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Sample records for circulating tumour cells

  1. Diagnostic technologies for circulating tumour cells and exosomes

    OpenAIRE

    Shao, Huilin; Chung, Jaehoon; Issadore, David

    2016-01-01

    Circulating tumour cells (CTCs) and exosomes are promising circulating biomarkers. They exist in easily accessible blood and carry large diversity of molecular information. As such, they can be easily and repeatedly obtained for minimally invasive cancer diagnosis and monitoring. Because of their intrinsic differences in counts, size and molecular contents, CTCs and exosomes pose unique sets of technical challenges for clinical translation–CTCs are rare whereas exosomes are small. Novel techn...

  2. Retracing Circulating Tumour Cells for Biomarker Characterization after Enumeration

    DEFF Research Database (Denmark)

    Frandsen, Anders; Fabisiewicz, Anna; Jagiello-Gruszfeld, Agnieszka;

    2015-01-01

    Background: Retracing and biomarker characterization of individual circulating tumour cells (CTCs) may potentially contribute to personalized metastatic cancer therapy. This is relevant when a biopsy of the metastasis is complicated or impossible to acquire. Methods: A novel disc format was used ...

  3. Biosensors for the Detection of Circulating Tumour Cells

    Directory of Open Access Journals (Sweden)

    Clotilde Costa

    2014-03-01

    Full Text Available Metastasis is the cause of most cancer deaths. Circulating tumour cells (CTCs are cells released from the primary tumour into the bloodstream that are considered the main promoters of metastasis. Therefore, these cells are targets for understanding tumour biology and improving clinical management of the disease. Several techniques have emerged in recent years to isolate, detect, and characterise CTCs. As CTCs are a rare event, their study requires multidisciplinary considerations of both biological and physical properties. In addition, as isolation of viable cells may give further insights into metastatic development, cell recovery must be done with minimal cell damage. The ideal system for CTCs analysis must include maximum efficiency of detection in real time. In this sense, new approaches used to enrich CTCs from clinical samples have provided an important improvement in cell recovery. However, this progress should be accompanied by more efficient strategies of cell quantification. A range of biosensor platforms are being introduced into the technology for CTCs quantification with promising results. This review provides an update on recent progress in CTCs identification using different approaches based on sensor signaling.

  4. Circulating Cell-Free Tumour DNA in the Management of Cancer

    Science.gov (United States)

    Francis, Glenn; Stein, Sandra

    2015-01-01

    With the development of new sensitive molecular techniques, circulating cell-free tumour DNA containing mutations can be identified in the plasma of cancer patients. The applications of this technology may result in significant changes to the care and management of cancer patients. Whilst, currently, these “liquid biopsies” are used to supplement the histological diagnosis of cancer and metastatic disease, in the future these assays may replace the need for invasive procedures. Applications include the monitoring of tumour burden, the monitoring of minimal residual disease, monitoring of tumour heterogeneity, monitoring of molecular resistance and early diagnosis of tumours and metastatic disease. PMID:26101870

  5. Circulating Cell-Free Tumour DNA in the Management of Cancer

    Directory of Open Access Journals (Sweden)

    Glenn Francis

    2015-06-01

    Full Text Available With the development of new sensitive molecular techniques, circulating cell-free tumour DNA containing mutations can be identified in the plasma of cancer patients. The applications of this technology may result in significant changes to the care and management of cancer patients. Whilst, currently, these “liquid biopsies” are used to supplement the histological diagnosis of cancer and metastatic disease, in the future these assays may replace the need for invasive procedures. Applications include the monitoring of tumour burden, the monitoring of minimal residual disease, monitoring of tumour heterogeneity, monitoring of molecular resistance and early diagnosis of tumours and metastatic disease.

  6. A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas

    OpenAIRE

    Farace, F.; Massard, C; Vimond, N.; Drusch, F; Jacques, N; Billiot, F.; Laplanche, A; Chauchereau, A; Lacroix, L; Planchard, D.; Le Moulec, S.; André, F.; Fizazi, K; Soria, J. C.; Vielh, P

    2011-01-01

    Background: Circulating tumour cells (CTCs) can provide information on patient prognosis and treatment efficacy. However, there is no universal method to detect CTC currently available. Here, we compared the performance of two CTC detection systems based on the expression of the EpCAM antigen (CellSearch assay) or on cell size (ISET assay). Methods: Circulating tumour cells were enumerated in 60 patients with metastatic carcinomas of breast, prostate and lung origins using CellSearch accordin...

  7. Unbiased and automated identification of a circulating tumour cell definition that associates with overall survival.

    OpenAIRE

    Ligthart, Sjoerd T.; Frank A W Coumans; Gerhardt Attard; Amy Mulick Cassidy; de Bono, Johann S.; Terstappen, Leon W. M. M.

    2011-01-01

    Circulating tumour cells (CTC) in patients with metastatic carcinomas are associated with poor survival and can be used to guide therapy. Classification of CTC however remains subjective, as they are morphologically heterogeneous. We acquired digital images, using the CellSearch™ system, from blood of 185 castration resistant prostate cancer (CRPC) patients and 68 healthy subjects to define CTC by computer algorithms. Patient survival data was used as the training parameter for the computer t...

  8. Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer

    OpenAIRE

    Lindsay, C. R.; Le Moulec, S.; Billiot, F.; Loriot, Y; Ngo-Camus, M.; Vielh, P; Fizazi, K; Massard, C; Farace, F.

    2016-01-01

    Background High circulating tumor cell (CTC) counts are associated with poor prognosis in advanced prostate cancer, and recently CTC number was suggested to be a surrogate for survival in metastatic castrate-resistant prostate cancer (mCRPC). Ki67 and vimentin are well-characterised markers of tumour cell proliferation and the epithelial-mesenchymal transition (EMT), respectively. Here we asked if the expression of vimentin and Ki67 in CTCs offered prognostic or predictive information in mCRP...

  9. Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets

    Science.gov (United States)

    Yoon, Hyeun Joong; Kim, Tae Hyun; Zhang, Zhuo; Azizi, Ebrahim; Pham, Trinh M.; Paoletti, Costanza; Lin, Jules; Ramnath, Nithya; Wicha, Max S.; Hayes, Daniel F.; Simeone, Diane M.; Nagrath, Sunitha

    2013-10-01

    The spread of cancer throughout the body is driven by circulating tumour cells (CTCs). These cells detach from the primary tumour and move from the bloodstream to a new site of subsequent tumour growth. They also carry information about the primary tumour and have the potential to be valuable biomarkers for disease diagnosis and progression, and for the molecular characterization of certain biological properties of the tumour. However, the limited sensitivity and specificity of current methods for measuring and studying these cells in patient blood samples prevents the realization of their full clinical potential. The use of microfluidic devices is a promising method for isolating CTCs. However, the devices are reliant on three-dimensional structures, which limits further characterization and expansion of cells on the chip. Here we demonstrate an effective approach to isolating CTCs from blood samples of pancreatic, breast and lung cancer patients, by using functionalized graphene oxide nanosheets on a patterned gold surface. CTCs were captured with high sensitivity at a low concentration of target cells (73 +/- 32.4% at 3-5 cells per ml blood).

  10. Detection of Circulating Tumour Cells from Blood of Breast Cancer Patients via RT-qPCR

    Energy Technology Data Exchange (ETDEWEB)

    Andergassen, Ulrich; Kölbl, Alexandra C.; Hutter, Stefan; Friese, Klaus; Jeschke, Udo, E-mail: udo.jeschke@med.uni-muenchen.de [Department of Obstetrics and Gynaecology, Ludwig Maximilians University of Munich, Munich, Maistrasse 11, D-80337 Munich (Germany)

    2013-09-25

    Breast cancer is still the most frequent cause of cancer-related death in women worldwide. Often death is not caused only by the primary tumour itself, but also by metastatic lesions. Today it is largely accepted, that these remote metastases arise out of cells, which detach from the primary tumour, enter circulation, settle down at secondary sites in the body and are called Circulating Tumour Cells (CTCs). The occurrence of such minimal residual diseases in the blood of breast cancer patients is mostly linked to a worse prognosis for therapy outcome and overall survival. Due to their very low frequency, the detection of CTCs is, still a technical challenge. RT-qPCR as a highly sensitive method could be an approach for CTC-detection from peripheral blood of breast cancer patients. This assumption is based on the fact that CTCs are of epithelial origin and therefore express a different gene panel than surrounding blood cells. For the technical approach it is necessary to identify appropriate marker genes and to correlate their gene expression levels to the number of tumour cells within a sample in an in vitro approach. After that, samples from adjuvant and metastatic patients can be analysed. This approach may lead to new concepts in diagnosis and treatment.

  11. Detection of Circulating Tumour Cells from Blood of Breast Cancer Patients via RT-qPCR

    Directory of Open Access Journals (Sweden)

    Udo Jeschke

    2013-09-01

    Full Text Available Breast cancer is still the most frequent cause of cancer-related death in women worldwide. Often death is not caused only by the primary tumour itself, but also by metastatic lesions. Today it is largely accepted, that these remote metastases arise out of cells, which detach from the primary tumour, enter circulation, settle down at secondary sites in the body and are called Circulating Tumour Cells (CTCs. The occurrence of such minimal residual diseases in the blood of breast cancer patients is mostly linked to a worse prognosis for therapy outcome and overall survival. Due to their very low frequency, the detection of CTCs is, still a technical challenge. RT-qPCR as a highly sensitive method could be an approach for CTC-detection from peripheral blood of breast cancer patients. This assumption is based on the fact that CTCs are of epithelial origin and therefore express a different gene panel than surrounding blood cells. For the technical approach it is necessary to identify appropriate marker genes and to correlate their gene expression levels to the number of tumour cells within a sample in an in vitro approach. After that, samples from adjuvant and metastatic patients can be analysed. This approach may lead to new concepts in diagnosis and treatment.

  12. Detection of Circulating Tumour Cells from Blood of Breast Cancer Patients via RT-qPCR

    International Nuclear Information System (INIS)

    Breast cancer is still the most frequent cause of cancer-related death in women worldwide. Often death is not caused only by the primary tumour itself, but also by metastatic lesions. Today it is largely accepted, that these remote metastases arise out of cells, which detach from the primary tumour, enter circulation, settle down at secondary sites in the body and are called Circulating Tumour Cells (CTCs). The occurrence of such minimal residual diseases in the blood of breast cancer patients is mostly linked to a worse prognosis for therapy outcome and overall survival. Due to their very low frequency, the detection of CTCs is, still a technical challenge. RT-qPCR as a highly sensitive method could be an approach for CTC-detection from peripheral blood of breast cancer patients. This assumption is based on the fact that CTCs are of epithelial origin and therefore express a different gene panel than surrounding blood cells. For the technical approach it is necessary to identify appropriate marker genes and to correlate their gene expression levels to the number of tumour cells within a sample in an in vitro approach. After that, samples from adjuvant and metastatic patients can be analysed. This approach may lead to new concepts in diagnosis and treatment

  13. Genetic profiling of tumours using both circulating free DNA and circulating tumour cells isolated from the same preserved whole blood sample.

