thirty-seven dogs with an ultrasonographically visible gastrointestinal mass and a histopathologic diagnosis of spindle cell neoplasia were examined. Immunohistochemistry staining was performed for retrieved tissue samples to further differentiate the tumor type and each sample was interpreted by a single veterinary pathologist. Ultrasonographic features recorded examined included mass echogenicity, homogeneity, presence of cavitation, layer of origin, bowel wall symmetry, and loss of wall layering, location, size, vascularity, and evidence of perforation or ulceration. Tumor types included 19 GISTs, eight leiomyosarcomas, six leiomyomas, and four nonspecified sarcomas. Gastrointestinal stromal tumors were significantly more likely to be associated (P < 0.03) with abdominal effusion than other tumor types. There was overlap between the anatomical locations of all tumors types with the exception of the cecum where all eight tumors identified were GISTs. Besides location, there were no unique ultrasound features of GISTs that would allow distinction from other gastrointestinal spindle cell tumors. Similar to previous studies, GISTs appeared to be the most common spindle cell tumor associated with the cecum in our sample of dogs. The high frequency of abdominal effusion with GIST's was of unknown etiology could possibly have been due to septic peritonitis. PMID:25846814

  11. Giant Cell Tumor of the Peroneus Brevis Tendon Sheath

    PubMed Central

    Ch, Li; TH, Lui

    2015-01-01

    Introduction: Giant cell tumor of the tendon sheath is most commonly found in the flexor aspect of hand and wrist and is rare in the foot and ankle. Case report: A 49-year-old lady noticed a right lateral foot mass for 10 years. Magnetic resonance imaging suggested that the mass is originated from the peroneal tendons. The mass was excised and intra-operative findings showed that the tumor came from the peroneus brevis tendon sheath. Histological study confirmed the diagnosis of giant cell tumor. Conclusion: Giant cell tumor, although rare, should be one of the differential diagnoses of tendon sheath tumor of the foot and ankle. PMID:27299104

  12. Molecular genetics of testicular germ cell tumors

    PubMed Central

    Sheikine, Yuri; Genega, Elizabeth; Melamed, Jonathan; Lee, Peng; Reuter, Victor E.; Ye, Huihui

    2012-01-01

    Testicular germ cell tumors (TGCT) are the most common malignancy in young men. While most TGCT are potentially curable, approximately 5% of patients with TGCT may develop chemoresistance and die from the disease. This review article summarizes current knowledge in genetics underlying the development, progression and chemoresistance of TGCT. Most post-pubertal TGCT originate from intratubular germ cell neoplasia unclassified (IGCNU), which are transformed fetal gonocytes. Development of IGCNU may involve aberrantly activated KITLG/KIT pathway and overexpression of embryonic transcription factors such as NANOG and POU5F1, which leads to suppression of apoptosis, increased proliferation, and accumulation of mutations in gonocytes. Invasive TGCT consistently show gain of chromosome 12p, typically isochromosome 12p. Single gene mutations are uncommon in TGCT. KIT, TP53, KRAS/NRAS, and BRAF are genes most commonly mutated in TGCT and implicated in their pathogenesis. Different histologic subtypes of TGCT possess different gene expression profiles that reflect different directions of differentiation. Their distinct gene expression profiles are likely caused by epigenetic regulation, in particular DNA methylation, but not by gene copy number alterations. Resistance of TGCT to chemotherapy has been linked to karyotypic aberrations, single-gene mutations, and epigenetic regulation of gene expression in small-scale studies. The study of TGCT genetics could ultimately translate into development of new molecular diagnostic and therapeutic modalities for these tumors and improve the care of patients with these malignancies. PMID:22432056

  13. Micro FT-IR Characterization Of Human Lung Tumor Cells

    NASA Astrophysics Data System (ADS)

    Benedetti, Enzo; Teodori, L.; Vergamini, Piergiorgio; Trinca, M. L.; Mauro, F.; Salvati, F.; Spremolla, Giuliano

    1989-12-01

    FT-IR spectroscopy has opened up a new approach to the analytical study of cell transformation. Investigations carried out in normal and leukemic lymphocytes have evidenced an increase in DNA with respect to proteic components in neoplastic cells.(1) The evaluation of the ratio of the integrated areas(A) of the bands at 1080 cm-1 (mainly DNA) and at 1540 cm-1 (proteic components) has allowed us to establish a parameter which indicates, for values above 1.5, the neoplastic nature of cells. Recently, this approach has been applied to the study of human lung tumor cells. Several monocellular suspension procedures of the tissue fragment (mechanical and/or chemical) were tested to obtain reproducible and reliable spectra able to differentiate clearly between normal and patological cells. Chemical treatment (EDTA, Pepsin, Collagenase, etc.) produced additional bands in the spectra of the cells causing distortion of the profiles of some absorptions, and as a result, mechanical treatment was preferred. The normal and neoplastic cells homogeneously distributed by cytospin preparation on BaF2 windows were examined by means of FT-IR microscopy. An examination of several microareas of each sample yielded reproducible spectra, with values of the A 1080 cm-1 / A 1540 cm-1 parameter within a very narrow range for each sample, even if certain differences still remained among the different cases, in good agreement with the results obtained for leukemic cells.(1) The value of this parameter was found to be lower for cells isolated from the normal area of lung, than in the case of those corresponding to the tumoral area, meaning that an increase occurs in DNA with respect to the proteic components. These insights, which provide a basis to obtain indications at the molecular level, can open up new possibilities in clinical practice, in order to obtain diagnosis confirmation, to detect early stages of disease and to offer additional indications in cases of dubious interpretation.

  14. An innovative pre-targeting strategy for tumor cell specific imaging and therapy

    NASA Astrophysics Data System (ADS)

    Qin, Si-Yong; Peng, Meng-Yun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Cheng, Si-Xue; Feng, Jun; Zhang, Xian-Zheng

    2015-08-01

    A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the ``biotin-avidin'' interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments.A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the ``biotin-avidin'' interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging

  15. Pharmacogenomics of Scopoletin in Tumor Cells.

    PubMed

    Seo, Ean-Jeong; Saeed, Mohamed; Law, Betty Yuen Kwan; Wu, An Guo; Kadioglu, Onat; Greten, Henry Johannes; Efferth, Thomas

    2016-01-01

    Drug resistance and the severe side effects of chemotherapy necessitate the development of novel anticancer drugs. Natural products are a valuable source for drug development. Scopoletin is a coumarin compound, which can be found in several Artemisia species and other plant genera. Microarray-based RNA expression profiling of the NCI cell line panel showed that cellular response of scopoletin did not correlate to the expression of ATP-binding cassette (ABC) transporters as classical drug resistance mechanisms (ABCB1, ABCB5, ABCC1, ABCG2). This was also true for the expression of the oncogene EGFR and the mutational status of the tumor suppressor gene, TP53. However, mutations in the RAS oncogenes and the slow proliferative activity in terms of cell doubling times significantly correlated with scopoletin resistance. COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression resulted in a set of 40 genes, which all harbored binding motifs in their promoter sequences for the transcription factor, NF-κB, which is known to be associated with drug resistance. RAS mutations, slow proliferative activity, and NF-κB may hamper its effectiveness. By in silico molecular docking studies, we found that scopoletin bound to NF-κB and its regulator IκB. Scopoletin activated NF-κB in a SEAP-driven NF-κB reporter cell line, indicating that NF-κB might be a resistance factor for scopoletin. In conclusion, scopoletin might serve as lead compound for drug development because of its favorable activity against tumor cells with ABC-transporter expression, although NF-κB activation may be considered as resistance factor for this compound. Further investigations are warranted to explore the full therapeutic potential of this natural product. PMID:27092478

  16. Neuronatin in a Subset of Glioblastoma Multiforme Tumor Progenitor Cells Is Associated with Increased Cell Proliferation and Shorter Patient Survival

    PubMed Central

    Bründl, Elisabeth; Brawanski, Alexander; Fang, Xueping; Lee, Cheng S.; Weil, Robert J.; Zhuang, Zhengping; Lonser, Russell R.

    2012-01-01

    Glioblastoma multiforme is the most common and malignant primary brain tumor. Recent evidence indicates that a subset of glioblastoma tumor cells have a stem cell like phenotype that underlies chemotherapy resistance and tumor recurrence. We utilized a new “multidimensional” capillary isoelectric focusing nano-reversed-phase liquid chromatography platform with tandem mass spectrometry to compare the proteomes of isolated glioblastoma tumor stem cell and differentiated tumor cell populations. This proteomic analysis yielded new candidate proteins that were differentially expressed. Specifically, two isoforms of the membrane proteolipid neuronatin (NNAT) were expressed exclusively within the tumor stem cells. We surveyed the expression of NNAT across 10 WHO grade II and III gliomas and 23 glioblastoma (grade IV) human tumor samples and found NNAT was expressed in a subset of primary glioblastoma tumors. Through additional in vitro studies utilizing the U87 glioma cell line, we found that expression of NNAT is associated with significant increases in cellular proliferation. Paralleling the in vitro results, when NNAT levels were evaluated in tumor specimens from a consecutive cohort of 59 glioblastoma patients, the presence of increased levels of NNAT were found to be a an independent risk factor (P = 0.006) for decreased patient survival through Kaplan-Meier and multivariate analysis. These findings indicate that NNAT may have utility as a prognostic biomarker, as well as a cell-surface target for chemotherapeutic agents. PMID:22624064

  17. An overlooked tumor promoting immunoregulation by non-hematopoietic stromal cells.

    PubMed

    Bose, Anamika; Ghosh, Tithi; Baral, Rathindranath

    2016-08-01

    Multidirectional complex communication between tumor-residing hematopoietic and non-hematopoietic stromal cells (NHSCs) decisively regulates cancer development, progression and therapeutic responses. HSCs predominantly participate in the immune regulations, while, NHSCs, provide parenchymal support or serve as a conduit for other cells or support angiogenesis. However, recent reports suggest NHSCs can additionally participate in ongoing tumor promoting immune reactions within tumor-microenvironment (TME). In this review, based on the state-of-art knowledge and accumulated evidence by us, we discuss the role of quite a few NHSCs in tumor from immunological perspectives. Understanding such consequence of NHSCs will surely pave the way in crafting effective cancer management. PMID:27311851

  18. Cancer stem cells: targeting tumors at the source.

    PubMed

    Zhang, P-Y; Yang, Y-J; Xue, Y; Fu, J; Zhang, C-X; Wang, Y; Yang, Y; Shi, H

    2015-05-01

    The cancer stem cell hypothesis states that tumors rely exclusively on the continued proliferation of a subset of cancer cells that originated from normal adult stem cells. These cells have two key traits: multipotency, and self-renewal. The prolonged lifespan of stem cells makes them perfect candidates for the accumulation of carcinogenic mutations that would convert them into cancer stem cells (CSCs) no longer responsive to the many regulatory pathways in place that are responsible for tight governance of proliferation and differentiation in normal stem cells. Comprehending what these regulatory pathways are, and how their derailment contributes to oncogenic transformation, can hold the key to finding new strategies to target CSCs in order to effectively treat cancer. Additionally, what environmental factors are involved in promoting or suppressing CSC tumorigenicity requires attention. The possibility that some cancers may have clonal origins in non-stem cell populations that were able to acquire stem cell-like properties, and the lack of complete cell autonomy in carcinogenesis, suggests that the CSC hypothesis is continually evolving. Continued research in this field can shed light on how effective selective elimination of CSCs as opposed to generalized targeting of cancer cells will be in the treatment of cancer. PMID:26044226

  19. Tumor infiltrating immune cells in gliomas and meningiomas.

    PubMed

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Miranda, David; Ruiz, Laura; Sousa, Pablo; Ciudad, Juana; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2016-03-01

    Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors-gliomas and meningiomas-, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control. PMID:26216710

  20. Concise Review: Paracrine Role of Stem Cells in Pituitary Tumors: A Focus on Adamantinomatous Craniopharyngioma

    PubMed Central

    2016-01-01

    Abstract The existence of tissue‐specific progenitor/stem cells in the adult pituitary gland of the mouse has been demonstrated recently using genetic tracing experiments. These cells have the capacity to differentiate into all of the different cell lineages of the anterior pituitary and self‐propagate in vitro and can therefore contribute to normal homeostasis of the gland. In addition, they play a critical role in tumor formation, specifically in the etiology of human adamantinomatous craniopharyngioma, a clinically relevant tumor that is associated with mutations in CTNNB1 (gene encoding β‐catenin). Mouse studies have shown that only pituitary embryonic precursors or adult stem cells are able to generate tumors when targeted with oncogenic β‐catenin, suggesting that the cell context is critical for mutant β‐catenin to exert its oncogenic effect. Surprisingly, the bulk of the tumor cells are not derived from the mutant progenitor/stem cells, suggesting that tumors are induced in a paracrine manner. Therefore, the cell sustaining the mutation in β‐catenin and the cell‐of‐origin of the tumors are different. In this review, we will discuss the in vitro and in vivo evidence demonstrating the presence of stem cells in the adult pituitary and analyze the evidence showing a potential role of these stem cells in pituitary tumors. Stem Cells 2016;34:268–276 PMID:26763580

  1. Generation and identification of tumor-evoked regulatory B cells

    PubMed Central

    Biragyn, Arya; Lee-Chang, Catalina; Bodogai, Monica

    2014-01-01

    The involvement of Bregs in cancer remains poorly understood despite their well-documented regulation of responses to the self and protection from harmful autoimmunity. We recently discovered a unique regulatory B cell subset evoked by breast cancer to mediate protection of metastasizing cancer cells. These results together with the wealth of findings of the last 40 years on B cells in tumorigenesis suggest the existence of additional cancer Bregs modulating anticancer responses. To facilitate the search for them, here we provide our detailed protocol for the characterization and generation of tumor-evoked regulatory B cells. Wherever applicable, we also discuss nuances and uniqueness of a Breg study in cancer to warn potential pitfalls. PMID:25015287

  2. Cannabinoid-associated cell death mechanisms in tumor models (review).

    PubMed

    Calvaruso, Giuseppe; Pellerito, Ornella; Notaro, Antonietta; Giuliano, Michela

    2012-08-01

    In recent years, cannabinoids (the active components of Cannabis sativa) and their derivatives have received considerable interest due to findings that they can affect the viability and invasiveness of a variety of different cancer cells. Moreover, in addition to their inhibitory effects on tumor growth and migration, angiogenesis and metastasis, the ability of these compounds to induce different pathways of cell death has been highlighted. Here, we review the most recent results generating interest in the field of death mechanisms induced by cannabinoids in cancer cells. In particular, we analyze the pathways triggered by cannabinoids to induce apoptosis or autophagy and investigate the interplay between the two processes. Overall, the results reported here suggest that the exploration of molecular mechanisms induced by cannabinoids in cancer cells can contribute to the development of safe and effective treatments in cancer therapy. PMID:22614735

  3. Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance.

    PubMed

    Schmidt, Felix; Efferth, Thomas

    2016-01-01

    Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients. PMID:27322289

  4. Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance

    PubMed Central

    Schmidt, Felix; Efferth, Thomas

    2016-01-01

    Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients. PMID:27322289

  5. Dendritic-Tumor Fusion Cell-Based Cancer Vaccines

    PubMed Central

    Koido, Shigeo

    2016-01-01

    Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the induction of antitumor immunity. Therefore, various strategies have been developed to deliver tumor-associated antigens (TAAs) to DCs as cancer vaccines. The fusion of DCs and whole tumor cells to generate DC-tumor fusion cells (DC-tumor FCs) is an alternative strategy to treat cancer patients. The cell fusion method allows DCs to be exposed to the broad array of TAAs originally expressed by whole tumor cells. DCs then process TAAs endogenously and present them through major histocompatibility complex (MHC) class I and II pathways in the context of costimulatory molecules, resulting in simultaneous activation of both CD4+ and CD8+ T cells. DC-tumor FCs require optimized enhanced immunogenicity of both DCs and whole tumor cells. In this context, an effective fusion strategy also needs to produce immunogenic DC-tumor FCs. We discuss the potential ability of DC-tumor FCs and the recent progress in improving clinical outcomes by DC-tumor FC-based cancer vaccines. PMID:27240347

  6. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

    PubMed Central

    Duewell, P; Steger, A; Lohr, H; Bourhis, H; Hoelz, H; Kirchleitner, S V; Stieg, M R; Grassmann, S; Kobold, S; Siveke, J T; Endres, S; Schnurr, M

    2014-01-01

    Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8α+ DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8+ T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity. PMID:25012502

  7. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

    PubMed Central

    Ugel, Stefano; De Sanctis, Francesco; Mandruzzato, Susanna; Bronte, Vincenzo

    2015-01-01

    The generation of an inflammatory environment is favorable and often decisive for the growth of both primary tumors and metastases. Tumor cells either express membrane molecules or release tumor-derived soluble factors able to alter myelopoiesis. Tumor-reprogrammed myeloid cells not only create a tolerogenic environment by blocking T cell functions and proliferation, but also directly drive tumor growth by promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. In this Review, we discuss the interplay between immunosuppressive and protumoral myeloid cells and detail their immune-regulatory mechanisms, the molecular pathways involved in their differentiation, as well as their potential role as prognostic and diagnostic biomarkers and prospective targets for innovative approaches to treat tumor-bearing hosts. PMID:26325033

  8. Pseudopapillary Granulosa Cell Tumor: A Case of This Rare Subtype.

    PubMed

    Heller, Debra; Haddad, Andrew; Cracchiolo, Bernadette

    2016-08-01

    Background The pseudopapillary pattern of granulosa cell tumor is rare. Case We describe the case of a 35-year-old woman who presented with an initial diagnosis of papillary serous cystadenocarcinoma. Results Evaluation, including immunohistochemistry, led to the diagnosis of pseudopapillary granulosa cell tumor. Conclusion The pseudopapillary pattern of granulosa cell tumor is rare and must be suspected in order to utilize appropriate immunohistochemistry and reach the correct diagnosis. Inhibin positivity is particularly helpful. PMID:27020373

  9. Lysis of small cell carcinoma of the lung tumor cell lines by gamma interferon-activated allogeneic peripheral blood mononuclear cells: abrogation of killing by pretreatment of tumor cells with gamma interferon.

    PubMed

    Ball, E D; Nichols, K E; Pettengill, O S; Sorenson, G D; Fanger, M W

    1986-01-01

    Interferon has been shown to enhance the ability of nonspecific cytotoxic mononuclear cells to lyse some, but not all, tumor cells. We have examined the effect of recombinant human gamma interferon (rIFN gamma) on the cell-mediated cytolysis of tumor target cells derived from continuously cultured lines of small cell carcinoma of the lung (SCCL). Cells from the SCCL lines DMS 44, 53, 79, 92, and 406 were labeled with 51Cr and incubated with normal and rIFN gamma-stimulated peripheral blood mononuclear cells for 18 h at 37 degrees C and tumor cell lysis estimated by measuring 51Cr release. Although cells from certain SCCL lines were good targets for cell mediated cytotoxicity, susceptibility to lysis was heterogeneous among the different SCCL lines. DMS 406 and 79 were, on average, maximally lysed, while DMS 44, 53, and 92 showed less susceptibility to lysis by either control or rIFN gamma-stimulated effector cells. In addition, although pretreatment with rIFN gamma increased the cytolytic capacity of normal peripheral blood mononuclear cells from several different donors, preincubation of the tumor cell lines with rIFN gamma resulted in inhibition of cytolysis mediated by both control and IFN-activated effector cells. These findings suggest that although rIFN gamma may enhance cell-mediated lysis of SCCL tumor cells, it may also decrease susceptibility to lysis. PMID:3015408

  10. Tumor-Related Methylated Cell-Free DNA and Circulating Tumor Cells in Melanoma

    PubMed Central

    Salvianti, Francesca; Orlando, Claudio; Massi, Daniela; De Giorgi, Vincenzo; Grazzini, Marta; Pazzagli, Mario; Pinzani, Pamela

    2016-01-01

    Solid tumor release into the circulation cell-free DNA (cfDNA) and circulating tumor cells (CTCs) which represent promising biomarkers for cancer diagnosis. Circulating tumor DNA may be studied in plasma from cancer patients by detecting tumor specific alterations, such as genetic or epigenetic modifications. Ras association domain family 1 isoform A (RASSF1A) is a tumor suppressor gene silenced by promoter hypermethylation in a variety of human cancers including melanoma. The aim of the present study was to assess the diagnostic performance of a tumor-related methylated cfDNA marker in melanoma patients and to compare this parameter with the presence of CTCs. RASSF1A promoter methylation was quantified in cfDNA by qPCR in a consecutive series of 84 melanoma patients and 68 healthy controls. In a subset of 68 cases, the presence of CTCs was assessed by a filtration method (Isolation by Size of Epithelial Tumor Cells, ISET) as well as by an indirect method based on the detection of tyrosinase mRNA by RT-qPCR. The distribution of RASSF1A methylated cfDNA was investigated in cases and controls and the predictive capability of this parameter was assessed by means of the area under the ROC curve (AUC). The percentage of cases with methylated RASSF1A promoter in cfDNA was significantly higher in each class of melanoma patients (in situ, invasive and metastatic) than in healthy subjects (Pearson chi-squared test, p < 0.001). The concentration of RASSF1A methylated cfDNA in the subjects with a detectable quantity of methylated alleles was significantly higher in melanoma patients than in controls. The biomarker showed a good predictive capability (in terms of AUC) in discriminating between melanoma patients and healthy controls. This epigenetic marker associated to cfDNA did not show a significant correlation with the presence of CTCs, but, when the two parameters are jointly considered, we obtain a higher sensitivity of the detection of positive cases in invasive and

  11. Detection and Characterization of Circulating Tumor Cells

    NASA Astrophysics Data System (ADS)

    Bruce, Richard

    2009-03-01

    Circulating tumor cells (CTCs) occur in blood below the concentration of 1 cell in a hundred thousand white blood cells and can provide prognostic and diagnostic information about the underlying disease. While numeration of CTCs has provided useful information on progression-free and overall survival, it does not provide guidance of treatment choice. Since CTCs are presumed contain features of the metastatic tissue, characterization of cancer markers on these cells could help selection of treatment. At such low concentrations, reliable location and identification of these cells represents a significant technical challenge. Automated digital microscopy (ADM) provides high levels of sensitivity, but the analysis time is prohibitively long for a clinical assay. Enrichment methods have been developed to reduce sample size but can result in cell loss. A major barrier in reliable enrichment stems from the biological heterogeneity of CTCs, exhibited in a wide range of genetic, biochemical, immunological and biological characteristics. We have developed an approach that uses fiber-optic array scanning technology (FAST) to detect CTCs. Here, laser-printing optics are used to excite 300,000 cells/sec, and fluorescence from immuno-labels is collected in an array of optical fibers that forms a wide collection aperture. The FAST cytometer can locate CTCs at a rate that is 500 times faster than an ADM with comparable sensitivity and improved specificity. With this high scan rate, no enrichment of CTCs is required. The target can be a cytoplasm protein with a very high expression level, which reduces sensitivity to CTC heterogeneity. We use this method to measure expression levels of multiple markers on CTCs to help predict effective cancer treatment.

  12. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

    PubMed Central

    Wu, Annie A; Drake, Virginia; Huang, Huai-Shiuan; Chiu, ShihChi; Zheng, Lei

    2015-01-01

    It has become evident that tumor-induced immuno-suppressive factors in the tumor microenvironment play a major role in suppressing normal functions of effector T cells. These factors serve as hurdles that limit the therapeutic potential of cancer immunotherapies. This review focuses on illustrating the molecular mechanisms of immunosuppression in the tumor microenvironment, including evasion of T-cell recognition, interference with T-cell trafficking, metabolism, and functions, induction of resistance to T-cell killing, and apoptosis of T cells. A better understanding of these mechanisms may help in the development of strategies to enhance the effectiveness of cancer immunotherapies. PMID:26140242

  13. Antiangiogenic Variant of TSP-1 Targets Tumor Cells in Glioblastomas

    PubMed Central

    Choi, Sung Hugh; Tamura, Kaoru; Khajuria, Rajiv Kumar; Bhere, Deepak; Nesterenko, Irina; Lawler, Jack; Shah, Khalid

    2015-01-01

    Three type-1 repeat (3TSR) domain of thrombospondin-1 is known to have anti-angiogenic effects by targeting tumor-associated endothelial cells, but its effect on tumor cells is unknown. This study explored the potential of 3TSR to target glioblastoma (GBM) cells in vitro and in vivo. We show that 3TSR upregulates death receptor (DR) 4/5 expression in a CD36-dependent manner and primes resistant GBMs to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)-induced caspase-8/3/7 mediated apoptosis. We engineered human mesenchymal stem cells (MSC) for on-site delivery of 3TSR and a potent and secretable variant of TRAIL (S-TRAIL) in an effort to simultaneously target tumor cells and associated endothelial cells and circumvent issues of systemic delivery of drugs across the blood–brain barrier. We show that MSC-3TSR/S-TRAIL inhibits tumor growth in an expanded spectrum of GBMs. In vivo, a single administration of MSC-3TSR/S-TRAIL significantly targets both tumor cells and vascular component of GBMs, inhibits tumor progression, and extends survival of mice bearing highly vascularized GBM. The ability of 3TSR/S-TRAIL to simultaneously act on tumor cells and tumor-associated endothelial cells offers a great potential to target a broad spectrum of cancers and translate 3TSR/TRAIL therapies into clinics. PMID:25358253

  14. Host cell infiltration into PDT-treated tumor

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Krosl, Gorazd; Dougherty, Graeme J.; Chaplin, David J.

    1992-06-01

    C3H mice bearing SCCVII squamous cell carcinoma were treated with photodynamic therapy (PDT) 24 hours after receiving Photofrin (25 mg/kg, i.v.). Single cell suspensions obtained by the enzymatic digestion of tumors excised either 30 minutes or 4 hours after PDT were analyzed for the content of host immune cells and colony forming ability of malignant cells. The results were compared to the data obtained with non-treated tumors. It is shown that there is a marked increase in the content of cells expressing Mac-1 (monocytes/macrophages or granulocytes) in the tumor 30 minutes post PDT, while a high level of other leucocytes are found within the tumors by 4 hours after PDT. As elaborated in Discussion, the infiltration rate of host immune cells, dying of malignant tumor cells, and yet unknown death rate of host cells originally present in PDT treated tumor occurring concomitantly during this time period complicates this analysis. The results of this study suggest a massive infiltration of macrophages and other leucocytes in PDT treated SCCVII tumor, supporting the suggestion that a potent immune reaction is one of the main characteristics of PDT action in solid tumors. It remains to be determined to what extent is the activity of tumor infiltrating immune cells responsible for its eradication by PDT.

  15. Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity

    PubMed Central

    Germain, Claire; Gnjatic, Sacha; Dieu-Nosjean, Marie-Caroline

    2015-01-01

    It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools. PMID:25755654

  16. Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity.

    PubMed

    Germain, Claire; Gnjatic, Sacha; Dieu-Nosjean, Marie-Caroline

    2015-01-01

    It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools. PMID:25755654

  17. Tumor-derived circulating endothelial cell clusters in colorectal cancer.

    PubMed

    Cima, Igor; Kong, Say Li; Sengupta, Debarka; Tan, Iain B; Phyo, Wai Min; Lee, Daniel; Hu, Min; Iliescu, Ciprian; Alexander, Irina; Goh, Wei Lin; Rahmani, Mehran; Suhaimi, Nur-Afidah Mohamed; Vo, Jess H; Tai, Joyce A; Tan, Joanna H; Chua, Clarinda; Ten, Rachel; Lim, Wan Jun; Chew, Min Hoe; Hauser, Charlotte A E; van Dam, Rob M; Lim, Wei-Yen; Prabhakar, Shyam; Lim, Bing; Koh, Poh Koon; Robson, Paul; Ying, Jackie Y; Hillmer, Axel M; Tan, Min-Han

    2016-06-29

    Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease. PMID:27358499

  18. Folate-conjugated immunoglobulin targets melanoma tumor cells for NK cell effector functions.

    PubMed

    Skinner, Cassandra C; McMichael, Elizabeth L; Jaime-Ramirez, Alena C; Abrams, Zachary B; Lee, Robert J; Carson, William E

    2016-08-01

    The folate receptor (FR) is overexpressed on the vascular side of cancerous cells including those of the breast, ovaries, testes, and cervix. We hypothesized that a folate-conjugated immunoglobulin (F-IgG) would bind to the FR that is overexpressed on melanoma tumor cells to target these cells for lysis by natural killer (NK) cells. Folate receptor expression was confirmed in the Mel-39 (human melanoma) cell line by flow cytometry and immunoblot analysis using KB (human oral epithelial) and F01 (human melanoma) as a positive and a negative control, respectively. FR-positive and FR-negative cell lines were treated with F-IgG or control immunoglobulin G in the presence or absence of cytokines to determine NK cell ability to lyse FR-positive cell lines. NK cell activation was significantly upregulated and lysis of Mel 39 tumor cells increased following treatment with F-IgG compared with control immunoglobulin G at all effector : target (E : T) ratios (P<0.01). This trend further increased by NK cell stimulation with the activating cytokine interleukin-12. NK cell production of cytokines such as interferon-gamma, macrophage inflammatory protein 1α, and regulated on activation normal T-cell expressed and secreted (RANTES) was also significantly increased in response to costimulation with interleukin-12 stimulation and F-IgG-coated Mel 39 target cells compared with controls (P<0.01). In contrast, F-IgG did not bind to the FR-negative cell line F01 and had no significant effect on NK cell lysis or cytokine production. This research indicates the potential use of F-IgG for its ability to induce an immune response from NK cells against FR-positive melanoma tumor cells, which can be further increased by the addition of cytokines. PMID:27035691

  19. Folate-conjugated immunoglobulin targets melanoma tumor cells for NK cell effector functions

    PubMed Central

    Skinner, Cassandra C.; McMichael, Elizabeth L.; Jaime-Ramirez, Alena C.; Abrams, Zachary B.; Lee, Robert J.; Carson, William E.

    2016-01-01

    The folate receptor (FR) is over-expressed on the vascular side of cancerous cells including those of the breast, ovaries, testes, and cervix. We hypothesized that a folate-conjugated immunoglobulin (F-IgG) would bind to the FR that is over-expressed on melanoma tumor cells to target these cells for lysis by natural killer (NK) cells. Folate receptor expression was confirmed in the Mel-39 (human melanoma) cell line by flow cytometry and immunoblot analysis, using KB (human oral epithelial) and F01 (human melanoma) as a positive and negative control, respectively. FR-positive and negative cell lines were treated with F-IgG or control immunoglobulin G (C-IgG) in the presence or absence of cytokines in order to determine NK cell ability to lyse FR-positive cell lines. NK cell activation was significantly upregulated and lysis of Mel 39 tumor cells enhanced following treatment with F-IgG, as compared to C-IgG at all effector:target (E:T) ratios (p<0.01). This trend was further enhanced by NK cell stimulation with the activating cytokine interleukin-12 (IL-12). NK cell production of cytokines such as interferon-gamma (IFN-γ), macrophage inflammatory protein 1 alpha (MIP-1α), and regulated on activation normal T-cell expressed and secreted (RANTES) were also significantly increased in response to co-stimulation with IL-12 stimulation and F-IgG-coated Mel 39 target cells, as compared to controls (p<0.01). In contrast, F-IgG did not bind to the FR-negative cell line F01 and had no significant effect on NK cell lysis or cytokine production. This research indicates the potential use of F-IgG for its ability to induce an immune response from NK cells against FR-positive melanoma tumor cells which can be further enhanced by the addition of cytokines. PMID:27035691

  20. Tumor loci and their interactions on mouse chromosome 19 that contribute to testicular germ cell tumors

    PubMed Central

    2014-01-01

    Background Complex genetic factors underlie testicular germ cell tumor (TGCT) development. One experimental approach to dissect the genetics of TGCT predisposition is to use chromosome substitution strains, such as the 129.MOLF-Chr 19 (M19). M19 carries chromosome (Chr) 19 from the MOLF whereas all other chromosomes are from the 129 strain. 71% of M19 males develop TGCTs in contrast to 5% in 129 strain. To identify and map tumor loci from M19 we generated congenic strains harboring MOLF chromosome 19 segments on 129 strain background and monitored their TGCT incidence. Results We found 3 congenic strains that each harbored tumor promoting loci that had high (14%-32%) whereas 2 other congenics had low (4%) TGCT incidences. To determine how multiple loci influence TGCT development, we created double and triple congenic strains. We found additive interactions were predominant when 2 loci were combined in double congenic strains. Surprisingly, we found an example where 2 loci, both which do not contribute significantly to TGCT, when combined in a double congenic strain resulted in greater than expected TGCT incidence (positive interaction). In an opposite example, when 2 loci with high TGCT incidences were combined, males of the double congenic showed lower than expected TGCT incidence (negative interaction). For the triple congenic strain, depending on the analysis, the overall TGCT incidence could be additive or could also be due to a positive interaction of one region with others. Additionally, we identified loci that promote bilateral tumors or testicular abnormalities. Conclusions The congenic strains each with their characteristic TGCT incidences, laterality of tumors and incidence of testicular abnormalities, are useful for identification of TGCT susceptibility modifier genes that map to Chr 19 and also for studies on the genetic and environmental causes of TGCT development. TGCTs are a consequence of aberrant germ cell and testis development. By defining

  1. DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells

    PubMed Central

    Karamitopoulou, Eva; Dawson, Heather; Koelzer, Viktor Hendrik; Agaimy, Abbas; Garreis, Fabian; Söder, Stephan; Laqua, William; Lugli, Alessandro; Hartmann, Arndt; Rau, Tilman T.; Schneider-Stock, Regine

    2015-01-01

    Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK's catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation. PMID:26405175

  2. Identification of Novel Fusion Genes in Testicular Germ Cell Tumors.

    PubMed

    Hoff, Andreas M; Alagaratnam, Sharmini; Zhao, Sen; Bruun, Jarle; Andrews, Peter W; Lothe, Ragnhild A; Skotheim, Rolf I

    2016-01-01

    Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men ages 15 to 44 years. Embryonal carcinomas (EC) comprise a subset of TGCTs that exhibit pluripotent characteristics similar to embryonic stem (ES) cells, but the genetic drivers underlying malignant transformation of ECs are unknown. To elucidate the abnormal genetic events potentially contributing to TGCT malignancy, such as the existence of fusion genes or aberrant fusion transcript expression, we performed RNA sequencing of EC cell lines and their nonmalignant ES cell line counterparts. We identified eight novel fusion transcripts and one gene with alternative promoter usage, ETV6. Four out of nine transcripts were found recurrently expressed in an extended panel of primary TGCTs and additional EC cell lines, but not in normal parenchyma of the testis, implying tumor-specific expression. Two of the recurrent transcripts involved an intrachromosomal fusion between RCC1 and HENMT1 located 80 Mbp apart and an interchromosomal fusion between RCC1 and ABHD12B. RCC1-ABHD12B and the ETV6 transcript variant were found to be preferentially expressed in the more undifferentiated TGCT subtypes. In vitro differentiation of the NTERA2 EC cell line resulted in significantly reduced expression of both fusion transcripts involving RCC1 and the ETV6 transcript variant, indicating that they are markers of pluripotency in a malignant setting. In conclusion, we identified eight novel fusion transcripts that, to our knowledge, are the first fusion genes described in TGCT and may therefore potentially serve as genomic biomarkers of malignant progression. PMID:26659575

  3. Identification of novel fusion genes in testicular germ cell tumors

    PubMed Central

    Hoff, Andreas M.; Alagaratnam, Sharmini; Zhao, Sen; Bruun, Jarle; Andrews, Peter W.; Lothe, Ragnhild A.; Skotheim, Rolf I.