    Science.gov (United States)

    Rothwell, Dominic G; Smith, Nigel; Morris, Daniel; Leong, Hui Sun; Li, Yaoyong; Hollebecque, Antoine; Ayub, Mahmood; Carter, Louise; Antonello, Jenny; Franklin, Lynsey; Miller, Crispin; Blackhall, Fiona; Dive, Caroline; Brady, Ged

    2016-04-01

    Molecular information obtained from cancer patients' blood is an emerging and powerful research tool with immense potential as a companion diagnostic for patient stratification and monitoring. Blood, which can be sampled routinely, provides a means of inferring the current genetic status of patients' tumours via analysis of circulating tumour cells (CTCs) or circulating tumour DNA (ctDNA). However, accurate assessment of both CTCs and ctDNA requires all blood cells to be maintained intact until samples are processed. This dictates for ctDNA analysis EDTA blood samples must be processed with 4 h of draw, severely limiting the use of ctDNA in multi-site trials. Here we describe a blood collection protocol that is amenable for analysis of both CTCs and ctDNA up to four days after blood collection. We demonstrate that yields of circulating free DNA (cfDNA) obtained from whole blood CellSave samples are equivalent to those obtained from conventional EDTA plasma processed within 4 h of blood draw. Targeted and genome-wide NGS revealed comparable DNA quality and resultant sequence information from cfDNA within CellSave and EDTA samples. We also demonstrate that CTCs and ctDNA can be isolated from the same patient blood sample, and give the same patterns of CNA enabling direct analysis of the genetic status of patients' tumours. In summary, our results demonstrate the utility of a simple approach that enabling robust molecular analysis of CTCs and cfDNA for genotype-directed therapies in multi-site clinical trials and represent a significant methodological improvement for clinical benefit. PMID:26639657

  14. Circulating Cell-Free Tumour DNA in the Management of Cancer

    OpenAIRE

    Glenn Francis; Sandra Stein

    2015-01-01

    With the development of new sensitive molecular techniques, circulating cell-free tumour DNA containing mutations can be identified in the plasma of cancer patients. The applications of this technology may result in significant changes to the care and management of cancer patients. Whilst, currently, these “liquid biopsies” are used to supplement the histological diagnosis of cancer and metastatic disease, in the future these assays may replace the need for invasive procedures. Applications ...

  15. Minimal residual disease in breast cancer: an overview of circulating and disseminated tumour cells.

    Science.gov (United States)

    Tachtsidis, A; McInnes, L M; Jacobsen, N; Thompson, E W; Saunders, C M

    2016-08-01

    Within the field of cancer research, focus on the study of minimal residual disease (MRD) in the context of carcinoma has grown exponentially over the past several years. MRD encompasses circulating tumour cells (CTCs)-cancer cells on the move via the circulatory or lymphatic system, disseminated tumour cells (DTCs)-cancer cells which have escaped into a distant site (most studies have focused on bone marrow), and resistant cancer cells surviving therapy-be they local or distant, all of which may ultimately give rise to local relapse or overt metastasis. Initial studies simply recorded the presence and number of CTCs and DTCs; however recent advances are allowing assessment of the relationship between their persistence, patient prognosis and the biological properties of MRD, leading to a better understanding of the metastatic process. Technological developments for the isolation and analysis of circulating and disseminated tumour cells continue to emerge, creating new opportunities to monitor disease progression and perhaps alter disease outcome. This review outlines our knowledge to date on both measurement and categorisation of MRD in the form of CTCs and DTCs with respect to how this relates to cancer outcomes, and the hurdles and future of research into both CTCs and DTCs. PMID:27189371

  16. Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer

    OpenAIRE

    Flores, L M; Kindelberger, D W; Ligon, A H; Capelletti, M.; Fiorentino, M.; Loda, M; Cibas, E S; Jänne, P.A.; Krop, I. E.

    2010-01-01

    Background: Circulating tumour cells (CTCs) offer a non-invasive approach to obtain and characterise metastatic tumour cells, but their usefulness has been limited by low CTC yields from conventional isolation methods. Methods: To improve CTC yields and facilitate their molecular characterisation we compared the Food and Drug Administration-approved CellSearch Epithelial Kit (CEK) to a simplified CTC capture method, CellSearch Profile Kit (CPK), on paired blood samples from patients with meta...

  17. Long term survival following the detection of circulating tumour cells in head and neck squamous cell carcinoma

    International Nuclear Information System (INIS)

    Techniques for detecting circulating tumor cells in the peripheral blood of patients with head and neck cancers may identify individuals likely to benefit from early systemic treatment. Reconstruction experiments were used to optimise immunomagnetic enrichment and RT-PCR detection of circulating tumor cells using four markers (ELF3, CK19, EGFR and EphB4). This method was then tested in a pilot study using samples from 16 patients with advanced head and neck carcinomas. Seven patients were positive for circulating tumour cells both prior to and after surgery, 4 patients were positive prior to but not after surgery, 3 patients were positive after but not prior to surgery and 2 patients were negative. Two patients tested positive for circulating cells but there was no other evidence of tumor spread. Given this patient cohort had mostly advanced disease, as expected the detection of circulating tumour cells was not associated with significant differences in overall or disease free survival. For the first time, we show that almost all patients with advanced head and neck cancers have circulating cells at the time of surgery. The clinical application of techniques for detection of spreading disease, such as the immunomagnetic enrichment RT-PCR analysis used in this study, should be explored further

  18. Method validation of circulating tumour cell enumeration at low cell counts

    International Nuclear Information System (INIS)

    Circulating tumour cells (CTC) are receiving increasing attention as prognostic, predictive and pharmacodynamic biomarkers in cancer patients. However, their clinical significance can be dependent on an accurate determination of CTC around cut-off values at low cell counts (<10 cells/7.5 ml). Consequently, we have conducted method validation of the CellSearch™ system focusing on clinical samples containing CTC in the cut-off region. Analytical accuracy was first assessed employing quality controls (QC) and spiked healthy volunteer blood specimens. Results were analysed by β-expectation tolerance intervals (BETI). Inter-operator error (6 different readers) was then characterised in 38 different patient samples, 68% of which had ≤5 CTC and data were analysed by β-content γ-confidence tolerance intervals (BCTI). Results from QCs and spiked blood confirmed a 3-4-fold higher degree of imprecision at the low (48 cells, BETI = + 0.288/-0.345, β = 95%) compared to the high QC (987 cells, BETI = +0.065/-0.140, β = 95%). However, when data for individual analysts were interrogated characteristic systematic errors were detected. In the analysis of patient samples again individual analysts introduced a highly specific error into the interpretation of CTC images, which correlated to the level of training and experience. When readers were selected based on BETI and BCTI results, the high level of between-operator error (up to 170%) observed at CTC of ≤ 5 was reduced to < 30%. Inter-operator variability in enumeration of CTC at low cell counts can be considerable, but is also potentially avoidable by following simple guidance steps

  19. Separable Bilayer Microfiltration Device for Viable Label-free Enrichment of Circulating Tumour Cells

    Science.gov (United States)

    Zhou, Ming-Da; Hao, Sijie; Williams, Anthony J.; Harouaka, Ramdane A.; Schrand, Brett; Rawal, Siddarth; Ao, Zheng; Brennaman, Randall; Gilboa, Eli; Lu, Bo; Wang, Shuwen; Zhu, Jiyue; Datar, Ram; Cote, Richard; Tai, Yu-Chong; Zheng, Si-Yang

    2014-12-01

    The analysis of circulating tumour cells (CTCs) in cancer patients could provide important information for therapeutic management. Enrichment of viable CTCs could permit performance of functional analyses on CTCs to broaden understanding of metastatic disease. However, this has not been widely accomplished. Addressing this challenge, we present a separable bilayer (SB) microfilter for viable size-based CTC capture. Unlike other single-layer CTC microfilters, the precise gap between the two layers and the architecture of pore alignment result in drastic reduction in mechanical stress on CTCs, capturing them viably. Using multiple cancer cell lines spiked in healthy donor blood, the SB microfilter demonstrated high capture efficiency (78-83%), high retention of cell viability (71-74%), high tumour cell enrichment against leukocytes (1.7-2 × 103), and widespread ability to establish cultures post-capture (100% of cell lines tested). In a metastatic mouse model, SB microfilters successfully enriched viable mouse CTCs from 0.4-0.6 mL whole mouse blood samples and established in vitro cultures for further genetic and functional analysis. Our preliminary studies reflect the efficacy of the SB microfilter device to efficiently and reliably enrich viable CTCs in animal model studies, constituting an exciting technology for new insights in cancer research.

  20. A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas

    Science.gov (United States)

    Farace, F; Massard, C; Vimond, N; Drusch, F; Jacques, N; Billiot, F; Laplanche, A; Chauchereau, A; Lacroix, L; Planchard, D; Le Moulec, S; André, F; Fizazi, K; Soria, J C; Vielh, P

    2011-01-01

    Background: Circulating tumour cells (CTCs) can provide information on patient prognosis and treatment efficacy. However, there is no universal method to detect CTC currently available. Here, we compared the performance of two CTC detection systems based on the expression of the EpCAM antigen (CellSearch assay) or on cell size (ISET assay). Methods: Circulating tumour cells were enumerated in 60 patients with metastatic carcinomas of breast, prostate and lung origins using CellSearch according to the manufacturer's protocol and ISET by studying cytomorphology and immunolabelling with anti-cytokeratin or lineage-specific antibodies. Results: Concordant results were obtained in 55% (11 out of 20) of the patients with breast cancer, in 60% (12 out of 20) of the patients with prostate cancer and in only 20% (4 out of 20) of lung cancer patients. Conclusion: Our results highlight important discrepancies between the numbers of CTC enumerated by both techniques. These differences depend mostly on the tumour type. These results suggest that technologies limiting CTC capture to EpCAM-positive cells, may present important limitations, especially in patients with metastatic lung carcinoma. PMID:21829190

  1. Optimisation of immunofluorescence methods to determine MCT1 and MCT4 expression in circulating tumour cells

    International Nuclear Information System (INIS)

    The monocarboxylate transporter-1 (MCT1) represents a novel target in rational anticancer drug design while AZD3965 was developed as an inhibitor of this transporter and is undergoing Phase I clinical trials (http://www.clinicaltrials.gov/show/NCT01791595). We describe the optimisation of an immunofluorescence (IF) method for determination of MCT1 and MCT4 in circulating tumour cells (CTC) as potential prognostic and predictive biomarkers of AZD3965 in cancer patients. Antibody selectivity was investigated by western blotting (WB) in K562 and MDAMB231 cell lines acting as positive controls for MCT1 and MCT4 respectively and by flow cytometry also employing the control cell lines. Ability to detect MCT1 and MCT4 in CTC as a 4th channel marker utilising the Veridex™ CellSearch system was conducted in both human volunteer blood spiked with control cells and in samples collected from small cell lung cancer (SCLC) patients. Experimental conditions were established which yielded a 10-fold dynamic range (DR) for detection of MCT1 over MCT4 (antibody concentration 6.25 μg/mL; integration time 0.4 seconds) and a 5-fold DR of MCT4 over MCT 1 (8 μg/100 μL and 0.8 seconds). The IF method was sufficiently sensitive to detect both MCT1 and MCT4 in CTCs harvested from cancer patients. The first IF method has been developed and optimised for detection of MCT 1 and MCT4 in cancer patient CTC

  2. Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer

    OpenAIRE

    Lecharpentier, A; Vielh, P; Perez-Moreno, P; Planchard, D.; Soria, J. C.; Farace, F.

    2011-01-01

    Background: Circulating tumour cells (CTC) have a crucial role in metastasis formation and can consistently provide information on patient prognosis. Epithelial-mesenchymal transition (EMT) is considered as an essential process in the metastatic cascade, but there is currently very few data demonstrating directly the existence of the EMT process in CTCs. Methods: CTCs were enriched by blood filtration using ISET (isolation by size of epithelial tumour cells), triply labelled with fluorescent ...

  3. Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Gorges Tobias M

    2012-05-01

    Full Text Available Abstract Background Circulating tumour cells (CTCs have shown prognostic relevance in metastatic breast, prostate, colon and pancreatic cancer. For further development of CTCs as a biomarker, we compared the performance of different protocols for CTC detection in murine breast cancer xenograft models (MDA-MB-231, MDA-MB-468 and KPL-4. Blood samples were taken from tumour bearing animals (20 to 200 mm2 and analysed for CTCs using 1. an epithelial marker based enrichment method (AdnaTest, 2. an antibody independent technique, targeting human gene transcripts (qualitative PCR, and 3. an antibody-independent approach, targeting human DNA-sequences (quantitative PCR. Further, gene expression changes associated with epithelial-to-mesenchymal transition (EMT were determined with an EMT-specific PCR assay. Methods We used the commercially available Adna Test, RT-PCR on human housekeeping genes and a PCR on AluJ sequences to detect CTCs in xenografts models. Phenotypic changes in CTCs were tested with the commercially available “Human Epithelial to Mesenchymal Transition RT-Profiler PCR Array”. Results Although the AdnaTest detects as few as 1 tumour cell in 1 ml of mouse blood spiking experiments, no CTCs were detectable with this approach in vivo despite visible metastasis formation. The presence of CTCs could, however, be demonstrated by PCR targeting human transcripts or DNA-sequences - without epithelial pre-enrichment. The failure of CTC detection by the AdnaTest resulted from downregulation of EpCAM, whereas mesenchymal markers like Twist and EGFR were upregulated on CTCs. Such a change in the expression profile during metastatic spread of tumour cells has already been reported and was linked to a biological program termed epithelial-mesenchymal transition (EMT. Conclusions The use of EpCAM-based enrichment techniques leads to the failure to detect CTC populations that have undergone EMT. Our findings may explain clinical results where low

  4. Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition

    International Nuclear Information System (INIS)

    Circulating tumour cells (CTCs) have shown prognostic relevance in metastatic breast, prostate, colon and pancreatic cancer. For further development of CTCs as a biomarker, we compared the performance of different protocols for CTC detection in murine breast cancer xenograft models (MDA-MB-231, MDA-MB-468 and KPL-4). Blood samples were taken from tumour bearing animals (20 to 200 mm2) and analysed for CTCs using 1. an epithelial marker based enrichment method (AdnaTest), 2. an antibody independent technique, targeting human gene transcripts (qualitative PCR), and 3. an antibody-independent approach, targeting human DNA-sequences (quantitative PCR). Further, gene expression changes associated with epithelial-to-mesenchymal transition (EMT) were determined with an EMT-specific PCR assay. We used the commercially available Adna Test, RT-PCR on human housekeeping genes and a PCR on AluJ sequences to detect CTCs in xenografts models. Phenotypic changes in CTCs were tested with the commercially available “Human Epithelial to Mesenchymal Transition RT-Profiler PCR Array”. Although the AdnaTest detects as few as 1 tumour cell in 1 ml of mouse blood spiking experiments, no CTCs were detectable with this approach in vivo despite visible metastasis formation. The presence of CTCs could, however, be demonstrated by PCR targeting human transcripts or DNA-sequences - without epithelial pre-enrichment. The failure of CTC detection by the AdnaTest resulted from downregulation of EpCAM, whereas mesenchymal markers like Twist and EGFR were upregulated on CTCs. Such a change in the expression profile during metastatic spread of tumour cells has already been reported and was linked to a biological program termed epithelial-mesenchymal transition (EMT). The use of EpCAM-based enrichment techniques leads to the failure to detect CTC populations that have undergone EMT. Our findings may explain clinical results where low CTC numbers have been reported even in patients with late

  5. Optimisation of an immunohistochemistry method for the determination of androgen receptor expression levels in circulating tumour cells

    International Nuclear Information System (INIS)

    AZD3514 inhibits and down regulates the androgen receptor (AR) and has undergone clinical trials in prostate cancer. To provide proof-of-mechanism (POM) in patients, an immunohistochemistry (IHC) method for determination of AR in circulating tumour cells (CTC) was developed and validated. After an assessment of specificity validation focused on intra- and inter-operator reproducibility utilising a novel modification of incurred sample reanalysis (ISR). β-Content γ-confidence tolerance intervals (BCTI) and Cohen’s Kappa (κ) were employed in statistical analysis of results. In a first set of IHC reproducibility experiments, almost perfect agreement was recorded (κ=0.94) when two different operators scored CTC as overall positive or negative for AR. However, BCTI analysis identified a specific bias in scoring staining intensity, where one operator favoured moderate over strong assignments, whereas the reverse was the case with the second operator. After a period of additional training involving deployment of a panel of standardised images, a second set of validation experiments were conducted. These showed correction of the inter-operator bias by BCTI with κ for scoring intensity increasing from 0.59 to 0.81, indicative of almost perfect agreement. By application of BCTI to the validation of IHC, operator bias and therefore poor reproducibility can be identified, characterised and corrected to achieve a level of error normally associated with a quantitative biomarker assay, such as an ELISA. The methodological approach described herein can be applied to any generic IHC technique

  6. Application of optically-induced-dielectrophoresis in microfluidic system for purification of circulating tumour cells for gene expression analysis- Cancer cell line model.

    Science.gov (United States)

    Chiu, Tzu-Keng; Chou, Wen-Pin; Huang, Song-Bin; Wang, Hung-Ming; Lin, Yung-Chang; Hsieh, Chia-Hsun; Wu, Min-Hsien

    2016-01-01

    Circulating tumour cells (CTCs) in a blood circulation system are associated with cancer metastasis. The analysis of the drug-resistance gene expression of cancer patients' CTCs holds promise for selecting a more effective therapeutic regimen for an individual patient. However, the current CTC isolation schemes might not be able to harvest CTCs with sufficiently high purity for such applications. To address this issue, this study proposed to integrate the techniques of optically induced dielectrophoretic (ODEP) force-based cell manipulation and fluorescent microscopic imaging in a microfluidic system to further purify CTCs after the conventional CTC isolation methods. In this study, the microfluidic system was developed, and its optimal operating conditions and performance for CTC isolation were evaluated. The results revealed that the presented system was able to isolate CTCs with cell purity as high as 100%, beyond what is possible using the previously existing techniques. In the analysis of CTC gene expression, therefore, this method could exclude the interference of leukocytes in a cell sample and accordingly contribute to higher analytical sensitivity, as demonstrated in this study. Overall, this study has presented an ODEP-based microfluidic system capable of simply and effectively isolating a specific cell species from a cell mixture. PMID:27609546

  7. Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer

    Science.gov (United States)

    Lecharpentier, A; Vielh, P; Perez-Moreno, P; Planchard, D; Soria, J C; Farace, F

    2011-01-01

    Background: Circulating tumour cells (CTC) have a crucial role in metastasis formation and can consistently provide information on patient prognosis. Epithelial-mesenchymal transition (EMT) is considered as an essential process in the metastatic cascade, but there is currently very few data demonstrating directly the existence of the EMT process in CTCs. Methods: CTCs were enriched by blood filtration using ISET (isolation by size of epithelial tumour cells), triply labelled with fluorescent anti-vimentin, anti-pan-keratin antibodies and SYTOX orange nuclear dye, and examined by confocal microscopy in six patients with metastatic non-small cell lung cancer (NSCLC). In parallel, CTCs were morphocytologically identified by an experienced cytopathologist. Results: Isolated or clusters of dual CTCs strongly co-expressing vimentin and keratin were evidenced in all patients (range 5–88/5 ml). CTCs expressing only vimentin were detected in three patients, but were less frequent (range 3–15/5 ml). No CTC expressing only keratin was detected. Conclusion: We showed for the first time the existence of hybrid CTCs with an epithelial/mesenchymal phenotype in patients with NSCLC. Their characterisation should provide further insight on the significance of EMT in CTCs and on the mechanism of metastasis in patients with NSCLC. PMID:21970878

  8. A laser-based technology for fabricating a soda-lime glass based microfluidic device for circulating tumour cell capture.

    Science.gov (United States)

    Nieto, Daniel; Couceiro, Ramiro; Aymerich, Maria; Lopez-Lopez, Rafael; Abal, Miguel; Flores-Arias, María Teresa

    2015-10-01

    We developed a laser-based technique for fabricating microfluidic microchips on soda-lime glass substrates. The proposed methodology combines a laser direct writing, as a manufacturing tool for the fabrication of the microfluidics structures, followed by a post-thermal treatment with a CO2 laser. This treatment will allow reshaping and improving the morphological (roughness) and optical qualities (transparency) of the generated microfluidics structures. The use of lasers commonly implemented for material processing makes this technique highly competitive when compared with other glass microstructuring approaches. The manufactured chips were tested with tumour cells (Hec 1A) after being functionalized with an epithelial cell adhesion molecule (EpCAM) antibody coating. Cells were successfully arrested on the pillars after being flown through the device giving our technology a translational application in the field of cancer research. PMID:26218523

  9. Prognostic impact of detecting viable circulating tumour cells in gastric cancer patients using a telomerase-specific viral agent: a prospective study

    Directory of Open Access Journals (Sweden)

    Ito Hiroaki

    2012-08-01

    Full Text Available Abstract Background The identification of circulating tumour cells (CTCs in peripheral blood is a useful approach to estimate prognosis, monitor disease progression, and measure treatment effects in various malignancies. However, clinical relevance of CTCs is controversial. We attempted to detect viable CTCs in the peripheral blood of gastric cancer patients using a telomerase-specific viral agent. Methods We took a 7.5-ml blood sample from 65 treatment-negative gastric cancer patients before surgery and 10 healthy volunteers. We detected viable CTCs in the blood samples after incubating them with a telomerase-specific, replication-selective, oncolytic adenoviral agent carrying the green fluorescent protein (GFP gene (OBP-401. GFP-positive CTCs were defined as having a diameter of at least 7.735 μm; this threshold was determined by receiver operating characteristic curve analysis. GFP-positive cells were counted under a fluorescence microscope. Results There was a significant difference in overall survival among the patients with 0–4 and those with ≥5 GFP-positive CTCs in the stage I–IV disease group and stage II–IV advanced disease group. The number of GFP-positive CTCs was not related to cancer stage. Among the pathological findings, the number of GFP-positive CTCs was only significantly related to venous invasion, although there were trends towards more GFP-positive CTCs with disease progression (tumour depth, lymph node metastasis, distant metastasis, lymphatic invasion, and histological type. Conclusions There was a significant relationship between the number of GFP-positive CTCs and overall survival in the patients with gastric cancer. The detection of CTCs using OBP-401 may be useful for prognostic evaluation. Trial registration University Hospital Medical Information Network in Japan, UMIN000002018.