    2015-01-01

    Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men ages 15 to 44 years. Embryonal carcinomas (EC) comprise a subset of TGCTs that exhibit pluripotent characteristics similar to embryonic stem (ES) cells, but the genetic drivers underlying malignant transformation of ECs are unknown. To elucidate the abnormal genetic events potentially contributing to TGCT malignancy, such as the existence of fusion genes or aberrant fusion transcript expression, we performed RNA sequencing of EC cell lines and their non-malignant ES cell line counterparts. We identified eight novel fusion transcripts and one gene with alternative promoter usage, ETV6. Four out of nine transcripts were found recurrently expressed in an extended panel of primary TGCTs and additional EC cell lines, but not in normal parenchyma of the testis, implying tumor-specific expression. Two of the recurrent transcripts involved an intrachromosomal fusion between RCC1 and HENMT1 located 80 Mbp apart and an interchromosomal fusion between RCC1 and ABHD12B. RCC1-ABHD12B and the ETV6 transcript variant were found to be preferentially expressed in the more undifferentiated TGCT subtypes. In vitro differentiation of the NTERA2 EC cell line resulted in significantly reduced expression of both fusion transcripts involving RCC1 and the ETV6 transcript variant, indicating that they are markers of pluripotency in a malignant setting. In conclusion, we identified eight novel fusion transcripts that, to our knowledge, are the first fusion genes described in TGCT and may therefore potentially serve as genomic biomarkers of malignant progression. PMID:26659575

  4. IGFBP2 promotes glioma tumor stem cell expansion and survival

    SciTech Connect

    Hsieh, David; Hsieh, Antony; Stea, Baldassarre; Ellsworth, Ron

    2010-06-25

    IGFBP2 is overexpressed in the most common brain tumor, glioblastoma (GBM), and its expression is inversely correlated to GBM patient survival. Previous reports have demonstrated a role for IGFBP2 in glioma cell invasion and astrocytoma development. However, the function of IGFBP2 in the restricted, self-renewing, and tumorigenic GBM cell population comprised of tumor-initiating stem cells has yet to be determined. Herein we demonstrate that IGFBP2 is overexpressed within the stem cell compartment of GBMs and is integral for the clonal expansion and proliferative properties of glioma stem cells (GSCs). In addition, IGFBP2 inhibition reduced Akt-dependent GSC genotoxic and drug resistance. These results suggest that IGFBP2 is a selective malignant factor that may contribute significantly to GBM pathogenesis by enriching for GSCs and mediating their survival. Given the current dearth of selective molecular targets against GSCs, we anticipate our results to be of high therapeutic relevance in combating the rapid and lethal course of GBM.

  5. Studies on porphyrin photoproducts in solution, cells, and tumor tissue

    NASA Astrophysics Data System (ADS)

    Koenig, Karsten; Schneckenburger, Herbert; Rueck, Angelika C.; Koenig, Roland

    1994-07-01

    Light excitation of photosensitizing porphyrins leads to cytotoxic reactions. In addition, photobleaching and photoproduct formation occur indicating photosensitizer destruction. Photoproducts from hematoporphyrin (HP) fluoresce in aqueous solution at 642 nm, whereas photoproducts from protoporphyrin (PP) in hydrophobic environment emit around 670 nm and exhibit pronounced absorption at 665 nm. Photoproduct formation depends on singlet oxygen. The photoproducts exhibit faster fluorescence decay kinetics compared with nonirradiated porphyrins, as shown by time-grated spectroscopy and fluorescence decay measurements. Photoproduct fluorescence was observed during light exposure of cells and of tumor-bearing, nude mice, following administration of Hematoporphyrin Derivative (HpD), tetramethyl-HP, and PP. Photoconversion was also detected with naturally-occurring porphyrins (PP-producing bacteria) and ALA-simulated biosynthesis of PP in tumor tissue and in skin lesions of patients (psoriasis, mycosis fungoides). The efficiency of PDT with porphyrin photoproducts was found to be low in spite of the strong electronic transitions in the red spectral region.

  6. Nanostructured substrates for isolation of circulating tumor cells

    PubMed Central

    Wang, Lixue; Asghar, Waseem; Demirci, Utkan; Wan, Yuan

    2014-01-01

    Summary Circulating tumor cells (CTCs) originate from the primary tumor mass and enter into the peripheral bloodstream. CTCs hold the key to understanding the biology of metastasis and also play a vital role in cancer diagnosis, prognosis, disease monitoring, and personalized therapy. However, CTCs are rare in blood and hard to isolate. Additionally, the viability of CTCs can easily be compromised under high shear stress while releasing them from a surface. The heterogeneity of CTCs in biomarker expression makes their isolation quite challenging; the isolation efficiency and specificity of current approaches need to be improved. Nanostructured substrates have emerged as a promising biosensing platform since they provide better isolation sensitivity at the cost of specificity for CTC isolation. This review discusses major challenges faced by CTC isolation techniques and focuses on nanostructured substrates as a platform for CTC isolation. PMID:24944563

  7. Transcriptional targeting of tumor endothelial cells for gene therapy

    PubMed Central

    Dong, Zhihong; Nör, Jacques E.

    2009-01-01

    It is well known that angiogenesis plays a critical role in the pathobiology of tumors. Recent clinical trials have shown that inhibition of angiogenesis can be an effective therapeutic strategy for patients with cancer. However, one of the outstanding issues in anti-angiogenic treatment for cancer is the development of toxicities related to off-target effects of drugs. Transcriptional targeting of tumor endothelial cells involves the use of specific promoters for selective expression of therapeutic genes in the endothelial cells lining the blood vessels of tumors. Recently, several genes that are expressed specifically in tumor-associated endothelial cells have been identified and characterized. These discoveries have enhanced the prospectus of transcriptionaly targeting tumor endothelial cells for cancer gene therapy. In this manuscript, we review the promoters, vectors, and therapeutic genes that have been used for transcriptional targeting of tumor endothelial cells, and discuss the prospects of such approaches for cancer gene therapy. PMID:19393703

  8. Mathematical Modeling of Tumor Cell Growth and Immune System Interactions

    NASA Astrophysics Data System (ADS)

    Rihan, Fathalla A.; Safan, Muntaser; Abdeen, Mohamed A.; Abdel-Rahman, Duaa H.

    In this paper, we provide a family of ordinary and delay differential equations to describe the dynamics of tumor-growth and immunotherapy interactions. We explore the effects of adoptive cellular immunotherapy on the model and describe under what circumstances the tumor can be eliminated. The possibility of clearing the tumor, with a strategy, is based on two parameters in the model: the rate of influx of the effector cells, and the rate of influx of IL2. The critical tumor-growth rate, below which endemic tumor does not exist, has been found. One can use the model to make predictions about tumor-dormancy.

  9. Different toxic effects of YTX in tumor K-562 and lymphoblastoid cell lines

    PubMed Central

    Fernández-Araujo, Andrea; Sánchez, Jon A.; Alfonso, Amparo; Vieytes, Mercedes R.; Botana, Luis M.

    2015-01-01

    Yessotoxin (YTX) modulates cellular phosphodiesterases (PDEs). In this regard, opposite effects had been described in the tumor model K-562 cell line and fresh human lymphocytes in terms of cell viability, cyclic adenosine 3',5'-cyclic monophosphate (cAMP) production and protein expression after YTX treatment. Studies in depth of the pathways activated by YTX in K-562 cell line, have demonstrated the activation of two different cell death types, apoptosis, and autophagy after 24 and 48 h of treatment, respectively. Furthermore, the key role of type 4A PDE (PDE4A) in both pathways activated by YTX was demonstrated. Therefore, taking into account the differences between cellular lines and fresh cells, a study of cell death pathways activated by YTX in a non-tumor cell line with mitotic activity, was performed. The cellular model used was the lymphoblastoid cell line that represents a non-tumor model with normal apoptotic and mitotic machinery. In this context, cell viability and cell proliferation, expression of proteins involved in cell death activated by YTX and mitochondrial mass, were studied after the incubation with the toxin. Opposite to the tumor model, no cell death activation was observed in lymphoblastoid cell line in the presence of YTX. In this sense, variations in apoptosis hallmarks were not detected in the lymphoblastoid cell line after YTX incubation, whereas this type I of programmed cell death was observed in K-562 cells. On the other hand, autophagy cell death was triggered in this cellular line, while other autophagic process is suggested in lymphoblastoid cells. These YTX effects are related to PDE4A in both cellular lines. In addition, while cell death is triggered in K-562 cells after YTX treatment, in lymphoblastoid cells the toxin stops cellular proliferation. These results point to YTX as a specific toxic compound of tumor cells, since in the non-tumor lymphoblastoid cell line, no cell death hallmarks are observed. PMID:26136685

  10. Selective expression of constitutively active pro-apoptotic protein BikDD gene in primary mammary tumors inhibits tumor growth and reduces tumor initiating cells

    PubMed Central

    Rahal, Omar M; Nie, Lei; Chan, Li-Chuan; Li, Chia-Wei; Hsu, Yi-Hsin; Hsu, Jennifer; Yu, Dihua; Hung, Mien-Chie

    2015-01-01

    Our previous study showed that specifically delivering BikDD, a constitutive active mutant of pro-apoptotic protein Bik, to breast cancer cell xenografts in immunocompromised mice has a potent activity against tumor initiating cells (TICs), and that the combination between tyrosine kinase inhibitors (TKI) and BikDD gene therapy yielded synergistic effect on EGFR and HER2 positive breast cancer cells in immunodeficient nude mice. Those encouraging results have allowed us to propose a clinical trial using the liposome-complexing plasmid DNA expressing BikDD gene which has been approved by the NIH RAC Advisory committee. However, it is imperative to test whether systemic delivery of BikDD-expressing plasmid DNAs with liposomes into immunocompetent mice has therapeutic efficacy and tolerable side effects as what we observed in the nude mice model. In this study, we investigated the effects of BikDD gene-therapy on the primary mammary tumors, especially on tumor initiating cells (TICs), of a genetically engineered immunocompetent mouse harboring normal microenvironment and immune response. The effects on TIC population in tumors were determined by FACS analysis with different sets of murine specific TIC markers, CD49fhighCD61high and CD24+Jagged1-. First we showed in vitro that ectopic expression of BikDD in murine N202 cells derived from MMTV-HER2/Neu transgenic mouse tumors induced apoptosis and decreased the number of TICs. Consistently, systemic delivery of VISA-Claudin4-BikDD by liposome complexes significantly inhibited mammary tumor growth and slowed down residual tumor growth post cessation of therapy in MMTV-HER2/Neu transgenic mice compared to the controls. In addition, the anti-tumor effects of BikDD in vivo were consistent with decreased TIC population assessed by FACS analysis and in vitro tumorsphere formation assay of freshly isolated tumor cells. Importantly, systemic administration of BikDD did not cause significant cytotoxic response in standard

  11. Selective expression of constitutively active pro-apoptotic protein BikDD gene in primary mammary tumors inhibits tumor growth and reduces tumor initiating cells.

    PubMed

    Rahal, Omar M; Nie, Lei; Chan, Li-Chuan; Li, Chia-Wei; Hsu, Yi-Hsin; Hsu, Jennifer; Yu, Dihua; Hung, Mien-Chie

    2015-01-01

    Our previous study showed that specifically delivering BikDD, a constitutive active mutant of pro-apoptotic protein Bik, to breast cancer cell xenografts in immunocompromised mice has a potent activity against tumor initiating cells (TICs), and that the combination between tyrosine kinase inhibitors (TKI) and BikDD gene therapy yielded synergistic effect on EGFR and HER2 positive breast cancer cells in immunodeficient nude mice. Those encouraging results have allowed us to propose a clinical trial using the liposome-complexing plasmid DNA expressing BikDD gene which has been approved by the NIH RAC Advisory committee. However, it is imperative to test whether systemic delivery of BikDD-expressing plasmid DNAs with liposomes into immunocompetent mice has therapeutic efficacy and tolerable side effects as what we observed in the nude mice model. In this study, we investigated the effects of BikDD gene-therapy on the primary mammary tumors, especially on tumor initiating cells (TICs), of a genetically engineered immunocompetent mouse harboring normal microenvironment and immune response. The effects on TIC population in tumors were determined by FACS analysis with different sets of murine specific TIC markers, CD49f(high)CD61(high) and CD24(+)Jagged1(-). First we showed in vitro that ectopic expression of BikDD in murine N202 cells derived from MMTV-HER2/Neu transgenic mouse tumors induced apoptosis and decreased the number of TICs. Consistently, systemic delivery of VISA-Claudin4-BikDD by liposome complexes significantly inhibited mammary tumor growth and slowed down residual tumor growth post cessation of therapy in MMTV-HER2/Neu transgenic mice compared to the controls. In addition, the anti-tumor effects of BikDD in vivo were consistent with decreased TIC population assessed by FACS analysis and in vitro tumorsphere formation assay of freshly isolated tumor cells. Importantly, systemic administration of BikDD did not cause significant cytotoxic response in

  12. Myeloid Cells as Targets for Therapy in Solid Tumors.

    PubMed

    Cotechini, Tiziana; Medler, Terry R; Coussens, Lisa M

    2015-01-01

    It is well established that cancer development ensues based on reciprocal interactions between genomically altered neoplastic cells and diverse populations of recruited "host" cells co-opted to support malignant progression. Among the host cells recruited into tumor microenvironments, several subtypes of myeloid cells, including macrophages, monocytes, dendritic cells, and granulocytes contribute to tumor development by providing tumor-promoting factors as well as a spectrum of molecules that suppress cytotoxic activities of T lymphocytes. Based on compelling preclinical data revealing that inhibition of critical myeloid-based programs leads to tumor suppression, novel immune-based therapies and approaches are now entering the clinic for evaluation. This review discusses mechanisms underlying protumorigenic programming of myeloid cells and discusses how targeting of these has potential to attenuate solid tumor progression via the induction and of mobilization CD8 cytotoxic T cell immunity. PMID:26222088

  13. Myeloid Cells as Targets for Therapy in Solid Tumors

    PubMed Central

    Cotechini, Tiziana; Medler, Terry R.; Coussens, Lisa M.

    2016-01-01

    It is well established that cancer development ensues based on reciprocal interactions between genomically altered neoplastic cells and diverse populations of recruited “host” cells co-opted to support malignant progression. Among the host cells recruited into tumor microenvironments, several subtypes of myeloid cells, including macrophages, monocytes, dendritic cells, and granulocytes contribute to tumor development by providing tumor-promoting factors as well as a spectrum of molecules that suppress cytotoxic activities of T lymphocytes. Based on compelling preclinical data revealing that inhibition of critical myeloid-based programs leads to tumor suppression, novel immune-based therapies and approaches are now entering the clinic for evaluation. This review discusses mechanisms underlying protumorigenic programming of myeloid cells and discusses how targeting of these has potential to attenuate solid tumor progression via the induction and of mobilization CD8+ cytotoxic T cell immunity. PMID:26222088

  14. Structural Features Facilitating Tumor Cell Targeting and Internalization by Bleomycin and Its Disaccharide

    PubMed Central

    2016-01-01

    We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5** conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide–cytotoxin conjugates. PMID:25905565

  15. Breast cancer cell behaviors on staged tumorigenesis-mimicking matrices derived from tumor cells at various malignant stages

    SciTech Connect

    Hoshiba, Takashi; Tanaka, Masaru

    2013-09-20

    Highlights: •Models mimicking ECM in tumor with different malignancy were prepared. •Cancer cell proliferation was suppressed on benign tumor ECM. •Benign tumor cell proliferation was suppressed on cancerous ECM. •Chemoresistance of cancer cell was enhanced on cancerous ECM. -- Abstract: Extracellular matrix (ECM) has been focused to understand tumor progression in addition to the genetic mutation of cancer cells. Here, we prepared “staged tumorigenesis-mimicking matrices” which mimic in vivo ECM in tumor tissue at each malignant stage to understand the roles of ECM in tumor progression. Breast tumor cells, MDA-MB-231 (invasive), MCF-7 (non-invasive), and MCF-10A (benign) cells, were cultured to form their own ECM beneath the cells and formed ECM was prepared as staged tumorigenesis-mimicking matrices by decellularization treatment. Cells showed weak attachment on the matrices derived from MDA-MB-231 cancer cells. The proliferations of MDA-MB-231 and MCF-7 was promoted on the matrices derived from MDA-MB-231 cancer cells whereas MCF-10A cell proliferation was not promoted. MCF-10A cell proliferation was promoted on the matrices derived from MCF-10A cells. Chemoresistance of MDA-MB-231 cells against 5-fluorouracil increased on only matrices derived from MDA-MB-231 cells. Our results showed that the cells showed different behaviors on staged tumorigenesis-mimicking matrices according to the malignancy of cell sources for ECM preparation. Therefore, staged tumorigenesis-mimicking matrices might be a useful in vitro ECM models to investigate the roles of ECM in tumor progression.

  16. Platelets surrounding primary tumor cells are related to chemoresistance.

    PubMed

    Ishikawa, Satoko; Miyashita, Tomoharu; Inokuchi, Masafumi; Hayashi, Hironori; Oyama, Katsunobu; Tajima, Hidehiro; Takamura, Hironori; Ninomiya, Itasu; Ahmed, A Karim; Harman, John W; Fushida, Sachio; Ohta, Tetsuo

    2016-08-01

    Platelets are crucial components of the tumor microenvironment that function to promote tumor progression and metastasis. In the circulation, the interaction between tumor cells and platelets increases invasiveness, protects tumor cells from shear stress and immune surveillance, and facilitates tumor cell extravasation to distant sites. However, the role and presence of platelets in the primary tumor have not been fully determined. Here, we investigated the presence of platelets around breast cancer primary tumor cells and the associations between these cells. We further investigated the associations among platelets, tumor cells, chemoresistance, and epithelial-mesenchymal transition (EMT). We retrospectively analyzed data from 74 patients with human epidermal growth factor receptor 2 (HER2)‑negative breast cancer who underwent biopsies before treatment and subsequent neo-adjuvant chemotherapy. In biopsy specimens, we evaluated the expression of platelet-specific markers and EMT markers using immunohistochemistry. The associations among the expression of platelet‑specific markers in biopsy specimens, EMT, response to neo‑adjuvant chemotherapy, and survival were analyzed. The presence of platelets was observed in 44 out of 74 (59%) primary breast cancer biopsy specimens. Platelet‑positive tumor cells showed EMT‑like morphological changes and EMT marker expression. Primary tumor cells associated with platelets were less responsive to neo‑adjuvant chemotherapy (pCR rate: 10 vs. 50%, respectively; p=0.0001). Platelets were an independent predictor of the response to chemotherapy upon multivariable analysis (p<0.0001). In conclusion, there was a significant association between platelets surrounding primary tumor cells in the biopsy specimens and the chemotherapeutic response in breast cancer. Platelets surrounding primary tumor cells may represent novel predictors of chemotherapeutic responses. PMID:27349611

  17. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

    PubMed Central

    Yang, Li; Pang, Yanli; Moses, Harold L.

    2010-01-01

    Transforming growth factor β (TGF-β) plays an important role in tumor initiation and progression, functioning as both a suppressor and a promoter. The mechanisms underlying this dual role of TGF-β remain unclear. TGF-β exerts systemic immune suppression and inhibits host immunosurveillance. Neutralizing TGF-β enhances CD8+ T-cell- and NK-cell-mediated anti-tumor immune responses. It also increases neutrophil-attracting chemokines resulting in recruitment and activation of neutrophils with an antitumor phenotype. In addition to its systemic effects, TGF-β regulates infiltration of inflammatory/immune cells and cancer-associated fibroblasts in the tumor microenvironment causing direct changes in tumor cells. Understanding TGF-β regulation at the interface of tumor and host immunity should provide insights into developing effective TGF-β antagonists and biomarkers for patient selection and efficacy of TGF-β antagonist treatment. PMID:20538542

  18. Continued malignant cell proliferation in head and neck tumors during cytotoxic therapy.

    PubMed

    Preisler, H D; Kotelnikov, V M; LaFollette, S; Taylor, S; Mundle, S; Wood, N; Coon, J S; Hutchinson, J; Panje, W; Caldarelli, D D; Griem, K

    1996-09-01

    The effect of cytotoxic therapy on the proliferation of squamous cell carcinoma of the head and neck in vivo in patients was evaluated before and 15-35 days after the start of therapy. To accomplish this, iododeoxyuridine was administered at t = 0, and bromodeoxyuridine was administered 15-35 days later during treatment with a tumor biopsy obtained for study immediately after each pyrimidine infusion. Monoclonal antibodies specific for the halogenated pyrimidines were used to identify cells that were in the S-phase at the time of the infusions. Eleven patients were studied prior to treatment. Of those, the intratreatment biopsy of eight patients contained tumor tissue. In the other three patients, tumor tissue was not present in the second biopsy. Continued precursor incorporation into DNA-synthesizing cells during treatment was detected in six of eight tumor specimens. In two tumor specimens, an increase in the percentage of S-phase cells was noted, in two specimens tumor cells synthesizing DNA were not detected, and in four specimens the percentage of S-phase tumor cells was lower than that in the pretherapy specimen. Patients in whom there were no S-phase cells detected during treatment or in whom no tumor was detected in the second biopsy had a favorable treatment outcome in comparison to those patients in whom continued tumor proliferation during treatment was detected. The number of cells in S-phase prior to the initiation of treatment was not predictive of whether or not proliferation would continue during cytotoxic therapy. Evidence for reentry of kinetically quiescent cells into the cycle during treatment was noted. Additionally, cytotoxic therapy altered the proliferation pattern of normal-appearing mucosa as well. The results of this study demonstrate that tumor cell proliferation does continue in some squamous cell carcinoma of the head and neck during intensive cytotoxic therapy. PMID:9816320

  19. [Updated genomics of testicular germ cell tumor].

    PubMed

    Zhang, Meng; He, An-bang; Cai, Zhi-ming; Wu, Song

    2015-04-01

    Testicular germ cell tumor (TGCT) is a most common testicular malignancy with an increasing incidence, and its pathogenesis and mechanisms are not yet clear. The next generation sequencing has become the main tool to uncover the underlying mechanisms of TGCT. The differential gene expressions, gene mutation, predisposing gene-dominated signaling pathways, and changes of the relevant genes in the sex chromosome are largely involved in the occurrence and development of TGCT. Studies on the genomics of TGCT contribute a lot to identifying the pivotal pathogenic genes and paving a theoretical ground for the early screening and targeted therapy of TGCT. This paper summarizes the advances in the studies of the genomics of TGCT so as to reveal thetmechanisms of the disease at the genetic level. PMID:26027106

  20. Tumor-Initiating Cells and Methods of Use

    NASA Technical Reports Server (NTRS)

    Hlatky, Lynn (Inventor)

    2014-01-01

    Provided herein are an isolated or enriched population of tumor initiating cells derived from normal cells, cells susceptible to neoplasia, or neoplastic cells. Methods of use of the cells for screening for anti-hyperproliferative agents, and use of the cells for animal models of hyperproliferative disorders including metastatic cancer, diagnostic methods, and therapeutic methods are provided.

  1. IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death

    PubMed Central

    Czystowska, M; Han, J; Szczepanski, MJ; Szajnik, M; Quadrini, K; Brandwein, H; Hadden, JW; Signorelli, K; Whiteside, TL

    2013-01-01

    IRX-2 is a cytokine-based biologic agent that has the potential to enhance antitumor immune responses. We investigated whether IRX-2 can protect T cells from tumor-induced apoptosis. Tumor-derived microvesicles (MV) expressing FasL were purified from supernatants of tumor cells and incubated with activated CD8+ T cells. MV induced significant CD8+ T-cell apoptosis, as evidenced by Annexin binding (64.4±6.4%), caspase activation (58.1±7.6%), a loss of mitochondrial membrane potential (82.9±3.9%) and DNA fragmentation. T-cell pretreatment with IRX-2 prevented apoptosis. IRX-2-mediated cytoprotection was dose and time dependent and was comparable to effects of IL-2, IL-7 or IL-15. IRX-2 prevented MV-induced downregulation of JAK3 and TCRζ chain and induced STAT5 activation in T cells. IRX-2 prevented MV-induced Bax and Bim upregulation (P<0.005–0.05), prevented cytochrome c release and Bid cleavage, and concurrently restored the expression of Bcl-2, Bcl-xL, FLIP and Mcl-1 (P<0.005–0.01) in T cells. In addition, IRX-2 reversed MV-induced inhibition of the PI3K/Akt pathway. An Akt inhibitor (Akti-1/2) abrogated protective effects of IRX-2, suggesting that Akt is a downstream target of IRX-2 signaling. Thus, ex vivo pretreatment of CD8+ T cells with IRX-2 provided potent protection from tumor-induced apoptosis. IRX-2 application to future cancer biotherapies could improve their effectiveness by bolstering T-cell resistance to tumor-induced immunosuppression. PMID:19180118

  2. Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy

    PubMed Central

    Qiu, Yu; Li, Peng; Ji, Chunyan

    2015-01-01

    Hypoxia, which is common during tumor progression, plays important roles in tumor biology. Failure in cell death in response to hypoxia contributes to progression and metastasis of tumors. On the one hand, the metabolic and oxidative stress following hypoxia could lead to cell death by triggering signal cascades, like LKB1/AMPK, PI3K/AKT/mTOR, and altering the levels of effective components, such as the Bcl-2 family, Atg and p62. On the other hand, hypoxia-induced autophagy can serve as a mechanism to turn over nutrients, so as to mitigate the adverse condition and then avoid cell death potentially. Due to the effective role of hypoxia, this review focuses on the crosstalk in cell death under hypoxia in tumor progression. Additionally, the illumination of cell death in hypoxia could shed light on the clinical applications of cell death targeted therapy. PMID:26512660

  3. B7H6-specific bispecific T cell engagers (BiTEs) lead to tumor elimination and host anti-tumor immunity1,2

    PubMed Central

    Wu, Ming-Ru; Zhang, Tong; Gacerez, Albert T.; Coupet, Tiffany A.; DeMars, Leslie R.; Sentman, Charles L.

    2015-01-01

    Substantial evidence showed that T cells are the key effectors in immune-mediated tumor eradication. However, most T cells do not exhibit anti-tumor specificity. In this study, a bispecific T cell engager (BiTE) approach was utilized to direct T cells to recognize B7H6+ tumor cells. B7H6 is a specific ligand for the NK cell activating receptor, NKp30. B7H6 is expressed on various types of primary human tumors, including leukemia, lymphoma, and gastrointestinal stromal tumors (GISTs), but it is not constitutively expressed on normal tissues. In this study, data show that B7H6-specific BiTEs direct T cells to mediate cellular cytotoxicity and IFN-γ secretion upon co-culturing with B7H6+ tumors. Furthermore, B7H6-specific BiTE exhibited no self-reactivity to pro-inflammatory monocytes. In vivo, B7H6-specific BiTE greatly enhanced the survival benefit of RMA/B7H6 lymphoma bearing mice through perforin and IFN-γ effector mechanisms. In addition, long term survivor mice were protected against a RMA lymphoma tumor re-challenge. The B7H6-specific BiTE therapy also decreased tumor burden in murine melanoma and ovarian cancer models. In conclusion, B7H6-specific BiTE activates host T cells and has the potential to treat various B7H6+ hematological and solid tumors. PMID:25911747

  4. Dielectrophoretic Capture and Genetic Analysis of Single Neuroblastoma Tumor Cells

    PubMed Central

    Carpenter, Erica L.; Rader, JulieAnn; Ruden, Jacob; Rappaport, Eric F.; Hunter, Kristen N.; Hallberg, Paul L.; Krytska, Kate; O’Dwyer, Peter J.; Mosse, Yael P.

    2014-01-01

    Our understanding of the diversity of cells that escape the primary tumor and seed micrometastases remains rudimentary, and approaches for studying circulating and disseminated tumor cells have been limited by low throughput and sensitivity, reliance on single parameter sorting, and a focus on enumeration rather than phenotypic and genetic characterization. Here, we utilize a highly sensitive microfluidic and dielectrophoretic approach for the isolation and genetic analysis of individual tumor cells. We employed fluorescence labeling to isolate 208 single cells from spiking experiments conducted with 11 cell lines, including 8 neuroblastoma cell lines, and achieved a capture sensitivity of 1 tumor cell per 106 white blood cells (WBCs). Sample fixation or freezing had no detectable effect on cell capture. Point mutations were accurately detected in the whole genome amplification product of captured single tumor cells but not in negative control WBCs. We applied this approach to capture 144 single tumor cells from 10 bone marrow samples of patients suffering from neuroblastoma. In this pediatric malignancy, high-risk patients often exhibit wide-spread hematogenous metastasis, but access to primary tumor can be difficult or impossible. Here, we used flow-based sorting to pre-enrich samples with tumor involvement below 0.02%. For all patients for whom a mutation in the Anaplastic Lymphoma Kinase gene had already been detected in their primary tumor, the same mutation was detected in single cells from their marrow. These findings demonstrate a novel, non-invasive, and adaptable method for the capture and genetic analysis of single tumor cells from cancer patients. PMID:25133137

  5. FOXL2-induced follistatin attenuates activin A-stimulated cell proliferation in human granulosa cell tumors

    SciTech Connect

    Cheng, Jung-Chien; Chang, Hsun-Ming; Qiu, Xin; Fang, Lanlan; Leung, Peter C.K.

    2014-01-10

    Highlights: •Activin A stimulates cell proliferation in KGN human granulosa cell tumor-derived cell line. •Cyclin D2 mediates activin A-induced KGN cell proliferation. •FOXL2 induces follistatin expression in KGN cells. •FOXL2-induced follistatin attenuates activin A-stimulated KGN cell proliferation. -- Abstract: Human granulosa cell tumors (GCTs) are rare, and their etiology remains largely unknown. Recently, the FOXL2 402C > G (C134W) mutation was found to be specifically expressed in human adult-type GCTs; however, its function in the development of human GCTs is not fully understood. Activins are members of the transforming growth factor-beta superfamily, which has been shown to stimulate normal granulosa cell proliferation; however, little is known regarding the function of activins in human GCTs. In this study, we examined the effect of activin A on cell proliferation in the human GCT-derived cell line KGN. We show that activin A treatment stimulates KGN cell proliferation. Treatment with the activin type I receptor inhibitor SB431542 blocks activin A-stimulated cell proliferation. In addition, our results show that cyclin D2 is induced by treatment with activin A and is involved in activin A-stimulated cell proliferation. Moreover, the activation of Smad signaling is required for activin A-induced cyclin D2 expression. Finally, we show that the overexpression of the wild-type FOXL2 but not the C134W mutant FOXL2 induced follistatin production. Treatment with exogenous follistatin blocks activin A-stimulated cell proliferation, and the overexpression of wild-type FOXL2 attenuates activin A-stimulated cell proliferation. These results suggest that FOXL2 may act as a tumor suppressor in human adult-type GCTs by inducing follistatin expression, which subsequently inhibits activin-stimulated cell proliferation.

  6. Antitumor efficacy of vaccinia virus-modified tumor cell vaccine

    SciTech Connect

    Ito, T.; Wang, D.Q.; Maru, M.; Nakajima, K.; Kato, S.; Kurimura, T.; Wakamiya, N. )

    1990-11-01

    The antitumor efficacies of vaccinia virus-modified tumor cell vaccines were examined in murine syngeneic MH134 and X5563 tumor cells. UV-inactivated vaccinia virus was inoculated i.p. into C3H/HeN mice that had received whole body X-irradiation at 150 rads. After 3 weeks, the vaccines were administered i.p. 3 times at weekly intervals. One week after the last injection, mice were challenged i.p. with various doses of syngeneic MH134 or X5563 viable tumor cells. Four methods were used for preparing tumor cell vaccines: X-ray irradiation; fixation with paraformaldehyde for 1 h or 3 months; and purification of the membrane fraction. All four vaccines were effective, but the former two vaccines were the most effective. A mixture of the membrane fraction of untreated tumor cells and UV-inactivated vaccinia virus also had an antitumor effect. These results indicate that vaccine with the complete cell structure is the most effective. The membrane fraction of UV-inactivated vaccinia virus-absorbed tumor cells was also effective. UV-inactivated vaccinia virus can react with not only intact tumor cells but also the purified membrane fraction of tumor cells and augment antitumor activity.

  7. [High-dose chemotherapy and residual tumor resection in male germ cell tumors].

    PubMed

    Lorch, A; Albers, P; Winter, C; Beyer, J

    2011-09-01

    As a consequence of the unsatisfactory results of conventional dose salvage regimens, in particular for patients with poor prognostic features at the time of relapse or in patients with refractory disease, high-dose chemotherapy (HDCT) was introduced into clinical practice in the late 1980s. The combination of carboplatin and etoposide (CE) still remains the backbone of most high-dose regimens. Multiple modifications with more dose escalations or addition of further drugs have been explored, most often with increased toxicity. With improved expertise in supportive care and the use of peripheral blood stem cells, hematopoetic recovery has been significantly shortened and the initial high treatment-related mortality reduced from more than 10% to about 3%. Since the incorporation of HDCT, even patients with unfavorable prognostic features or patients with second or subsequent relapses can achieve long-term remission. Following HDCT residual tumor resection plays a major role in achieving these long-term results. The proportion of vital residual tumor after HDCT is much higher than in patients after conventional chemotherapy. The role of HDCT remains controversial particularly as a first-line treatment and less so in the first salvage setting. As these patients are rare HDCT and residual tumor resection should only be be provided by high-volume centers with sufficient expertise in performing these complex procedures. PMID:21845425

  8. Dying tumor cells stimulate proliferation of living tumor cells via caspase-dependent protein kinase Cδ activation in pancreatic ductal adenocarcinoma.

    PubMed

    Cheng, Jin; Tian, Ling; Ma, Jingjing; Gong, Yanping; Zhang, Zhengxiang; Chen, Zhiwei; Xu, Bing; Xiong, Hui; Li, Chuanyuan; Huang, Qian

    2015-01-01

    Pancreatic cancer is one of the most lethal human cancers, and radiotherapy is often implemented for locally advanced pancreatic ductal adenocarcinoma. Tumor cell repopulation is a major challenge in treating cancers after radiotherapy. In order to address the problem of tumor repopulation, our previous studies have demonstrated that dying cells stimulate the proliferation of living tumor cells after radiotherapy. In particular, dying cells undergoing apoptosis also activate survival or proliferation signals and release growth factors to surrounding living cells. In the present study, we used an in vitro model to examine the possible mechanisms for dying cell stimulated tumor repopulation in pancreatic cancer. In this model, a small number of living, luciferase-labeled pancreatic cancer cells (reporter) were seeded onto a layer of a much larger number of irradiated, unlabeled pancreatic cancer cells and the growth of the living cells was measured over time as a gage of tumor repopulation. Our results indicate that irradiated, dying Panc1 feeder cells significantly stimulated the proliferation of living Panc1 reporter cells. Importantly, we identified that the percentage of apoptotic cells and the cleavage of caspases 3 and 7 and protein kinase Cδ (PKCδ) were increased in irradiated Panc1 cells. We presumed that caspases 3 and 7 and PKCδ as integral mediators in the process of dying pancreatic cancer cell stimulation of living tumor cell growth. In order to demonstrate the importance of caspases 3, 7 and PKCδ, we introduced dominant-negative mutants of caspase 3 (DN_C3), caspase 7 (DN_C7), or PKCδ (DN_PKCδ) into Panc1 cells using lentiviral vectors. The stably transduced Panc1 cells were irradiated and used as feeders and we found a significant decrease in the growth of living Panc1 reporter cells when compared with irradiated wild-type Panc1 cells as feeders. Moreover, the role of PKCδ in the growth stimulation of living tumor cells was further confirmed

  9. A Rare Cause of Prepubertal Gynecomastia: Sertoli Cell Tumor

    PubMed Central

    Dursun, Fatma; Su Dur, Şeyma Meliha; Şahin, Ceyhan; Kırmızıbekmez, Heves; Karabulut, Murat Hakan; Yörük, Asım

    2015-01-01

    Prepubertal gynecomastia due to testis tumors is a very rare condition. Nearly 5% of the patients with testicular mass present with gynecomastia. Sertoli cell tumors are sporadic in 60% of the reported cases, while the remaining is a component of multiple neoplasia syndromes such as Peutz-Jeghers syndrome and Carney complex. We present a 4-year-old boy with gynecomastia due to Sertoli cell tumor with no evidence of Peutz-Jeghers syndrome or Carney complex. PMID:26366315

  10. A Study of CD45RA+ Depleted Haploidentical Stem Cell Transplantation in Children With Relapsed or Refractory Solid Tumors and Lymphomas

    ClinicalTrials.gov

    2016-04-15

    Ewing Sarcoma; Gastrointestinal Tumor; Germ Cell Tumor; Hepatic Tumor; Lymphoma; Wilms Tumor; Rhabdoid Tumor; Clear Cell Carcinoma; Renal Cell Carcinoma; Melanoma; Neuroblastoma; Rhabdomyosarcoma; Non-rhabdomyosarcoma

  11. The impact of additional malignancies in patients diagnosed with gastrointestinal stromal tumors.

    PubMed

    Smith, Myles J; Smith, Henry G; Mahar, Alyson L; Law, Calvin; Ko, Yoo-Joung

    2016-10-15

    A higher incidence of additional malignancies has been described in patients diagnosed with gastrointestinal stromal tumors (GIST). This study aimed to identify risk factors for developing additional malignancies in patients diagnosed with GIST and evaluate the impact on survival. Individuals diagnosed with GIST from 2001 to2009 were identified from the SEER database. Logistic regression was used to identify predictors of additional malignancies and Cox-proportional hazards regression used to identify predictors of survival. In the study period, 1705 cases of GIST were identified, with 181 (10.6%) patients developing additional malignancies. Colorectal cancer was the most common cancer developing within 6 months of GIST diagnosis (30%). The median time to diagnosis of a malignancy after 6 months of GIST diagnosis was 21.9 months. Older age (p < 0.0001) and extraoesophagogastric GIST (p = 0.0027) were significant prognostic factors associated with additional malignancies. The overall 5-year survival was 65%, with the presence of additional malignancies within 6 months of GIST diagnosis associated with poor overall survival (54%, HR 1.55 1.05-2.3 95% CI, p = 0.04). Predictive factors of additional malignancies in patients diagnosed with GIST are increasing age and the primary disease site. Developing additional malignancies within 6 months of GIST diagnosis is associated with poorer overall survival. Targeted surveillance may be warranted in patients diagnosed with GIST that are at high risk of developing additional malignancies. PMID:27299364

  12. Okadaic acid: An additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter

    SciTech Connect

    Suganuma, Masami; Fujiki, Hirota; Suguri, Hiroko; Yoshizawa, Shigeru; Hirota, Mitsuru; Nakayasu, Michie ); Ojika, Makoto; Wakamatsu, Kazumasa; Yamada, Kiyoyuki ); Sugimura, Takashi )

    1988-03-01

    Okadaic acid is a polyether compound of a C{sub 38} fatty acid, isolated from a black sponge, Halichondria okadai. Previous studies showed that okadaic acid is a skin irritant and induces ornithine decarboxylase in mouse skin 4 hr after its application to the skin. This induction was strongly inhibited by pretreatment of the skin with 13-cis-retinoic acid. A two-stage carcinogenesis experiment in mouse skin initiated by a single application of 100 {mu}g of 7,12-dimethylbenz(a)anthracene (DMBA) and followed by application of 10 {mu}g of okadaic acid twice a week revealed that okadaic acid is a potent additional tumor promoter: tumors developed in 93% of the mice treated with DMBA and okadaic acid by week 16. In contrast, tumors were found in only one mouse each in the groups treated with DMBA alone or okadaic acid alone. An average of 2.6 tumors per mouse was found in week 30 in the group treated with DMBA and okadaic acid. Unlike phorbol 12-tetradecanoate 13-acetate (TPA), teleocidin, and aplysiatoxin, okadaic acid did not inhibit the specific binding of ({sup 3}H)TPA to a mouse skin particulate fraction when added up to 100 {mu}M or activate calcium-activated, phospholipid-dependent protein kinase (protein kinase C) in vitro when added up to 1.2 {mu}M. Therefore, the actions of okadaic acid and phorbol ester may be mediated in different ways. These results show that okadaic acid is a non-TPA-type tumor promoter in mouse skin carcinogenesis.

  13. Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance.

    PubMed

    Gotthardt, Dagmar; Putz, Eva M; Straka, Elisabeth; Kudweis, Petra; Biaggio, Mario; Poli, Valeria; Strobl, Birgit; Müller, Mathias; Sexl, Veronika

    2014-10-01

    The members of the signal transducer and activator of transcription (STAT) family of transcription factors modulate the development and function of natural killer (NK) cells. NK cell-mediated tumor surveillance is particularly important in the body's defense against hematological malignancies such as leukemia. STAT3 inhibitors are currently being developed, although their potential effects on NK cells are not clear. We have investigated the function of STAT3 in NK cells with Stat3(Δ/Δ)Ncr1-iCreTg mice, whose NK cells lack STAT3. In the absence of STAT3, NK cells develop normally and in normal numbers, but display alterations in the kinetics of interferon-γ (IFN-γ) production. We report that STAT3 directly binds the IFN-γ promoter. In various in vivo models of hematological diseases, loss of STAT3 in NK cells enhances tumor surveillance. The reduced tumor burden is paralleled by increased expression of the activating receptor DNAM-1 and the lytic enzymes perforin and granzyme B. Our findings imply that STAT3 inhibitors will stimulate the cytolytic activity of NK cells against leukemia, thereby providing an additional therapeutic benefit. PMID:25185262

  14. Multiple Subsets of Brain Tumor Initiating Cells Coexist in Glioblastoma.

    PubMed

    Rennert, Robert C; Achrol, Achal S; Januszyk, Michael; Kahn, Suzana A; Liu, Tiffany T; Liu, Yi; Sahoo, Debashis; Rodrigues, Melanie; Maan, Zeshaan N; Wong, Victor W; Cheshier, Samuel H; Chang, Steven D; Steinberg, Gary K; Harsh, Griffith R; Gurtner, Geoffrey C

    2016-06-01

    Brain tumor-initiating cells (BTICs) are self-renewing multipotent cells critical for tumor maintenance and growth. Using single-cell microfluidic profiling, we identified multiple subpopulations of BTICs coexisting in human glioblastoma, characterized by distinct surface marker expression and single-cell molecular profiles relating to divergent bulk tissue molecular subtypes. These data suggest BTIC subpopulation heterogeneity as an underlying source of intra-tumoral bulk tissue molecular heterogeneity, and will support future studies into BTIC subpopulation-specific therapies. Stem Cells 2016;34:1702-1707. PMID:26991945

  15. Identifying cancer origin using circulating tumor cells

    PubMed Central

    Lu, Si-Hong; Tsai, Wen-Sy; Chang, Ying-Hsu; Chou, Teh-Ying; Pang, See-Tong; Lin, Po-Hung; Tsai, Chun-Ming; Chang, Ying-Chih

    2016-01-01

    ABSTRACT Circulating tumor cells (CTCs) have become an established clinical evaluation biomarker. CTC count provides a good correlation with the prognosis of cancer patients, but has only been used with known cancer patients, and has been unable to predict the origin of the CTCs. This study demonstrates the analysis of CTCs for the identification of their primary cancer source. Twelve mL blood samples were equally dispensed on 6 CMx chips, microfluidic chips coated with an anti-EpCAM-conjugated supported lipid bilayer, for CTC capture and isolation. Captured CTCs were eluted to an immunofluorescence (IF) staining panel consisting of 6 groups of antibodies: anti-panCK, anti-CK18, anti-CK7, anti-TTF-1, anti-CK20/anti-CDX2, and anti-PSA/anti-PSMA. Cancer cell lines of lung (H1975), colorectal (DLD-1, HCT-116), and prostate (PC3, DU145, LNCaP) were selected to establish the sensitivity and specificity for distinguishing CTCs from lung, colorectal, and prostate cancer. Spiking experiments performed in 2mL of culture medium or whole blood proved the CMx platform can enumerate cancer cells of lung, colorectal, and prostate. The IF panel was tested on blood samples from lung cancer patients (n = 3), colorectal cancer patients (n = 5), prostate cancer patients (n = 5), and healthy individuals (n = 12). Peripheral blood samples found panCK+ and CK18+ CTCs in lung, colorectal, and prostate cancers. CTCs expressing CK7+ or TTF-1+, (CK20/ CDX2)+, or (PSA/ PSMA)+ corresponded to lung, colorectal, or prostate cancer, respectively. In conclusion, we have designed an immunofluorescence staining panel to identify CTCs in peripheral blood to correctly identify cancer cell origin. PMID:26828696

  16. Identifying cancer origin using circulating tumor cells.

    PubMed

    Lu, Si-Hong; Tsai, Wen-Sy; Chang, Ying-Hsu; Chou, Teh-Ying; Pang, See-Tong; Lin, Po-Hung; Tsai, Chun-Ming; Chang, Ying-Chih

    2016-04-01

    Circulating tumor cells (CTCs) have become an established clinical evaluation biomarker. CTC count provides a good correlation with the prognosis of cancer patients, but has only been used with known cancer patients, and has been unable to predict the origin of the CTCs. This study demonstrates the analysis of CTCs for the identification of their primary cancer source. Twelve mL blood samples were equally dispensed on 6 CMx chips, microfluidic chips coated with an anti-EpCAM-conjugated supported lipid bilayer, for CTC capture and isolation. Captured CTCs were eluted to an immunofluorescence (IF) staining panel consisting of 6 groups of antibodies: anti-panCK, anti-CK18, anti-CK7, anti-TTF-1, anti-CK20/anti-CDX2, and anti-PSA/anti-PSMA. Cancer cell lines of lung (H1975), colorectal (DLD-1, HCT-116), and prostate (PC3, DU145, LNCaP) were selected to establish the sensitivity and specificity for distinguishing CTCs from lung, colorectal, and prostate cancer. Spiking experiments performed in 2mL of culture medium or whole blood proved the CMx platform can enumerate cancer cells of lung, colorectal, and prostate. The IF panel was tested on blood samples from lung cancer patients (n = 3), colorectal cancer patients (n = 5), prostate cancer patients (n = 5), and healthy individuals (n = 12). Peripheral blood samples found panCK(+) and CK18(+) CTCs in lung, colorectal, and prostate cancers. CTCs expressing CK7(+) or TTF-1(+), (CK20/ CDX2)(+), or (PSA/ PSMA)(+) corresponded to lung, colorectal, or prostate cancer, respectively. In conclusion, we have designed an immunofluorescence staining panel to identify CTCs in peripheral blood to correctly identify cancer cell origin. PMID:26828696

  17. Co-culture with podoplanin+ cells protects leukemic blast cells with leukemia-associated antigens in the tumor microenvironment

    PubMed Central

    LEE, JI YOON; HAN, A-REUM; LEE, SUNG-EUN; MIN, WOO-SUNG; KIM, HEE-JE

    2016-01-01

    Podoplanin+ cells are indispensable in the tumor microenvironment. Increasing evidence suggests that podoplanin may support the growth and metastasis of solid tumors; however, to the best of our knowledge no studies have determined whether or not podoplanin serves a supportive role in acute myeloid leukemia (AML). The effects of co-culture with podoplanin+ cells on the cellular activities of the leukemic cells, such as apoptosis and cell proliferation, in addition to the expression of podoplanin in leukemic cells, were investigated. Due to the fact that genetic abnormalities are the primary cause of leukemogenesis, the overexpression of the fibromyalgia-like tyrosine kinase-3 gene in colony forming units was also examined following cell sorting. Podoplanin+ cells were found to play a protective role against apoptosis in leukemic cells and to promote cell proliferation. Tumor-associated antigens, including Wilms' tumor gene 1 and survivin, were increased when leukemic cells were co-cultured with podoplanin+ cells. In combination, the present results also suggest that podoplanin+ cells can function as stromal cells for blast cell retention in the AML tumor microenvironment. PMID:27035421

  18. Changes in expression of differentiation markers between normal ovarian cells and derived tumors.

    PubMed Central

    Van Niekerk, C. C.; Ramaekers, F. C.; Hanselaar, A. G.; Aldeweireldt, J.; Poels, L. G.

    1993-01-01

    The marker profile of 18 samples of normal human ovarian tissues and 138 samples of their derived tumors was established using 51 monoclonal antibodies directed against intermediate filaments, ovarian carcinoma-specific antigens, general tumor-associated antigens and MHC-I/II antigens. Our data show that vimentin and keratins 7, 8, 18, and 19 were found in both epithelial and some nonepithelial ovarian tumors. Several tumor samples contained additional keratins 4, 10, 13, and 14, as well as desmin. BW 495/36 and to a lesser extent HMFG-2 were usually found in all ovarian tumors that contained simple epithelial keratins, except the absence of HMFG-2 in gonadal tumors as well as in dysgerminomas. In contrast to the keratin antibodies, these two panepithelial antibodies were negative in normal mesothelial cells and granulosa cells of the ovarian follicles. In general, the marker TAG-72 appeared useful for its discrimination between positively stained mucinous adenomas, the ovarian carcinomas as well as germ cell tumors, and the negatively stained gonadal tumors, serous adenomas, and cystomas. OV632 appeared useful in the distinction between negatively stained serous adenomas and positively stained serous carcinomas. In contrast, the monoclonal antibodies OC 125, OV-TL 3, OV-TL 16, and MOv 18 can be considered as pan-ovarian carcinoma markers, however without the discriminative capability as seen for OV632. These ovarian carcinoma-associated antigens were hardly found expressed in gonadal and germ cell tumors, except in the group of endodermal sinus tumors. HLA-I was found to be expressed in almost all nucleated cells, although loss of HLA-I expression was seen in areas of tumor cells. HLA-DR was negative in normal ovarian tissue, but heterogeneous expression was noticed in most of the epithelial tumors. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7678716

  19. Cytolytic activity against tumor cells by macrophage cell lines and augmentation by macrophage stimulants.

    PubMed

    Taniyama, T; Holden, H T

    1980-07-15

    Previous studies have shown that macrophage cell lines retained the ability to phagocytize, to secrete lysosomal enzymes, and to function as effector cells in antibody-dependent cellular cytoxicity. In this paper, the cytolytic activity of murine macrophage cell lines against tumor target cells was assessed using an 18-h 51Cr release assay. Of the macrophage cell lines tested, RAW 264, PU5-1.8 and IC-21 had intermediate to high levels of spontaneous cytolytic activity, P388D, and J774 had low to intermediate levels, while /WEHI-3 showed little or no cytolytic activity against RBL-5, MBL-2 and TU-5 target cells. Tumor-cell killing by macrophage cell lines could be augmented by the addition of macrophage stimulants, such as bacterial lipopolysaccharide and poly I:C, indicating that the activation of macrophages by these stimulants does not require the participation of other cell types. Treatment with interferon also augmented the tumor-cell killing by macrophage cell lines. Although the mechanism by which these cell lines exert their spontaneous or boosted cytotoxic activity is not clear, it does not appear to be due to depletion of nutrients since cell lines with high metabolic and proliferative activities, such as WEHI-3 and RBL-5, showed little or no cytotoxicity and supernatants from the macrophage cell lines did not exert any cytotoxic effects in their essay. Thus, it appears that the different macrophage cell lines represent different levels of activation and/or differentiation and may be useful for studying the development of these processes as well as providing a useful tool for analyzing the mechanisms of macrophage-mediated cytolysis. PMID:6165690

  20. Spider Silk-Based Gene Carriers for Tumor Cell-Specific Delivery

    PubMed Central

    Numata, Keiji; Reagan, Michaela R; Goldstein, Robert H; Rosenblatt, Michael; Kaplan, David L

    2011-01-01

    The present study demonstrates pDNA complexes of recombinant silk proteins containing poly(L-lysine) and tumor-homing peptides (THPs), which are globular and approximately 150–250 nm in diameter, show significant enhancement of target specificity to tumor cells by additions of F3 and CGKRK THPs. We report herein the preparation and study of novel nano-scale silk-based ionic complexes containing pDNA able to home specifically to tumor cells. Particular focus was on how the THP, F3 (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK) and CGKRK, enhanced transfection specificity to tumor cells. Genetically engineered silk proteins containing both poly(L-lysine) domains to interact with pDNA and the THP to bind to specific tumor cells for target-specific pDNA delivery were prepared using Escherichia coli, followed by in-vitro and in-vivo transfection experiments into MDA-MB-435 melanoma cells and highly metastatic human breast tumor MDA-MB-231 cells. Non-tumorigenic MCF-10A breast epithelial cells were used as a control cell line for in-vitro tumor-specific delivery studies. These results demonstrate that combination of the bioengineered silk delivery systems and THP can serve as a versatile and useful new platform for non-viral gene delivery. PMID:21739966

  1. Characteristics of Si Solar Cells with the Addition of Frits and Additives to Al Pastes

    NASA Astrophysics Data System (ADS)

    Kim, Dongsun; Kim, Jongwoo; Lee, Jungki; Kim, Hyungsun

    2011-11-01

    Thick Al films are used widely as the backside electrode material of Si solar cells. The formation of Al and a back surface field reduce the back-surface recombination and improve the cell performance. This study examined the characteristics of Si solar cells with the addition of frits and additives to Al pastes after firing. The reactions among Al powders, frits and additives were studied. The wetting behavior between each powder (Al powder, frit, additive) and Si, Al substrates was also measured as a function of the temperature. These preliminary studies show that the frits affect the adhesion between Al and Si. In addition, the proper additives prevent the bowing of Si wafer.

  2. MOLECULAR AND CYTOGENETIC ANALYSIS OF LUNG TUMOR CELL LINES

    EPA Science Inventory

    We have measured the levels of amplification of oncogenes and tumor marker genes or other genes of interest in nine human lung tumor cell lines in comparison to normal human bronchial epithelial cells or normal blood lymphocytes to test the hypothesis that aberrant amplification ...

  3. Intraorbital Granular Cell Tumor Ophthalmologic and Radiologic Findings

    PubMed Central

    de la Vega, Gabriela; Villegas, Victor M; Velazquez, Jose; Barrios, Mirelys; Murray, Timothy G; Elhammady, Mohamed Samy

    2015-01-01

    Granular cell tumor is a rare soft tissue neoplasm that commonly affects the head and neck regions. We describe a case of a granular cell tumor of the orbit including its clinical presentation, histopathology, and magnetic resonance imaging findings. PMID:25963156

  4. Malignant mast cell tumor in an African hedgehog (Atelerix albiventris).

    PubMed

    Raymond, J T; White, M R; Janovitz, E B

    1997-01-01

    In November 1995, a malignant mast cell tumor (mastocytoma) was diagnosed in an adult African hedgehog (Atelerix albiventris) from a zoological park (West Lafayette, Indiana, USA). The primary mast cell tumor presented as a firm subcutaneous mass along the ventrum of the neck. Metastasis to the right submandibular lymph node occurred. PMID:9027702

  5. Therapeutic attack of hypoxic cells of solid tumors: presidential address.

    PubMed

    Sartorelli, A C

    1988-02-15

    Hypoxic cells of solid tumors are relatively resistant to therapeutic assault. Studies have demonstrated that oxygen-deficient tumor cells exist in an environment conducive to reductive reactions making hypoxic cells particularly sensitive to bioreductive alkylating agents. Mitomycin C, the prototype bioreductive alkylating agent available for clinical use, is capable of preferentially killing oxygen-deficient cells both in vitro and in vivo. This phenomenon is at least in part the result of differences in the uptake and metabolism of mitomycin C by hypoxic and oxygenated tumor cells, with the ultimate critical lesion being the cross-linking of DNA by the mitomycin antibiotic. The combination of mitomycin C with X-irradiation, to attack hypoxic and oxygenated tumor cell populations, respectively, has led to enhanced antitumor effects in mice bearing solid tumor implants and in patients with cancer of the head and neck. More efficacious kill of hypoxic tumor cells may be possible by the use of dicoumarol in combination with mitomycin or by the use of the related antibiotic porfiromycin. The findings support the use of an agent with specificity for hypoxic tumor cells in potentially curative regimens for solid tumors. PMID:3123053

  6. Malignant giant cell tumor of soft parts in a mare

    PubMed Central

    Marryatt, Paige A.

    2003-01-01

    Two subcutaneous masses were removed from the elbow of a mare. Histologically they were composed of islands of polygonal to plump spindlelioid cells with large nuclei, coarsely stippled chromatin, and eosinophilic cytoplasm. Findings were diagnostic for a malignant giant cell tumor of soft parts, a rare tumor with a fair prognosis. PMID:14524631

  7. Targeted delivery of let-7b to reprogramme tumor-associated macrophages and tumor infiltrating dendritic cells for tumor rejection.

    PubMed

    Huang, Zhen; Gan, Jingjing; Long, Ziyan; Guo, Guangxing; Shi, Xiafei; Wang, Chunming; Zang, Yuhui; Ding, Zhi; Chen, Jiangning; Zhang, Junfeng; Dong, Lei

    2016-06-01

    Both tumor associated macrophages (TAMs) and tumor infiltrating dendritic cells (TIDCs) are important components in the tumor microenvironment that mediate tumor immunosuppression and promote cancer progression. Targeting these cells and altering their phenotypes may become a new strategy to recover their anti-tumor activities and thereby restore the local immune surveillance against tumor. In this study, we constructed a nucleic acid delivery system for the delivery of let-7b, a synthetic microRNA mimic. Our carrier has an affinity for the mannose receptors on TAMs/TIDCs and is responsive to the low-pH tumor microenvironment. The delivery of let-7b could reactivate TAMs/TIDCs by acting as a TLR-7 agonist and suppressing IL-10 production in vitro. In a breast cancer mouse model, let-7b delivered by this system efficiently reprogrammed the functions of TAMs/TIDCs, reversed the suppressive tumor microenvironment, and inhibited tumor growth. Taken together, this strategy, designed based upon TAMs/TIDCs-targeting delivery and the dual biological functions of let-7b (TLR-7 ligand and IL-10 inhibitor), may provide a new approach for cancer immunotherapy. PMID:26994345

  8. Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors

    PubMed Central

    Zhang, Xiaonan; de Milito, Angelo; Olofsson, Maria Hägg; Gullbo, Joachim; D’Arcy, Padraig; Linder, Stig

    2015-01-01

    The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS) or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an “Achilles heel” for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations. PMID:26580606

  9. Heterogeneous expansion of CD4+ tumor-infiltrating T-lymphocytes in clear cell renal cell carcinomas.

    PubMed

    Zhang, Qian; Jia, Qingzhu; Deng, Tianxing; Song, Bo; Li, Longkun

    2015-02-27

    Aberrant expression of tumor-associated antigens (TAAs) mediates the effective mounting of adaptive immunity in human solid tumors. The foundations of this tumor-host interaction strongly depend on specific recognition via TAA-cognate-receptors in T-cell repertoires. Previous studies focused on the phenotypic and functional properties of CD4+/CD8+ tumor-infiltrating T-lymphocytes (TILs), but the detailed composition of T-cell repertoires of these fundamental subsets remains largely unknown. This study recruited 10 clear cell renal cell carcinoma (ccRCC) patients and obtained samples from various tissues, including tumors, adjacent healthy renal tissue and peripheral blood. We utilized deep sequencing of T-cell receptor beta chains (TCRB), which serve as a unique identifier for each T clonotype, to characterize the CD4+/CD8+ TIL repertoire in ccRCC patients, assess the diversity and clonality of infiltrated T-cells in distinct tissues from patients and depict the clonal expansion events that occur in anti-tumor immune responses. We found that the CD4+ TIL repertoire exhibited signatures of heterogeneous T-cell expansion, which were characterized by divergent TRBV/J usage and an enrichment of expanded dominant clones. Taken together, our findings provide additional evidence of CD4+ T-cell-mediated anti-tumor immunity. The identification of the underlying molecular mechanisms of this process may provide novel avenues for targeted immunotherapeutic interventions. PMID:25637538

  10. Addition of a hypoxic cell selective cytotoxic agent (mitomycin C or porfiromycin) to Fluosol-DA/carbogen/radiation.

    PubMed

    Holden, S A; Herman, T S; Teicher, B A

    1990-05-01

    In an effort to develop effective combination treatments for use with radiation against solid tumors, the cytotoxic effects of the addition of mitomycin C or porfiromycin on treatment with Fluosol-DA/carbogen (95% O2/5% CO2) breathing and radiation in the FSaIIC tumor system were studied. In vitro mitomycin C and porfiromycin were both preferentially cytotoxic toward hypoxic FSaIIC cells. After in vivo exposure, however, the cytotoxicity of mitomycin C toward single cell tumor suspensions obtained from whole tumors was exponential over the dose range studied, but for porfiromycin a plateau in cell killing was observed. With Fluosol-DA/carbogen breathing and single dose radiation, addition of either mitomycin C or porfiromycin increased the tumor cell kill achieved at 5 Gy by approximately 1.2 and 1.0 logs, respectively. Less effect was seen with addition of the drugs at the 10 and 15 Gy radiation doses. In tumor growth delay experiments, the addition of either mitomycin C or porfiromycin to Fluosol-DA/carbogen breathing and radiation resulted in primarily an additive increase in tumor growth delay. The survival of Hoechst 33342 dye-selected tumor cell subpopulations indicated that Fluosol-DA/carbogen breathing increased the cytotoxicity of radiation (10 Gy) more in the bright cell subpopulation (4-fold) than in the dim cell subpopulation (2-fold) resulting in an overall 4-fold sparing of the dim subpopulation. Mitomycin C and porfiromycin were both more toxic toward the dim cell subpopulations. Addition of mitomycin C or porfiromycin to Fluosol-DA/carbogen breathing and radiation (10 Gy) resulted in a primarily additive effect of the drugs and radiation killing in both tumor cell subpopulations. Thus, with mitomycin C/Fluosol-DA/carbogen and radiation there was a 2-fold sparing of dim cells and with porfiromycin in the combined treatment a 1.6-fold sparing of the dim cell population. Our results indicate that treatment strategies directed against both oxic and

  11. Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity

    PubMed Central

    Albini, Adriana; Bruno, Antonino; Gallo, Cristina; Pajardi, Giorgio; Noonan, Douglas M.; Dallaglio, Katiuscia

    2015-01-01

    Abstract Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a “proliferating” cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases. PMID:26291921

  12. Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity.

    PubMed

    Albini, Adriana; Bruno, Antonino; Gallo, Cristina; Pajardi, Giorgio; Noonan, Douglas M; Dallaglio, Katiuscia

    2015-01-01

    Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases. PMID:26291921

  13. Solid tumor therapy by selectively targeting stromal endothelial cells.

    PubMed

    Liu, Shihui; Liu, Jie; Ma, Qian; Cao, Liu; Fattah, Rasem J; Yu, Zuxi; Bugge, Thomas H; Finkel, Toren; Leppla, Stephen H

    2016-07-12

    Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors. PMID:27357689

  14. Rare Presentation of Supratentorial Primitive Neuroectodermal Tumors Mimicking Bifocal Germ Cell Tumors: 2 Case Reports.

    PubMed

    Phuakpet, Kamon; Larouche, Valerie; Hawkins, Cynthia; Huang, Annie; Tabori, Uri; Bartels, Ute K; Bouffet, Eric

    2016-03-01

    Bifocal pineal and suprasellar tumors have only been described in the context of germ cell tumors in the pediatric age group. We report 2 patients with radiologic findings of bifocal pineal and suprasellar lesions, with a histologic diagnosis of supratentorial primitive neuroectodermal tumor. The absence of diabetes insipidus and other endocrine abnormalities was noteworthy in both cases. This observation challenges previous reports on the pathognomonic value of this clinico-radiologic entity. PMID:26241725

  15. Trifunctional bispecific antibodies induce tumor-specific T cells and elicit a vaccination effect.

    PubMed

    Eissler, Nina; Ruf, Peter; Mysliwietz, Josef; Lindhofer, Horst; Mocikat, Ralph

    2012-08-15

    A major goal of tumor immunotherapy is the induction of long-lasting systemic T-cell immunity. Bispecific antibodies (bsAbs) that lack the immunoglobulin Fc region confer T-cell-mediated killing of tumor cells but do not induce long-term memory. In contrast, trifunctional bsAbs comprise an appropriate Fc region and, therefore, not only recruit T cells but also accessory cells that bear activating Fcγ receptors (FcγR), providing additional T-cell-activating signals and securing presentation of tumor-derived antigens to T cells. In this study, we show that trifunctional bsAbs induce a polyvalent T-cell response and, therefore, a vaccination effect. Mice were treated with melanoma cells and with a trifunctional bsAb directed against the melanoma target antigen ganglioside GD2 in addition to murine CD3. The trifunctional bsAb activated dendritic cells and induced a systemic immune response that was not replicated by treatment with the F(ab')2-counterpart lacking the Fc region. Restimulation of spleen and lymph node cells in vitro yielded T-cell lines that specifically produced interferon-γ in response to tumor. In addition, trifunctional bsAb-induced T cells recognized various specific peptides derived from melanoma-associated antigens. Moreover, these polyvalent responses proved to be tumor-suppressive and could not be induced by the corresponding bsF(ab')2-fragment. Taken together, our findings provide preclinical proof of concept that trifunctional bsAbs can induce tumor-specific T cells with defined antigen specificity. PMID:22745368

  16. CCL9 Induced by TGFβ Signaling in Myeloid Cells Enhances Tumor Cell Survival in the Premetastatic Organ.

    PubMed

    Yan, Hangyi H; Jiang, Jian; Pang, Yanli; Achyut, B R; Lizardo, Michael; Liang, Xinhua; Hunter, Kent; Khanna, Chand; Hollander, Christine; Yang, Li

    2015-12-15

    Tumor cell survival in the hostile distant organ is a rate-limiting step in cancer metastasis. Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor-promoting microenvironment. However, it is unclear whether these myeloid cells in the premetastatic site have any direct effect on tumor cell survival. Here, we report that chemokine CCL9 was highly induced in Gr-1(+)CD11b(+) immature myeloid cells and in premetastatic lung in tumor-bearing mice. Knockdown of CCL9 in myeloid cells decreased tumor cell survival and metastasis. Importantly, CCL9 overexpression in myeloid cells lacking TGFβ signaling rescued the tumor metastasis defect observed in mice with myeloid-specific Tgfbr2 deletion. The expression level of CCL23, the human orthologue for CCL9, in peripheral blood mononuclear cells correlated with progression and survival of cancer patients. Our study demonstrates that CCL9 could serve as a good candidate for anti-metastasis treatment by targeting the rate-limiting step of cancer cell survival. In addition, targeting CCL9 may avoid the adverse effects of TGFβ-targeted therapy. PMID:26483204

  17. Recruitment of Mesenchymal Stem Cells Into Prostate Tumors Promotes Metastasis

    PubMed Central

    Jung, Younghun; Kim, Jin Koo; Shiozawa, Yusuke; Wang, Jingcheng; Mishra, Anjali; Joseph, Jeena; Berry, Janice E.; McGee, Samantha; Lee, Eunsohl; Sun, Hongli; Wang, Jianhua; Jin, Taocong; Zhang, Honglai; Dai, Jinlu; Krebsbach, Paul H.; Keller, Evan T.; Pienta, Kenneth J.; Taichman, Russell S.

    2013-01-01

    Tumors recruit mesenchymal stem cells (MSCs) to facilitate healing, which induces their conversion into cancer-associated fibroblasts that facilitate metastasis. However, this process is poorly understood on the molecular level. Here we show that the CXCR6 ligand CXCL16 facilitates MSC or Very Small Embryonic-Like (VSEL) cells recruitment into prostate tumors. CXCR6 signaling stimulates the conversion of MSCs into cancer-associated fibroblasts, which secrete stromal-derived factor-1, also known as CXCL12. CXCL12 expressed by cancer-associated fibroblasts then binds to CXCR4 on tumor cells and induces an epithelial to mesenchymal transition, which ultimately promotes metastasis to secondary tumor sites. Our results provide the molecular basis for MSC recruitment into tumors and how this process leads to tumor metastasis. PMID:23653207

  18. Tumor-stem cells interactions by fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Meleshina, Aleksandra V.; Cherkasova, Elena I.; Sergeeva, Ekaterina; Turchin, Ilya V.; Kiseleva, Ekaterina V.; Dashinimaev, Erdem B.; Shirmanova, Marina V.; Zagaynova, Elena V.

    2013-02-01

    Recently, great deal of interest is investigation the function of the stem cells (SC) in tumors. In this study, we studied «recipient-tumor- fluorescent stem cells » system using the methods of in vivo imaging and laser scanning microscopy (LSM). We used adipose-derived adult stem (ADAS) cells of human lentiviral transfected with the gene of fluorescent protein Turbo FP635. ADAS cells were administrated into nude mice with transplanted tumor HeLa Kyoto (human cervical carcinoma) at different stages of tumor growth (0-8 days) intravenously or into tumor. In vivo imaging was performed on the experimental setup for epi - luminescence bioimaging (IAP RAS, Nizhny Novgorod). The results of the imaging showed localization of fluorophore tagged stem cells in the spleen on day 5-9 after injection. The sensitivity of the technique may be improved by spectral separation autofluorescence and fluorescence of stem cells. We compared the results of in vivo imaging and confocal laser scanning microscopy (LSM 510 META, Carl Zeiss, Germany). Internal organs of the animals and tumor tissue were investigated. It was shown that with i.v. injection of ADAS, bright fluorescent structures with spectral characteristics corresponding to TurboFP635 protein are locally accumulated in the marrow, lungs and tumors of animals. These findings indicate that ADAS cells integrate in the animal body with transplanted tumor and can be identified by fluorescence bioimaging techniques in vivo and ex vivo.