  10. Prognostic impact of detecting viable circulating tumour cells in gastric cancer patients using a telomerase-specific viral agent: a prospective study

    International Nuclear Information System (INIS)

    The identification of circulating tumour cells (CTCs) in peripheral blood is a useful approach to estimate prognosis, monitor disease progression, and measure treatment effects in various malignancies. However, clinical relevance of CTCs is controversial. We attempted to detect viable CTCs in the peripheral blood of gastric cancer patients using a telomerase-specific viral agent. We took a 7.5-ml blood sample from 65 treatment-negative gastric cancer patients before surgery and 10 healthy volunteers. We detected viable CTCs in the blood samples after incubating them with a telomerase-specific, replication-selective, oncolytic adenoviral agent carrying the green fluorescent protein (GFP) gene (OBP-401). GFP-positive CTCs were defined as having a diameter of at least 7.735 μm; this threshold was determined by receiver operating characteristic curve analysis. GFP-positive cells were counted under a fluorescence microscope. There was a significant difference in overall survival among the patients with 0–4 and those with ≥5 GFP-positive CTCs in the stage I–IV disease group and stage II–IV advanced disease group. The number of GFP-positive CTCs was not related to cancer stage. Among the pathological findings, the number of GFP-positive CTCs was only significantly related to venous invasion, although there were trends towards more GFP-positive CTCs with disease progression (tumour depth, lymph node metastasis, distant metastasis, lymphatic invasion, and histological type). There was a significant relationship between the number of GFP-positive CTCs and overall survival in the patients with gastric cancer. The detection of CTCs using OBP-401 may be useful for prognostic evaluation. University Hospital Medical Information Network in Japan, UMIN000002018

  11. Monitoring changes in circulating tumour cells as a prognostic indicator of overall survival and treatment response in patients with metastatic melanoma

    International Nuclear Information System (INIS)

    New effective treatments for metastatic melanoma greatly improve survival in a proportion of patients. However biomarkers to identify patients that are more likely to benefit from a particular treatment are needed. We previously reported on a multimarker approach for the detection of heterogenous melanoma circulating tumour cells (CTCs). Here we evaluated the prognostic value of this multimarker quantification of CTCs and investigated whether changes in CTC levels during therapy can be used as a biomarker of treatment response and survival outcomes. CTCs were captured by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271. CTCs were quantified in 27 metastatic melanoma patients treated by surgery or with vemurafenib, ipilimumab or dacarbazine. Patients were enrolled prospectively and CTC counts performed at baseline (prior to treatment), during and after treatment. Baseline CTC numbers were not found to be prognostic of overall survival nor of progression free survival. However, a low baseline CTC number was associated with a rapid response to vemurafenib therapy. A decrease in CTCs after treatment initiation was associated with response to treatment and prolonged overall survival in vemurafenib treated patients. Measuring changes in CTC numbers during treatment is useful for monitoring therapy response in melanoma patients and for providing prognostic information relating to overall survival. Further studies with larger sample sizes are required to confirm the utility of CTC quantification as a companion diagnostic for metastatic melanoma treatment

  12. Leydig cell tumours in childhood.

    Science.gov (United States)

    Mengel, W; Knorr, D

    1983-01-01

    Two cases of Leydig cell tumours in childhood are presented. In one case, delayed diagnosis and operation led to pubertas praecox vera whereas in the other case normal growth and development occurred after early diagnosis and operation. PMID:6878724

  13. Paediatric laryngeal granular cell tumour

    Directory of Open Access Journals (Sweden)

    Dauda Ayuba

    2009-01-01

    Full Text Available Granular cell tumour (GCT affecting the larynx is not common, especially in children. Most cases are apt to be confused with respiratory papilloma and may even be mistaken for a malignant neoplasia. We present a case of laryngeal GCT in a 12-year-old child to emphasize that the tumour should be regarded in the differential of growths affecting the larynx in children.

  14. Neurohypophysis granular cell tumours. Upon neurohypophysis rare tumours

    International Nuclear Information System (INIS)

    Granular cell tumours of neurohypophysis are rare. These tumours are more often encountered as incidental autopsy findings seen in up to 17 % of unselected adult autopsy cases. There are few reports of para-sellar granular cell tumours large enough to cause symptoms. We present three cases of neurohypophysis granular cell tumour and a review of the literature. In one patient, the asymptomatic granular cell tumour was incidentally discovered at surgical removal of a corticotrophic micro-adenoma. The remaining 2 patients had a symptomatic tumour which caused neurological symptoms such as visual disturbance and headaches and endocrine disorders such as hypopituitarism or hyper-prolactinaemia. In these 2 cases, computerized tomography showed a well-circumscribed, contrast-enhanced, intra-sellar and supra-sellar mass. Magnetic resonance imaging demonstrated an isointense gadolinium-enhanced mass in T1-weighted-images. Trans-sphenoidal partial resection was performed and histology was interpreted as a granular cell tumour. The immunohistochemical study was positive for glial fibrillary acidic protein (GEAP) and neuron specific enolase (NSE) in 1 of the 2 tumours and positive for S100 protein and vimentin in both tumours but negative for CD68. The histogenesis of neurohypophysis granular cell tumours is still controversial but ultrastructural and immunohistochemical studies support the theory that may arise from pituicytes, the glial cells of neurohypophysis. Management of these benign, slow growing, tumours is based mainly on neurosurgical resection. Data from the literature do not support a beneficial effect of post operative radiation therapy on postoperative recurrences. (authors). 23 refs., 4 figs., 1 tab

  15. Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumour delivery

    Science.gov (United States)

    Smith, Bryan Ronain; Ghosn, Eliver Eid Bou; Rallapalli, Harikrishna; Prescher, Jennifer A.; Larson, Timothy; Herzenberg, Leonore A.; Gambhir, Sanjiv Sam

    2014-06-01

    In cancer imaging, nanoparticle biodistribution is typically visualized in living subjects using `bulk' imaging modalities such as magnetic resonance imaging, computerized tomography and whole-body fluorescence. Accordingly, nanoparticle influx is observed only macroscopically, and the mechanisms by which they target cancer remain elusive. Nanoparticles are assumed to accumulate via several targeting mechanisms, particularly extravasation (leakage into tumour). Here, we show that, in addition to conventional nanoparticle-uptake mechanisms, single-walled carbon nanotubes are almost exclusively taken up by a single immune cell subset, Ly-6Chi monocytes (almost 100% uptake in Ly-6Chi monocytes, below 3% in all other circulating cells), and delivered to the tumour in mice. We also demonstrate that a targeting ligand (RGD) conjugated to nanotubes significantly enhances the number of single-walled carbon nanotube-loaded monocytes reaching the tumour (P < 0.001, day 7 post-injection). The remarkable selectivity of this tumour-targeting mechanism demonstrates an advanced immune-based delivery strategy for enhancing specific tumour delivery with substantial penetration.

  16. Nutrition, anthropometry, gastrointestinal dysfunction, and circulating levels of tumour necrosis factor alpha receptor I and interleukin-1 receptor antagonist in children during stem cell transplantation

    DEFF Research Database (Denmark)

    Andreassen, B. U.; Pærregaard, Anders; Michaelsen, Kim F.; Andersen, J.; Heilmann, C. J.; Muller, Klaus; Andreassen, B U; Pærregaard, A; Michaelsen, K F; Andersen, J; Heilmann, C J; Müller, K

    2008-01-01

    To evaluate anthropometry, nutrition and gastrointestinal dysfunction, and to characterize the relation between these parameters and the inflammatory activity evaluated by plasma levels of soluble tumour necrosis factor alpha receptor I (sTNFRI) and interleukin-1 receptor antagonist (IL-1Ra) levels...... during stem cell transplantation (SCT) in children. Clinical assessments and blood sampling were performed on days -3, 0, +7, +15 and +31 in eight children undergoing SCT. Energy intake, anthropometry, gastrointestinal dysfunction (WHO toxicity score) and sTNFRI and IL-1Ra were evaluated. The energy...... intake was below recommended levels. There was a loss of lean body mass (arm muscle area)(median, 2031 mm(2) (day -3) vs 1477 mm(2) (day 31); p = 0.04), and of fat mass (arm fat area) (791 mm(2) (day -3) vs 648 mm(2) (day +31); p = 0.04). sTNFRI was elevated throughout the course of transplantation, and...

  17. Targeting hypoxic tumour cells to overcome metastasis

    International Nuclear Information System (INIS)

    The microenvironment within solid tumours can influence the metastatic dissemination of tumour cells, and recent evidence suggests that poorly oxygenated (hypoxic) cells in primary tumours can also affect the survival and proliferation of metastatic tumour cells in distant organs. Hypoxic tumour cells have been historically targeted during radiation therapy in attempts to improve loco-regional control rates of primary tumours since hypoxic cells are known to be resistant to ionizing radiation-induced DNA damage. There are, therefore, a number of therapeutic strategies to directly target hypoxic cells in primary (and metastatic) tumours, and several compounds are becoming available to functionally inhibit hypoxia-induced proteins that are known to promote metastasis. This mini-review summarizes several established and emerging experimental strategies to target hypoxic cells in primary tumours with potential clinical application to the treatment of patients with tumour metastases or patients at high risk of developing metastatic disease. Targeting hypoxic tumour cells to reduce metastatic disease represents an important advance in the way scientists and clinicians view the influence of tumour hypoxia on therapeutic outcome

  18. Myoepithelial cells in canine mammary tumours.

    Science.gov (United States)

    Sánchez-Céspedes, Raquel; Millán, Yolanda; Guil-Luna, Silvia; Reymundo, Carlos; Espinosa de Los Monteros, Antonio; Martín de Las Mulas, Juana

    2016-01-01

    Mammary tumours are the most common neoplasms of female dogs. Compared to mammary tumours of humans and cats, myoepithelial (ME) cell involvement is common in canine mammary tumours (CMT) of any subtype. Since ME cell involvement in CMT influences both histogenetic tumour classification and prognosis, correct identification of ME cells is important. This review describes immunohistochemical methods for identification of canine mammary ME cells used in vivo. In addition, phenotypic and genotypic methods to isolate ME cells for in vitro studies to analyse tumour-suppressor protein production and gene expression are discussed. The contribution of ME cells to both histogenetic classifications and the prognosis of CMT is compared with other species and the potential use of ME cells as a method to identify carcinoma in situ is discussed. PMID:26639832

  19. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan

    Science.gov (United States)

    Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko

    2016-01-01

    Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191

  20. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

    Science.gov (United States)

    Chabon, Jacob J.; Simmons, Andrew D.; Lovejoy, Alexander F.; Esfahani, Mohammad S.; Newman, Aaron M.; Haringsma, Henry J.; Kurtz, David M.; Stehr, Henning; Scherer, Florian; Karlovich, Chris A.; Harding, Thomas C.; Durkin, Kathleen A.; Otterson, Gregory A.; Purcell, W. Thomas; Camidge, D. Ross; Goldman, Jonathan W.; Sequist, Lecia V.; Piotrowska, Zofia; Wakelee, Heather A.; Neal, Joel W.; Alizadeh, Ash A.; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  1. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.