  19. Genetic traits for hematogeneous tumor cell dissemination in cancer patients.

    PubMed

    Joosse, Simon A; Pantel, Klaus

    2016-03-01

    Metastatic relapse in patients with solid tumors is the consequence of cancer cells that disseminated to distant sites, adapted to the new microenvironment, and escaped systemic adjuvant therapy. There is increasing evidence that hematogeneous dissemination starts at an early stage of cancer progression with single tumor cells or cell clusters leaving the primary site and entering the blood circulation. These circulating tumor cells (CTCs) can extravasate into secondary tissues where they become disseminated tumor cells (DTCs). Patients might relapse years after initial resection of the primary tumor when DTCs become overt metastases. Current diagnostic strategies for stratification of therapies against metastatic cells focus on the primary tumor tissue. This approach is based on the availability of stored primary tumors obtained at primary surgery, but it ignores that the DTCs might have evolved over years, which can affect the antimetastatic drug response. However, taking biopsies from metastatic tissues is an invasive procedure, and multiple metastases located at different sites in an individual patient show marked genomic heterogeneity. Thus, capturing CTCs from the peripheral blood as a "liquid biopsy" has obvious advantages in particular when repeated sampling is required for monitoring therapies in cancer patients. However, the biology behind tumor cell dissemination and its contribution to metastatic progression in cancer patients is still subject to controversial discussions. This manuscript reviews current theories on the genetic traits behind the spread of CTCs and progression of DTCs into overt metastases. PMID:26931653

  20. Targeted Proapoptotic Peptides Depleting Adipose Stromal Cells Inhibit Tumor Growth.

    PubMed

    Daquinag, Alexes C; Tseng, Chieh; Zhang, Yan; Amaya-Manzanares, Felipe; Florez, Fernando; Dadbin, Ali; Zhang, Tao; Kolonin, Mikhail G

    2016-02-01

    Progression of many cancers is associated with tumor infiltration by mesenchymal stromal cells (MSC). Adipose stromal cells (ASC) are MSC that serve as adipocyte progenitors and endothelium-supporting cells in white adipose tissue (WAT). Clinical and animal model studies indicate that ASC mobilized from WAT are recruited by tumors. Direct evidence for ASC function in tumor microenvironment has been lacking due to unavailability of approaches to specifically inactivate these cells. Here, we investigate the effects of a proteolysis-resistant targeted hunter-killer peptide D-WAT composed of a cyclic domain CSWKYWFGEC homing to ASC and of a proapoptotic domain KLAKLAK2. Using mouse bone marrow transplantation models, we show that D-WAT treatment specifically depletes tumor stromal and perivascular cells without directly killing malignant cells or tumor-infiltrating leukocytes. In several mouse carcinoma models, targeted ASC cytoablation reduced tumor vascularity and cell proliferation resulting in hemorrhaging, necrosis, and suppressed tumor growth. We also validated a D-WAT derivative with a proapoptotic domain KFAKFAK2 that was found to have an improved cytoablative activity. Our results for the first time demonstrate that ASC, recruited as a component of tumor microenvironment, support cancer progression. We propose that drugs targeting ASC can be developed as a combination therapy complementing conventional cancer treatments. PMID:26316391

  1. Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors

    PubMed Central

    Wainwright, Derek A.; Sengupta, Sadhak; Han, Yu; Lesniak, Maciej S.

    2011-01-01

    Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an average survival time of 15 months. Previously, we and others demonstrated that CD4+FoxP3+ regulatory T cells (Tregs) infiltrate human GBM as well as mouse models that recapitulate malignant brain tumors. However, whether brain tumor-resident Tregs are thymus-derived natural Tregs (nTregs) or induced Tregs (iTregs), by the conversion of conventional CD4+ T cells, has not been established. To investigate this question, we utilized the i.c. implanted GL261 cell-based orthotopic mouse model, the RasB8 transgenic astrocytoma mouse model, and a human GBM tissue microarray. We demonstrate that Tregs in brain tumors are predominantly thymus derived, since thymectomy, prior to i.c. GL261 cell implantation, significantly decreased the level of Tregs in mice with brain tumors. Accordingly, most Tregs in human GBM and mouse brain tumors expressed the nTreg transcription factor, Helios. Interestingly, a significant effect of the brain tumor microenvironment on Treg lineage programming was observed, based on higher levels of brain tumor-resident Tregs expressing glucocorticoid-induced tumor necrosis factor receptor and CD103 and lower levels of Tregs expressing CD62L and CD45RB compared with peripheral Tregs. Furthermore, there was a higher level of nTregs in brain tumors that expressed the proliferative marker Ki67 compared with iTregs and conventional CD4+ T cells. Our study demonstrates that future Treg-depleting therapies should aim to selectively target systemic rather than intratumoral nTregs in brain tumor-specific immunotherapeutic strategies. PMID:21908444

  2. Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors.

    PubMed

    Wainwright, Derek A; Sengupta, Sadhak; Han, Yu; Lesniak, Maciej S

    2011-12-01

    Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an average survival time of 15 months. Previously, we and others demonstrated that CD4(+)FoxP3(+) regulatory T cells (Tregs) infiltrate human GBM as well as mouse models that recapitulate malignant brain tumors. However, whether brain tumor-resident Tregs are thymus-derived natural Tregs (nTregs) or induced Tregs (iTregs), by the conversion of conventional CD4(+) T cells, has not been established. To investigate this question, we utilized the i.c. implanted GL261 cell-based orthotopic mouse model, the RasB8 transgenic astrocytoma mouse model, and a human GBM tissue microarray. We demonstrate that Tregs in brain tumors are predominantly thymus derived, since thymectomy, prior to i.c. GL261 cell implantation, significantly decreased the level of Tregs in mice with brain tumors. Accordingly, most Tregs in human GBM and mouse brain tumors expressed the nTreg transcription factor, Helios. Interestingly, a significant effect of the brain tumor microenvironment on Treg lineage programming was observed, based on higher levels of brain tumor-resident Tregs expressing glucocorticoid-induced tumor necrosis factor receptor and CD103 and lower levels of Tregs expressing CD62L and CD45RB compared with peripheral Tregs. Furthermore, there was a higher level of nTregs in brain tumors that expressed the proliferative marker Ki67 compared with iTregs and conventional CD4(+) T cells. Our study demonstrates that future Treg-depleting therapies should aim to selectively target systemic rather than intratumoral nTregs in brain tumor-specific immunotherapeutic strategies. PMID:21908444

  3. Violacein induces p44/42 mitogen-activated protein kinase-mediated solid tumor cell death and inhibits tumor cell migration

    PubMed Central

    MEHTA, TORAL; VERCRUYSSE, KOEN; JOHNSON, TERRANCE; EJIOFOR, ANTHONY OKECHUKWU; MYLES, ELBERT; QUICK, QUINCY ANTOINE

    2015-01-01

    Microbial secondary metabolites have emerged as alternative novel drugs for the treatment of human cancers. Violacein, a purple pigment produced by Chromobacterium violaceum, was investigated in the present study for its anti-tumor properties in tumor cell lines. Clinically applicable concentrations of violacein were demonstrated to inhibit the proliferative capacity of tumor cell lines according to a crystal violet proliferation assay. The underlying mechanism was the promotion of apoptotic cell death, as indicated by poly(ADP ribose) polymerase cleavage and p44/42 mitogen-activated protein kinase signaling determined by western blot analysis. Collectively, this provided mechanistic evidence that violacein elicits extracellular-signal regulated kinase-induced apoptosis via the intrinsic pathway. The anti-malignant properties of violacein in the present study were further demonstrated by its inhibitory effects on brain tumor cell migration, specifically glioblastomas, one of the most invasive and therapeutically resistant neoplasms in the clinic. Additionally, solid tumors examined in the present study displayed differential cellular responses and sensitivities to violacein as observed by morphologically induced cellular changes that contributed to its anti-migratory properties. In conclusion, violacein is a novel natural product with the potential to kill several types of human tumor cell lines, as well as prevent disease recurrence by antagonizing cellular processes that contribute to metastatic invasion. PMID:25816226

  4. Tumor targeting with a (99m)Tc-labeled AS1411 aptamer in prostate tumor cells.

    PubMed

    Noaparast, Zohreh; Hosseinimehr, Seyed Jalal; Piramoon, Majid; Abedi, Seyed Mohammad

    2015-01-01

    AS1411, a 26-base guanine-rich oligonucleotide aptamer, has high affinity to nucleolin, mainly on tumor cell surfaces. In this study, a modified AS1411 was labeled with (99m)Tc and evaluated as a potential tumor-targeting agent for imaging. The AS1411 aptamer was conjugated with HYNIC and labeled with (99m)Tc in the presence a co-ligand. Radiochemical purity and stability testing of the (99m)Tc-HYNIC-AS1411 aptamer were carried out with thin layer chromatography and a size-exclusion column in normal saline and human serum. Cellular nucleolin-specific binding, cellular internalization in DU-145 cells, as high levels of nucleolin expression, were performed. Additionally, biodistribution in normal mice and DU-145 tumour-bearing mice was assessed. Radiolabeling of the aptamer resulted in a reasonable yield and radiochemical purity after purification. The aptamer was stable in normal saline and human serum, and cellular experiments demonstrated specific binding of the AS1411 aptamer to the nucleolin protein. Based on biodistribution assessment of (99m)Tc-HYNIC-AS1411, rapid blood clearance was seen after injection and it appears that the excretion route was via the urinary system at 1 h post-injection. Tumours also showed a higher accumulation of radioactivity with this labeled aptamer. (99m)Tc-AS1411 can be a potential tool for the molecular imaging of nucleolin-overexpressing cancers. PMID:25673264

  5. Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine.

    PubMed

    Du, Michael; Zhang, Linna; Scorsone, Kathleen A; Woodfield, Sarah E; Zage, Peter E

    2016-01-01

    Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. Tumor cells were then treated with combinations of nifurtimox and BSO and evaluated for viability using MTT assays. All neural tumor cell lines were sensitive to nifurtimox, and IC50 values ranged from approximately 20 to 210 μM. Nifurtimox treatment inhibited ERK phosphorylation and induced apoptosis in tumor cells. Furthermore, the combination of nifurtimox and BSO demonstrated significant synergistic efficacy in all tested cell lines. Additional preclinical and clinical studies of the combination of nifurtimox and BSO in patients with neural tumors are warranted. PMID:27282514

  6. Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

    PubMed Central

    Alkasalias, Twana; Flaberg, Emilie; Kashuba, Vladimir; Alexeyenko, Andrey; Pavlova, Tatiana; Savchenko, Andrii; Szekely, Laszlo; Klein, George; Guven, Hayrettin

    2014-01-01

    Normal human and murine fibroblasts can inhibit proliferation of tumor cells when cocultured in vitro. The inhibitory capacity varies depending on the donor and the site of origin of the fibroblast. We showed previously that effective inhibition requires formation of a morphologically intact fibroblast monolayer before seeding of the tumor cells. Here we show that inhibition is extended to motility of tumor cells and we dissect the factors responsible for these inhibitory functions. We find that inhibition is due to two different sets of molecules: (i) the extracellular matrix (ECM) and other surface proteins of the fibroblasts, which are responsible for contact-dependent inhibition of tumor cell proliferation; and (ii) soluble factors secreted by fibroblasts when confronted with tumor cells (confronted conditioned media, CCM) contribute to inhibition of tumor cell proliferation and motility. However, conditioned media (CM) obtained from fibroblasts alone (nonconfronted conditioned media, NCM) did not inhibit tumor cell proliferation and motility. In addition, quantitative PCR (Q-PCR) data show up-regulation of proinflammatory genes. Moreover, comparison of CCM and NCM with an antibody array for 507 different soluble human proteins revealed differential expression of growth differentiation factor 15, dickkopf-related protein 1, endothelial-monocyte-activating polypeptide II, ectodysplasin A2, Galectin-3, chemokine (C-X-C motif) ligand 2, Nidogen1, urokinase, and matrix metalloproteinase 3. PMID:25404301

  7. Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine

    PubMed Central

    Du, Michael; Zhang, Linna; Scorsone, Kathleen A.; Woodfield, Sarah E.; Zage, Peter E.

    2016-01-01

    Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. Tumor cells were then treated with combinations of nifurtimox and BSO and evaluated for viability using MTT assays. All neural tumor cell lines were sensitive to nifurtimox, and IC50 values ranged from approximately 20 to 210 μM. Nifurtimox treatment inhibited ERK phosphorylation and induced apoptosis in tumor cells. Furthermore, the combination of nifurtimox and BSO demonstrated significant synergistic efficacy in all tested cell lines. Additional preclinical and clinical studies of the combination of nifurtimox and BSO in patients with neural tumors are warranted. PMID:27282514

  8. Lactate Contribution to the Tumor Microenvironment: Mechanisms, Effects on Immune Cells and Therapeutic Relevance

    PubMed Central

    Romero-Garcia, Susana; Moreno-Altamirano, María Maximina B.; Prado-Garcia, Heriberto; Sánchez-García, Francisco Javier

    2016-01-01

    Malignant transformation of cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate, even under normoxic conditions; this phenomenon of aerobic glycolysis is largely known as the Warburg effect. This metabolic reprograming serves to generate biosynthetic precursors, thus facilitating the survival of rapidly proliferating malignant cells. Extracellular lactate directs the metabolic reprograming of tumor cells, thereby serving as an additional selective pressure. Besides tumor cells, stromal cells are another source of lactate production in the tumor microenvironment, whose role in both tumor growth and the antitumor immune response is the subject of intense research. In this review, we provide an integral perspective of the relationship between lactate and the overall tumor microenvironment, from lactate structure to metabolic pathways for its synthesis, receptors, signaling pathways, lactate-producing cells, lactate-responding cells, and how all contribute to the tumor outcome. We discuss the role of lactate as an immunosuppressor molecule that contributes to tumor evasion and we explore the possibility of targeting lactate metabolism for cancer treatment, as well as of using lactate as a prognostic biomarker. PMID:26909082

  9. The commonly used antimicrobial additive triclosan is a liver tumor promoter

    PubMed Central

    Yueh, Mei-Fei; Taniguchi, Koji; Chen, Shujuan; Evans, Ronald M.; Hammock, Bruce D.; Karin, Michael; Tukey, Robert H.

    2014-01-01

    Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated. PMID:25404284

  10. The commonly used antimicrobial additive triclosan is a liver tumor promoter.

    PubMed

    Yueh, Mei-Fei; Taniguchi, Koji; Chen, Shujuan; Evans, Ronald M; Hammock, Bruce D; Karin, Michael; Tukey, Robert H

    2014-12-01

    Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated. PMID:25404284

  11. Tumor Biomarkers in Spindle Cell Variant Squamous Cell Carcinoma of the Head and Neck

    PubMed Central

    Rosko, Andrew J.; Birkeland, Andrew C.; Wilson, Kevin F.; Muenz, Daniel G.; Bellile, Emily; Bradford, Carol R.; McHugh, Jonathan B.; Spector, Matthew E.

    2016-01-01

    Objective To determine biomarkers of recurrence and survival in patients with spindle cell variant squamous cell carcinoma (SpSCC) of the head and neck. Study Design Retrospective case control study. Setting Tertiary academic center. Subjects and Methods Thirty-two SpSCC patients (mean age, 68.8) between 1987 and 2009 were identified and reviewed. A tissue microarray (TMA) was constructed from tumor specimens. Tumor biomarkers under study included p16, EGFR, p53, EZH2, Cyclin D1, CD104, HGFa, p21, and cMET. An additional TMA was constructed from patients with non-SpSCC oral cavity squamous cell carcinoma for comparative purposes. The main outcomes were overall survival (OS), disease specific survival (DSS) and recurrence free survival (RFS). Results In the SpSCC cohort, tumors positive for cMet had worse OS (p<0.001). Patients positive for cMet (p=0.007), Cyclin D1 (p=0.019), and p16 (p=0.004) had worse DSS. RFS was also worse in patients with tumors positive for cMet (p=0.037), Cyclin D1 (p=0.012), and p16 (p<0.001). Compared to the oral cavity cohort there was a significantly larger proportion of patients in the SpSCC group with tumors staining positive for cMet and a lower proportion of tumors positive for cyclin D1. Conclusion cMet, Cyclin D1, p16 are predictive tumor biomarkers for risk of recurrence and worse disease specific survival in patients with SpSCC. PMID:26980915

  12. Immune signature of tumor infiltrating immune cells in renal cancer

    PubMed Central

    Geissler, Katharina; Fornara, Paolo; Lautenschläger, Christine; Holzhausen, Hans-Jürgen; Seliger, Barbara; Riemann, Dagmar

    2015-01-01

    Tumor-associated immune cells have been discussed as an essential factor for the prediction of the outcome of tumor patients. Lymphocyte-specific genes are associated with a favorable prognosis in colorectal cancer but with poor survival in renal cell carcinoma (RCC). Flow cytometric analyses combined with immunohistochemistry were performed to study the phenotypic profiles of tumor infiltrating lymphocytes (TIL) and the frequency of T cells and macrophages in RCC lesions. Data were correlated with clinicopathological parameters and survival of patients. Comparing oncocytoma and clear cell (cc)RCC, T cell numbers as well as activation-associated T cell markers were higher in ccRCC, whereas the frequency of NK cells was higher in oncocytoma. An intratumoral increase of T cell numbers was found with higher tumor grades (G1:G2:G3/4 = 1:3:4). Tumor-associated macrophages slightly increased with dedifferentiation, although the macrophage-to-T cell ratio was highest in G1 tumor lesions. A high expression of CD57 was found in T cells of early tumor grades, whereas T cells in dedifferentiated RCC lesions expressed higher levels of CD69 and CTLA4. TIL composition did not differ between older (>70 y) and younger (<58 y) patients. Enhanced patients’ survival was associated with a higher percentage of tumor infiltrating NK cells and Th1 markers, e.g. HLA-DR+ and CXCR3+ T cells, whereas a high number of T cells, especially with high CD69 expression correlated with a worse prognosis of patients. Our results suggest that immunomonitoring of RCC patients might represent a useful tool for the prediction of the outcome of RCC patients. PMID:25949868

  13. NKT cells as an ideal anti-tumor immunotherapeutic.

    PubMed

    Fujii, Shin-Ichiro; Shimizu, Kanako; Okamoto, Yoshitaka; Kunii, Naoki; Nakayama, Toshinori; Motohashi, Shinichiro; Taniguchi, Masaru

    2013-01-01

    Human natural killer T (NKT) cells are characterized by their expression of an invariant T cell antigen receptor α chain variable region encoded by a Vα24Jα18 rearrangement. These NKT cells recognize α-galactosylceramide (α-GalCer) in conjunction with the MHC class I-like CD1d molecule and bridge the innate and acquired immune systems to mediate efficient and augmented immune responses. A prime example of one such function is adjuvant activity: NKT cells augment anti-tumor responses because they can rapidly produce large amounts of IFN-γ, which acts on NK cells to eliminate MHC negative tumors and also on CD8 cytotoxic T cells to kill MHC positive tumors. Thus, upon administration of α-GalCer-pulsed DCs, both MHC negative and positive tumor cells can be effectively eliminated, resulting in complete tumor eradication without tumor recurrence. Clinical trials have been completed in a cohort of 17 patients with advanced non-small cell lung cancers and 10 cases of head and neck tumors. Sixty percent of advanced lung cancer patients with high IFN-γ production had significantly prolonged median survival times of 29.3 months with only the primary treatment. In the case of head and neck tumors, 10 patients who completed the trial all had stable disease or partial responses 5 weeks after the combination therapy of α-GalCer-DCs and activated NKT cells. We now focus on two potential powerful treatment options for the future. One is to establish artificial adjuvant vector cells containing tumor mRNA and α-GalCer/CD1d. This stimulates host NKT cells followed by DC maturation and NK cell activation but also induces tumor-specific long-term memory CD8 killer T cell responses, suppressing tumor metastasis even 1 year after the initial single injection. The other approach is to establish induced pluripotent stem (iPS) cells that can generate unlimited numbers of NKT cells with adjuvant activity. Such iPS-derived NKT cells produce IFN-γ in vitro and in vivo upon

  14. X-ray sensitivity of human tumor cells in vitro

    SciTech Connect

    Weichselbaum, R.R.; Nove, J.; Little, J.B.

    1980-04-01

    Clonally-derived cells from ten human malignant tumors considered radiocurable (breast, neuroblastoma, medulloblastoma) or non-radiocurable (osteosarcoma, hypernephroma, glioblastoma, melanoma) were studied in cell culture and their in vitro x-ray survival curve parameters determined (anti n, D/sub 0/). There were no significant differences among the tumor cell lines suggesting that survival parameters in vitro do not explain differences in clinical radiocurability. Preliminary investigation with density inhibited human tumor cells indicate that such an approach may yield information regarding inherent cellular differences in radiocurability.

  15. Synergistic action of tiazofurin with hypoxanthine and allopurinol in human neuroectodermal tumor cell lines.

    PubMed

    Szekeres, T; Schuchter, K; Chiba, P; Ressmann, G; Lhotka, C; Gharehbaghi, K; Szalay, S M; Pillwein, K

    1993-12-01

    The activity of IMP dehydrogenase (EC 1.2.1.14), the key enzyme of de novo guanylate biosynthesis, was shown to be increased in tumor cells. Tiazofurin (TR), a potent and specific inhibitor of this enzyme, proved to be effective in the treatment of refractory granulocytic leukemia in blast crisis. We examined the effects of tiazofurin as a single agent and in combination with hypoxanthine and allopurinol in six different neuroectodermal tumor cell lines, the STA-BT-3 and 146-18 human glioblastoma cell lines, the SK-N-SH, LA-N-1 and LA-N-5 human neuroblastoma cell lines, and the STA-ET-1 Ewing tumor cell line. Tiazofurin inhibited tumor cell growth with IC50 values between 2.2 microM (LA-N-1 cell line) and 550 microM (LA-N-5 cells) and caused a significant decrease of intracellular GTP pools (GTP concentrations decreased to 39-79% of control). Incorporation of [8-14C]guanine into GTP pools was determined as a measure of guanylate salvage activity; incubation with 100 microM hypoxanthine caused a 62-96% inhibition of the salvage pathway. Incubation with tiazofurin (100 microM) and hypoxanthine (100 microM) synergistically inhibited tumor cell growth, and the addition of allopurinol (100 microM) strengthened these effects. Therefore, this drug combination, inhibiting guanylate de novo and salvage pathways, may prove useful in the treatment of human neuroectodermal tumors. PMID:7903533

  16. Targeting of tumor endothelial cells combining 2 Gy/day of X-ray with Everolimus is the effective modality for overcoming clinically relevant radioresistant tumors.

    PubMed

    Kuwahara, Yoshikazu; Mori, Miyuki; Kitahara, Shuji; Fukumoto, Motoi; Ezaki, Taichi; Mori, Shiro; Echigo, Seishi; Ohkubo, Yasuhito; Fukumoto, Manabu

    2014-04-01

    Radiotherapy is widely used to treat cancer because it has the advantage of physically and functionally conserving the affected organ. To improve radiotherapy and investigate the molecular mechanisms of cellular radioresistance, we established a clinically relevant radioresistant (CRR) cell line, SAS-R, from SAS cells. SAS-R cells continue to proliferate when exposed to fractionated radiation (FR) of 2 Gy/day for more than 30 days in vitro. A xenograft tumor model of SAS-R was also resistant to 2 Gy/day of X-rays for 30 days. The density of blood vessels in SAS-R tumors was higher than in SAS tumors. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, sensitized microvascular endothelial cells to radiation, but failed to radiosensitize SAS and SAS-R cells in vitro. Everolimus with FR markedly reduced SAS and SAS-R tumor volumes. Additionally, the apoptosis of endothelial cells (ECs) increased in SAS-R tumor tissues when both Everolimus and radiation were administered. Both CD34-positive and tomato lectin-positive blood vessel densities in SAS-R tumor tissues decreased remarkably after the Everolimus and radiation treatment. Everolimus-induced apoptosis of vascular ECs in response to radiation was also followed by thrombus formation that leads to tumor necrosis. We conclude that FR combined with Everolimus may be an effective modality to overcome radioresistant tumors via targeting tumor ECs. PMID:24464839

  17. Regulatory T cells actively infiltrate metastatic brain tumors.

    PubMed

    Sugihara, Adam Quasar; Rolle, Cleo E; Lesniak, Maciej S

    2009-06-01

    Regulatory T cells (CD4+CD25+FoxP3+, Treg) have been shown to play a major role in suppression of the immune response to malignant gliomas. In this study, we investigated the kinetics of Treg infiltration in metastatic brain tumor models, including melanoma, breast and colon cancers. Our data indicate that both CD4+ and Treg infiltration are significantly increased throughout the time of metastatic tumor progression. These findings were recapitulated in human CNS tumor samples of metastatic melanoma and non-small cell lung carcinoma. Collectively, these data support investigating immunotherapeutic strategies targeting Treg in metastatic CNS tumors. PMID:19424570

  18. Malignant phyllodes tumors display mesenchymal stem cell features and aldehyde dehydrogenase/disialoganglioside identify their tumor stem cells

    PubMed Central

    2014-01-01

    Introduction Although breast phyllodes tumors are rare, there is no effective therapy other than surgery. Little is known about their tumor biology. A malignant phyllodes tumor contains heterologous stromal elements, and can transform into rhabdomyosarcoma, liposarcoma and osteosarcoma. These versatile properties prompted us to explore their possible relationship to mesenchymal stem cells (MSCs) and to search for the presence of cancer stem cells (CSCs) in phyllodes tumors. Methods Paraffin sections of malignant phyllodes tumors were examined for various markers by immunohistochemical staining. Xenografts of human primary phyllodes tumors were established by injecting freshly isolated tumor cells into the mammary fat pad of non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. To search for CSCs, xenografted tumor cells were sorted into various subpopulations by flow cytometry and examined for their in vitro mammosphere forming capacity, in vivo tumorigenicity in NOD-SCID mice and their ability to undergo differentiation. Results Immunohistochemical analysis revealed the expression of the following 10 markers: CD44, CD29, CD106, CD166, CD105, CD90, disialoganglioside (GD2), CD117, Aldehyde dehydrogenase 1 (ALDH), and Oct-4, and 7 clinically relevant markers (CD10, CD34, p53, p63, Ki-67, Bcl-2, vimentin, and Globo H) in all 51 malignant phyllodes tumors examined, albeit to different extents. Four xenografts were successfully established from human primary phyllodes tumors. In vitro, ALDH+ cells sorted from xenografts displayed approximately 10-fold greater mammosphere-forming capacity than ALDH- cells. GD2+ cells showed a 3.9-fold greater capacity than GD2- cells. ALDH+/GD2+cells displayed 12.8-fold greater mammosphere forming ability than ALDH-/GD2- cells. In vivo, the tumor-initiating frequency of ALDH+/GD2+ cells were up to 33-fold higher than that of ALDH+ cells, with as few as 50 ALDH+/GD2+ cells being sufficient for engraftment. Moreover, we

  19. Hypoxic cell turnover in different solid tumor lines

    SciTech Connect

    Ljungkvist, Anna S.E. . E-mail: a.ljungkvist@rther.umcn.nl; Bussink, Johan; Kaanders, Johannes H.A.M.; Rijken, Paulus F.J.W.; Begg, Adrian C.; Raleigh, James A.; Kogel, Albert J. van der

    2005-07-15

    Purpose: Most solid tumors contain hypoxic cells, and the amount of tumor hypoxia has been shown to have a negative impact on the outcome of radiotherapy. The efficacy of combined modality treatments depends both on the sequence and timing of the treatments. Hypoxic cell turnover in tumors may be important for optimal scheduling of combined modality treatments, especially when hypoxic cell targeting is involved. Methods and Materials: Previously we have shown that a double bioreductive hypoxic marker assay could be used to detect changes of tumor hypoxia in relation to the tumor vasculature after carbogen and hydralazine treatments. This assay was used in the current study to establish the turnover rate of hypoxic cells in three different tumor models. The first hypoxic marker, pimonidazole, was administered at variable times before tumor harvest, and the second hypoxic marker, CCI-103F, was injected at a fixed time before harvest. Hypoxic cell turnover was defined as loss of pimonidazole (first marker) relative to CCI-103F (second marker). Results: The half-life of hypoxic cell turnover was 17 h in the murine C38 colon carcinoma line, 23 h and 49 h in the human xenograft lines MEC82 and SCCNij3, respectively. Within 24 h, loss of pimonidazole-stained areas in C38 and MEC82 occurred concurrent with the appearance of pimonidazole positive cell debris in necrotic regions. In C38 and MEC82, most of the hypoxic cells had disappeared after 48 h, whereas in SCCNij3, viable cells that had been labeled with pimonidazole were still observed after 5 days. Conclusions: The present study demonstrates that the double hypoxia marker assay can be used to study changes in both the proportion of hypoxic tumor cells and their lifespan at the same time. The present study shows that large differences in hypoxic cell turnover rates may exist among tumor lines, with half-lives ranging from 17-49 h.

  20. Dendritic cells loaded with apoptotic antibody-coated tumor cells provide protective immunity against B-cell lymphoma in vivo.

    PubMed

    Franki, Suzanne N; Steward, Kristopher K; Betting, David J; Kafi, Kamran; Yamada, Reiko E; Timmerman, John M

    2008-02-01

    The in vitro priming of tumor-specific T cells by dendritic cells (DCs) phagocytosing killed tumor cells can be augmented in the presence of antitumor monoclonal antibody (mAb). We investigated whether DCs phagocytosing killed lymphoma cells coated with tumor-specific antibody could elicit antitumor immunity in vivo. Irradiated murine 38C13 lymphoma cells were cocultured with bone marrow-derived DCs in the presence or absence of tumor-specific mAb. Mice vaccinated with DCs cocultured with mAb-coated tumor cells were protected from tumor challenge (60% long-term survival), whereas DCs loaded with tumor cells alone were much less effective. The opsonized whole tumor cell-DC vaccine elicited significantly better tumor protection than a traditional lymphoma idiotype (Id) protein vaccine, and in combination with chemotherapy could eradicate preexisting tumor. Moreover, the DC vaccine protected animals from both wild-type and Id-negative variant tumor cells, indicating that Id is not a major target of the induced tumor immunity. Protection was critically dependent upon CD8(+) T cells, with lesser contribution by CD4(+) T cells. Importantly, opsonized whole tumor cell-DC vaccination did not result in tissue-specific autoimmunity. Since opsonized whole tumor cell-DC and Id vaccines appear to target distinct tumor antigens, optimal antilymphoma immunity might be achieved by combining these approaches. PMID:17993615

  1. Multi-photon Imaging of Tumor Cell Invasion in an Orthotopic Mouse Model of Oral Squamous Cell Carcinoma

    PubMed Central

    Gatesman Ammer, Amanda; Hayes, Karen E.; Martin, Karen H.; Zhang, Lingqing; Spirou, George A.; Weed, Scott A.

    2011-01-01

    Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient management strategies. Orthotopic mouse models of oral cancer have been developed to facilitate the study of factors that impact invasion and serve as model system for evaluating anti-tumor therapeutics. In these systems, visualization of disseminated tumor cells within oral cavity tissues has typically been conducted by either conventional histology or with in vivo bioluminescent methods. A primary drawback of these techniques is the inherent inability to accurately visualize and quantify early tumor cell invasion arising from the primary site in three dimensions. Here we describe a protocol that combines an established model for squamous cell carcinoma of the tongue (SCOT) with two-photon imaging to allow multi-vectorial visualization of lingual tumor spread. The OSC-19 head and neck tumor cell line was stably engineered to express the F-actin binding peptide LifeAct fused to the mCherry fluorescent protein (LifeAct-mCherry). Fox1nu/nu mice injected with these cells reliably form tumors that allow the tongue to be visualized by ex-vivo application of two-photon microscopy. This technique allows for the orthotopic visualization of the tumor mass and locally invading cells in excised tongues without disruption of the regional tumor microenvironment. In addition, this system allows for the quantification of tumor cell invasion by calculating distances that invaded cells move from the primary tumor site. Overall this procedure provides an enhanced model system for analyzing factors that contribute to SCOT invasion and therapeutic treatments tailored to prevent local invasion and distant metastatic spread. This method also has the potential to be ultimately combined with other imaging modalities in an in vivo setting. PMID:21808230

  2. Tumor cell lysates as immunogenic sources for cancer vaccine design

    PubMed Central

    González, Fermín E; Gleisner, Alejandra; Falcón-Beas, Felipe; Osorio, Fabiola; López, Mercedes N; Salazar-Onfray, Flavio

    2015-01-01

    Autologous dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) are a promising immunological tool for cancer therapy. These stimulate the antitumor response and immunological memory generation. Nevertheless, many patients remain refractory to DC approaches. Antigen (Ag) delivery to DCs is relevant to vaccine success, and antigen peptides, tumor-associated proteins, tumor cells, autologous tumor lysates, and tumor-derived mRNA have been tested as Ag sources. Recently, DCs loaded with allogeneic tumor cell lysates were used to induce a potent immunological response. This strategy provides a reproducible pool of almost all potential Ags suitable for patient use, independent of MHC haplotypes or autologous tumor tissue availability. However, optimizing autologous tumor cell lysate preparation is crucial to enhancing efficacy. This review considers the role of cancer cell-derived lysates as a relevant source of antigens and as an activating factor for ex vivo therapeutic DCs capable of responding to neoplastic cells. These promising therapies are associated with the prolonged survival of advanced cancer patients. PMID:25625929

  3. Tumor cell lysates as immunogenic sources for cancer vaccine design.

    PubMed

    González, Fermín E; Gleisner, Alejandra; Falcón-Beas, Felipe; Osorio, Fabiola; López, Mercedes N; Salazar-Onfray, Flavio

    2014-01-01

    Autologous dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) are a promising immunological tool for cancer therapy. These stimulate the antitumor response and immunological memory generation. Nevertheless, many patients remain refractory to DC approaches. Antigen (Ag) delivery to DCs is relevant to vaccine success, and antigen peptides, tumor-associated proteins, tumor cells, autologous tumor lysates, and tumor-derived mRNA have been tested as Ag sources. Recently, DCs loaded with allogeneic tumor cell lysates were used to induce a potent immunological response. This strategy provides a reproducible pool of almost all potential Ags suitable for patient use, independent of MHC haplotypes or autologous tumor tissue availability. However, optimizing autologous tumor cell lysate preparation is crucial to enhancing efficacy. This review considers the role of cancer cell-derived lysates as a relevant source of antigens and as an activating factor for ex vivo therapeutic DCs capable of responding to neoplastic cells. These promising therapies are associated with the prolonged survival of advanced cancer patients. PMID:25625929

  4. Multiple keratocystic odontogenic tumors in nevoid basal cell carcinoma syndrome

    PubMed Central

    Pereira, Treville; Tamgadge, Avinash; Sapdhare, Swati; Pujar, Ashwini

    2015-01-01

    Keratocystic odontogenic tumor (KCOT) is of particular interest because its recurrence rate is high and its behavior is aggressive. Nevoid basal cell carcinoma syndrome (NBCCS), which is also known as Gorlin syndrome, is a hereditary condition characterized by a wide range of developmental abnormalities and with a predisposition to neoplasms. These multiple KCOTs have warranted an aggressive treatment at the earliest because of the damage and possible complications. Recurrence of these lesions is a characteristic feature that has to be considered while explaining the prognosis to the patient. Here, we report a case of a 14-year-old boy with clinical features of basal cell nevus syndrome and multiple KCOTs. In addition to the other common features, congenitally missing third molars in all the four quadrants is a feature which has not been previously reported in association with NBCCS in Indian patients. PMID:26981489

  5. Adjuvants for enhancing the immunogenicity of whole tumor cell vaccines.

    PubMed

    Chiang, Cheryl Lai-Lai; Kandalaft, Lana E; Coukos, George

    2011-01-01

    Whole tumor cell lysates can serve as excellent multivalent vaccines for priming tumor-specific CD8(+) and CD4(+) T cells. Whole cell vaccines can be prepared with hypochlorous acid oxidation, UVB-irradiation and repeat cycles of freeze and thaw. One major obstacle to successful immunotherapy is breaking self-tolerance to tumor antigens. Clinically approved adjuvants, including Montanide™ ISA-51 and 720, and keyhole-limpet proteins can be used to enhance tumor cell immunogenicity by stimulating both humoral and cellular anti-tumor responses. Other potential adjuvants, such as Toll-like receptor agonists (e.g., CpG, MPLA and PolyI:C), and cytokines (e.g., granulocyte-macrophage colony stimulating factor), have also been investigated. PMID:21557641

  6. Mixed ovarian germ cell tumor composed of immature teratoma, yolk sac tumor and embryonal carcinoma.

    PubMed

    Wang, Ying; Zhou, Feng; Qian, Zhida; Qing, Jiale; Zhao, Mengdam; Huang, Lili

    2014-11-01

    We report the case of a 19-year-old woman experiencing lower abdominal distension and pain. Laboratory tests indicated elevated serum levels of Alpha-Fetoprotein (AFP) and human Chorionic Gonadotropin (hCG). A large mass was detected in the abdomen by physical examination and by transvaginal ultrasonography. Exploratory laparotomy was performed, and a smooth-surfaced, spherical, solid tumor was found on the left ovary, measuring 11.5 x 9.9 x 6.9 cm. Histological evaluation revealed that the tumor consisted of a combination of immature teratoma, Yolk Sac Tumor, and embryonal carcinoma; this is a very rare combination in mixed germ cell tumors. PMID:25518772

  7. Circulating tumor cells in lung cancer.

    PubMed

    Young, Rachel; Pailler, Emma; Billiot, Fanny; Drusch, Françoise; Barthelemy, Amélie; Oulhen, Marianne; Besse, Benjamin; Soria, Jean-Charles; Farace, Françoise; Vielh, Philippe

    2012-01-01

    Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a 'liquid biopsy' is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment. PMID:23207444

  8. Genetic background affects susceptibility to tumoral stem cell reprogramming

    PubMed Central

    García-Ramírez, Idoia; Ruiz-Roca, Lucía; Martín-Lorenzo, Alberto; Blanco, Óscar; García-Cenador, María Begoña; García-Criado, Francisco Javier; Vicente-Dueñas, Carolina; Sánchez-García, Isidro

    2013-01-01

    The latest studies of the interactions between oncogenes and its target cell have shown that certain oncogenes may act as passengers to reprogram tissue-specific stem/progenitor cell into a malignant cancer stem cell state. In this study, we show that the genetic background influences this tumoral stem cell reprogramming capacity of the oncogenes using as a model the Sca1-BCRABLp210 mice, where the type of tumor they develop, chronic myeloid leukemia (CML), is a function of tumoral stem cell reprogramming. Sca1-BCRABLp210 mice containing FVB genetic components were significantly more resistant to CML. However, pure Sca1-BCRABLp210 FVB mice developed thymomas that were not seen in the Sca1-BCRABLp210 mice into the B6 background. Collectively, our results demonstrate for the first time that tumoral stem cell reprogramming fate is subject to polymorphic genetic control. PMID:23839033

  9. Plasma-activated medium induced apoptosis on tumor cells

    NASA Astrophysics Data System (ADS)

    Hori, Masaru; Tanaka, Hiromasa; Mizuno, Masaaki; Nakamura, Kae; Kajiyama, Hiroaki; Takeda, Keigo; Ishikawa, Kenji; Kano, Hiroyuki; Kikkawa, Fumitaka

    2013-09-01

    The non-equilibrium atmospheric pressure plasma (NEAPP) has attracted attention in cancer therapy. In this study, the fresh medium was treated with our developed NEAPP, ultra-high electron density (approximately 2 × 1016 cm-3). The medium called the plasma-activated medium (PAM) killed not normal cells but tumor cells through induction of apoptosis. Cell proliferation assays showed that the tumor cells were selectively killed by the PAM. Those cells induced apoptosis using an apoptotic molecular marker, cleaved Caspase3/7. The molecular mechanisms of PAM-mediated apoptosis in the tumor cells were also found that the PAM downregulated the expression of AKT kinase, a marker molecule in a survival signal transduction pathway. These results suggest that PAM may be a promising tool for tumor therapy by downregulating the survival signals in cancers.

  10. Tumor and Endothelial Cell Hybrids Participate in Glioblastoma Vasculature

    PubMed Central

    El Hallani, Soufiane; Colin, Carole; El Houfi, Younas; Boisselier, Blandine; Marie, Yannick; Ravassard, Philippe; Labussière, Marianne; Mokhtari, Karima; Thomas, Jean-Léon; Delattre, Jean-Yves; Eichmann, Anne; Sanson, Marc

    2014-01-01

    Background. Recently antiangiogenic therapy with bevacizumab has shown a high but transient efficacy in glioblastoma (GBM). Indeed, GBM is one of the most angiogenic human tumors and endothelial proliferation is a hallmark of the disease. We therefore hypothesized that tumor cells may participate in endothelial proliferation of GBM. Materials and Methods. We used EGFR FISH Probe to detect EGFR amplification and anti-CD31, CD105, VE-cadherin, and vWF to identify endothelial cells. Endothelial and GBM cells were grown separately, labeled with GFP and DsRed lentiviruses, and then cocultured with or without contact. Results. In a subset of GBM tissues, we found that several tumor endothelial cells carry EGFR amplification, characteristic of GBM tumor cells. This observation was reproduced in vitro: when tumor stem cells derived from GBM were grown in the presence of human endothelial cells, a fraction of them acquired endothelial markers (CD31, CD105, VE-cadherin, and vWF). By transduction with GFP and DsRed expressing lentiviral vectors, we demonstrate that this phenomenon is due to cell fusion and not transdifferentiation. Conclusion. A fraction of GBM stem cells thus has the capacity to fuse with endothelial cells and the resulting hybrids may participate in tumor microvascular proliferation and in treatment resistance. PMID:24868550

  11. Aberrant cell cycle regulation in rat liver cells induced by post-initiation treatment with hepatocarcinogens/hepatocarcinogenic tumor promoters.

    PubMed

    Kimura, Masayuki; Mizukami, Sayaka; Watanabe, Yousuke; Onda, Nobuhiko; Yoshida, Toshinori; Shibutani, Makoto

    2016-08-01

    The present study aimed to determine the onset time of hepatocarcinogen/hepatocarcinogenic tumor promoter-specific cell proliferation, apoptosis and aberrant cell cycle regulation after post-initiation treatment. Six-week-old rats were treated with the genotoxic hepatocarcinogen, carbadox (CRB), the marginally hepatocarcinogenic leucomalachite green (LMG), the tumor promoter, β-naphthoflavone (BNF) or the non-carcinogenic hepatotoxicant, acetaminophen, for 2, 4 or 6 weeks during the post-initiation phase using a medium-term liver bioassay. Cell proliferation activity, expression of G2 to M phase- and spindle checkpoint-related molecules, and apoptosis were immunohistochemically analyzed at week 2 and 4, and tumor promotion activity was assessed at week 6. At week 2, hepatocarcinogen/tumor promoter-specific aberrant cell cycle regulation was not observed. At week 4, BNF and LMG increased cell proliferation together with hepatotoxicity, while CRB did not. Additionally, BNF and CRB reduced the number of cells expressing phosphorylated-histone H3 in both ubiquitin D (UBD)(+) cells and Ki-67(+) proliferating cells, suggesting development of spindle checkpoint dysfunction, regardless of cell proliferation activity. At week 6, examined hepatocarcinogens/tumor promoters increased preneoplastic hepatic foci expressing glutathione S-transferase placental form. These results suggest that some hepatocarcinogens/tumor promoters increase their toxicity after post-initiation treatment, causing regenerative cell proliferation. In contrast, some genotoxic hepatocarcinogens may disrupt the spindle checkpoint without facilitating cell proliferation at the early stage of tumor promotion. This suggests that facilitation of cell proliferation and disruption of spindle checkpoint function are induced by different mechanisms during hepatocarcinogenesis. Four weeks of post-initiation treatment may be sufficient to induce hepatocarcinogen/tumor promoter-specific cellular responses. PMID

  12. Tumor-derived factors modulating dendritic cell function.

    PubMed

    Zong, Jinbao; Keskinov, Anton A; Shurin, Galina V; Shurin, Michael R

    2016-07-01

    Dendritic cells (DC) play unique and diverse roles in the tumor occurrence, development, progression and response to therapy. First of all, DC can actively uptake tumor-associated antigens, process them and present antigenic peptides to T cells inducing and maintaining tumor-specific T cell responses. DC interaction with different immune effector cells may also support innate antitumor immunity, as well as humoral responses also known to inhibit tumor development in certain cases. On the other hand, DC are recruited to the tumor site by specific tumor-derived and stroma-derived factors, which may also impair DC maturation, differentiation and function, thus resulting in the deficient formation of antitumor immune response or development of DC-mediated tolerance and immune suppression. Identification of DC-stimulating and DC-suppressing/polarizing factors in the tumor environment and the mechanism of DC modulation are important for designing effective DC-based vaccines and for recovery of immunodeficient resident DC responsible for maintenance of clinically relevant antitumor immunity in patients with cancer. DC-targeting tumor-derived factors and their effects on resident and administered DC in the tumor milieu are described and discussed in this review. PMID:26984847

  13. miRNA-1297 induces cell proliferation by targeting phosphatase and tensin homolog in testicular germ cell tumor cells.

    PubMed

    Yang, Nian-Qin; Zhang, Jian; Tang, Qun-Ye; Guo, Jian-Ming; Wang, Guo-Min

    2014-01-01

    To investigate the role of miR-1297 and the tumor suppressor gene PTEN in cell proliferation of testicular germ cell tumors (TGCT). MTT assays were used to test the effect of miR-1297 on proliferation of the NCCIT testicular germ cell tumor cell line. In NCCIT cells, the expression of PTEN was assessed by Western blotting further. In order to confirm target association between miR-1297 and 3'-UTR of PTEN, a luciferase reporter activity assay was employed. Moreover, roles of PTEN in proliferation of NCCIT cells were evaluated by transfection of PTEN siRNA. Proliferation of NCCIT cells was promoted by miR-1297 in a concentration-dependent manner. In addition, miR-1297 could bind to the 3'-UTR of PTEN based on luciferase reporter activity assay, and reduced expression of PTEN at protein level was found. Proliferation of NCCIT cells was significantly enhanced after knockdown of PTEN by siRNA. miR-1297 as a potential oncogene could induce cell proliferation by targeting PTEN in NCCIT cells. PMID:25124605

  14. Galectin-3 Determines Tumor Cell Adaptive Strategies in Stressed Tumor Microenvironments.

    PubMed

    Cardoso, Ana Carolina Ferreira; Andrade, Luciana Nogueira de Sousa; Bustos, Silvina Odete; Chammas, Roger

    2016-01-01

    Galectin-3 is a member of the β-galactoside-binding lectin family, whose expression is often dysregulated in cancers. While galectin-3 is usually an intracellular protein found in the nucleus and in the cytoplasm, under certain conditions, galectin-3 can be secreted by an yet unknown mechanism. Under stressing conditions (e.g., hypoxia and nutrient deprivation) galectin-3 is upregulated, through the activity of transcription factors, such as HIF-1α and NF-κB. Here, we review evidence that indicates a positive role for galectin-3 in MAPK family signal transduction, leading to cell proliferation and cell survival. Galectin-3 serves as a scaffold protein, which favors the spatial organization of signaling proteins as K-RAS. Upon secretion, extracellular galectin-3 interacts with a variety of cell surface glycoproteins, such as growth factor receptors, integrins, cadherins, and members of the Notch family, among other glycoproteins, besides different extracellular matrix molecules. Through its ability to oligomerize, galectin-3 forms lectin lattices that act as scaffolds that sustain the spatial organization of signaling receptors on the cell surface, dictating its maintenance on the plasma membrane or their endocytosis. Galectin-3 induces tumor cell, endothelial cell, and leukocyte migration, favoring either the exit of tumor cells from a stressed microenvironment or the entry of endothelial cells and leukocytes, such as monocytes/macrophages into the tumor organoid. Therefore, galectin-3 plays homeostatic roles in tumors, as (i) it favors tumor cell adaptation for survival in stressed conditions; (ii) upon secretion, galectin-3 induces tumor cell detachment and migration; and (iii) it attracts monocyte/macrophage and endothelial cells to the tumor mass, inducing both directly and indirectly the process of angiogenesis. The two latter activities are potentially targetable, and specific interventions may be designed to counteract the protumoral role of extracellular

  15. Galectin-3 Determines Tumor Cell Adaptive Strategies in Stressed Tumor Microenvironments

    PubMed Central

    Cardoso, Ana Carolina Ferreira; Andrade, Luciana Nogueira de Sousa; Bustos, Silvina Odete; Chammas, Roger

    2016-01-01

    Galectin-3 is a member of the β-galactoside-binding lectin family, whose expression is often dysregulated in cancers. While galectin-3 is usually an intracellular protein found in the nucleus and in the cytoplasm, under certain conditions, galectin-3 can be secreted by an yet unknown mechanism. Under stressing conditions (e.g., hypoxia and nutrient deprivation) galectin-3 is upregulated, through the activity of transcription factors, such as HIF-1α and NF-κB. Here, we review evidence that indicates a positive role for galectin-3 in MAPK family signal transduction, leading to cell proliferation and cell survival. Galectin-3 serves as a scaffold protein, which favors the spatial organization of signaling proteins as K-RAS. Upon secretion, extracellular galectin-3 interacts with a variety of cell surface glycoproteins, such as growth factor receptors, integrins, cadherins, and members of the Notch family, among other glycoproteins, besides different extracellular matrix molecules. Through its ability to oligomerize, galectin-3 forms lectin lattices that act as scaffolds that sustain the spatial organization of signaling receptors on the cell surface, dictating its maintenance on the plasma membrane or their endocytosis. Galectin-3 induces tumor cell, endothelial cell, and leukocyte migration, favoring either the exit of tumor cells from a stressed microenvironment or the entry of endothelial cells and leukocytes, such as monocytes/macrophages into the tumor organoid. Therefore, galectin-3 plays homeostatic roles in tumors, as (i) it favors tumor cell adaptation for survival in stressed conditions; (ii) upon secretion, galectin-3 induces tumor cell detachment and migration; and (iii) it attracts monocyte/macrophage and endothelial cells to the tumor mass, inducing both directly and indirectly the process of angiogenesis. The two latter activities are potentially targetable, and specific interventions may be designed to counteract the protumoral role of extracellular

  16. The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors

    PubMed Central

    Lai, Wen-Lin; Harn, Horng-jyh; Hung, Pei-Hsiu; Hsieh, Ming-Chang; Chang, Kai-Fu; Huang, Xiao-Fan; Liao, Kuang-Wen; Lee, Ming-Shih; Tsai, Nu-Man

    2013-01-01

    Glioblastoma multiforme (GBM) is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer. PMID:24319475

  17. Targeting cancer stem cells in solid tumors by vitamin D

    PubMed Central

    Jae Young, So; Nanjoo, Suh

    2014-01-01

    Cancer stem cells (CSCs) are a small subset of cells that may be responsible for initiation, progression and recurrence of tumors. Recent studies have demonstrated that CSCs are highly tumorigenic and resistant to conventional chemotherapies, making them a promising target for the development of preventive/therapeutic agents. A single or combination of various markers, such as CD44, EpCAM, CD49f, CD133, CXCR4, ALDH-1 and CD24, were utilized to isolate CSCs fromvarious types of human cancers. Notch, Hedgehog, Wnt, and TGF-β signalingregulate self-renewal and differentiation of normal stem cells andare aberrantly activated in CSCs. In addition, many studies have demonstrated that these stem cell-associated signaling pathways are required for the maintenance of CSCs in differentmalignancies, including breast, colorectal, prostate and pancreatic cancers. Accumulating evidence hasshowninhibitory effects of vitamin D and its analogs on the cancer stem cell signaling pathways, suggesting vitamin D as a potential preventive/therapeutic agent against CSCs.In this review, we summarize recent findings about the roles of Notch, Hedgehog, Wnt, and TGF-β signaling in CSCs as well as the effects of vitamin D on these stem cell signaling pathways. PMID:25460302

  18. Development and characterization of a three-dimensional co-culture model of tumor T cell infiltration.

    PubMed

    Alonso-Nocelo, M; Abuín, C; López-López, R; de la Fuente, M

    2016-01-01

    Tumor growth and metastasis entangle the alteration and recruitment of non-malignant cells to the primary tumor, among them immune cells, constituting the tumor microenvironment (TME). Communication between tumor cells and their stroma has been shown as a fundamental driving force of the tumoral process. A great deal of effort has been focused on depicting their specific interactions and crosstalk. However, most research has been carried out in 2D conventional cultures that alter cell morphology and intracellular signaling processes. Considering these premises, we have developed a 3D cell co-culture model to mimic T cell infiltration into the tumor mass and explore tumor-immune cells interactions in the TME. Expression of specific cell markers and assessment of cell proliferation were carried out to characterize the proposed 3D co-culture model. Additionally, the study and profiling of the secretome revealed a subset of particular cancer-related inflammation proteins prompted upon 3D cultivation of tumor cells in presence of lymphocytes, pointing out an intercellular communication. Altogether, these results suggest that our 3D cell co-culture model can be a useful tool to identify and study critical factors mediating the crosstalk between tumor and immune cells in the TME. Finally, the potential of this model as a drug-screening platform has been explored using docetaxel as a model antitumoral compound. PMID:27078888

  19. Cimetidine induces apoptosis of human salivary gland tumor cells.

    PubMed

    Fukuda, Masakatsu; Tanaka, Shin; Suzuki, Seiji; Kusama, Kaoru; Kaneko, Tadayoshi; Sakashita, Hideaki

    2007-03-01

    It has been reported that cimetidine, a histamine type-2 receptor (H2R) antagonist, inhibits the growth of glandular tumors such as colorectal cancer. However, its effects against salivary gland tumors are still unknown. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express the neural cell adhesion molecule (NCAM) and also that HSG cell proliferation could be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. In the present study, we investigated the effects of cimetidine via the expression of NCAM on tumor growth and perineural/neural invasion in salivary gland tumor cells. Expression of both NCAM mRNA and protein was found to decrease in a dose-dependent manner upon treatment with cimetidine for 24 h. The MTT assay and confocal laser microscopy clearly showed that HSG cells underwent apoptosis after treatment with cimetidine. Activation of caspases 3, 7, 8 and 9 was observed in HSG cells after cimetidine treatment, thus confirming that the apoptosis was induced by the activated caspases. Apaf-1 activity was also detected in HSG cells in a dose-dependent manner after treatment with cimetidine. We also found that the cimetidine-mediated down-regulation of NCAM expression in HSG cells did not occur via blocking of the histamine receptor, even though H2R expression was observed on HSG cells, as two other H2R antagonists, famotidine and ranitidine, did not show similar effects. We demonstrated for the first time that cimetidine can induce significant apoptosis of salivary gland tumor cells, which express NCAM, at least in part by down-regulation of NCAM expression on the cells. These findings suggest that the growth, development and perineural/neural invasion of salivary gland tumor cells can be blocked by cimetidine administration through down-regulation of NCAM expression, as well as induction of apoptosis. PMID:17273750

  20. Molecular Communication between Tumor-Associated Fibroblasts and Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Leef, George; Thomas, Sufi Mary

    2013-01-01

    Over the past few decades, it has become increasingly clear that the lethality of cancers depends on more than the malignant cells themselves. The environment those malignant cells are exposed to is just as important a determinant of their behavior. Head and neck squamous cell carcinoma (HNSCC) is both common and deadly. It is the 6th most frequently occurring cancers, and prognosis is still generally poor. Recent evidence indicates that activated fibroblasts residing within the tumor stroma play a significant role in promoting the aggressive spread often seen in head and neck cancer. Tumor associated fibroblasts (TAFs) have also been implicated in facilitating angiogenesis and suppressing the normal anti-tumor function of immune cells. Studying the signaling molecules involved in these processes will facilitate the development of promising targets and inhibitors to prevent tumor-associated fibroblasts from exerting their reinforcing effects on the tumor. In this article, we review the recent literature on the signals used in tumor associated fibroblast communication, with a focus on potential therapeutic targets. Further, we highlight the lead candidates for TAF-targeted therapeutic interventions. Future anticancer strategies may achieve better results than current approaches by targeting the support cells in tumor stroma in addition to the cancerous cells. PMID:23357526

  1. New Strategies for the Treatment of Solid Tumors with CAR-T Cells

    PubMed Central

    Zhang, Hao; Ye, Zhen-long; Yuan, Zhen-gang; Luo, Zheng-qiang; Jin, Hua-jun; qian, Qi-jun

    2016-01-01

    Recent years, we have witnessed significant progresses in both basic and clinical studies regarding novel therapeutic strategies with genetically engineered T cells. Modification with chimeric antigen receptors (CARs) endows T cells with tumor specific cytotoxicity and thus induce anti-tumor immunity against malignancies. However, targeting solid tumors is more challenging than targeting B-cell malignancies with CAR-T cells because of the histopathological structure features, specific antigens shortage and strong immunosuppressive environment of solid tumors. Meanwhile, the on-target/off-tumor toxicity caused by relative expression of target on normal tissues is another issue that should be reckoned. Optimization of the design of CAR vectors, exploration of new targets, addition of safe switches and combination with other treatments bring new vitality to the CAR-T cell based immunotherapy against solid tumors. In this review, we focus on the major obstacles limiting the application of CAR-T cell therapy toward solid tumors and summarize the measures to refine this new cancer therapeutic modality. PMID:27194949

  2. Culture and Isolation of Brain Tumor Initiating Cells.

    PubMed

    Vora, Parvez; Venugopal, Chitra; McFarlane, Nicole; Singh, Sheila K

    2015-01-01

    Brain tumors are typically composed of heterogeneous cells that exhibit distinct phenotypic characteristics and proliferative potentials. Only a relatively small fraction of cells in the tumor with stem cell properties, termed brain tumor initiating cells (BTICs), possess an ability to differentiate along multiple lineages, self-renew, and initiate tumors in vivo. This unit describes protocols for the culture and isolation BTICs. We applied culture conditions and assays originally used for normal neural stem cells (NSCs) in vitro to a variety of brain tumors. Using fluorescence-activated cell sorting for the neural precursor cell surface marker CD133/CD15, BTICs can be isolated and studied prospectively. Isolation of BTICs from GBM bulk tumor will enable examination of dissimilar morphologies, self-renewal capacities, tumorigenicity, and therapeutic sensitivities. As cancer is also considered a disease of unregulated self-renewal and differentiation, an understanding of BTICs is fundamental to understanding tumor growth. Ultimately, it will lead to novel drug discovery approaches that strategically target the functionally relevant BTIC population. PMID:26237571

  3. Adenovirus-mediated gene transfer to tumor cells.

    PubMed

    Cascalló, Manel; Alemany, Ramon

    2004-01-01

    Cell transduction in vitro is only the first step toward proving that a genetherapy vector can be useful to treat tumors. However, tumor targeting in vivo is now the milestone for gene therapy to succeed against disseminated cancer. Therefore, most valuable information is obtained from studies of vector biodistribution. Owing to the hepatotropism of adenoviral vectors, a particularly important parameter is the tumor/liver ratio. This ratio can be given at the level of gene expression if the amount of transgene expression is measured. To optimize the targeting, however, the levels of viral particles that reach the tumor compared to other organs must be studied. Most of this chapter deals with methods to quantify the virus fate in tumor-bearing animals. We present a radioactive labeling method that can be used to study biodistribution. After a small section dealing with tumor models, we describe methods to quantify different parameters related to adenovirus-mediated tumor targeting. PMID:14970588

  4. Expanding Roles for CD4 T Cells and Their Subpopulations in Tumor Immunity and Therapy

    PubMed Central

    Dobrzanski, Mark J.

    2013-01-01

    The importance of CD4 T cells in orchestrating the immune system and their role in inducing effective T cell-mediated therapies for the treatment of patients with select established malignancies are undisputable. Through a complex and balanced array of direct and indirect mechanisms of cellular activation and regulation, this functionally diverse family of lymphocytes can potentially promote tumor eradication, long-term tumor immunity, and aid in establishing and/or rebalancing immune cell homeostasis through interaction with other immune cell populations within the highly dynamic tumor environment. However, recent studies have uncovered additional functions and roles for CD4 T cells, some of which are independent of other lymphocytes, that can not only influence and contribute to tumor immunity but paradoxically promote tumor growth and progression. Here, we review the recent advances in our understanding of the various CD4 T cell lineages and their signature cytokines in disease progression and/or regression. We discuss their direct and indirect mechanistic interplay among themselves and with other responding cells of the antitumor response, their potential roles and abilities for “plasticity” and memory cell generation within the hostile tumor environment, and their potentials in cancer treatment and immunotherapy. PMID:23533029

  5. CD47 Blockade Triggers T cell-mediated Destruction of Immunogenic Tumors

    PubMed Central

    Liu, Xiaojuan; Pu, Yang; Cron, Kyle; Deng, Liufu; Kline, Justin; Frazier, William A.; Xu, Hairong; Peng, Hua; Fu, Yang-Xin; Xu, Meng Michelle

    2015-01-01

    Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Using syngeneic immunocompetent tumor models, we reveal that in the therapeutic effects of CD47 blockade depend on dendritic cell (DC) but not macrophage cross-priming of T cell responses in immunocompetent mice. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the anti-tumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of anti-tumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors. PMID:26322579

  6. FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development.

    PubMed

    Liu, Zhilin; Ren, Yi A; Pangas, Stephanie A; Adams, Jaye; Zhou, Wei; Castrillon, Diego H; Wilhelm, Dagmar; Richards, JoAnne S

    2015-07-01

    The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of

  7. The expression of SPARC in human tumors is consistent with its role during cell competition

    PubMed Central

    Petrova, Evgeniya

    2011-01-01

    In Drosophila, the elimination of viable but suboptimal cells is mediated by cell competition, ensuring that these cells do not accumulate during development. In addition, certain genes such as the Drosophila homologue of human c-myc (dmyc) are able to transform cells into supercompetitors, which eliminate neighboring wild-type cells by apoptosis and overproliferate leaving total cell numbers unchanged. We have recently identified Drosophila SPARC as an early marker transcriptionally upregulated in loser cells that provides a transient protection by inhibiting caspase activation in outcompeted cells. Here, we explore whether the expression of SPARC in human tumors is consistent with a role for cell competition during human cancer and find that, consistent with the existence of competitive interactions between cancer and normal cells, SPARC is upregulated at the tumor-host boundaries in several types of human cancer. PMID:21655431

  8. Significance of DNA quantification in testicular germ cell tumors.

    PubMed

    Codesal, J; Paniagua, R; Regadera, J; Fachal, C; Nistal, M

    1991-01-01

    A cytophotometric quantification of DNA in tumor cells was performed in histological sections of orchidectomy specimens from 36 men with testicular germ cell tumors (TGCT), 7 of them showing more than one tumor type. Among the variants of seminoma (classic and spermatocytic) the lowest DNA content were in spermatocytic seminoma. With respect to non-seminomatous tumors (yolk sac tumor, embryonal carcinoma, teratoma, and choriocarcinoma), choriocarcinomas showed the highest DNA content, and the lowest value was found in teratomas. No significant differences were found between the average DNA content of seminomas (all types) and non-seminomatous tumors (all types). Both embryonal carcinoma and yolk sac tumor showed similar DNA content when they were the sole tumor and when they were found associated with other tumors. In this study, except for the 4 cases of teratoma and the case of spermatocytic seminoma, all TGCT examined did not show modal values of DNA content in the diploid range. Such an elevated frequency of aneuploidism in these tumors may be helpful for their diagnosis. PMID:1666273

  9. Eosinophilic and granular cell tumors of the breast.

    PubMed

    Damiani, S; Dina, R; Eusebi, V

    1999-05-01

    Eosinophilic and granular cell tumors of the breast are a heterogeneous group encompassing both epithelial and mesenchymal lesions. A granular appearance of the cytoplasm may be caused by the accumulation of secretory granules, mitochondria, or lysosomes. In the breast, mucoid carcinomas, carcinomas showing apocrine differentiation, and neuroendocrine carcinomas are well known entities, while tumors with oncocytic and acinic cell differentiation have been only recently recognized. An abundance of lysosomes is characteristic of Schwannian granular cell neoplasms, but smooth muscle cell tumors also may have this cytoplasmic feature. Awareness of all these possibilities when granular cells are found in breast lesions improves diagnostic accuracy and helps to avoid misdiagnosis of both benign lesions and malignant tumors. PMID:10452577

  10. Multipotent Mesenchymal Stromal Cells: Possible Culprits in Solid Tumors?

    PubMed Central

    Johann, Pascal David; Müller, Ingo

    2015-01-01

    The clinical use of bone marrow derived multipotent mesenchymal stromal cells (BM-MSCs) in different settings ranging from tissue engineering to immunotherapies has prompted investigations on the properties of these cells in a variety of other tissues. Particularly the role of MSCs in solid tumors has been the subject of many experimental approaches. While a clear phenotypical distinction of tumor associated fibroblasts (TAFs) and MSCs within the tumor microenvironment is still missing, the homing of bone marrow MSCs in tumor sites has been extensively studied. Both, tumor-promoting and tumor-inhibiting effects of BM-MSCs have been described in this context. This ambiguity requires a reappraisal of the different studies and experimental methods employed. Here, we review the current literature on tumor-promoting and tumor-inhibiting effects of BM-MSCs with a particular emphasis on their interplay with components of the immune system and also highlight a potential role of MSCs as cell of origin for certain mesenchymal tumors. PMID:26273308

  11. Radiation-induced cell cycle delay measured in two mouse tumors in vivo using bromodeoxyuridine

    SciTech Connect

    Wilson, G.D.; Martindale, C.A.; Soranson, J.A.; Bourhis, J.; Carl, U.M.; McNally, N.J. )

    1994-02-01

    The magnitude of the delay of cells in the phases of the cell cycle after irradiation may be related to the radioresponsiveness of tumor cell populations. In this study we have quantified division delay in two mouse tumors in vivo after single and fractionated doses of X rays and single doses of neutrons. The incorporation of bromodeoxyuridine and flow cytometry provided a sensitive and quantitative method to detect cell cycle perturbations after radiation treatment. The more rapidly growing SAF tumor showed less G[sub 2]-phase delay per gray than a more slowly proliferating tumor, the Rh (0.9 vs 1.8 h). In addition, the SAF tumor failed to show any G[sub 1]/S-phase delay while the Rh tumor experienced a longer G[sub 1]-phase delay while the Rh tumor experienced a longer G[sub 1]-phase delay than that measured for G[sub 2] phase (3.1 vs 1.8 h). There was a trend in both tumors for lower doses to be more effective in producing cell cycle delays. Neutrons caused longer G[sub 2]-phase delays on a unit dose basis, 2.5 and 5.4 h for the SAF and Rh tumors, respectively. The RBE for neutrons for division delay was found to be 2.9 and 2.8 for the SAF and Rh tumors, while the RBE for growth delay was 3.4 and 3.5. Fractionation of the X-ray dose caused a reduction in division delay at higher total doses (10 or 12 Gy) but was without effect at the lower dose studied (6 Gy). These studies show the feasibility of measuring cell cycle delays in vivo, and future developments are suggested for a possible predictive test in patients receiving radiotherapy. 17 refs., 6 figs., 2 tabs.

  12. Dendritic cells loaded with apoptotic antibody-coated tumor cells provide protective immunity against B-cell lymphoma in vivo

    PubMed Central

    Franki, Suzanne N.; Steward, Kristopher K.; Betting, David J.; Kafi, Kamran; Yamada, Reiko E.

    2008-01-01

    The in vitro priming of tumor-specific T cells by dendritic cells (DCs) phagocytosing killed tumor cells can be augmented in the presence of antitumor monoclonal antibody (mAb). We investigated whether DCs phagocytosing killed lymphoma cells coated with tumor-specific antibody could elicit antitumor immunity in vivo. Irradiated murine 38C13 lymphoma cells were cocultured with bone marrow–derived DCs in the presence or absence of tumor-specific mAb. Mice vaccinated with DCs cocultured with mAb-coated tumor cells were protected from tumor challenge (60% long-term survival), whereas DCs loaded with tumor cells alone were much less effective. The opsonized whole tumor cell–DC vaccine elicited significantly better tumor protection than a traditional lymphoma idiotype (Id) protein vaccine, and in combination with chemotherapy could eradicate preexisting tumor. Moreover, the DC vaccine protected animals from both wild-type and Id-negative variant tumor cells, indicating that Id is not a major target of the induced tumor immunity. Protection was critically dependent upon CD8+ T cells, with lesser contribution by CD4+ T cells. Importantly, opsonized whole tumor cell–DC vaccination did not result in tissue-specific autoimmunity. Since opsonized whole tumor cell–DC and Id vaccines appear to target distinct tumor antigens, optimal antilymphoma immunity might be achieved by combining these approaches. PMID:17993615

  13. The interplay between invasion and proliferation in tumor cell navigation

    NASA Astrophysics Data System (ADS)

    Ben-Jacob, Eshel

    2013-03-01

    Tumor cells can employ different cellular and molecular modes of invasion. The two main phenotypic mechanisms are: 1. Amoeboid (or ``path finder'') cells that can squeeze through small gaps in the ECM (extracellular matrix). 2. Mesenchymal (or ``path generator'') cells that are more rigid and can decompose the ECM to pass through. In addition there is interplay between energy directed to more rapid motility vs. energy used for proliferation. Understanding the relative contributions of these distinct mechanisms and the balance between motility and proliferation to the efficiency of metastatic cancer migration is fundamental to the therapeutic targeting of cancer. We present a conceptual and modeling framework for the analysis and assessment of the success rate, time-to-target, and survival probability of amoeboid vs. mesenchymal modes. Similarly, we contrast invasion with and without proliferation. We treat the complex ECM geometry as a maze and employ semi-realistic modeling of cell motility. Our approach includes metabolic and timing degrees of freedom. The theoretical studies were compared with experimental efforts of cell navigation in specially designed microfluidic devices. Center for Theoretical Biological Physics sponsored by the NSF (Grant PHY-0822283) Rice University, The Tauber Family Foundation and the Maguy-Glass Chair in Physics of Complex Systems at Tel Aviv University.

  14. Tumor-Induced STAT3 Signaling in Myeloid Cells Impairs Dendritic Cell Generation by Decreasing PKCβII Abundance

    PubMed Central

    Farren, Matthew R.; Carlson, Louise M.; Netherby, Colleen S.; Lindner, Inna; Li, Pui-Kai; Gabrilovich, Dmitry I.; Abrams, Scott I.; Lee, Kelvin P.