    Science.gov (United States)

    Chabon, Jacob J; Simmons, Andrew D; Lovejoy, Alexander F; Esfahani, Mohammad S; Newman, Aaron M; Haringsma, Henry J; Kurtz, David M; Stehr, Henning; Scherer, Florian; Karlovich, Chris A; Harding, Thomas C; Durkin, Kathleen A; Otterson, Gregory A; Purcell, W Thomas; Camidge, D Ross; Goldman, Jonathan W; Sequist, Lecia V; Piotrowska, Zofia; Wakelee, Heather A; Neal, Joel W; Alizadeh, Ash A; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  2. Anti-tumour activity of oncolytic Western Reserve vaccinia viruses in canine tumour cell lines, xenografts, and fresh tumour biopsies.

    Science.gov (United States)

    Autio, K; Knuuttila, A; Kipar, A; Ahonen, M; Parviainen, S; Diaconu, I; Kanerva, A; Hakonen, T; Vähä-Koskela, M; Hemminki, A

    2014-10-10

    Cancer is one of the most common reasons for death in dogs. One promising approach is oncolytic virotherapy. We assessed the oncolytic effect of genetically modified vaccinia viruses in canine cancer cells, in freshly excised tumour biopsies, and in mice harbouring canine tumour xenografts. Tumour transduction efficacy was assessed using virus expressing luciferase or fluorescent marker genes and oncolysis was quantified by a colorimetric cell viability assay. Oncolytic efficacy in vivo was evaluated in a nude mouse xenograft model. Vaccinia virus was shown to infect most tested canine cancer cell lines and primary surgical tumour tissues. Virus infection significantly reduced tumour growth in the xenograft model. Oncolytic vaccinia virus has antitumour effects against canine cancer cells and experimental tumours and is able to replicate in freshly excised patient tumour tissue. Our results suggest that oncolytic vaccinia virus may offer an effective treatment option for otherwise incurable canine tumours. PMID:25302859

  3. Ovarian stimulation and granulosa-cell tumour.

    Science.gov (United States)

    Willemsen, W; Kruitwagen, R; Bastiaans, B; Hanselaar, T; Rolland, R

    1993-04-17

    Ovarian stimulation in the treatment of infertility is far from physiological because patients and their ovaries are exposed to high concentrations of gonadotropins. Many studies have focused on the two most common side-effects of ovarian stimulation--ie, hyperstimulation and multiple pregnancy. We describe 12 patients in whom granulosa-cell tumour was discovered after ovarian stimulation treatment with clomiphene citrate and/or gonadotropins. Although we cannot prove a causal link between the tumour and the medication, investigations in animals have shown a relation between gonadotropin exposition and the development of granulosa-cell tumours. The possible relation of ovarian stimulation and granulosa-cell tumours in human beings has not been published before. We postulate three explanations for this finding; first, the granulosa-cell tumour is present in the ovary, waiting for a hormonal trigger; second, increased follicle stimulating hormone concentrations are oncogenic to granulosa cell; and third, the onset of the granulosa-cell tumour during ovarian stimulation is coincidental. We recommend that ovarian stimulation is done only if there is a valid indication after proper assessment of the ovaries, and that women who have had ovarian stimulation are followed for longer than at present. PMID:8096944

  4. Granular cell tumour of the neurohypophysis: a rare sellar tumour with specific radiological and operative features.

    LENUS (Irish Health Repository)

    Aquilina, K

    2012-02-03

    Symptomatic granular cell tumours of the neurohypophysis are rare sellar lesions. Preoperative prediction of the diagnosis on the basis of radiological appearance is useful as these tumours carry specific surgical difficulties. This is possible when the tumour arises from the pituitary stalk, rostral to a normal pituitary gland. This has not been emphasized previously.

  5. MRI of intracranial germ cell tumours

    Energy Technology Data Exchange (ETDEWEB)

    Sumida, M. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Uozumi, T. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Kiya, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Mukada, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Arita, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Kurisu, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Sugiyama, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Onda, J. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Satoh, H. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Ikawa, F. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Migita, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan)

    1995-01-01

    We reviewed MRI findings in proven intracranial germ cell tumours in 22 cases, 12 of whom received Gd-DTPA. On T1-weighted images, the signal intensity of the tumour parenchyma was moderately low in 19 cases and isointense in 3; on T2-weighted images, it was high in all cases. Regions of different intensity thought to be cysts were found in 17 (77 %): 7 of 12 patients with germinoma (58 %) and in all other cases. Of the 13 patients with pineal lesions T1-weighted sagittal images showed the aqueduct to be obstructed in 5, stenotic in 7 and normal in 1. Strong contrast enhancement was observed in all 12 cases. Of the 14 patients with suprasellar lesions, 5 were found to have an intrasellar extension, and in 3 of these, the normal pituitary gland, which could be distinguished from the tumour, was displaced anteriorly. Ten patients (45 %) had multiple lesions. (orig.)

  6. Cell metabolism, tumour diagnosis and multispectral FLIM

    Science.gov (United States)

    Rück, A.; Hauser, C.; Lorenz, S.; Mosch, S.; Rotte, S.; Kessler, M.; Kalinina, S.

    2013-02-01

    Fluorescence guided diagnosis of tumour tissue is in many cases insufficient, because false positive results are interfering with the outcome. Discrimination between tumour and inflammation could be therefore difficult. Improvement of fluorescence diagnosis through observation of cell metabolism could be the solution, which needs a detailed understanding of the origin of autofluorescence. However, a complex combination of fluorophores give rise to the emission signal. Also in PDD (photodynamic diagnosis) different photosensitizer metabolites contribute to the fluorescence signal. Therefore, the fluorescence decay in many cases does not show a simple monoexponential profile. In those cases a considerable improvement could be achieved when time-resolved and spectral-resolved techniques are simultaneously incorporated. The discussion will focus on the detection of NADH, FAD and 5-ALA induced porphyrins. With respect to NADH and FAD the discrimination between protein bound and free coenzyme was investigated with multispectral FLIM in normal oral keratinocytes and squamous carcinoma cells from different origin. The redox ratio, which can be correlated with the fluorescence lifetimes of NADH and FAD changed depending on the state of the cells. Most of the investigations were done in monolayer cell cultures. However, in order to get information from a more realistic in vivo situation additionally the chorioallantoismembrane (CAM) of fertilized eggs was used where tumour cells or biopsies were allowed to grow. The results of theses measurements will be discussed as well.

  7. Pedunculated islet-cell tumour of the duodenum.

    Science.gov (United States)

    Britt, R P

    1966-05-01

    An unusual islet-cell tumour found at necropsy in a patient who had died from a myocardial infarction is described. Of particular interest were the pedunculated nature and large size of the tumour. The clinical features of the case are considered. Four islet-cell tumours in the duodenum have previously been reported and it seems probable that such tumours arise in heterotopic pancreas. PMID:4287114

  8. MicroRNA Regulation of Brain Tumour Initiating Cells in Central Nervous System Tumours

    Directory of Open Access Journals (Sweden)

    Neha Garg

    2015-01-01

    Full Text Available CNS tumours occur in both pediatric and adult patients and many of these tumours are associated with poor clinical outcome. Due to a paradigm shift in thinking for the last several years, these tumours are now considered to originate from a small population of stem-like cells within the bulk tumour tissue. These cells, termed as brain tumour initiating cells (BTICs, are perceived to be regulated by microRNAs at the posttranscriptional/translational levels. Proliferation, stemness, differentiation, invasion, angiogenesis, metastasis, apoptosis, and cell cycle constitute some of the significant processes modulated by microRNAs in cancer initiation and progression. Characterization and functional studies on oncogenic or tumour suppressive microRNAs are made possible because of developments in sequencing and microarray techniques. In the current review, we bring recent knowledge of the role of microRNAs in BTIC formation and therapy. Special attention is paid to two highly aggressive and well-characterized brain tumours: gliomas and medulloblastoma. As microRNA seems to be altered in the pathogenesis of many human diseases, “microRNA therapy” may now have potential to improve outcomes for brain tumour patients. In this rapidly evolving field, further understanding of miRNA biology and its contribution towards cancer can be mined for new therapeutic tools.

  9. MRI of intracranial germ-cell tumours

    International Nuclear Information System (INIS)

    Abstract. Our aim was to review the MRI appearances of primary intracranial germ-cell tumours (GCT). We reviewed the MRI studies of 32 patients: 19 with germinomas, five with teratomas, one with an embryonal carcinoma, five with mixed and two with malignant nongerminomatous GCT. Eleven were in the pineal region, 12 suprasellar, five in the both sites, two in the basal ganglia and two in the corpus callosum. Contrast-enhanced images were available for 27 patients. The solid parts of GCT were nearly isointense with grey matter on both T1- and T2-weighted images. In seven patients with nongerminomatous GCT high-signal components were found on T1-weighted images, representing haemorrhage, high-protein fluid or fat. Cystic components were detected in 17 of 27 patients; eight germinomas and all nine nongerminomatous GCT had cysts. The solid components of germinomas enhanced homogeneously in eight cases and heterogeneously in 10, while all nongerminomatous GCT showed heterogeneous enhancement. MRI features tumours can facilitate correct diagnosis of GCT, including histological subtypes. (orig.)