    2014-01-01

    A major mechanism by which cancers escape control by the immune system is by blocking the differentiation of myeloid cells into dendritic cells (DCs), immunostimulatory cells that activate anti-tumor T cells. Tumor-dependent activation of signal transducer and activator of transcription 3 (STAT3) signaling in myeloid progenitor cells is thought to cause this block in their differentiation. In addition, a signaling pathway through protein kinase C βII (PKCβII) is essential for the differentiation of myeloid cells into DCs. Here, we found in humans and mice that breast cancer cells substantially decreased the abundance of PKCβII in myeloid progenitor cells through a mechanism involving the enhanced activation of STAT3 signaling by soluble, tumor-derived factors (TDFs). STAT3 bound to previously undescribed negative regulatory elements within the promoter of PRKCB, which encodes PKCβII. We also found a previously undescribed counter-regulatory mechanism through which the activity of PKCβII inhibited tumor-dependent STAT3 signaling by decreasing the abundance of cell-surface receptors, such as cytokine and growth factor receptors, that are activated by TDFs. Together, these data suggest that a previously unrecognized crosstalk mechanism between the STAT3 and PKCβII signaling pathways provides the molecular basis for the tumor-induced blockade in the differentiation of myeloid cells, and suggest that enhancing PKCβII activity may be a therapeutic strategy to alleviate cancer-mediated suppression of the immune system. PMID:24550541

  15. Multiplicity of virus-encoded helper T-cell epitopes expressed on FBL-3 tumor cells.

    PubMed Central

    Iwashiro, M; Kondo, T; Shimizu, T; Yamagishi, H; Takahashi, K; Matsubayashi, Y; Masuda, T; Otaka, A; Fujii, N; Ishimoto, A

    1993-01-01

    To identify retroviral antigenic determinants recognized by CD4+ T helper cells during tumor rejection, we established four noncytolytic, helper-type, CD4+ T-cell clones by limiting dilution cultures of mixed lymphocyte-tumor cultures from mice immune to a Friend virus-induced tumor, FBL-3. Among these, three T helper cell clones were isolated from C57BL/6 mice and the fourth was isolated from a (BALB/c x C57BL/6)F1 mouse. All these clones proliferated in response to the immunizing FBL-3 tumor cells in a major histocompatibility complex class II-restricted manner. Each clone expressed a distinct T-cell receptor with a characteristic combination of alpha and beta chains. The localization of helper T-cell determinants on viral proteins was analyzed with recombinant vaccinia viruses expressing Friend murine leukemia virus (F-MuLV) gag or env genes or shorter fragments of the env gene. Epitopes recognized by these T-cell clones were mapped to at least two distinct portions in the env region of the F-MuLV genome. These epitopes were identified more precisely with synthetic peptides derived from the F-MuLV envelope protein sequence. One of these epitopes was common to Friend and Moloney MuLVs and was located in the N-terminal region of the gp70 glycoprotein at amino acids 122 to 141. The second epitope, which was recognized in the context of hybrid I-Eb/d major histocompatibility complex class II molecule, was located close to the C-terminal end of gp70 at amino acids 462 to 479. In addition, a possible third epitope was located in the N-terminal half of the gp70 sequence and differed from the first epitope in that it was not cross-reactive with the Moloney MuLV envelope protein. PMID:7687300

  16. Endothelial progenitor cells promote tumor growth and progression by enhancing new vessel formation

    PubMed Central

    Zhao, Xin; Liu, Huan-Qiu; Li, Ji; Liu, Xiao-Liang

    2016-01-01

    Tumor growth and progression require new blood vessel formation to deliver nutrients and oxygen for further cell proliferation and to create a neovascular network exit for tumor cell metastasis. Endothelial progenitor cells (EPCs) are a bone marrow (BM)-derived stem cell population that circulates in the peripheral circulation and homes to the tumor bed to participate in new blood vessel formation. In addition to structural support to nascent vessels, these cells can also regulate the angiogenic process by paracrine secretion of a number of proangiogenic growth factors and cytokines, thus playing a crucial role in tumor neovascularization and development. Inhibition of EPC-mediated new vessel formation may be a promising therapeutic strategy in tumor treatment. EPC-mediated neovascularization is a complex process that includes multiple steps and requires a series of cytokines and modulators, thus understanding the underlying mechanisms may provide anti-neovasculogenesis targets that may be blocked for the prevention of tumor development. The present review stresses the process and contribution of EPCs to the formation of new blood vessels in solid tumors, in an attempt to gain an improved understanding of the underlying cellular and molecular mechanisms involved, and to provide a potential effective therapeutic target for cancer treatment. PMID:27446353

  17. Aldh1 Expression and Activity Increase During Tumor Evolution in Sarcoma Cancer Stem Cell Populations

    PubMed Central

    Martinez-Cruzado, Lucia; Tornin, Juan; Santos, Laura; Rodriguez, Aida; García-Castro, Javier; Morís, Francisco; Rodriguez, Rene

    2016-01-01

    Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs that present MSC features have been identified in sarcomas due to their ability to grow as self-renewed floating spheres (tumorspheres). Accordingly, we previously developed sarcoma models using human MSCs transformed with relevant oncogenic events. To study the evolution/emergence of CSC subpopulations during tumor progression, we compared the tumorigenic properties of bulk adherent cultures and tumorsphere-forming subpopulations both in the sarcoma cell-of-origin models (transformed MSCs) and in their corresponding tumor xenograft-derived cells. Tumor formation assays showed that the tumorsphere cultures from xenograft-derived cells, but not from the cell-of-origin models, were enriched in CSCs, providing evidence of the emergence of bona fide CSCs subpopulations during tumor progression. Relevant CSC-related factors, such as ALDH1 and SOX2, were increasingly upregulated in CSCs during tumor progression, and importantly, the increased levels and activity of ALDH1 in these subpopulations were associated with enhanced tumorigenicity. In addition to being a CSC marker, our findings indicate that ALDH1 could also be useful for tracking the malignant potential of CSC subpopulations during sarcoma evolution. PMID:27292183

  18. Aldh1 Expression and Activity Increase During Tumor Evolution in Sarcoma Cancer Stem Cell Populations.

    PubMed

    Martinez-Cruzado, Lucia; Tornin, Juan; Santos, Laura; Rodriguez, Aida; García-Castro, Javier; Morís, Francisco; Rodriguez, Rene

    2016-01-01

    Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs that present MSC features have been identified in sarcomas due to their ability to grow as self-renewed floating spheres (tumorspheres). Accordingly, we previously developed sarcoma models using human MSCs transformed with relevant oncogenic events. To study the evolution/emergence of CSC subpopulations during tumor progression, we compared the tumorigenic properties of bulk adherent cultures and tumorsphere-forming subpopulations both in the sarcoma cell-of-origin models (transformed MSCs) and in their corresponding tumor xenograft-derived cells. Tumor formation assays showed that the tumorsphere cultures from xenograft-derived cells, but not from the cell-of-origin models, were enriched in CSCs, providing evidence of the emergence of bona fide CSCs subpopulations during tumor progression. Relevant CSC-related factors, such as ALDH1 and SOX2, were increasingly upregulated in CSCs during tumor progression, and importantly, the increased levels and activity of ALDH1 in these subpopulations were associated with enhanced tumorigenicity. In addition to being a CSC marker, our findings indicate that ALDH1 could also be useful for tracking the malignant potential of CSC subpopulations during sarcoma evolution. PMID:27292183

  19. In vivo imaging of tumor vascular endothelial cells

    NASA Astrophysics Data System (ADS)

    Zhao, Dawen; Stafford, Jason H.; Zhou, Heling; Thorpe, Philip E.

    2013-02-01

    Phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, becomes exposed on the outer surface of viable (non-apoptotic) endothelial cells in tumor blood vessels, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we optically imaged exposed PS on tumor vasculature in vivo using PGN635, a novel human monoclonal antibody that targets PS. PGN635 F(ab')2 was labeled with the near infrared (NIR) dye, IRDye 800CW. Human glioma U87 cells or breast cancer MDA-MB-231 cells were implanted subcutaneously or orthotopically into nude mice. When the tumors reached ~5 mm in diameter, 800CW- PGN635 was injected via a tail vein and in vivo dynamic NIR imaging was performed. For U87 gliomas, NIR imaging allowed clear detection of tumors as early as 4 h later, which improved over time to give a maximal tumor/normal ratio (TNR = 2.9 +/- 0.5) 24 h later. Similar results were observed for orthotopic MDA-MB-231 breast tumors. Localization of 800CW-PGN635 to tumors was antigen specific since 800CW-Aurexis, a control probe of irrelevant specificity, did not localize to the tumors, and pre-administration of unlabeled PGN635 blocked the uptake of 800CW-PGN635. Fluorescence microscopy confirmed that 800CW-PGN635 was binding to PS-positive tumor vascular endothelium. Our studies suggest that tumor vasculature can be successfully imaged in vivo to provide sensitive tumor detection.

  20. Targeting Tumor Vasculature Endothelial Cells and Tumor Cells for Immunotherapy of Human Melanoma in a Mouse Xenograft Model

    NASA Astrophysics Data System (ADS)

    Hu, Zhiwei; Sun, Ying; Garen, Alan

    1999-07-01

    An immunotherapy treatment for cancer that targets both the tumor vasculature and tumor cells has shown promising results in a severe combined immunodeficient mouse xenograft model of human melanoma. The treatment involves systemic delivery of an immunoconjugate molecule composed of a tumor-targeting domain conjugated to the Fc effector domain of human IgG1. The effector domain induces a cytolytic immune response against the targeted cells by natural killer cells and complement. Two types of targeting domains were used. One targeting domain is a human single-chain Fv molecule that binds to a chondroitin sulfate proteoglycan expressed on the surface of most human melanoma cells. Another targeting domain is factor VII (fVII), a zymogen that binds with high specificity and affinity to the transmembrane receptor tissue factor (TF) to initiate the blood coagulation cascade. TF is expressed by endothelial cells lining the tumor vasculature but not the normal vasculature, and also by many types of tumor cells including melanoma. Because the binding of a fVII immunoconjugate to TF might cause disseminated intravascular coagulation, the active site of fVII was mutated to inhibit coagulation without affecting the affinity for TF. The immunoconjugates were encoded as secreted molecules in a replication-defective adenovirus vector, which was injected into the tail vein of severe combined immunodeficient mice. The results demonstrate that a mutated fVII immunoconjugate, administered separately or together with a single-chain Fv immunoconjugate that binds to the tumor cells, can inhibit the growth or cause regression of an established human tumor xenograft. This procedure could be effective in treating a broad spectrum of human solid tumors that express TF on vascular endothelial cells and tumor cells.

  1. Concise review: transmissible animal tumors as models of the cancer stem-cell process.

    PubMed

    O'Neill, Iain D

    2011-12-01

    Tasmanian devil facial tumor disease (DFTD) and canine transmissible venereal tumor (CTVT) are highly unusual cancers capable of being transmitted between animals as an allograft. The concept that these tumors represent a cancer stem-cell process has never been formally evaluated. For each, evidence of self-renewal is found in the natural history of these tumors in the wild, tumor initiation in recipient animals, and serial transplantation studies. Additional data for stem-cell-specific genes and markers in DFTD also exist. Although both tumor types manifest as undifferentiated cancers, immunocytohistochemistry supports a histiocytic phenotype for CTVT and a neural crest origin, possibly a Schwann-cell phenotype, for DFTD. In these data, differential expression of lineage markers is seen which may suggest some capacity for differentiation toward a heterogeneous variety of cell types. It is proposed that DFTD and CTVT may represent and may serve as models of the cancer stem-cell process, but formal investigation is required to clarify this. Appreciation of any such role may act as a stimulus to ongoing research in the pathology of DFTD and CTVT, including further characterization of their origin and phenotype and possible therapeutic approaches. Additionally, they may provide valuable models for future studies of their analogous human cancers, including any putative CSC component. PMID:21956952

  2. Increased IMP dehydrogenase gene expression in solid tumor tissues and tumor cell lines

    SciTech Connect

    Collart, F.R.; Chubb, C.B.; Mirkin, B.L.; Huberman, E.

    1992-07-10

    IMP dehydrogenase, a regulatory enzyme of guanine nucleotide biosynthesis, may play a role in cell proliferation and malignancy. To assess this possibility, we examined IMP dehydrogenase expression in a series of human solid tumor tissues and tumor cell lines in comparison with their normal counterparts. Increased IMP dehydrogenase gene expression was observed in brain tumors relative to normal brain tissue and in sarcoma cells relative to normal fibroblasts. Similarly, in several B- and T-lymphoid leukemia cell lines, elevated levels of IMP dehydrogenase mRNA and cellular enzyme were observed in comparison with the levels in peripheral blood lymphocytes. These results are consistent with an association between increased IMP dehydrogenase expression and either enhanced cell proliferation or malignant transformation.

  3. Chondrocytic differentiation of peripheral neuroectodermal tumor cell line in nude mouse xenograft.

    PubMed

    Goji, J; Sano, K; Nakamura, H; Ito, H

    1992-08-01

    We have established a cell line (KU-SN) from a peripheral neuroectodermal tumor originating in the left scapula of a 4-year-old girl. The original tumor was immunoreactive with antibodies for neurofilament proteins, neuron-specific enolase, vimentin, S100 protein, and beta 2-microglobulin. Dense core granules, 50-150 nm in diameter, were identified by electron microscopy. The cell line was established from tumor cells in metastatic lung fluid. KU-SN cells were immunoreactive with the antibodies for neurofilament proteins, vimentin, neuron-specific enolase, S100 protein, glial fibrillary acidic protein, cytokeratin, and carcinoembryonic antigen. Besides these neuronal features, KU-SN cells express type 2 collagen and insulin-like growth factor 1 receptor. The addition of insulin-like growth factor 1 (100 ng/ml) increased the growth rate of KU-SN cells 2.1-fold over control. Some cells were positive for Alcian blue and alkaline phosphatase staining. Cytogenetic analysis of KU-SN cells disclosed a reciprocal chromosomal translocation [t(11,22)]. Northern blot analysis of KU-SN cells demonstrated amplified expression of the c-myc gene but not the N-myc gene. When tumor cells were transplanted into nude mice, cartilage was formed. The cartilage was immunoreactive with the antibody for HLA-ABC, indicating that it was derived from the tumor cells, not from mouse tissue. Chondrocytic differentiation was not observed in xenografts of Ewing's sarcoma cell lines SK-ES or RD-ES or the peripheral neuroectodermal tumor cell line SK-N-MC. These results indicate that KU-SN cells represent primitive neural crest cells having the potential for chondrocytic differentiation. PMID:1379122

  4. Nano-Scaled Particles of Titanium Dioxide Convert Benign Mouse Fibrosarcoma Cells into Aggressive Tumor Cells

    PubMed Central

    Onuma, Kunishige; Sato, Yu; Ogawara, Satomi; Shirasawa, Nobuyuki; Kobayashi, Masanobu; Yoshitake, Jun; Yoshimura, Tetsuhiko; Iigo, Masaaki; Fujii, Junichi; Okada, Futoshi

    2009-01-01

    Nanoparticles are prevalent in both commercial and medicinal products; however, the contribution of nanomaterials to carcinogenesis remains unclear. We therefore examined the effects of nano-sized titanium dioxide (TiO2) on poorly tumorigenic and nonmetastatic QR-32 fibrosarcoma cells. We found that mice that were cotransplanted subcutaneously with QR-32 cells and nano-sized TiO2, either uncoated (TiO2−1, hydrophilic) or coated with stearic acid (TiO2−2, hydrophobic), did not form tumors. However, QR-32 cells became tumorigenic after injection into sites previously implanted with TiO2−1, but not TiO2−2, and these developing tumors acquired metastatic phenotypes. No differences were observed either histologically or in inflammatory cytokine mRNA expression between TiO2−1 and TiO2−2 treatments. However, TiO2−2, but not TiO2−1, generated high levels of reactive oxygen species (ROS) in cell-free conditions. Although both TiO2−1 and TiO2−2 resulted in intracellular ROS formation, TiO2−2 elicited a stronger response, resulting in cytotoxicity to the QR-32 cells. Moreover, TiO2−2, but not TiO2−1, led to the development of nuclear interstices and multinucleate cells. Cells that survived the TiO2 toxicity acquired a tumorigenic phenotype. TiO2-induced ROS formation and its related cell injury were inhibited by the addition of antioxidant N-acetyl-l-cysteine. These results indicate that nano-sized TiO2 has the potential to convert benign tumor cells into malignant ones through the generation of ROS in the target cells. PMID:19815711

  5. Identification of peptides that bind to irradiated pancreatic tumor cells

    SciTech Connect

    Huang Canhui; Liu, Xiang Y.; Rehemtulla, Alnawaz; Lawrence, Theodore S. . E-mail: tsl@med.umich.edu

    2005-08-01

    Purpose: Peptides targeting tumor vascular cells or tumor cells themselves have the potential to be used as vectors for delivering either DNA in gene therapy or antitumor agents in chemotherapy. We wished to determine if peptides identified by phage display could be used to target irradiated pancreatic cancer cells. Methods and Materials: Irradiated Capan-2 cells were incubated with 5 x 10{sup 12} plaque-forming units of a phage display library. Internalized phage were recovered and absorbed against unirradiated cells. After five such cycles of enrichment, the recovered phage were subjected to DNA sequencing analysis and synthetic peptides made. The binding of both phage and synthetic peptides was evaluated by fluorescence staining and flow cytometry in vitro and in vivo. Results: We identified one 12-mer peptide (PA1) that binds to irradiated Capan-2 pancreatic adenocarcinoma cells but not to unirradiated cells. The binding of peptide was significant after 48 h incubation with cells. In vivo experiments with Capan-2 xenografts in nude mice demonstrated that these small peptides are able to penetrate tumor tissue after intravenous injections and bind specifically to irradiated tumor cells. Conclusion: These data suggest that peptides can be identified that target tumors with radiation-induced cell markers and may be clinically useful.

  6. Tumor cell-secreted angiogenin induces angiogenic activity of endothelial cells by suppressing miR-542-3p.

    PubMed

    He, Ting; Qi, Feifei; Jia, Lin; Wang, Shan; Wang, Chunying; Song, Nan; Fu, Yan; Li, Lin; Luo, Yongzhang

    2015-11-01

    Therapeutic strategies for targeting angiogenesis have been proven as successful treatments for divergent cancers. We previously discovered an anti-angiogenic miR-542-3p, which directly targeted the key angiogenesis-promoting protein Angiopoietin-2 to inhibit tumor angiogenesis in breast cancer models. In this study, to further investigate the mechanism of miR-542-3p induced angiogenic inhibition, we screened for tumor cell derived factors which were responsible for miR-542-3p alteration in endothelial cells. We found that tumor cell-derived angiogenin downregulated miR-542-3p in endothelial cells. Overexpression of angiogenin in tumor cells facilitated angiogenic activation in both in vitro and in vivo models via inhibition of miR-542-3p. Furthermore, our results showed that angiogenin could suppress CEBPB and POU2F1, which were transcription factors for miR-542-3p, suggesting a novel tumor cell-endothelial cell signal pathway. In addition, the level of angiogenin in primary breast carcinomas correlated with clinical progression. Serum levels of angiogenin were associated with metastatic development of breast cancer patients. Together, these findings reveal a novel regulatory pathway whereby tumor-derived angiogenin directly activates angiogenesis through inhibition of miR-542-3p, suggesting that angiogenin may represent a promising target for anti-angiogenic therapy and a potential marker for monitoring disease progression. PMID:26272182

  7. Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduced hypoxia in tumors

    PubMed Central

    Sasajima, Junpei; Mizukami, Yusuke; Sugiyama, Yoshiaki; Nakamura, Kazumasa; Kawamoto, Toru; Koizumi, Kazuya; Fujii, Rie; Motomura, Wataru; Sato, Kazuya; Suzuki, Yasuaki; Tanno, Satoshi; Fujiya, Mikihiro; Sasaki, Katsunori; Shimizu, Norihiko; Karasaki, Hidenori; Kono, Toru; Kawabe, Jun-ichi; Ii, Masaaki; Yoshiara, Hiroki; Kamiyama, Naohisa; Ashida, Toshifumi; Bardeesy, Nabeel; Chung, Daniel C.; Kohgo, Yutaka

    2011-01-01

    Blood vessels deliver oxygen and nutrients to tissues and vascular networks are spatially organized to meet metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair “injured” blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in tumor vasculature. Culturing BMMNC with endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with pro-angiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-KrasG12D;p53lox/+ genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in the vascularized area within VPC-injected xenografts were visualized with the ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional “normalization” of the tumor vasculature. In addition, gene expression profiles on the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and “stemness” of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve delivery and efficacy of anti-cancer drugs to hypoxic tumors. PMID:20631070

  8. Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors.

    PubMed

    Sasajima, Junpei; Mizukami, Yusuke; Sugiyama, Yoshiaki; Nakamura, Kazumasa; Kawamoto, Toru; Koizumi, Kazuya; Fujii, Rie; Motomura, Wataru; Sato, Kazuya; Suzuki, Yasuaki; Tanno, Satoshi; Fujiya, Mikihiro; Sasaki, Katsunori; Shimizu, Norihiko; Karasaki, Hidenori; Kono, Toru; Kawabe, Jun-ichi; Ii, Masaaki; Yoshiara, Hiroki; Kamiyama, Naohisa; Ashida, Toshifumi; Bardeesy, Nabeel; Chung, Daniel C; Kohgo, Yutaka

    2010-08-01

    Blood vessels deliver oxygen and nutrients to tissues, and vascular networks are spatially organized to meet the metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair "injured" blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in the tumor vasculature. Culturing BMMNCs in endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with proangiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-Kras(G12D);p53(lox/+) genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in vascularized areas within VPC-injected xenografts were visualized with an ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional "normalization" of the tumor vasculature. In addition, gene expression profiles in the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and "stemness" of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve the delivery and efficacy of anticancer drugs to hypoxic tumors. PMID:20631070

  9. Inhibitory effects of a dendritic cell vaccine loaded with radiation-induced apoptotic tumor cells on tumor cell antigens in mouse bladder cancer.

    PubMed

    Xie, X F; Ding, Q; Hou, J G; Chen, G

    2015-01-01

    Herein, the preparation of a dendritic cell (DC) vaccine with radiation-induced apoptotic tumor cells and its immunological effects on bladder cancer in C57BL/6 mice was investigated. We used radiation to obtain a MB49 cell antigen that was sensitive to bone marrow-derived DCs to prepare a DC vaccine. An animal model of tumor-bearing mice was established with the MB49 mouse bladder cancer cell line. Animals were randomly allocated to an experimental group or control group. DC vaccine or phosphate-buffered saline was given 7 days before inoculation with tumor cells. Each group consisted of 2 subgroups in which tumor volume and the survival of tumor-bearing mice were recorded. Tumor volumes and average tumor masses of mice administered DC vaccine loaded with radiation-induced apoptotic cells were significantly lower than those in the control group (P < 0.01). Survival in the experimental group was also longer than that in the control group, and 2 mice survived without tumor formation. In the DC vaccine group, 2 mice were alive without tumor growth after 30 days, and no tumor was observed at 30 days after subcutaneous inoculation of MB49 cells. The DC vaccine loaded with radiation-induced apoptotic tumor cells had an anti-tumor effect and was associated with increased survival in a bladder cancer model in mice. PMID:26214433

  10. Chimeric antigen receptor T-cell therapy for solid tumors

    PubMed Central

    Newick, Kheng; Moon, Edmund; Albelda, Steven M

    2016-01-01

    Chimeric antigen receptor (CAR) T cells are engineered constructs composed of synthetic receptors that direct T cells to surface antigens for subsequent elimination. Many CAR constructs are also manufactured with elements that augment T-cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematological malignancies (e.g., CD19 CARs in leukemias). This success is not yet extrapolated to solid tumors, and the reasons for this are being actively investigated. Here in this mini-review, we discuss some of the key hurdles encountered by CAR T cells in the solid tumor microenvironment. PMID:27162934

  11. Allogeneic IgG combined with dendritic cell stimuli induces anti-tumor T cell immunity

    PubMed Central

    Carmi, Yaron; Spitzer, Matthew H.; Linde, Ian L.; Burt, Bryan M; Prestwood, Tyler R.; Perlman, Nikola; Davidson, Matthew G.; Kenkel, Justin A.; Segal, Ehud; Pusapati, Ganesh V.; Bhattacharya, Nupur; Engleman, Edgar G.

    2015-01-01

    While cancers grow in their hosts and evade host immunity through immunoediting and immunosuppression1–5, tumors are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumors are reliably rejected by host T cells, even when the tumor and host share the same major histocompatibility complex (MHC) alleles, the most potent determinants of transplant rejection6–10. How such tumor-eradicating immunity is initiated remains unknown, though elucidating this process could provide a roadmap for inducing similar responses against naturally arising tumors. We found that allogeneic tumor rejection is initiated by naturally occurring tumor-binding IgG antibodies, which enable dendritic cells (DC) to internalize tumor antigens and subsequently activate tumor-reactive T cells. We exploited this mechanism to successfully treat autologous and autochthonous tumors. Either systemic administration of DC loaded with allogeneic IgG (alloIgG)-coated tumor cells or intratumoral injection of alloIgG in combination with DC stimuli induced potent T cell mediated anti-tumor immune responses, resulting in tumor eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumors and metastases, as well as the injected primary tumors. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumor antigens after culture with alloIgG-loaded DC, recapitulating our findings in mice. These results reveal that tumor-binding alloIgG can induce powerful anti-tumor immunity that can be exploited for cancer immunotherapy. PMID:25924063

  12. (Study of plant cells and tumors): Progress report

    SciTech Connect

    Not Available

    1989-01-01

    Studies of the cell and molecular biology of animal cell tumors has long been recognized as a fertile and productive area for obtaining new and fundamental insights into mechanisms regulating the growth and differentiation of animal cells. As a novel approach to studying similar phenomena in plant cells, we have isolated a number of tumors in the small cruciferous plant Arabidopsis thaliana and have begun to characterize these at the cellular and molecular levels. Studies at the cellular level should lead to new insights into the relationships between hormones, cell growth and cell differentiation, while studies at the molecular level may reveal and allow us to isolate genes involved either in the hormone response, or in other important aspects of the cells' growth regulatory network. Tumors were induced on the plant by irradiation of seed or seedlings with Co-60 gamma rays. When placed in culture, these tumors were able to grow on hormone-free medium, in contrast to normal plant tissues which requires both an auxin and a cytokinin for growth. In the first phase of this project, we have concentrated on characterizing the growth, general phenotype, and hormonal sensitivity of the tumors. These studies will lead into a molecular analysis of the changes expressed in each tumor which may be responsible for the altered phenotype. 7 refs., 1 tab.

  13. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  14. ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma

    PubMed Central

    Kimura, Yasushi; Kasamatsu, Atsushi; Nakashima, Dai; Yamatoji, Masanobu; Minakawa, Yasuyuki; Koike, Kazuyuki; Fushimi, Kazuaki; Higo, Morihiro; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-01-01

    Aryl hydrocarbon receptor nuclear translocator (ARNT) 2 is a transcriptional factor related to adaptive responses against cellular stress from a xenobiotic substance. Recent evidence indicates ARNT is involved in carcinogenesis and cancer progression; however, little is known about the relevance of ARNT2 in the behavior of oral squamous cell carcinoma (OSCC). In the current study, we evaluated the ARNT2 mRNA and protein expression levels in OSCC in vitro and in vivo and the clinical relationship between ARNT2 expression levels in primary OSCCs and their clinicopathologic status by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry. Using ARNT2 overexpression models, we performed functional analyses to investigate the critical roles of ARNT2 in OSCC. ARNT2 mRNA and protein were down-regulated significantly (P < 0.05 for both comparisons) in nine OSCC-derived cells and primary OSCC (n=100 patients) compared with normal counterparts. In addition to the data from exogenous experiments that ARNT2-overexpressed cells showed decreased cellular proliferation, ARNT2-positive OSCC cases were correlated significantly (P < 0.05) with tumoral size. Since von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase, a negative regulator of hypoxia-inducible factor (HIF1)-α, is a downstream molecule of ARNT2, we speculated that HIF1-α and its downstream molecules would have key functions in cellular growth. Consistent with our hypothesis, overexpressed ARNT2 cells showed down-regulation of HIF1-α, which causes hypofunctioning of glucose transporter 1, leading to decreased cellular growth. Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs. Therefore, ARNT2 may be a potential therapeutic target against progression of OSCCs. PMID:27076852

  15. ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma.

    PubMed

    Kimura, Yasushi; Kasamatsu, Atsushi; Nakashima, Dai; Yamatoji, Masanobu; Minakawa, Yasuyuki; Koike, Kazuyuki; Fushimi, Kazuaki; Higo, Morihiro; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-01-01

    Aryl hydrocarbon receptor nuclear translocator (ARNT) 2 is a transcriptional factor related to adaptive responses against cellular stress from a xenobiotic substance. Recent evidence indicates ARNT is involved in carcinogenesis and cancer progression; however, little is known about the relevance of ARNT2 in the behavior of oral squamous cell carcinoma (OSCC). In the current study, we evaluated the ARNT2 mRNA and protein expression levels in OSCC in vitro and in vivo and the clinical relationship between ARNT2 expression levels in primary OSCCs and their clinicopathologic status by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry. Using ARNT2 overexpression models, we performed functional analyses to investigate the critical roles of ARNT2 in OSCC. ARNT2 mRNA and protein were down-regulated significantly (P < 0.05 for both comparisons) in nine OSCC-derived cells and primary OSCC (n=100 patients) compared with normal counterparts. In addition to the data from exogenous experiments that ARNT2-overexpressed cells showed decreased cellular proliferation, ARNT2-positive OSCC cases were correlated significantly (P < 0.05) with tumoral size. Since von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase, a negative regulator of hypoxia-inducible factor (HIF1)-α, is a downstream molecule of ARNT2, we speculated that HIF1-α and its downstream molecules would have key functions in cellular growth. Consistent with our hypothesis, overexpressed ARNT2 cells showed down-regulation of HIF1-α, which causes hypofunctioning of glucose transporter 1, leading to decreased cellular growth. Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs. Therefore, ARNT2 may be a potential therapeutic target against progression of OSCCs. PMID:27076852

  16. Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells.

    PubMed

    Chimento, A; Casaburi, I; Bartucci, M; Patrizii, M; Dattilo, R; Avena, P; Andò, S; Pezzi, V; Sirianni, R

    2013-01-01

    We have previously shown that estrogens binding to estrogen receptor (ER) α increase proliferation of Leydig tumor cells. Estrogens can also bind to G protein-coupled ER (GPER) and activation of this receptor can either increase or decrease cell proliferation of several tumor types. The aim of this study was to investigate GPER expression in R2C rat tumor Leydig cells, evaluate effects of its activation on Leydig tumor cell proliferation and define the molecular mechanisms triggered in response to its activation. R2C cells express GPER and its activation, using the specific ligand G-1, is associated with decreased cell proliferation and initiation of apoptosis. Apoptosis after G-1 treatment was asserted by appearance of DNA condensation and fragmentation, decrease in Bcl-2 and increase in Bax expression, cytochrome c release, caspase and poly (ADP-ribose) polymerase-1 (PARP-1) activation. These effects were dependent on GPER activation because after silencing of the gene, using a specific small interfering RNA, cyt c release, PARP-1 activation and decrease in cell proliferation were abrogated. These events required a rapid, however, sustained extracellular regulated kinase 1/2 activation. G-1 was able to decrease the growth of R2C xenograft tumors in CD1 nude mice while increasing the number of apoptotic cells. In addition, in vivo administration of G-1 to male CD1 mice did not cause any alteration in testicular morphology, while cisplatin, the cytotoxic drug currently used for the therapy of Leydig tumors, severely damaged testicular structure, an event associated with infertility in cisplatin-treated patients. These observations indicate that GPER targeting for the therapy of Leydig cell tumor may represent a good alternative to cisplatin to preserve fertility in Leydig tumor patients. PMID:23907461

  17. Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells

    PubMed Central

    Chimento, A; Casaburi, I; Bartucci, M; Patrizii, M; Dattilo, R; Avena, P; Andò, S; Pezzi, V; Sirianni, R

    2013-01-01

    We have previously shown that estrogens binding to estrogen receptor (ER) α increase proliferation of Leydig tumor cells. Estrogens can also bind to G protein-coupled ER (GPER) and activation of this receptor can either increase or decrease cell proliferation of several tumor types. The aim of this study was to investigate GPER expression in R2C rat tumor Leydig cells, evaluate effects of its activation on Leydig tumor cell proliferation and define the molecular mechanisms triggered in response to its activation. R2C cells express GPER and its activation, using the specific ligand G-1, is associated with decreased cell proliferation and initiation of apoptosis. Apoptosis after G-1 treatment was asserted by appearance of DNA condensation and fragmentation, decrease in Bcl-2 and increase in Bax expression, cytochrome c release, caspase and poly (ADP-ribose) polymerase-1 (PARP-1) activation. These effects were dependent on GPER activation because after silencing of the gene, using a specific small interfering RNA, cyt c release, PARP-1 activation and decrease in cell proliferation were abrogated. These events required a rapid, however, sustained extracellular regulated kinase 1/2 activation. G-1 was able to decrease the growth of R2C xenograft tumors in CD1 nude mice while increasing the number of apoptotic cells. In addition, in vivo administration of G-1 to male CD1 mice did not cause any alteration in testicular morphology, while cisplatin, the cytotoxic drug currently used for the therapy of Leydig tumors, severely damaged testicular structure, an event associated with infertility in cisplatin-treated patients. These observations indicate that GPER targeting for the therapy of Leydig cell tumor may represent a good alternative to cisplatin to preserve fertility in Leydig tumor patients. PMID:23907461

  18. C8-glycosphingolipids preferentially insert into tumor cell membranes and promote chemotherapeutic drug uptake.

    PubMed

    Cordeiro Pedrosa, Lília R; van Cappellen, Wiggert A; Steurer, Barbara; Ciceri, Dalila; ten Hagen, Timo L M; Eggermont, Alexander M M; Verheij, Marcel; Goñi, Felix María; Koning, Gerben A; Contreras, F-Xabier

    2015-08-01

    Insufficient drug delivery into tumor cells limits the therapeutic efficacy of chemotherapy. Co-delivery of liposome-encapsulated drug and synthetic short-chain glycosphingolipids (SC-GSLs) significantly improved drug bioavailability by enhancing intracellular drug uptake. Investigating the mechanisms underlying this SC-GSL-mediated drug uptake enhancement is the aim of this study. Fluorescence microscopy was used to visualize the cell membrane lipid transfer intracellular fate of fluorescently labeled C6-NBD-GalCer incorporated in liposomes in tumor and non-tumor cells. Additionally click chemistry was applied to image and quantify native SC-GSLs in tumor and non-tumor cell membranes. SC-GSL-mediated flip-flop was investigated in model membranes to confirm membrane-incorporation of SC-GSL and its effect on membrane remodeling. SC-GSL enriched liposomes containing doxorubicin (Dox) were incubated at 4°C and 37°C and intracellular drug uptake was studied in comparison to standard liposomes and free Dox. SC-GSL transfer to the cell membrane was independent of liposomal uptake and the majority of the transferred lipid remained in the plasma membrane. The transfer of SC-GSL was tumor cell-specific and induced membrane rearrangement as evidenced by a transbilayer flip-flop of pyrene-SM. However, pore formation was measured, as leakage of hydrophilic fluorescent probes was not observed. Moreover, drug uptake appeared to be mediated by SC-GSLs. SC-GSLs enhanced the interaction of doxorubicin (Dox) with the outer leaflet of the plasma membrane of tumor cells at 4°C. Our results demonstrate that SC-GSLs preferentially insert into tumor cell plasma membranes enhancing cell intrinsic capacity to translocate amphiphilic drugs such as Dox across the membrane via a biophysical process. PMID:25917957

  19. Significance of Circulating Tumor Cells in Soft Tissue Sarcoma

    PubMed Central

    Nicolazzo, Chiara; Gradilone, Angela

    2015-01-01

    Circulating tumor cells can be detected from the peripheral blood of cancer patients. Their prognostic value has been established in the last 10 years for metastatic colorectal, breast, and prostate cancer. On the contrary their presence in patients affected by sarcomas has been poorly investigated. The discovery of EpCAM mRNA expression in different sarcoma cell lines and in a small cohort of metastatic sarcoma patients supports further investigations on these rare tumors to deepen the importance of CTC isolation. Although it is not clear whether EpCAM expression might be originally present on tumor sarcoma cells or acquired during the mesenchymal-epithelial transition, the discovery of EpCAM on circulating sarcoma cells opens a new scenario in CTC detection in patients affected by a rare mesenchymal tumor. PMID:26167450

  20. General Information About Childhood Central Nervous System Germ Cell Tumors

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood CNS germ cell tumors may ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. Some cancer ...

  1. Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids.

    PubMed

    Mo, H; Elson, C E

    1999-04-01

    Diverse classes of phytochemicals initiate biological responses that effectively lower cancer risk. One class of phytochemicals, broadly defined as pure and mixed isoprenoids, encompasses an estimated 22,000 individual components. A representative mixed isoprenoid, gamma-tocotrienol, suppresses the growth of murine B16(F10) melanoma cells, and with greater potency, the growth of human breast adenocarcinoma (MCF-7) and human leukemic (HL-60) cells. beta-Ionone, a pure isoprenoid, suppresses the growth of B16 cells and with greater potency, the growth of MCF-7, HL-60 and human colon adenocarcinoma (Caco-2) cells. Results obtained with diverse cell lines differing in ras and p53 status showed that the isoprenoid-mediated suppression of growth is independent of mutated ras and p53 functions. beta-Ionone suppressed the growth of human colon fibroblasts (CCD-18Co) but only when present at three-fold the concentration required to suppress the growth of Caco-2 cells. The isoprenoids initiated apoptosis and, concomitantly arrested cells in the G1 phase of the cell cycle. Both suppress 3-hydroxy-3-methylglutaryl CoA reductase activity. beta-Ionone and lovastatin interfered with the posttranslational processing of lamin B, an activity essential to assembly of daughter nuclei. This interference, we postulate, renders neosynthesized DNA available to the endonuclease activities leading to apoptotic cell death. Lovastatin-imposed mevalonate starvation suppressed the glycosylation and translocation of growth factor receptors to the cell surface. As a consequence, cells were arrested in the G1 phase of the cell cycle. This rationale may apply to the isoprenoid-mediated G1-phase arrest of tumor cells. The additive and potentially synergistic actions of these isoprenoids in the suppression of tumor cell proliferation and initiation of apoptosis coupled with the mass action of the diverse isoprenoid constituents of plant products may explain, in part, the impact of fruit, vegetable

  2. Integrin receptors on tumor cells facilitate NK cell-mediated antibody-dependent cytotoxicity.

    PubMed

    Anikeeva, Nadia; Steblyanko, Maria; Fayngerts, Svetlana; Kopylova, Natalya; Marshall, Deborah J; Powers, Gordon D; Sato, Takami; Campbell, Kerry S; Sykulev, Yuri

    2014-08-01

    NK cells that mediate ADCC play an important role in tumor-specific immunity. We have examined factors limiting specific lysis of tumor cells by CD16.NK-92 cells induced by CNTO 95LF antibodies recognizing αV integrins that are overexpressed on many tumor cells. Although all tested tumor cells were killed by CD16.NK-92 effectors in the presence of the antibodies, the killing of target cells with a low level of ICAM-1 expression revealed a dramatic decrease in their specific lysis at high antibody concentration, revealing a dose limiting effect. A similar effect was also observed with primary human NK cells. The effect was erased after IFN-γ treatment of tumor cells resulting in upregulation of ICAM-1. Furthermore, killing of the same tumor cells induced by Herceptin antibody was significantly impaired in the presence of CNTO 95Ala-Ala antibody variant that blocks αV integrins but is incapable of binding to CD16. These data suggest that αV integrins on tumor cells could compensate for the loss of ICAM-1 molecules, thereby facilitating ADCC by NK cells. Thus, NK cells could exercise cytolytic activity against ICAM-1 deficient tumor cells in the absence of proinflammatory cytokines, emphasizing the importance of NK cells in tumor-specific immunity at early stages of cancer. PMID:24810893

  3. Training stem cells for treatment of malignant brain tumors

    PubMed Central

    Li, Shengwen Calvin; Kabeer, Mustafa H; Vu, Long T; Keschrumrus, Vic; Yin, Hong Zhen; Dethlefs, Brent A; Zhong, Jiang F; Weiss, John H; Loudon, William G

    2014-01-01

    The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for patients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution (i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system. PMID:25258664

  4. T cells induce terminal differentiation of transformed B cells to mature plasma cell tumors.

    PubMed

    Hilbert, D M; Shen, M Y; Rapp, U R; Rudikoff, S

    1995-01-31

    Major interest in the analysis of mature plasma cell neoplasias of mice and humans has focused on identification of precursor cells that give rise to mature malignant plasma cells. Although several laboratories have recently suggested that such cells are present in the granulomas of pristane-treated mice and the bone marrow of some multiple myeloma patients, the in vivo cellular interactions required for their differentiation into mature plasma cell tumors remains unclear. Given the extensive interactions of peripheral T cells and normal B cells, we assessed the potential role of T cells in plasma-cell tumor development, by using a myc, raf-containing retrovirus, J3V1, to induce plasmacytomas in normal BALB/c mice, T-cell-deficient nude mice, and T-cell-reconstituted nude mice. The B-lineage tumors arising in normal BALB/c mice were uniformly mature plasmacytomas, most of which secreted immunoglobulin. In contrast, nude mice yielded predominantly non-immunoglobulin-secreting B-cell lymphomas with a phenotype characteristic of peripheral B cells. T-cell reconstitution of nude mice prior to tumor induction resulted in a shift from B-cell lymphomas to plasmacytomas. These results imply that transformation can occur prior to terminal differentiation of B cells and that such transformed cells can be driven to terminal differentiation by peripheral T cells. These findings further suggest that, in human multiple myeloma, the ability of T cells to influence the differentiation state of transformed B cells may provide a mechanism by which malignant plasma cells found in the bone marrow could arise from clonotypically related less-mature B cells found in both the bone marrow and periphery. PMID:7846031

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

    PubMed Central

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

    2007-01-01

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

  6. Hybrid models of cell and tissue dynamics in tumor growth.

    PubMed

    Kim, Yangjin; Othmer, Hans G

    2015-12-01

    Hybrid models of tumor growth, in which some regions are described at the cell level and others at the continuum level, provide a flexible description that allows alterations of cell-level properties and detailed descriptions of the interaction with the tumor environment, yet retain the computational advantages of continuum models where appropriate. We review aspects of the general approach and discuss applications to breast cancer and glioblastoma. PMID:26775860

  7. Apoptosis by Direct Current Treatment in Tumor Cells and Tissues

    NASA Astrophysics Data System (ADS)

    Kim, Hongbae; Sim, Sungbo; Ahn, Saeyoung

    2003-10-01

    Electric field induces cell fusion, electroporation on biological cells, including apoptosis. Apoptosis is expressed in a series of natural enzymatic reactions for the natural elimination of unhealthy, genetically damaged, or otherwise aberrant cells that are not needed or not advantageous to the well-being of the organism. Its markers involve cell shrinkage, activation of intracellular caspase proteases, externalization of phosphatidylserine at the plasma membrane, and fragmentation of DNA. Direct electric fields using direct current have been exploited recently to investigate its effects on tumor cells and tissues, but the mechanism of direct electric fields has not been exhibited clearly other than by electroosmosis or pH changes. Direct electric field induces apoptosis in tumor cells cultured and tumor tissues as indicated by cell shrinkage, DNA fragmentation and tumor suppression. In our experiment that direct electric field was applied to tumor tissues via two needle electrodes inserted into tumor tissue 5mm at distance in parallel, pH changes resulted from electrochemical reaction, exhibiting about pH 9.0, 1.83, 2.0 in the vicinity of cathodic and anodic electrode, and at their mid-point, respectively. DNA fragmentation of tumor tissues destructed by direct electric field was analyzed by Tunel assay by ApopTag technology. As a result of this analysis, it showed that apoptosis in tumor tissue destructed was increased up to 59.1normal(control) tissues, showing 41.1, 31.1cathodic tissues. In vitro cell survival was exhibited that it was decreased with enhancing electric current intensity in the same condition of electrical charge 5C having different time applied. We will show results of apoptosis analyzed by flow cytometry in vitro.

  8. Human Leukocyte Antigen E Contributes to Protect Tumor Cells from Lysis by Natural Killer Cells12

    PubMed Central

    Monaco, Elisa Lo; Tremante, Elisa; Cerboni, Cristina; Melucci, Elisa; Sibilio, Leonardo; Zingoni, Alessandra; Nicotra, Maria Rita; Natali, Pier Giorgio; Giacomini, Patrizio

    2011-01-01

    The nonclassic class I human leukocyte antigen E (HLA-E) molecule engages the inhibitory NKG2A receptor on several cytotoxic effectors, including natural killer (NK) cells. Its tissue distribution was claimed to be wider in normal than in neoplastic tissues, and surface HLA-E was undetectable in most tumor cell lines. Herein, these issues were reinvestigated taking advantage of HLA-E-specific antibodies, immunohistochemistry, and biochemical methods detecting intracellular and surface HLA-E regardless of conformation. Contrary to published evidence, HLA-E was detected in a few normal epithelia and in a large fraction (approximately 1/3) of solid tumors, including those derived from HLA-E-negative/low-normal counterparts. Remarkably, HLA-E was detected in 30 of 30 tumor cell lines representative of major lymphoid and nonlymphoid lineages, and in 11 of 11, it was surface-expressed, although in a conformation poorly reactive with commonly used antibodies. Coexpression of HLA-E and HLA class I ligand donors was not required for surface expression but was associated with NKG2A-mediated protection from lysis by the cytotoxic cell line NKL and polyclonal NK cells from healthy donors, as demonstrated by antibody-mediated relief of protection in 10% to 20% of the tested target-effector combinations. NKG2A-mediated protection of additional targets became evident on NK effector blocking with antibodies to activating receptors (DNAM-1, natural cytotoxicity receptors, and NKG2D). Thus, initial evidence that the long-elusive HLA-E molecule is enhanced by malignant transformation and is functional in tumor cells is presented here, although its importance and precise functional role remain to be addressed in the context of a general understanding of the NK ligand-receptor network. PMID:21969815

  9. Human leukocyte antigen E contributes to protect tumor cells from lysis by natural killer cells.

    PubMed

    Lo Monaco, Elisa; Tremante, Elisa; Cerboni, Cristina; Melucci, Elisa; Sibilio, Leonardo; Zingoni, Alessandra; Nicotra, Maria Rita; Natali, Pier Giorgio; Giacomini, Patrizio

    2011-09-01

    The nonclassic class I human leukocyte antigen E (HLA-E) molecule engages the inhibitory NKG2A receptor on several cytotoxic effectors, including natural killer (NK) cells. Its tissue distribution was claimed to be wider in normal than in neoplastic tissues, and surface HLA-E was undetectable in most tumor cell lines. Herein, these issues were reinvestigated taking advantage of HLA-E-specific antibodies, immunohistochemistry, and biochemical methods detecting intracellular and surface HLA-E regardless of conformation. Contrary to published evidence, HLA-E was detected in a few normal epithelia and in a large fraction (approximately 1/3) of solid tumors, including those derived from HLA-E-negative/low-normal counterparts. Remarkably, HLA-E was detected in 30 of 30 tumor cell lines representative of major lymphoid and nonlymphoid lineages, and in 11 of 11, it was surface-expressed, although in a conformation poorly reactive with commonly used antibodies. Coexpression of HLA-E and HLA class I ligand donors was not required for surface expression but was associated with NKG2A-mediated protection from lysis by the cytotoxic cell line NKL and polyclonal NK cells from healthy donors, as demonstrated by antibody-mediated relief of protection in 10% to 20% of the tested target-effector combinations. NKG2A-mediated protection of additional targets became evident on NK effector blocking with antibodies to activating receptors (DNAM-1, natural cytotoxicity receptors, and NKG2D). Thus, initial evidence that the long-elusive HLA-E molecule is enhanced by malignant transformation and is functional in tumor cells is presented here, although its importance and precise functional role remain to be addressed in the context of a general understanding of the NK ligand-receptor network. PMID:21969815

  10. Collective Behavior of Brain Tumor Cells: the Role of Hypoxia

    NASA Astrophysics Data System (ADS)

    Khain, Evgeniy; Katakowski, Mark; Hopkins, Scott; Szalad, Alexandra; Zheng, Xuguang; Jiang, Feng; Chopp, Michael

    2013-03-01

    We consider emergent collective behavior of a multicellular biological system. Specifically we investigate the role of hypoxia (lack of oxygen) in migration of brain tumor cells. We performed two series of cell migration experiments. The first set of experiments was performed in a typical wound healing geometry: cells were placed on a substrate, and a scratch was done. In the second set of experiments, cell migration away from a tumor spheroid was investigated. Experiments show a controversy: cells under normal and hypoxic conditions have migrated the same distance in the ``spheroid'' experiment, while in the ``scratch'' experiment cells under normal conditions migrated much faster than under hypoxic conditions. To explain this paradox, we formulate a discrete stochastic model for cell dynamics. The theoretical model explains our experimental observations and suggests that hypoxia decreases both the motility of cells and the strength of cell-cell adhesion. The theoretical predictions were further verified in independent experiments.

  11. [Application of dendritic cells in clinical tumor therapy].

    PubMed

    Li, Yan; Xian, Li-jian

    2002-04-01

    The active immunotherapy of dendritic cells is hot in tumor therapy research area. This article is a review of the source of dendritic cells, loading antigen, immunotherapy pathway, clinical application, choice of patients, and so on. It makes preparation for further research of dendritic cells. PMID:12452029

  12. Secondary specific immune response in vitro to MSV tumor cells.

    PubMed

    Senik, A; Hebrero, F P; Levy, J P

    1975-12-15

    The interactions which occur between antigenic tumor cells and normal or immune lymphoid cells in a 3-day in vitro culture, have been studied with a murine sarcoma virus (MSV)-induced tumor. The 3H-thymidine incorporation of lymphoma cells growing in suspension, and the radioactive-chromium release of freshly sampled lymphoma cells regularly added to the culture, have been compared to determine the part played by immune lymphoid cells in cytolysis and cytostasis of the tumor-cell population. The cytolytic activity increases in the culture from day 0 to day 3. It is due, predominantly, to T-cells, and remains specific to antigens shared by MSV tumors and related lymphomas. This activity would be difficult to detect unless freshly sampled ascitic cells were used as targets, since the lymphoma cells spontaneously lose a part of their sensitivity to immune cytolysis during in vitro culture. The method used in the present experiments is a secondary chromium release test (SCRT), which measures the invitro secondary stimulation of cytotoxic T-lymphocytes (CTL) by tumor cells. In the absence of stimulatory cells, the CTL activity would have rapidly fallen in vitro. The cytostatic activity also increases during the 3 days in vitro, in parallel to the cytolytic activity: it is due to non-T-cells and remains mainly non-specific. The significance of these data for the interpretation of invitro demonstrated cell-mediated anti-tumor immune reactions is briefly discussed, as well as their relevance in the in vivo role of immune CTL. PMID:53210

  13. DNA Analysis in Samples From Younger Patients With Germ Cell Tumors and Their Parents or Siblings

    ClinicalTrials.gov

    2016-04-07

    Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Ovarian Choriocarcinoma; Ovarian Embryonal Carcinoma; Ovarian Mixed Germ Cell Tumor; Ovarian Teratoma; Ovarian Yolk Sac Tumor; Testicular Choriocarcinoma; Testicular Embryonal Carcinoma; Testicular Seminoma; Testicular Teratoma; Testicular Yolk Sac Tumor

  14. Stroma Cells in Tumor Microenvironment and Breast Cancer

    PubMed Central

    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

  15. Analysis of dendritic cell subpopulations in follicular lymphoma with respect to the tumor immune microenvironment.

    PubMed

    Chevalier, Nina; Mueller, Michael; Mougiakakos, Dimitrios; Ihorst, Gabriele; Marks, Reinhard; Schmitt-Graeff, Annette; Veelken, Hendrik

    2016-09-01

    The immune cell composition of the follicular lymphoma (FL) tumor microenvironment is increasingly recognized as an important determinant for clinical outcome. Here, we explored frequency and distribution of dendritic cell (DC) subtypes in relation to regulatory T cells (Treg) by immunohistochemistry in lymph node biopsies from patients with de novo FL. We found that neoplastic follicles contained lower DC and higher Treg frequencies than hyperplastic follicles in control lymph nodes. Treg numbers particularly correlated with the subset of conventional CD11c(+ )DCs. Additionally, both a high intra- to interfollicular ratio of CD11c(+ )DCs and increased intrafollicular Treg frequencies were associated with decreased overall survival. This suggests that functional interactions between these cells may be relevant for FL progression/recurrence. The presence of CD11c(+ )DCs in the tumor microenvironment may assist tumor infiltration by Tregs, thus contributing to the suppression of an otherwise beneficial T-cell-dominated FL microenvironment. PMID:26757600

  16. Immunization against strontium-90 induction of bone tumors with inactivated FBJ virus and irradiated syngeneic strontium-90-induced tumor cells

    SciTech Connect

    Reif, A.E.; Triest, W.E.

    1981-01-01

    Three hundred six C57BL/6J female mice were subdivided into a control group left untreated and an experimental group treated intraperitoneally with 1.0 ..mu..Ci strontium-90/g of body weight at an age of 66 days. Treatments for the groups were as follows: none, 6 injections of formalin-inactivated FBJ viral preparation, 6 injections of active FBJ viral preparation, and 2 injections of 10,000 rad irradiated transplantable osteosarcoma previously induced in C57BL/6J mice by strontium-90. In addition to the above groups, two other groups were treated with respectively 0.032 and 0.10 ..mu..Ci strontium-90/g body weight in order to obtain information on the dose-response relationship between the injection of strontium-90 and the yield of bone tumors. In the groups not treated with strontium-90, only 1 bone tumor developed; this occurred in the group injected with FBJ virus. The incidence of bone tumors in the groups treated with 1.0 ..mu..Ci strontium-90 was significantly lower (18.5% or 18.2%) in the two groups that had received injections of inactivated FBJ virus or irradiated isogenic osteosarcoma when compared to the group left uninjected, which developed 43.5% tumors. In contrast, the strontium-90-treated group that also received injections of active FBJ virus developed 63.0% tumors. Only a single bone tumor developed in the groups treated solely with intermediate doses of strontium-90. The results indicate that immunization with inactivated FBJ virus or with irradiated syngeneic strontium-90-induced tumor cells can significantly decrease the development of strontium-90-induced tumors.

  17. Inorganic nanovehicle for potential targeted drug delivery to tumor cells, tumor optical imaging.

    PubMed

    Yu, Shiyong; Gao, Xuechuan; Baigude, Huricha; Hai, Xiao; Zhang, Renfei; Gao, Xiaolong; Shen, Beibei; Li, Zhao; Tan, Zhibing; Su, Haiquan

    2015-03-11

    In this work, an inorganic multifunctional nanovehicle was tailored as a carrier to deliver anticancer drug for tumor optical imaging and therapy. The nanovehicle could be used as a dually targeted drug nanovehicle by bonded magnetical (passive) and folic acid (active) targeting capabilities. In addition, it was developed using rhodamine 6G (R6G) as a fluorescence reagent, and an α-zirconium phosphate nanoplatform (Zr(HPO4)2·H2O, abbreviated as α-ZrP) as the anticancer drug nanovehicle. The novel drug-release system was designed and fabricated by intercalation of α-ZrP with magnetic Fe3O4 nanoparticles and anticancer drug 5-fluorouracil (5-FU), followed by reacting with a folate acid-chitosan-rhodamine6G (FA-CHI-R6G) complex, and then α-ZrP intercalated with Fe3O4 nanoparticles and 5-fluorouracil (5-FU) was successfully encapsulated into chitosan (CHI). The resultant multifunctional drug delivery system was characterized by scanning electron microscopy, X-ray diffraction, energy-dispersive X-ray analysis, photoluminescence spectra, magnetometry, fluorescence microscopy imaging studies and other characterization methods. Simultaneously, the drug release in vitro on the obtained nanocomposites that exhibited a sustained release behavior was carried out in buffer solution at 37 °C, which demonstrated clearly that the nanocomposites shown a sustained release behavior. Meanwhile, cell culture experiments also indicated that the drug-release system had the potential to be used as an dually targeted drug nanovehicle into the tumor cells. PMID:25693506

  18. Carcinoembryonic antigen-related cell adhesion molecule 1 is expressed and as a function histotype in ovarian tumors.

    PubMed

    Li, Ning; Yang, Jing-Yan; Wang, Xiao-Ying; Wang, Hai-Tao; Guan, Bing-Xin; Zhou, Cheng-Jun

    2016-02-01

    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell-cell adhesion receptor and is implicated in several cellular functions. It is rarely reported in ovarian tumors. The aim of this study is to determine the expression of CEACAM1 in ovarian tumors, trying to see whether CEACAM1 has different expression patterns as a function of histotype. Antigen expression was examined by immunohistochemistry with mouse anti-human antibody for CEACAM1. Immunohistochemistry was performed using avidin-biotin-diaminobenzide staining. The results were expressed as average score ± SD (0, negative; 8, highest) for each histotype. In ovarian tumors, the benign serous and mucinous cystadenoma negatively or weakly expressed CEACAM1, the malignant epithelial tumors strongly expressed CEACAM1, and there was significant difference between benign epithelial tumor and adenocarcinoma (P < .05). The well-differentiated serous adenocarcinoma expressed CEACAM1 mainly with membrane pattern, and the intermediately and poorly differentiated serous adenocarcinomas expressed CEACAM1 mainly with cytoplasmic pattern (P < .05). In addition, CEACAM1 expression is elevated in solid tumors of ovary but variable as a function of histotype. Compared with membranous expression, the cytoplasmic expression was observed almost in metastatic carcinoma that might decrease the adhesive interactions of the carcinoma cells with the surrounding cells, especially with tumor cells, and this could facilitate the tumor cells to metastasize to distant regions. So, we thought that cytoplasmic CEACAM1 might play an important role in tumor progression, especially in tumor metastasis. PMID:26653024

  19. Targeting Survivin Enhances Chemosensitivity in Retinoblastoma Cells and Orthotopic Tumors.

    PubMed

    Ferrario, Angela; Luna, Marian; Rucker, Natalie; Wong, Sam; Lederman, Ariel; Kim, Jonathan; Gomer, Charles

    2016-01-01

    Treatments for retinoblastoma (Rb) vary depending on the size and location of the intraocular lesions and include chemotherapy and radiation therapy. We examined whether agents used to treat Rb induce a pro-survival phenotype associated with increased expression of survivin, a member of the inhibitor of apoptosis family of proteins. We document that exposure to carboplatin, topotecan or radiation resulted in elevated expression of survivin in two human Rb cell lines but not in normal retinal pigmented epithelial (RPE) cells. Cellular levels of survivin were attenuated in Rb cells exposed to an imidazolium-based survivin suppressant, Sepantronium bromide (YM155). Protein expression patterns of survivin in RPE cells were not altered following treatment protocols involving exposure to YM155. Including YM155 with chemotherapy or radiation increased levels of apoptosis in Rb cells but not in RPE cells. Intraocular luciferase expressing Rb tumors were generated from the Rb cell lines and used to evaluate the effects of carboplatin and YM155 on in-vivo survivin expression and tumor growth. Carboplatin induced expression of survivin while carboplatin combined with YM155 reduced survivin expression in tumor bearing eyes. The combination protocol was also most effective in reducing the rate of tumor regrowth. These results indicate that targeted inhibition of the anti-apoptotic protein survivin provides a therapeutic advantage for Rb cells and tumors treated with chemotherapy. PMID:27050416

  20. Targeting Survivin Enhances Chemosensitivity in Retinoblastoma Cells and Orthotopic Tumors

    PubMed Central

    Rucker, Natalie; Wong, Sam; Lederman, Ariel; Kim, Jonathan; Gomer, Charles

    2016-01-01

    Treatments for retinoblastoma (Rb) vary depending on the size and location of the intraocular lesions and include chemotherapy and radiation therapy. We examined whether agents used to treat Rb induce a pro-survival phenotype associated with increased expression of survivin, a member of the inhibitor of apoptosis family of proteins. We document that exposure to carboplatin, topotecan or radiation resulted in elevated expression of survivin in two human Rb cell lines but not in normal retinal pigmented epithelial (RPE) cells. Cellular levels of survivin were attenuated in Rb cells exposed to an imidazolium-based survivin suppressant, Sepantronium bromide (YM155). Protein expression patterns of survivin in RPE cells were not altered following treatment protocols involving exposure to YM155. Including YM155 with chemotherapy or radiation increased levels of apoptosis in Rb cells but not in RPE cells. Intraocular luciferase expressing Rb tumors were generated from the Rb cell lines and used to evaluate the effects of carboplatin and YM155 on in-vivo survivin expression and tumor growth. Carboplatin induced expression of survivin while carboplatin combined with YM155 reduced survivin expression in tumor bearing eyes. The combination protocol was also most effective in reducing the rate of tumor regrowth. These results indicate that targeted inhibition of the anti-apoptotic protein survivin provides a therapeutic advantage for Rb cells and tumors treated with chemotherapy. PMID:27050416

  1. Dysregulation of MicroRNA-34a Expression in Head and Neck Squamous Cell Carcinoma Promotes Tumor Growth and Tumor Angiogenesis

    PubMed Central

    Kumar, Bhavna; Yadav, Arti; Lang, James; Teknos, Theodoros N.; Kumar, Pawan

    2012-01-01

    Background MicroRNAs (miRs) are small non-coding RNAs that play an important role in cancer development where they can act as oncogenes or as tumor-suppressors. miR-34a is a tumor-suppressor that is frequently downregulated in a number of tumor types. However, little is known about the role of miR-34a in head and neck squamous cell carcinoma (HNSCC). Methods and Results miR-34a expression in tumor samples, HNSCC cell lines and endothelial cells was examined by real time PCR. Lipofectamine-2000 was used to transfect miR-34a in HNSCC cell lines and human endothelial cells. Cell-proliferation, migration and clonogenic survival was examined by MTT, Xcelligence system, scratch assay and colony formation assay. miR-34a effect on tumor growth and tumor angiogenesis was examined by in vivo SCID mouse xenograft model. Our results demonstrate that miR-34a is significantly downregulated in HNSCC tumors and cell lines. Ectopic expression of miR-34a in HNSCC cell lines significantly inhibited tumor cell proliferation, colony formation and migration. miR-34a overexpression also markedly downregulated E2F3 and survivin levels. Rescue experiments using microRNA resistant E2F3 isoforms suggest that miR-34a-mediated inhibition of cell proliferation and colony formation is predominantly mediated by E2F3a isoform. In addition, tumor samples from HNSCC patients showed an inverse relationship between miR-34a and survivin as well as miR-34a and E2F3 levels. Overexpression of E2F3a completely rescued survivin expression in miR-34a expressing cells, thereby suggesting that miR-34a may be regulating survivin expression via E2F3a. Ectopic expression of miR-34a also significantly inhibited tumor growth and tumor angiogenesis in a SCID mouse xenograft model. Interestingly, miR-34a inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell functions. Conclusions Taken together, these findings suggest that dysregulation of miR-34a

  2. Ribosome Profiling Reveals a Cell-Type-Specific Translational Landscape in Brain Tumors

    PubMed Central

    Gonzalez, Christian; Sims, Jennifer S.; Hornstein, Nicholas; Mela, Angeliki; Garcia, Franklin; Lei, Liang; Gass, David A.; Amendolara, Benjamin; Bruce, Jeffrey N.

    2014-01-01

    Glioma growth is driven by signaling that ultimately regulates protein synthesis. Gliomas are also complex at the cellular level and involve multiple cell types, including transformed and reactive cells in the brain tumor microenvironment. The distinct functions of the various cell types likely lead to different requirements and regulatory paradigms for protein synthesis. Proneural gliomas can arise from transformation of glial progenitors that are driven to proliferate via mitogenic signaling that affects translation. To investigate translational regulation in this system, we developed a RiboTag glioma mouse model that enables cell-type-specific, genome-wide ribosome profiling of tumor tissue. Infecting glial progenitors with Cre-recombinant retrovirus simultaneously activates expression of tagged ribosomes and delivers a tumor-initiating mutation. Remarkably, we find that although genes specific to transformed cells are highly translated, their translation efficiencies are low compared with normal brain. Ribosome positioning reveals sequence-dependent regulation of ribosomal activity in 5′-leaders upstream of annotated start codons, leading to differential translation in glioma compared with normal brain. Additionally, although transformed cells express a proneural signature, untransformed tumor-associated cells, including reactive astrocytes and microglia, express a mesenchymal signature. Finally, we observe the same phenomena in human disease by combining ribosome profiling of human proneural tumor and non-neoplastic brain tissue with computational deconvolution to assess cell-type-specific translational regulation. PMID:25122893

  3. Glomus tumor of the ovary masquerading as granulosa cell tumor: case report.

    PubMed

    Slone, Stephen P; Moore, Grace D; Parker, Lynn P; Rickard, Kyle A; Nixdorf-Miller, Allison S

    2010-01-01

    A solid right adnexal mass in a 73-year-old woman bled profusely with mobilization mimicking a granulosa cell tumor. There was almost complete replacement of the ovary by a circumscribed, 4.0 cm tumor with a hemorrhagic, solid cut surface. Morphologic and phenotypic correlation supported a diagnosis of glomus tumor. Large gaping vessels and small sinusoidal-type vessels formed an anastomotic vascular network with an inner endothelial lining (CD31+/CD34+) and an outer layer of glomocytes (actin+/desmin-/inhibin-). The hemangiopericytoma-like vasculature accounted for bleeding during surgery. PMID:19952942

  4. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth.

    PubMed

    El Ghazal, Roland; Yin, Xin; Johns, Scott C; Swanson, Lee; Macal, Monica; Ghosh, Pradipta; Zuniga, Elina I; Fuster, Mark M

    2016-05-01

    In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs) in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1) in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21)-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt) were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4-deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer. PMID:27237321

  5. Starved and Asphyxiated: How Can CD8+ T Cells within a Tumor Microenvironment Prevent Tumor Progression

    PubMed Central

    Zhang, Ying; Ertl, Hildegund C. J.

    2016-01-01

    Although cancer immunotherapy has achieved significant breakthroughs in recent years, its overall efficacy remains limited in the majority of patients. One major barrier is exhaustion of tumor antigen-specific CD8+ tumor-infiltrating lymphocytes (TILs), which conventionally has been attributed to persistent stimulation with antigen within the tumor microenvironment (TME). A series of recent studies have highlighted that the TME poses significant metabolic challenges to TILs, which may contribute to their functional exhaustion. Hypoxia increases the expression of coinhibitors on activated CD8+ T cells, which in general reduces the T cells’ effector functions. It also impairs the cells’ ability to gain energy through oxidative phosphorylation. Glucose limitation increases the expression of programed cell death protein-1 and reduces functions of activated CD8+ T cells. A combination of hypoxia and hypoglycemia, as is common in solid tumors, places CD8+ TILs at dual metabolic jeopardy by affecting both major pathways of energy production. Recently, a number of studies addressed the effects of metabolic stress on modulating CD8+ T cell metabolism, differentiation, and functions. Here, we discuss recent findings on how different types of metabolic stress within the TME shape the tumor-killing capacity of CD8+ T cells. We propose that manipulating the metabolism of TILs to more efficiently utilize nutrients, especially during intermittent periods of hypoxia could maximize their performance, prolong their survival and improve the efficacy of active cancer immunotherapy. PMID:26904023

  6. Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages.

    PubMed

    Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie; Wang, Yuzhen; Yu, Fang; Fan, Daping

    2016-08-01

    Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931-42. ©2016 AACR. PMID:27196773

  7. Adult granulosa cell tumor of the testis masquerading as hydrocele

    PubMed Central

    Vallonthaiel, Archana George; Kakkar, Aanchal; Singh, Animesh; Dogra, Prem N; Ray, Ruma

    2015-01-01

    ABSTRACT Adult testicular granulosa cell tumor is a rare, potentially malignant sex cord-stromal tumor, of which 30 cases have been described to date. We report the case of a 43-year-old male who complained of a left testicular swelling. Scrotal ultrasound showed a cystic lesion, suggestive of hydrocele. However, due to a clinical suspicion of a solid-cystic neoplasm, a high inguinal orchidectomy was performed, which, on pathological examination, was diagnosed as adult granulosa cell tumor. Adult testicular granulosa cell tumors have aggressive behaviour as compared to their ovarian counterparts. They may rarely be predominantly cystic and present as hydrocele. Lymph node and distant metastases have been reported in few cases. Role of MIB-1 labelling index in prognostication is not well defined. Therefore, their recognition and documentation of their behaviour is important from a diagnostic, prognostic and therapeutic point of view. PMID:26742984

  8. Metal-air cell with performance enhancing additive

    SciTech Connect

    Friesen, Cody A; Buttry, Daniel

    2015-11-10

    Systems and methods drawn to an electrochemical cell comprising a low temperature ionic liquid comprising positive ions and negative ions and a performance enhancing additive added to the low temperature ionic liquid. The additive dissolves in the ionic liquid to form cations, which are coordinated with one or more negative ions forming ion complexes. The electrochemical cell also includes an air electrode configured to absorb and reduce oxygen. The ion complexes improve oxygen reduction thermodynamics and/or kinetics relative to the ionic liquid without the additive.