  10. MRI of intracranial germ-cell tumours

    Energy Technology Data Exchange (ETDEWEB)

    Liang, L.; Korogi, Y.; Sugahara, T.; Ikushima, I.; Shigematsu, Y.; Okuda, T.; Takahashi, M. [Department of Radiology, Kumamoto University School of Medicine (Japan); Kochi, M.; Ushio, Y. [Department of Neurosurgery, Kumamoto University School of Medicine (Japan)

    2002-05-01

    Abstract. Our aim was to review the MRI appearances of primary intracranial germ-cell tumours (GCT). We reviewed the MRI studies of 32 patients: 19 with germinomas, five with teratomas, one with an embryonal carcinoma, five with mixed and two with malignant nongerminomatous GCT. Eleven were in the pineal region, 12 suprasellar, five in the both sites, two in the basal ganglia and two in the corpus callosum. Contrast-enhanced images were available for 27 patients. The solid parts of GCT were nearly isointense with grey matter on both T1- and T2-weighted images. In seven patients with nongerminomatous GCT high-signal components were found on T1-weighted images, representing haemorrhage, high-protein fluid or fat. Cystic components were detected in 17 of 27 patients; eight germinomas and all nine nongerminomatous GCT had cysts. The solid components of germinomas enhanced homogeneously in eight cases and heterogeneously in 10, while all nongerminomatous GCT showed heterogeneous enhancement. MRI features tumours can facilitate correct diagnosis of GCT, including histological subtypes. (orig.)

  11. An integrated on-chip platform for negative enrichment of tumour cells.

    Science.gov (United States)

    Bhuvanendran Nair Gourikutty, Sajay; Chang, Chia-Pin; Poenar, Daniel Puiu

    2016-08-15

    The study of cancer cells in blood, popularly called circulating tumour cells (CTCs), has exceptional prospects for cancer risk assessment and analysis. Separation and enrichment of CTCs by size-based methods suffer from a well-known recovery/purity trade-off while methods targeting certain specific surface proteins can lead to risk of losing CTCs due to Epithelial to Mesenchymal Transition (EMT) and thus adversely affect the separation efficiency. A negative selection approach is thus preferred for tumour cell isolation as it does not depend on biomarker expression or defines their physical property as the separation criteria. In this work, we developed a microfluidic chip to isolate CTCs from whole blood samples without targeting any tumour specific antigen. This chip employs a two-stage cell separation: firstly, magnetophoresis depletes the white blood cells (WBCs) from a whole blood sample and is then followed by a micro-slit membrane that enables depleting the red blood cells (RBCs) and retaining only the tumour cells. By creating strong magnetic field gradients along with customized antibody complexes to target WBCs, we are able to remove >99.9% of WBCs from 1:1 diluted blood at a sample processing rate of 500μL/min. This approach achieves an average of >80% recovery of spiked tumour cells from 2mL of whole blood in a total assay processing time of 50min without multiple processing steps. PMID:27344255

  12. Immunisation of colorectal cancer patients with autologous tumour cells

    DEFF Research Database (Denmark)

    Diederichsen, Axel Cosmus Pyndt; Stenholm, A C; Kronborg, O; Fenger, C; Jensenius, Jens Christian; Zeuthen, J; Kristensen, T; Christensen, P B

    1998-01-01

    Patients with colorectal cancer were entered into a clinical phase I trial of immunotherapy with an autologous tumour cell/bacillus Calmette-Guerin (BCG) vaccine. We attempted to describe the possible effects and side effects of the immunisation, and further to investigate whether expression of...... immune-response-related surface molecules on the tumour cells in the vaccine correlated with survival. The first and second vaccine comprised of 107 irradiated tumour cells mixed with BCG, the third of irradiated tumour cells only. Thirty-nine patients were considered, but only 6 patients fulfilled the...... criteria for inclusion. No serious side effects were observed. With three years of observation time, two patients are healthy, while the rest have had recurrence, and two of them have died. In all vaccines, all tumour cells expressed HLA class I, some expressed HLA class II and none expressed CD80. There...

  13. Magnetic resonance imaging of ganglion cell tumours

    International Nuclear Information System (INIS)

    The MRI and CT studies of four patients with ganglion cell tumours, one with a cerebellar gangliocytoma (Lhermitte-Duclos disease), and three with gangliogliomas are reported. MRI in Lhermitte-Duclos disease clearly demonstrated a mass of low signal intensity in the left cerebellum on T1-weighted spin-echo (SE) images and an area of high signal intensity with a blurred margin on T2-weighted SE images. These MRI studies were useful for delineating the lesion, which was verified at surgery. In the ganglioglioma, MRI demonstrated two isointense solid masses on T1-weighted SE images, which enhanced clearly with Gd-DTPA. The enhancement study was advantageous in planning surgery. (orig.)

  14. Single-cell Raman spectroscopy of irradiated tumour cells

    Science.gov (United States)

    Matthews, Quinn

    This work describes the development and application of a novel combination of single-cell Raman spectroscopy (RS), automated data processing, and principal component analysis (PCA) for investigating radiation induced biochemical responses in human tumour cells. The developed techniques are first validated for the analysis of large data sets (˜200 spectra) obtained from single cells. The effectiveness and robustness of the automated data processing methods is demonstrated, and potential pitfalls that may arise during the implementation of such methods are identified. The techniques are first applied to investigate the inherent sources of spectral variability between single cells of a human prostate tumour cell line (DU145) cultured in vitro. PCA is used to identify spectral differences that correlate with cell cycle progression and the changing confluency of a cell culture during the first 3-4 days after sub-culturing. Spectral variability arising from cell cycle progression is (i) expressed as varying intensities of protein and nucleic acid features relative to lipid features, (ii) well correlated with known biochemical changes in cells as they progress through the cell cycle, and (iii) shown to be the most significant source of inherent spectral variability between cells. This characterization provides a foundation for interpreting spectral variability in subsequent studies. The techniques are then applied to study the effects of ionizing radiation on human tumour cells. DU145 cells are cultured in vitro and irradiated to doses between 15 and 50 Gy with single fractions of 6 MV photons from a medical linear accelerator. Raman spectra are acquired from irradiated and unirradiated cells, up to 5 days post-irradiation. PCA is used to distinguish radiation induced spectral changes from inherent sources of spectral variability, such as those arising from cell cycle. Radiation induced spectral changes are found to correlate with both the irradiated dose and the

  15. Bacterial-mediated DNA delivery to tumour associated phagocytic cells.

    Science.gov (United States)

    Byrne, W L; Murphy, C T; Cronin, M; Wirth, T; Tangney, M

    2014-12-28

    Phagocytic cells including macrophages, dendritic cells and neutrophils are now recognised as playing a negative role in many disease settings including cancer. In particular, macrophages are known to play a pathophysiological role in multiple diseases and present a valid and ubiquitous therapeutic target. The technology to target these phagocytic cells in situ, both selectively and efficiently, is required in order to translate novel therapeutic modalities into clinical reality. We present a novel delivery strategy using non-pathogenic bacteria to effect gene delivery specifically to tumour-associated phagocytic cells. Non-invasive bacteria lack the ability to actively enter host cells, except for phagocytic cells. We exploit this natural property to effect 'passive transfection' of tumour-associated phagocytic cells following direct administration of transgene-loaded bacteria to tumour regions. Using an in vitro-differentiated human monocyte cell line and two in vivo mouse models (an ovarian cancer ascites and a solid colon tumour model) proof of delivery is demonstrated with bacteria carrying reporter constructs. The results confirm that the delivery strategy is specific for phagocytic cells and that the bacterial vector itself recruits more phagocytic cells to the tumour. While proof of delivery to phagocytic cells is demonstrated in vivo for solid and ascites tumour models, this strategy may be applied to other settings, including non-cancer related disease. PMID:25466954

  16. Breast spindle cell tumours: about eight cases

    Directory of Open Access Journals (Sweden)

    Abd El All Howayda S

    2006-07-01

    Full Text Available Abstract Background Breast spindle cell tumours (BSCTs, although rare, represent a heterogeneous group with different treatment modalities. This work was undertaken to evaluate the utility of fine needle aspiration cytology (FNAC, histopathology and immunohistochemistry (IHC in differentiating BSCTs. Methods FNAC of eight breast masses diagnosed cytologically as BSCTs was followed by wide excision biopsy. IHC using a panel of antibodies against vimentin, pan-cytokeratin, s100, desmin, smooth muscle actin, CD34, and CD10 was evaluated to define their nature. Results FNAC defined the tumors as benign (n = 4, suspicious (n = 2 and malignant (n = 3, based on the cytopathological criteria of malignancy. Following wide excision biopsy, the tumors were reclassified into benign (n = 5 and malignant (n = 3. In the benign group, the diagnosis was raised histologically and confirmed by IHC for 3 cases (one spindle cell lipoma, one myofibroblastoma and one leiomyoma. For the remaining two cases, the diagnosis was set up after IHC (one fibromatosis and one spindle cell variant of adenomyoepithelioma. In the malignant group, a leiomyosarcoma was diagnosed histologically, while IHC was crucial to set up the diagnosis of one case of spindle cell carcinoma and one malignant myoepithelioma. Conclusion FNAC in BSCTs is an insufficient tool and should be followed by wide excision biopsy. The latter technique differentiate benign from malignant BSCTs and is able in 50% of the cases to set up the definite diagnosis. IHC is of value to define the nature of different benign lesions and is mandatory in the malignant ones for optimal treatment. Awareness of the different types of BSCTs prevents unnecessary extensive therapeutic regimes.

  17. Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery

    DEFF Research Database (Denmark)

    Reinert, Thomas; Schøler, Lone Vedel; Thomsen, Rune;

    2016-01-01

    quantified in 151 serial plasma samples from six relapsing and five non-relapsing colorectal cancer (CRC) patients by droplet digital PCR, and correlated to clinical findings. RESULTS: Up to six personalised assays were designed for each patient. Our approach enabled efficient temporal assessment of disease......OBJECTIVE: To develop an affordable and robust pipeline for selection of patient-specific somatic structural variants (SSVs) being informative about radicality of the primary resection, response to adjuvant therapy, incipient recurrence and response to treatment performed in relation to diagnosis...... of recurrence. DESIGN: We have established efficient procedures for identification of SSVs by next-generation sequencing and subsequent quantification of 3-6 SSVs in plasma. The consequence of intratumour heterogeneity on our approach was assessed. The level of circulating tumour DNA (ctDNA) was...

  18. Increased cell membrane arachidonic acid in experimental colorectal tumours.

    OpenAIRE

    Nicholson, M. L.; Neoptolemos, J P; Clayton, H A; Talbot, I C; Bell, P R

    1991-01-01

    Tumour cell membrane fatty acid composition was investigated using an animal model of colorectal carcinogenesis. Eighty six male Wistar rats were fed experimental diets containing either 5% saturated fat or 20% saturated fat. Colorectal tumours were induced by intraperitoneal injection of azoxymethane, and control rats received saline. Animals were killed at intervals up to 26 weeks after the last injection of carcinogen for histology and lipid analysis. Cell membrane fatty acids in colonic m...

  19. Innate Lymphoid Cells: Roles In Tumour Genesis And Progression

    OpenAIRE

    Jovanovic Ivan; Gajovic Nevena; Radosavljevic Gordana; Pantic Jelena; Pejnovic Nada; Arsenijevic Nebojsa; Lukic Miodrag L.

    2015-01-01

    Innate lymphoid cells (ILCs) represent the most recently identified members of the innate immune system. These cells play important roles in inflammation, tissue remodelling and metabolic disease. ILCs can be subdivided into three major groups according to their cytokine production. The role of ILCs in tumourigenesis and tumour progression is not completely clarified. In this review, we discuss whether and how ILCs are involved in tumour genesis, growth and metastasis.