  9. Constitutional genomic instability, chromosome aberrations in tumor cells and retinoblastoma.

    PubMed

    Amare Kadam, P S; Ghule, P; Jose, J; Bamne, M; Kurkure, P; Banavali, S; Sarin, R; Advani, S

    2004-04-01

    Although retinoblastoma (Rb) is initiated as a result of biallelic inactivation of the RB1 gene, additional genetic events (M3) in tumor cells are indicative of their role in the full transformation of retinal cells. We investigated the constitutional genetic instability by fragile site (FS) expression studies and checked its relationship with loci of tumor cytogenetics in a series of 36 retinoblastoma patients (34 nonfamilial and 2 familial cases). Tumor cytogenetics revealed -13/+13, del/t(13)(q14) (50%), +1/del/t(1p/q) (65%), +6/i(6p) (60%), and del(16)(q13)/(q22 approximately q23) (60%). Conventional cytogenetics in leukocytes revealed constitutional del(13q14) in five unilateral Rb (URB) and one trilateral Rb (TRB). Constitutional del(16)(q22) and t(6;12) were also identified in two cases. Constitutional FS analysis showed a significant increase in the cellular fragility, with high prevalence at 13q14, 3p14, 6p23, 16q22 approximately q23, and 13q22 loci in retinoblastoma patients (P<0.05). Patients with constitutional del(13)(q14) demonstrated higher fragility than those with normal constitution. A strong correlation between loci of constitutional FSs and loci of recurrent chromosomal abnormalities in tumors strengthen and support the proposal that FS loci present as inherent genomic instability in retinoblastoma. The chromosomal changes and resultant genetic mutations, along with RB1 mutation events, probably contribute synergistically to the development and progression of Rb malignancy. Implementation of fluorescence in situ hybridization to nonfamilial Rb on a large scale (113 cases) could detect constitutional RB1 deletion in 12.3% of cases, with equally higher incidence in URB (14.7%) and bilateral Rb (13.6%), demonstrating that the true prevalence of patients with predisposition to RB1 mutation in sporadic URB is definitely higher in our populations. Also, higher incidence of constitutional RB1 deletion mosaicism in unilateral than in bilateral Rb

  10. Role of cell type and animal species in tumor metastasis

    NASA Astrophysics Data System (ADS)

    Solban, Nicolas; Georgakoudi, Irene; Rice, William L.; Lin, Charles; Hasan, Tayyaba

    2004-06-01

    Photodynamic therapy (PDT) is now a reasonably well-known therapeutic option and is approved as a first line treatment of age-related macular degeneration (AMD), a non-oncologic condition. For most cancer applications PDT is approved mainly as a palliative or adjunctive treatment often when all other options have failed. As the modality evolves toward becoming a first-line or curative option, long-term effects of processes involved will need to be studied. Cellular and tissue responses to PDT are more complex than responses to the more conventional therapies, perhaps because PDT is inherently a binary (or ternary) therapy. In addition to the nature and localization of the photosensitizer (PS), the timing of illumination after administration, the mode of administration and the PS and light doses, the efficacy and selectivity of responses are also determined by the physiology and geometry of tumors, the inherent survivability of tumor cells (in circulation and other anatomic sites) and cellular and molecular responses to PDT. The overall outcome of photodynamic treatment in the long term is determined by a combination, in varying degrees, of all of the above factors. In order to enhance and broaden the application of PDT to complex anatomical sites, an understanding of these factors would be useful. In the laboratory, the outcome is also dependent on the specific animal models being studied. This manuscript discusses preliminary studies along these lines using a variety of tools and implications, if any, of the results obtained.

  11. Analysis of tumor-infiltrating gamma delta T cells in rectal cancer

    PubMed Central

    Rong, Liang; Li, Ke; Li, Rui; Liu, Hui-Min; Sun, Rui; Liu, Xiao-Yan

    2016-01-01

    AIM: To investigate the regulatory effect of Vδ1 T cells and the antitumor activity of Vδ2 T cells in rectal cancer. METHODS: Peripheral blood, tumor tissues and para-carcinoma tissues from 20 rectal cancer patients were collected. Naïve CD4 T cells from the peripheral blood of rectal cancer patients were purified by negative selection using a Naive CD4+ T Cell Isolation Kit II (Miltenyi Biotec). Tumor tissues and para-carcinoma tissues were minced into small pieces and digested in a triple enzyme mixture containing collagenase type IV, hyaluronidase, and deoxyribonuclease for 2 h at room temperature. After digestion, the cells were washed twice in RPMI1640 and cultured in RPMI1640 containing 10% human serum supplemented with L-glutamine and 2-mercaptoethanol and 1000 U/mL of IL-2 for the generation of T cells. Vδ1 T cells and Vδ2 T cells from tumor tissues and para-carcinoma tissues were expanded by anti-TCR γδ antibodies. The inhibitory effects of Vδ1 T cells on naïve CD4 T cells were analyzed using the CFSE method. The cytotoxicity of Vδ2 T cells on rectal cancer lines was determined by the LDH method. RESULTS: The percentage of Vδ1 T cells in rectal tumor tissues from rectal cancer patients was significantly increased, and positively correlated with the T stage. The percentage of Vδ2 T cells in rectal tumor tissues from rectal cancer patients was significantly decreased, and negatively correlated with the T stage. After culture for 14 d with 1 μg/mL anti-TCR γδ antibodies, the percentage of Vδ1 T cells from para-carcinoma tissues was 21.45% ± 4.64%, and the percentage of Vδ2 T cells was 38.64% ± 8.05%. After culture for 14 d, the percentage of Vδ1 T cells from rectal cancer tissues was 67.45% ± 11.75% and the percentage of Vδ2 T cells was 8.94% ± 2.85%. Tumor-infiltrating Vδ1 T cells had strong inhibitory effects, and tumor-infiltrating Vδ2 T cells showed strong cytolytic activity. The inhibitory effects of Vδ1 T cells from para

  12. Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells.

    PubMed

    Henrich, Frederik C; Singer, Katrin; Poller, Kerstin; Bernhardt, Luise; Strobl, Carolin D; Limm, Katharina; Ritter, Axel P; Gottfried, Eva; Völkl, Simon; Jacobs, Benedikt; Peter, Katrin; Mougiakakos, Dimitrios; Dettmer, Katja; Oefner, Peter J; Bosserhoff, Anja-Katrin; Kreutz, Marina P; Aigner, Michael; Mackensen, Andreas

    2016-08-01

    The immunosuppressive tumor microenvironment represents one of the main obstacles for immunotherapy of cancer. The tumor milieu is among others shaped by tumor metabolites such as 5'-deoxy-5'-methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTA-catabolizing enzyme methylthioadenosine phosphorylase (MTAP) in tumor cells and are found in various tumor entities. Here, we demonstrate that MTA suppresses proliferation, activation, differentiation, and effector function of antigen-specific T cells without eliciting cell death. Conversely, if MTA is added to highly activated T cells, MTA exerts cytotoxic effects on T cells. We identified the Akt pathway, a critical signal pathway for T cell activation, as a target of MTA, while, for example, p38 remained unaffected. Next, we provide evidence that MTA exerts its immunosuppressive effects by interfering with protein methylation in T cells. To confirm the relevance of the suppressive effects of exogenously added MTA on human T cells, we used an MTAP-deficient tumor cell-line that was stably transfected with the MTAP-coding sequence. We observed that T cells stimulated with MTAP-transfected tumor cells revealed a higher proliferative capacity compared to T cells stimulated with Mock-transfected cells. In conclusion, our findings reveal a novel immune evasion strategy of human tumor cells that could be of interest for therapeutic targeting. PMID:27622058

  13. Malignant perivascular epithelioid cell tumor of the gallbladder: a case report and review of literature.

    PubMed

    Zhao, Liena; Anders, Karl H

    2014-09-01

    Perivascular epithelioid cell tumors are rare mesenchymal neoplasms composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. The perivascular epithelioid cell tumor family includes angiomyolipoma, clear cell sugar tumor of the lung, lymphangioleiomyomatosis, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomic sites. Perivascular epithelioid cell tumors have been reported previously in various sites, but to our knowledge not in the gallbladder. We report here, for the first time, a malignant perivascular epithelioid cell tumor arising in the gallbladder. PMID:25171708

  14. Alvocidib and Oxaliplatin With or Without Fluorouracil and Leucovorin Calcium in Treating Patients With Relapsed or Refractory Germ Cell Tumors

    ClinicalTrials.gov

    2015-05-11

    Recurrent Extragonadal Seminoma; Recurrent Malignant Extragonadal Germ Cell Tumor; Recurrent Malignant Extragonadal Non-Seminomatous Germ Cell Tumor; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage III Testicular Cancer; Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor; Stage IV Extragonadal Seminoma; Stage IV Ovarian Germ Cell Tumor

  15. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo

    PubMed Central

    Koneru, Mythili; Purdon, Terence J.; Spriggs, David; Koneru, Susmith; Brentjens, Renier J.

    2015-01-01

    A novel approach for the treatment of ovarian cancer includes immunotherapy with genetically engineered T cells targeted to ovarian cancer cell antigens. Using retroviral transduction, T cells can be created that express an artificial T cell receptor (TCR) termed a chimeric antigen receptor (CAR). We have generated a CAR, 4H11-28z, specific to MUC-16ecto antigen, which is the over-expressed on a majority of ovarian tumor cells and is the retained portion of MUC-16 after cleavage of CA-125. We previously demonstrated that T cells modified to express the 4H11-28z CAR eradicate orthotopic human ovarian cancer xenografts in SCID-Beige mice. However, despite the ability of CAR T cells to localize to tumors, their activation in the clinical setting can be inhibited by the tumor microenvironment, as is commonly seen for endogenous antitumor immune response. To potentially overcome this limitation, we have recently developed a construct that co-expresses both MUC16ecto CAR and IL-12 (4H11-28z/IL-12). In vitro, 4H11-28z/IL-12 CAR T cells show enhanced proliferation and robust IFNγ secretion compared to 4H11-28z CAR T cells. In SCID-Beige mice with human ovarian cancer xenografts, IL-12 secreting CAR T cells exhibit enhanced antitumor efficacy as determined by increased survival, prolonged persistence of T cells, and higher systemic IFNγ. Furthermore, in anticipation of translating these results into a phase I clinical trial which will be the first to study IL-12 secreting CAR T cells in ovarian cancer, an elimination gene has been included to allow for deletion of CAR T cells in the context of unforeseen or off-tumor on-target toxicity. PMID:25949921

  16. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    PubMed Central

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P.; Gonzalez-Perez, Ruben R.; Torroella-Kouri, Marta

    2015-01-01

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity. PMID:25599228

  17. Utility of transmission electron microscopy in small round cell tumors.

    PubMed

    Kim, Na Rae; Ha, Seung Yeon; Cho, Hyun Yee

    2015-03-01

    Small round cell tumors (SRCTs) are a heterogeneous group of neoplasms composed of small, primitive, and undifferentiated cells sharing similar histology under light microscopy. SRCTs include Ewing sarcoma/peripheral neuroectodermal tumor family tumors, neuroblastoma, desmoplastic SRCT, rhabdomyosarcoma, poorly differentiated round cell synovial sarcoma, mesenchymal chondrosarcoma, small cell osteosarcoma, small cell malignant peripheral nerve sheath tumor, and small cell schwannoma. Non-Hodgkin's malignant lymphoma, myeloid sarcoma, malignant melanoma, and gastrointestinal stromal tumor may also present as SRCT. The current shift towards immunohistochemistry and cytogenetic molecular techniques for SRCT may be inappropriate because of antigenic overlapping or inconclusive molecular results due to the lack of differentiation of primitive cells and unavailable genetic service or limited moleculocytogenetic experience. Although usage has declined, electron microscopy (EM) remains very useful and shows salient features for the diagnosis of SRCTs. Although EM is not always required, it provides reliability and validity in the diagnosis of SRCT. Here, the ultrastructural characteristics of SRCTs are reviewed and we suggest that EM would be utilized as one of the reliable modalities for the diagnosis of undifferentiated and poorly differentiated SRCTs. PMID:25812730

  18. Extravasation of leukocytes in comparison to tumor cells

    PubMed Central

    Strell, Carina; Entschladen, Frank

    2008-01-01

    The multi-step process of the emigration of cells from the blood stream through the vascular endothelium into the tissue has been termed extravasation. The extravasation of leukocytes is fairly well characterized down to the molecular level, and has been reviewed in several aspects. Comparatively little is known about the extravasation of tumor cells, which is part of the hematogenic metastasis formation. Although the steps of the process are basically the same in leukocytes and tumor cells, i.e. rolling, adhesion, transmigration (diapedesis), the molecules that are involved are different. A further important difference is that leukocyte interaction with the endothelium changes the endothelial integrity only temporarily, whereas tumor cell interaction leads to an irreversible damage of the endothelial architecture. Moreover, tumor cells utilize leukocytes for their extravasation as linkers to the endothelium. Thus, metastasis formation is indirectly susceptible to localization signals that are literally specific for the immune system. We herein compare the extravasation of leukocytes and tumor cells with regard to the involved receptors and the localization signals that direct the cells to certain organs and sites of the body. PMID:19055814

  19. Utility of Transmission Electron Microscopy in Small Round Cell Tumors

    PubMed Central

    Kim, Na Rae; Ha, Seung Yeon; Cho, Hyun Yee

    2015-01-01

    Small round cell tumors (SRCTs) are a heterogeneous group of neoplasms composed of small, primitive, and undifferentiated cells sharing similar histology under light microscopy. SRCTs include Ewing sarcoma/peripheral neuroectodermal tumor family tumors, neuroblastoma, desmoplastic SRCT, rhabdomyosarcoma, poorly differentiated round cell synovial sarcoma, mesenchymal chondrosarcoma, small cell osteosarcoma, small cell malignant peripheral nerve sheath tumor, and small cell schwannoma. Non-Hodgkin’s malignant lymphoma, myeloid sarcoma, malignant melanoma, and gastrointestinal stromal tumor may also present as SRCT. The current shift towards immunohistochemistry and cytogenetic molecular techniques for SRCT may be inappropriate because of antigenic overlapping or inconclusive molecular results due to the lack of differentiation of primitive cells and unavailable genetic service or limited moleculocytogenetic experience. Although usage has declined, electron microscopy (EM) remains very useful and shows salient features for the diagnosis of SRCTs. Although EM is not always required, it provides reliability and validity in the diagnosis of SRCT. Here, the ultrastructural characteristics of SRCTs are reviewed and we suggest that EM would be utilized as one of the reliable modalities for the diagnosis of undifferentiated and poorly differentiated SRCTs. PMID:25812730

  20. Three-dimensional chemotaxis-driven aggregation of tumor cells

    PubMed Central

    Puliafito, Alberto; De Simone, Alessandro; Seano, Giorgio; Gagliardi, Paolo Armando; Di Blasio, Laura; Chianale, Federica; Gamba, Andrea; Primo, Luca; Celani, Antonio

    2015-01-01

    One of the most important steps in tumor progression involves the transformation from a differentiated epithelial phenotype to an aggressive, highly motile phenotype, where tumor cells invade neighboring tissues. Invasion can occur either by isolated mesenchymal cells or by aggregates that migrate collectively and do not lose completely the epithelial phenotype. Here, we show that, in a three-dimensional cancer cell culture, collective migration of cells eventually leads to aggregation in large clusters. We present quantitative measurements of cluster velocity, coalescence rates, and proliferation rates. These results cannot be explained in terms of random aggregation. Instead, a model of chemotaxis-driven aggregation – mediated by a diffusible attractant – is able to capture several quantitative aspects of our results. Experimental assays of chemotaxis towards culture conditioned media confirm this hypothesis. Theoretical and numerical results further suggest an important role for chemotactic-driven aggregation in spreading and survival of tumor cells. PMID:26471876

  1. Three-dimensional chemotaxis-driven aggregation of tumor cells.

    PubMed

    Puliafito, Alberto; De Simone, Alessandro; Seano, Giorgio; Gagliardi, Paolo Armando; Di Blasio, Laura; Chianale, Federica; Gamba, Andrea; Primo, Luca; Celani, Antonio

    2015-01-01

    One of the most important steps in tumor progression involves the transformation from a differentiated epithelial phenotype to an aggressive, highly motile phenotype, where tumor cells invade neighboring tissues. Invasion can occur either by isolated mesenchymal cells or by aggregates that migrate collectively and do not lose completely the epithelial phenotype. Here, we show that, in a three-dimensional cancer cell culture, collective migration of cells eventually leads to aggregation in large clusters. We present quantitative measurements of cluster velocity, coalescence rates, and proliferation rates. These results cannot be explained in terms of random aggregation. Instead, a model of chemotaxis-driven aggregation - mediated by a diffusible attractant - is able to capture several quantitative aspects of our results. Experimental assays of chemotaxis towards culture conditioned media confirm this hypothesis. Theoretical and numerical results further suggest an important role for chemotactic-driven aggregation in spreading and survival of tumor cells. PMID:26471876

  2. Granular cell tumor of the penis: clinicopathologic evaluation of 9 cases.

    PubMed

    Laskin, William B; Fetsch, John F; Davis, Charles J; Sesterhenn, Isabell A

    2005-03-01

    The occurrence of granular cell tumor (GCT) in penile tissue is very rare, with only 9 examples reported to date in the English-language literature. Herein, we describe the clinicopathologic and immunohistochemical findings in 9 additional cases. The patients ranged in age from 20 to 60 years (mean, 42 years; median, 40 years) at time of diagnosis. All penile tumors were solitary and arose in the dermis of the penile shaft (n=4), prepuce (n=3), and corona (n=2). A patient had a history of multiple cutaneous GCTs. Duration of symptoms before surgery ranged from 5 days to 2 years with the presence of an asymptomatic nodule representing the most common tumor-related complaint (n=8). The lesions ranged in size from 0.6 to 2.5 cm (mean, 1.5 cm; median, 1.5 cm). Microscopically, the tumors were moderate to highly cellular and were composed of oval to polygonal-shaped cells with abundant coarsely granular eosinophilic cytoplasm. Tumor cells grew in infiltrating nests, cords, and trabeculae and showed neural (n=2) and vessel wall (n=1) invasion or formed a relatively well-marginated solid nodule. Bland cytological features with only rare cells showing nucleomegaly (n=7) or spindling (n=3) were exhibited by 8 tumors. A tumor demonstrated diffuse nuclear atypia and was classified as "atypical." Mitotic activity ranged from 0 to 8 mitoses (mean, 1.4 mitoses) per 50 high-powered fields with no atypical division figures identified. All tumors tested showed moderate to strong immunohistochemical expression of S100 protein (n=6) and low-affinity nerve growth factor receptor (n=5), which was useful for detecting small deposits of tumor and helpful in evaluating surgical margins. Focal tumor cell immunoreactivity was observed for calretinin (4/6 cases) and glial fibrillary acidic protein (1/6 cases). All patients underwent simple (local) excision of their tumor. Complete follow-up data (mean, 21 years; interval range, 0.5-28 years) were available for 6 patients. No patient

  3. [A mixed germ cell tumor that underwent dramatic size changes].

    PubMed

    Kuwayama, Kazuyuki; Takai, Hiroki; Nishiyama, Akira; Hirai, Satoshi; Yokosuka, Kimihiko; Toi, Hiroyuki; Hirano, Kazuhiro; Matsubara, Shunji; Uno, Masaaki; Nishimura, Hirotake

    2014-09-01

    This report describes a mixed germ cell tumor that underwent dramatic size changes. A 12-year-old boy presented to our hospital with a headache that had persisted for two months. Initial magnetic resonance imaging (MRI) revealed a pineal tumor and hydrocephalus. The patient required external ventricular drainage and underwent two endoscopic biopsies. His evaluation involved a total of nine computed tomography (CT) scans prior to the second biopsy;the tumor size had decreased before the second endoscopic biopsy. The tumor consisted of both a germinoma and a teratoma component. The patient was treated with three courses of carboplatin-etoposide (CBDCA-VP) chemotherapy and whole-ventricle radiotherapy (32.1 Gy). However, during the adjuvant therapy, the tumor size increased, necessitating total tumor resection. We speculate that the tumor's initial size reduction was caused by leakage of the cyst component and exposure to the brain CT irradiation. The tumor's subsequent increase in size was due to the recollection of the cystic components and intracranial growing teratoma syndrome (iGTS). Therefore, frequent brain CTs and angiography should be avoided before definitive pathological diagnosis is achieved. Further, the tumor size should be considered, with surgical resection being performed at the optimal time. PMID:25179200

  4. MUC-1 Tumor Antigen Agonist Epitopes for Enhancing T-cell Responses to Human Tumors | NCI Technology Transfer Center | TTC

    Cancer.gov

    Scientists at NIH have identified 7 new agonist epitopes of the MUC-1 tumor associated antigen. Compared to their native epitope counterparts, peptides reflecting these agonist epitopes have been shown to enhance the generation of human tumor cells, which in turn have a greater ability to kill human tumor cells endogenously expressing the native MUC-1 epitope.

  5. Extraosseous Benign Notochordal Cell Tumor Originating in the Lung

    PubMed Central

    Takahashi, Yusuke; Motoi, Toru; Harada, Masahiko; Fukuda, Yumiko; Hishima, Tsunekazu; Horio, Hirotoshi

    2015-01-01

    Abstract Benign notochordal cell tumors (BNCTs) are tumors originating in the axial skeleton, where chordomas occur. Although very rare, some cases of extraosseous chordoma, such as in the soft tissue and lungs, have been reported. We report a case of a primary tumor showing the notochordal characteristics of BNCTs within the axial skeleton. An asymptomatic 57-year-old woman presented with an abnormal shadow on her chest radiograph; chest computed tomography revealed a well-defined round nodule. The resected sample tissue contained a jelly-like small nodule. Histologically, it was identified as a BNCT, based on minimal nuclear atypia, extremely low mitotic activity within the tumor cells lying in a sheet-like arrangement, and focal immunopositivity for brachyury. This is the third case report of BNCT originating in the lungs; BNCTs are considered asymptomatic tumors that are identified by using highly developed chest imaging technology; however, our findings also suggest that these notochordal tumors may potentially originate from extraosseous sites that lack ideal precursor cells. Our case suggests that notochordal tumors can arise from organs that are unrelated to known notochordal development. PMID:25569657

  6. Gossypol effects on endothelial cells and tumor blood flow

    SciTech Connect

    Benz, C.C.; Iyer, S.B.; Asgari, H.S.; Matlin, S.A.; Aronson, F.R. ); Barchowsky, A. )

    1991-01-01

    Isomers (-,+) of the antitumor agent gossypol (G) were studied for their ability to reduce tumor ATP and blood flow in rats bearing subcutaneously implanted pancreatic tumors. A 50% reduction in tumor ATP/Pi within 1h of a single injection of -G was associated with a 60% decline in tumor blood flow. To determine if these changes in tumor physiology could be due to a direct drug effect on tumor endothelium, G isomers were compared for their ability to alter protein ({sup 125}1-BSA) permeability and metabolic ({sup 32}P) labelling of cultured endothelial cells. Treatments for 1h produced no endothelial cell leakage, but 24h exposures to either -G or +G produced complete permeability of the monolayers to {sup 125}1-BSA. In contrast, 0.5-1.0h exposures to -G or +G produced 2 to 3-fold increases in phosphorylated 27kDa heat-shock protein, hsp-27. Hsp-27 phosphoprotein isoforms were differentially labelled following -G and +G exposures with the phosphorylation profile of -G appearing most similar to that of oxyradical producing agents known to induce hsp-27 and injure endothelial cells. The authors postulate that the tumor ischemic effects of -G are mediated by endothelial response to oxyradical production in a mechanism similar to that of tissue ischemia-reperfusion injury.

  7. Soy Promotes Juvenile Granulosa Cell Tumor Development in Mice and in the Human Granulosa Cell Tumor-Derived COV434 Cell Line1

    PubMed Central

    Mansouri-Attia, Nadéra; James, Rebecca; Ligon, Alysse; Li, Xiaohui; Pangas, Stephanie A.

    2014-01-01

    ABSTRACT Soy attracts attention for its health benefits, such as lowering cholesterol or preventing breast and colon cancer. Soybeans contain isoflavones, which act as phytoestrogens. Even though isoflavones have beneficial health effects, a role for isoflavones in the initiation and progression of diseases including cancer is becoming increasingly recognized. While data from rodent studies suggest that neonatal exposure to genistein (the predominant isoflavone in soy) disrupts normal reproductive function, its role in ovarian cancers, particularly granulosa cell tumors (GCT), is largely unknown. Our study aimed to define the contribution of a soy diet in GCT development using a genetically modified mouse model for juvenile GCTs (JGCT; Smad1 Smad5 conditional double knockout mice) as well as a human JGCT cell line (COV434). While dietary soy cannot initiate JGCT development in mice, we show that it has dramatic effects on GCT growth and tumor progression compared to a soy-free diet. Loss of Smad1 and Smad5 alters estrogen receptor alpha (Esr1) expression in granulosa cells, perhaps sensitizing the cells to the effects of genistein. In addition, we found that genistein modulates estrogen receptor expression in the human JGCT cell line and positively promotes cell growth in part by suppressing caspase-dependent apoptosis. Combined, our work suggests that dietary soy consumption has deleterious effects on GCT development. PMID:25165122

  8. Soy promotes juvenile granulosa cell tumor development in mice and in the human granulosa cell tumor-derived COV434 cell line.

    PubMed

    Mansouri-Attia, Nadéra; James, Rebecca; Ligon, Alysse; Li, Xiaohui; Pangas, Stephanie A

    2014-10-01

    Soy attracts attention for its health benefits, such as lowering cholesterol or preventing breast and colon cancer. Soybeans contain isoflavones, which act as phytoestrogens. Even though isoflavones have beneficial health effects, a role for isoflavones in the initiation and progression of diseases including cancer is becoming increasingly recognized. While data from rodent studies suggest that neonatal exposure to genistein (the predominant isoflavone in soy) disrupts normal reproductive function, its role in ovarian cancers, particularly granulosa cell tumors (GCT), is largely unknown. Our study aimed to define the contribution of a soy diet in GCT development using a genetically modified mouse model for juvenile GCTs (JGCT; Smad1 Smad5 conditional double knockout mice) as well as a human JGCT cell line (COV434). While dietary soy cannot initiate JGCT development in mice, we show that it has dramatic effects on GCT growth and tumor progression compared to a soy-free diet. Loss of Smad1 and Smad5 alters estrogen receptor alpha (Esr1) expression in granulosa cells, perhaps sensitizing the cells to the effects of genistein. In addition, we found that genistein modulates estrogen receptor expression in the human JGCT cell line and positively promotes cell growth in part by suppressing caspase-dependent apoptosis. Combined, our work suggests that dietary soy consumption has deleterious effects on GCT development. PMID:25165122

  9. In vitro Enrichment of Ovarian Cancer Tumor-initiating Cells

    PubMed Central

    House, Carrie D.; Hernandez, Lidia; Annunziata, Christina M.

    2015-01-01

    Evidence suggests that small subpopulations of tumor cells maintain a unique self-renewing and differentiation capacity and may be responsible for tumor initiation and/or relapse. Clarifying the mechanisms by which these tumor-initiating cells (TICs) support tumor formation and progression could lead to the development of clinically favorable therapies. Ovarian cancer is a heterogeneous and highly recurrent disease. Recent studies suggest TICs may play an important role in disease biology. We have identified culture conditions that enrich for TICs from ovarian cancer cell lines. Growing either adherent cells or non-adherent ‘floater’ cells in a low attachment plate with serum free media in the presence of growth factors supports the propagation of ovarian cancer TICs with stem cell markers (CD133 and ALDH activity) and increased tumorigenicity without the need to physically separate the TICs from other cell types within the culture. Although the presence of floater cells is not common for all cell lines, this population of cells with innate low adherence may have high tumorigenic potential.Compared to adherent cells grown in the presence of serum, TICs readily form spheres, are significantly more tumorigenic in mice, and express putative stem cell markers. The conditions are easy to establish in a timely manner and can be used to study signaling pathways important for maintaining stem characteristics, and to identify drugs or combinations of drugs targeting TICs. The culture conditions described herein are applicable for a variety of ovarian cancer cells of epithelial origin and will be critical in providing new information about the role of TICs in tumor initiation, progression, and relapse. PMID:25742116

  10. Induction of Suppressor Cells and Increased Tumor Growth following Chronic Psychosocial Stress in Male Mice

    PubMed Central

    Schmidt, Dominic; Peterlik, Daniel; Reber, Stefan O.; Lechner, Anja; Männel, Daniela N.

    2016-01-01

    To study the impact of psychosocial stress on the immune system, male mice were subjected to chronic subordinate colony housing (CSC), a preclinically validated mouse model for chronic psychosocial stress. CSC substantially affected the cell composition of the bone marrow, blood, and spleen by inducing myelopoiesis and enhancing the frequency of regulatory T cells in the CD4 population. Expansion of the myeloid cell compartment was due to cells identified as immature inflammatory myeloid cells having the phenotype of myeloid-derived suppressor cells of either the granulocytic or the monocytic type. Catecholaminergic as well as TNF signaling were implicated in these CSC-induced cellular shifts. Although the frequency of regulatory cells was enhanced following CSC, the high capacity for inflammatory cytokine secretion of total splenocytes indicated an inflammatory immune status in CSC mice. Furthermore, CSC enhanced the suppressive activity of bone marrow-derived myeloid-derived suppressor cells towards proliferating T cells. In line with the occurrence of suppressor cell types such as regulatory T cells and myeloid-derived suppressor cells, transplanted syngeneic fibrosarcoma cells grew better in CSC mice than in controls, a process accompanied by pronounced angiogenesis and clustering of immature myeloid cells in the tumor tissue. In addition, tumor implantation after CSC reinforced the CSC-induced increase in myeloid-derived suppressor cells and regulatory T cell frequencies while the CSC-induced cellular changes eased off in mice without tumor. Together, our data suggest a role for suppressor cells such as regulatory T cells and myeloid-derived suppressor cells in the enhanced tumor growth after chronic psychosocial stress. PMID:27391954

  11. PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments

    PubMed Central

    Tanjoni, Isabelle; Walsh, Colin; Uryu, Sean; Tomar, Alok; Nam, Ju-Ock; Mielgo, Ainhoa; Lim, Ssang-Taek; Liang, Congxin; Koenig, Marcel; Patel, Neela; Kwok, Cheni; McMahon, Gerald; Stupack, Dwayne G.; Schlaepfer, David D.

    2010-01-01

    Tumor cells can grow in an anchorage-independent manner. This is mediated in part through survival signals that bypass normal growth restraints controlled by integrin cell surface receptors. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase that associates with integrins and modulates various cellular processes including growth, survival, and migration. As increased FAK expression and tyrosine phosphorylation are associated with tumor progression, inhibitors of FAK are being tested for anti-tumor effects. Here, we analyze PND-1186, a substituted pyridine reversible inhibitor of FAK activity with a 50% inhibitory concentration (IC50) of 1.5 nM in vitro. PND-1186 has an IC50 of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. PND-1186 did not alter c-Src or p130Cas tyrosine phosphorylation in adherent cells, yet functioned to restrain cell movement. Whereas 1.0 µM PND-1186 (>5-fold above IC50) had limited effects on cell proliferation, under non-adherent conditions or when grown as spheroids or colonies in soft agar, 0.1 µM PND-1186 blocked FAK and p130Cas tyrosine phosphorylation, promoted caspase-3 activation, and triggered cell apoptosis. PND-1186 inhibited 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activation. Addition of PND-1186 to the drinking water of mice was well tolerated and inhibited ascites-associated ovarian carcinoma tumor growth associated with the inhibition of FAK tyrosine phosphorylation. Our results with low-level PND-1186 treatment support the conclusion that FAK activity selectively promotes tumor cell survival in three-dimensional environments. PMID:20234191

  12. Differential regulation and function of tumor-infiltrating T cells in different stages of breast cancer patients.

    PubMed

    Zhu, Shiguang; Lin, Jun; Qiao, Guangdong; Xu, Yanping; Zou, Haidong

    2015-09-01

    Breast cancer survival was associated with higher frequencies of CD8(+) T cytotoxic T cells in infiltrating lymphocytes. On the other hand, the frequency of CD4(+)CD25(+)FoxP3(+) regulatory T cells was inversely correlated with clinical outcomes of breast cancer. The regulation and interaction of different types of tumor-infiltrating T cells in different stages of breast cancer patients are still unclear. In this study, we examined the functions and regulations of CD8(+) T cells and CD4(+)CD25(+)FoxP3(+) T cells from resected tumors from 12 stage I, 24 stage II, and 20 stage III untreated breast cancer patients. We found that tumor-infiltrating CD8(+) T cells from stage III patients were more refractory to T cell receptor (TCR) stimulation than those from stage I and stage II patients in terms of interferon gamma (IFN-γ) production and proliferation. On the other hand, tumor-infiltrating CD4(+)CD25(+)FoxP3(+) T cells had higher proliferation in stage III tumors than in stage I and stage II tumors. In addition, we found that tumor-infiltrating CD4(+)CD25(+) T cells can suppress CD8(+) T cell inflammation ex vivo. Altogether, our data demonstrated that stage III tumors in breast cancer patients had a more immunosuppressive microenvironment. PMID:25953262

  13. Mesenchymal stem cells as delivery vectors for anti-tumor therapy

    PubMed Central

    Li, Zhenzhen; Fan, Dongmei

    2015-01-01

    Recent studies have demonstrated mesenchymal stem cells (MSCs) are able to migrate specifically to tumors and their metastatic sites when administered intravenously. This characteristic tumor tropism has opened up an emerging field to utilize MSCs as vectors to deliver anti-cancer agents for targeted therapies. Genetically engineered MSCs can specifically migrate to various tumors and locally secrete therapeutic proteins, such as interferon β (IFN-β) and IFN-γ, interleukin 12 and 24, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or suicide gene/enzyme prodrug. In addition, MSCs have also been engineered to deliver oncolytic viruses and drug-loaded nanoparticles. Here, we present the characteristics of MSCs, the current progress on MSC mediated anti-cancer agents delivery systems and the interaction between MSCs and tumors.

  14. A Pathway Toward Tumor Cell-Selective CPPs?

    PubMed

    Alves, Isabel D; Carré, Manon; Lavielle, Solange

    2015-01-01

    Despite the great potential of CPPs in therapeutics and diagnosis, their application still suffers from a non-negligible drawback: a complete lack of cell-type specificity. In the innumerous routes proposed for CPP cell entry there is common agreement that electrostatic interactions between cationic CPPs and anionic components in membranes, including lipids and glycosaminoglycans, play a crucial role. Tumor cells have been shown to overexpress certain glycosaminoglycans at the cell membrane surface and to possess a higher amount of anionic lipids in their outer leaflet when compared with healthy cells. Such molecules confer tumor cell membranes an enhanced anionic character, a property that could be exploited by CPPs to preferentially target these cells. Herein, these aspects are discussed in an attempt to confer CPPs certain selectivity toward cancer cells. PMID:26202276

  15. Development of a Biomimetic Chondroitin Sulfate-modified Hydrogel to Enhance the Metastasis of Tumor Cells

    PubMed Central

    Liu, Yang; Wang, Shujun; Sun, Dongsheng; Liu, Yongdong; Liu, Yang; Wang, Yang; Liu, Chang; Wu, Hao; Lv, Yan; Ren, Ying; Guo, Xin; Sun, Guangwei; Ma, Xiaojun

    2016-01-01

    Tumor metastasis with resistance to anticancer therapies is the main cause of death in cancer patients. It is necessary to develop reliable tumor metastasis models that can closely recapitulate the pathophysiological features of the native tumor tissue. In this study, chondroitin sulfate (CS)-modified alginate hydrogel beads (ALG-CS) are developed to mimic the in vivo tumor microenvironment with an abnormally increased expression of CS for the promotion of tumor cell metastasis. The modification mechanism of CS on alginate hydrogel is due to the cross-linking between CS and alginate molecules via coordination of calcium ions, which enables ALG-CS to possess significantly different physical characteristics than the traditional alginate beads (ALG). And quantum chemistry calculations show that in addition to the traditional egg-box structure, novel asymmetric egg-box-like structures based on the interaction between these two kinds of polymers are also formed within ALG-CS. Moreover, tumor cell metastasis is significantly enhanced in ALG-CS compared with that in ALG, as confirmed by the increased expression of MMP genes and proteins and greater in vitro invasion ability. Therefore, ALG-CS could be a convenient and effective 3D biomimetic scaffold that would be used to construct standardized tumor metastasis models for tumor research and anticancer drug screening. PMID:27432752

  16. Local hyperthermia treatment of