  20. Innate Lymphoid Cells: Roles In Tumour Genesis And Progression

    Directory of Open Access Journals (Sweden)

    Jovanovic Ivan

    2015-06-01

    Full Text Available Innate lymphoid cells (ILCs represent the most recently identified members of the innate immune system. These cells play important roles in inflammation, tissue remodelling and metabolic disease. ILCs can be subdivided into three major groups according to their cytokine production. The role of ILCs in tumourigenesis and tumour progression is not completely clarified. In this review, we discuss whether and how ILCs are involved in tumour genesis, growth and metastasis.

  1. Multimodal therapy for synergic inhibition of tumour cell invasion and tumour-induced angiogenesis

    International Nuclear Information System (INIS)

    Squamous cell carcinoma of the head and neck (SCCHN) are highly invasive tumours with frequent local and distant recurrence. Metastasis formation requires degradation of the extracellular matrix, which is fulfilled by membrane-associated proteases such as the urokinase plasminogen activator (uPA). WX-UK1 is a competitive active site inhibitor of the protease function of uPA that impairs on the capacity of tumour cells to invade in vitro. In the present study, effects of combinations of WX-UK1 with matrix metalloprotease inhibitors (MMP, galardin®) and cyclooxygenase-2 (COX-2, celecoxib®) inhibitors on tumour cell proliferation, invasion, and angiogenesis induction were evaluated. Matrigel invasion chambers and a spheroid co-cultivation model with human fibroblast served to determine the invasive potential of both FaDu (SCCHN) and HeLa (cervical carcinoma) cells, each treated with combinations of Celecoxib®, Galardin®, and WX-UK1. Blocking of single protease systems resulted in a significant 50% reduction of tumour cell invasion using WX-UK1, while the triple combination was even more effective with 80% reduction of invasion. Additionally, a sprouting assay with HUVEC was used to test the anti-angiogenetic potential of the triple combination, resulting in a 40% decrease in the sprouting rate. A combined approach targeting different families of proteases and cyclooxygenases represents a promising adjuvant therapy

  2. Immunotherapy with irradiated tumour cells and BCG in experimental osteosarcoma

    International Nuclear Information System (INIS)

    The effects of immunotherapy with irradiated tumour cells and BCG were studied in a non-metastasizing variety of the Dunn osteosarcoma transplantable in mice. Experimental animals which had been preimmunized with three injections of 0.7 to 1.4 x 106 irradiated tumour cells each 1 to 3 weeks before administration of 1 x 106 living tumour cells, showed a tumour incidence of 23 per cent. This was significantly (P<0.005) lower than the 92 per cent tumour incidence in the control animals. Non-specific immunotherapy with BCG given subcutaneously at a dose of 1.0 mg of dry-weight bacterial mass three times at 3-weeks intervals was found to have no protective effect against the osteosarcoma. The tumour incidence was 90 per cent for BCG-treated and 94 per cent for control animals. The osteosarcomas were studied light and electron microscopically and also with regard to the histochemical alkaline phosphatase activity. No structural difference was found between the tumours of the various groups. The demonstrated immunotherapeutic response is in contrast o the low degree of immunogenicity of the osteosarcoma, which we will report elsewhere. (author)

  3. Brain tumour stem cells: the undercurrents of human brain cancer and their relationship to neural stem cells

    OpenAIRE

    Dirks, Peter B.

    2007-01-01

    Conceptual and technical advances in neural stem cell biology are being applied to the study of human brain tumours. These studies suggest that human brain tumours are organized as a hierarchy and are maintained by a small number of tumour cells that have stem cell properties. Most of the bulk population of human brain tumours comprise cells that have lost the ability to initiate and maintain tumour growth. Although the cell of origin for human brain tumours is uncertain, recent evidence poin...

  4. Enhanced casein kinase II activity in human tumour cell cultures

    DEFF Research Database (Denmark)

    Prowald, K; Fischer, H; Issinger, O G

    1984-01-01

    Casein kinase II (CKII) activity is enhanced as much as 2-3 fold in established and 4-5-fold in transformed human cell lines when compared to that of fibroblasts and primary human tumour cell cultures where CKII activity never exceeded a basic level. The high activity of CKII in transformed cells...... and in established cell lines was reduced to about the same basic level after treatment with heparin, a highly specific inhibitor of CKII activity. The activity of the cAMP-dependent protein kinase was virtually the same in fibroblasts and various human tumour cell lines investigated....

  5. TH17 cells in tumour immunity and immunotherapy

    OpenAIRE

    Zou, Weiping; Restifo, Nicholas P

    2010-01-01

    T helper 17 (TH17) cells have well-described roles in autoimmune disease. Recent evidence suggests that this effector T cell subset is also involved in tumour immunology and may be a target for cancer therapy. In this Review, we summarize recent findings regarding the nature and relevance of TH17 cells in mouse models of cancer and human disease. We describe the interplay between TH17 cells and other immune cells in the tumour microenvironment, and we assess both the potential antitumorigenic...

  6. Mediastinal germ cell tumour with massive pulmonary involvement

    OpenAIRE

    Kawamukai, Kenji; Di Saverio, Salomone; Antonacci, Filippo; Lacava, Nicola; Boaron, Maurizio

    2011-01-01

    Multimodality treatment, with chemotherapy and surgery, is potentially curative in case of non-seminomatous germ cell tumours. The authors present the case of a primitive mediastinal GTC with bilateral lung metastases. The patient was treated with five cycles of chemotherapy. Restaging showed reduction of the extent and of 18 FDG intake and β-HCG serum levels. The patient underwent two-step surgical excision of the tumours: mediastinal lesion and 35 lung metastases were resected by a right th...

  7. Niche appropriation by Drosophila intestinal stem cell tumours.

    Science.gov (United States)

    Patel, Parthive H; Dutta, Devanjali; Edgar, Bruce A

    2015-09-01

    Mutations that inhibit differentiation in stem cell lineages are a common early step in cancer development, but precisely how a loss of differentiation initiates tumorigenesis is unclear. We investigated Drosophila intestinal stem cell (ISC) tumours generated by suppressing Notch (N) signalling, which blocks differentiation. Notch-defective ISCs require stress-induced divisions for tumour initiation and an autocrine EGFR ligand, Spitz, during early tumour growth. On achieving a critical mass these tumours displace surrounding enterocytes, competing with them for basement membrane space and causing their detachment, extrusion and apoptosis. This loss of epithelial integrity induces JNK and Yki/YAP activity in enterocytes and, consequently, their expression of stress-dependent cytokines (Upd2, Upd3). These paracrine signals, normally used within the stem cell niche to trigger regeneration, propel tumour growth without the need for secondary mutations in growth signalling pathways. The appropriation of niche signalling by differentiation-defective stem cells may be a common mechanism of early tumorigenesis. PMID:26237646

  8. Malignant granular cell tumour of the sciatic nerve

    International Nuclear Information System (INIS)

    A case of malignant granular cell tumour of the sciatic nerve is presented. Computed tomography demonstrated isodensity with muscle and minimal enhancement. Magnetic resonance demonstrated T1 isointensity with muscle with marked enhancement, and isointensity with fat on proton and T2 images. Pathological evidence is presented for its probable Schwann cell histogenesis. 9 refs., 3 figs

  9. Extramedullary Myeloid Cell Tumour Presenting As Leukaemia Cutis

    Directory of Open Access Journals (Sweden)

    Thappa Devinder Mohan

    2002-01-01

    Full Text Available We herewith report a case of extramedullary myeloid cell tumour presenting as leukaemia cutis for its rarity. It occurred in a 50 year old male patient who presented to us with a 40 days history of painless raised solid skin swellings over the trunk. Histopathological examination of the skin biopsy and bone marrow biopsy showed features suggestive of non-Hodgkin’s lymphoma. Immunophenotyping on skin biopsy specimens and bone marrow biopsy found tumour cells expressing CD43 and Tdt but were negative for CD3 and CD20. These features were consistent with extramedullary myeloid cell tumour involving skin and subcutis (cutaneous manifestation of acute myeloid leukaemia.

  10. Active removal of radioactivity in the blood circulation using biotin-bearing liposomes and avidin for rapid tumour imaging

    International Nuclear Information System (INIS)

    In order to shorten the delay between the administration of tumour-imaging agents and obtainment of scintigrams, rapid delivery of radionuclide to tumours followed by rapid clearance from the blood is required. We used liposomes with biotin bound on their surface (B-liposomes) as carriers for rapid delivery. For rapid blood clearance, we employed avidin in the expectation that the strong affinity between biotin and avidin would result in the aggregation of B-liposomes in the blood circulation, and that these aggregates would be taken up rapidly by the reticuloendothelial system, resulting in the rapid elimination of liposomes and the radionuclide encapsulated in them. When B-liposomes encapsulating gallium-67 deferoxamine were intravenously administered to mice bearing sarcoma 180, large amounts of 67Ga were delivered to tumours by 4 h after injection, though the 67Ga blood level remained high. On the other hand, administration of avidin 4 h after administration of the B-liposomes dramatically reduced the blood level so that it was only 5% of that in the non-treated group 1 h later. As a result, the tumour-to-blood ratio reached nearly 14 and 5 h after radionuclide administration, suggesting that rapid tumour-imaging will be feasible by means of this method. (orig.)

  11. The genomic landscape of epithelioid sarcoma cell lines and tumours.

    Science.gov (United States)

    Jamshidi, Farzad; Bashashati, Ali; Shumansky, Karey; Dickson, Brendan; Gokgoz, Nalan; Wunder, Jay S; Andrulis, Irene L; Lazar, Alexander J; Shah, Sohrab P; Huntsman, David G; Nielsen, Torsten O

    2016-01-01

    We carried out whole genome and transcriptome sequencing on four tumour/normal pairs of epithelioid sarcoma. These index cases were supplemented with whole transcriptome sequencing of three additional tumours and three cell lines. Unlike rhabdoid tumour (the other major group of SMARCB1-negative cancers), epithelioid sarcoma shows a complex genome with a higher mutational rate, comparable to that of ovarian carcinoma. Despite this mutational burden, SMARCB1 mutations remain the most frequently recurring event and are probably critical drivers of tumour formation. Several cases show heterozygous SMARCB1 mutations without inactivation of the second allele, and we explore this further in vitro. Finding CDKN2A deletions in our discovery cohort, we evaluated CDKN2A protein expression in a tissue microarray. Six out of 16 cases had lost CDKN2A in greater than or equal to 90% of cells, while the remaining cases had retained the protein. Expression analysis of epithelioid sarcoma cell lines by transcriptome sequencing shows a unique profile that does not cluster with any particular tissue type or with other SWI/SNF-aberrant lines. Evaluation of the levels of members of the SWI/SNF complex other than SMARCB1 revealed that these proteins are expressed as part of a residual complex, similarly to previously studied rhabdoid tumour lines. This residual SWI/SNF is susceptible to synthetic lethality and may therefore indicate a therapeutic opportunity. PMID:26365879

  12. Testicular germ cell tumours in dogs are predominantly of spermatocytic seminoma type and are frequently associated with somatic cell tumours

    DEFF Research Database (Denmark)

    Bush, J M; Gardiner, D W; Palmer, J S; Rajpert-De Meyts, E; Veeramachaneni, D N R

    Unlike seminomas in humans, seminomas in animals are not typically sub-classified as classical or spermatocytic types. To compare testicular germ cell tumours (TGCT) in dogs with those of men, archived tissues from 347 cases of canine testicular tumours were morphologically evaluated and characte......Unlike seminomas in humans, seminomas in animals are not typically sub-classified as classical or spermatocytic types. To compare testicular germ cell tumours (TGCT) in dogs with those of men, archived tissues from 347 cases of canine testicular tumours were morphologically evaluated and...... characterized using human classification criteria. Histopathological and immunohistological analysis of PLAP, KIT, DAZ and DMRT1 expression revealed that canine seminomas closely resemble human spermatocytic seminomas. In addition, a relatively frequent concomitant presence of somatic cell tumours was noted in...... canine TGCT. None of the canine TGCT evaluated demonstrated the presence of carcinoma in situ cells, a standard feature of human classical seminomas, suggesting that classical seminomas either do not occur in dogs or are rare in occurrence. Canine spermatocytic seminomas may provide a useful model for...

  13. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients

    DEFF Research Database (Denmark)

    Sausen, Mark; Phallen, Jillian; Adleff, Vilmos;

    2015-01-01

    Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine...... imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention....

  14. New evidence for the origin of intracranial germ cell tumours from primordial germ cells

    DEFF Research Database (Denmark)

    Hoei-Hansen, C E; Sehested, A; Juhler, M;

    2006-01-01

    , suggesting that it is not required for the initiation of malignant germ cell transformation. The expression of genes associated with embryonic stem cell pluripotency in CNS germ cell tumours strongly suggests that these tumours are derived from cells that retain, at least partially, an embryonic stem cell...... germ cell tumours and analysed expression of a wide panel of stem cell-related proteins (C-KIT, OCT-3/4 (POU5F1), AP-2gamma (TFAP2C), and NANOG) and developmentally regulated germ cell-specific proteins (including MAGE-A4, NY-ESO-1, and TSPY). Expression at the protein level was analysed in 21 children...... and young adults with intracranial germinomas and non-germinomas, contributing to a careful description of these unusual tumours and adding to the understanding of pathogenesis. Stem cell related proteins were highly expressed in intracranial germ cell tumours, and many similarities were detected with...

  15. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    Energy Technology Data Exchange (ETDEWEB)

    Peres, Elodie A.; Valable, Samuel [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Guillamo, Jean-Sebastien [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Departement de Neurologie, CHU de Caen (France); Marteau, Lena [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Bernaudin, Jean-Francois [Service d' Histologie-Biologie Tumorale, ER2UPMC, Universite Paris 6, Hopital Tenon, Paris (France); Roussel, Simon [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Lechapt-Zalcman, Emmanuele [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Service d' Anatomie Pathologique, CHU de Caen (France); Bernaudin, Myriam [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Petit, Edwige, E-mail: epetit@cyceron.fr [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France)

    2011-10-01

    Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

  16. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    International Nuclear Information System (INIS)

    Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

  17. Tumour growth delay and cell survival in rat R-1 tumours after radiation and methotrexate treatment

    International Nuclear Information System (INIS)

    The rat R-1 rhabdomyosarcoma which forms colonies in vitro has been used to investigate the effectiveness of radiochemotherapy. Tumour growth delay data were compared with those on survival of cells derived from tumours treated in situ. Methotrexate (MTX) was administered i.p. in three doses of 10 mg per kg body weight at intervals of 4 h. A dose of 10 Gy of 300 kV X rays was given at different time intervals before or after the MTX treatment. The observed tumour growth delays for the combined treatment for intervals of up to 4 d were less than the sum of those following separate treatments. An excess in growth delay was observed when MTX was given 6 to 8 days after or 5 days before a dose of 10 Gy. The radiation treatment resulted in fractions of surviving cells which remained constant for up to 6 days after treatment. The effectiveness of the MTX treatment could be assessed at 3d after administration of the drug, that of the combined treatments as at least 3 days after the MTX treatment. (Auth.)

  18. Systemic therapy for selected skull base sarcomas: Chondrosarcoma, chordoma, giant cell tumour and solitary fibrous tumour/hemangiopericytoma.

    Science.gov (United States)

    Colia, Vittoria; Provenzano, Salvatore; Hindi, Nadia; Casali, Paolo G; Stacchiotti, Silvia

    2016-01-01

    This review highlights the data currently available on the activity of systemic therapy in chondrosarcoma, chordoma, giant cell tumour of the bone (GCTB) and solitary fibrous tumour, i.e., four rare sarcomas amongst mesenchymal malignancy arising from the skull base. PMID:27330421

  19. Vascular mimicry in cultured head and neck tumour cell lines

    OpenAIRE

    Upile, Tahwinder; Jerjes, Waseem; Radhi, Hani; Al-Khawalde, Mohammed; Kafas, Panagiotis; Nouraei, Seyed; Sudhoff, Holger

    2011-01-01

    Introduction Vascuologenesis is the de novo establishment of blood vessels and vascular networks from mesoderm-derived endothelial cell precursors (angioblasts). Recently a novel mechanism, by which some genetically deregulated and aggressive tumour cells generate "micro-vascular" channels without the participation of endothelial cells and independent of angiogenesis, has been proposed. This has been termed "vasculogenic mimicry" and has implications beyond angiogenesis and adds another layer...

  20. Mitochondria: An intriguing target for killing tumour-initiating cells

    Czech Academy of Sciences Publication Activity Database

    Yan, B.; Dong, L.; Neužil, Jiří

    2016-01-01

    Roč. 26, JAN 2016 (2016), s. 86-93. ISSN 1567-7249 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Tumour-initiating cells * ALPHA-TOCOPHERYL SUCCINATE * Therapeutic resistance * Mitochondria Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.249, year: 2014

  1. Future use of mitocans against tumour-initiating cells?

    Czech Academy of Sciences Publication Activity Database

    Morrison, B.J.; Anděra, Ladislav; Reynolds, B.A.; Ralph, S.J.; Neužil, Jiří

    2009-01-01

    Roč. 53, č. 1 (2009), s. 147-153. ISSN 1613-4125 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : mitocans * tumour-initiating cells * metastasis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.356, year: 2009

  2. Genetic analysis of neonatal and infantile germ cell tumours

    NARCIS (Netherlands)

    Veltman, I.M.

    2006-01-01

    Human germ cell tumours (GCTs) can be classified into five distinct types, based on differences in anatomical location, histology, clinical outcome, age and genotype. The first type, the type I GCTs primarily occur in neonates and infants under the age of five years and include teratomas and yolk sa

  3. Tumour-initiating cells vs. cancer 'stem' cells and CD133: What's in the name?

    International Nuclear Information System (INIS)

    Recent evidence suggests that a subset of cells within a tumour have 'stem-like' characteristics. These tumour-initiating cells, distinct from non-malignant stem cells, show low proliferative rates, high self-renewing capacity, propensity to differentiate into actively proliferating tumour cells, resistance to chemotherapy or radiation, and they are often characterised by elevated expression of the stem cell surface marker CD133. Understanding the molecular biology of the CD133+ cancer cells is now essential for developing more effective cancer treatments. These may include drugs targeting organelles, such as mitochondria or lysosomes, using highly efficient and selective inducers of apoptosis. Alternatively, agents or treatment regimens that enhance sensitivity of these therapy-resistant 'tumour stem cells' to the current or emerging anti-tumour drugs would be of interest as well

  4. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.

    Science.gov (United States)

    Sousa, Cristovão M; Biancur, Douglas E; Wang, Xiaoxu; Halbrook, Christopher J; Sherman, Mara H; Zhang, Li; Kremer, Daniel; Hwang, Rosa F; Witkiewicz, Agnes K; Ying, Haoqiang; Asara, John M; Evans, Ronald M; Cantley, Lewis C; Lyssiotis, Costas A; Kimmelman, Alec C

    2016-08-25

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour’s dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment. PMID:27509858

  5. The influence of tumour cell DNA content on survival in colorectal cancer: a detailed analysis.

    OpenAIRE

    Armitage, N C; Ballantyne, K. C.; Evans, D F; Clarke, P; Sheffield, J.; Hardcastle, J. D.

    1990-01-01

    We have investigated the influence of tumour cell DNA content (ploidy) on survival of 416 patients undergoing excisional surgery for colorectal cancer. Two hundred and eleven (51%) tumours had an abnormal DNA content (aneuploid or tetraploid). There was no correlation between ploidy status, sex, age and pathological stage, histological grade, tumour site, local tumour extension or assessment of curability. Patients with tumours with an abnormal DNA content had a poorer survival 68/211 (32%) t...

  6. Isolation of Circulating Tumor Cells by Dielectrophoresis

    OpenAIRE

    Gascoyne, Peter R.C.; Sangjo Shim

    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...

  7. Selective assessment of in vitro radiosensitivity of tumour cells and fibroblasts from single tumour biopsies using immunocytochemical identification of colonies in the soft agar clonogenic assay

    International Nuclear Information System (INIS)

    The assumed selective growth of tumour cells has formed the basis for the use of the soft agar clonogenic assay to test in vitro radio- and chemosensitivity of tumours. However, recent studies have demonstrated that fibroblasts proliferate in soft agar in addition to tumour cells. The present study was initiated to quantify the contaminating growth of non-malignant cells in the modified form of the Courtenay-Mills soft agar assay, in order to establish a reliable assay for estimating tumour cell radiosensitivity in squamous cell carcinomas of the head and neck. DNA flow cytometry analysis confirmed that 'tumour fibroblasts' (fibroblasts obtained from tumour biopsies) grow in soft agar. In contrast, white blood cells did not form colonies. Different media were tested with soft agar, but a selective medium for tumour cells was not found. Therefore, a colony filter-technique combined with an immunocytochemical analysis was developed to quantify the number of tumour cell and fibroblast colonies. In 12 tumour biopsies, 2-33% of the colonies were Cytokeratin AE1-3 positive, whereas 83-100% of the colonies were 5B5 fibroblast antibody positive. The parameter normally reported, the overall SF2 (surviving cell fraction at 2 Gy) based on colonies in agar, was found to be statistically significantly correlated to the fibroblast SF2, but not to the tumour cell SF2. The overall SF2 was significantly different from the tumour cell SF2 in half of the tumours. Furthermore, the tumour cell SF2 was not correlated to fibroblast SF2. In consequence of our findings, correcting for fibroblast contamination is a necessity, when studying in vitro sensitivity of tumour cells. Combining the soft agar clonogenic assay with the new colony filter-technique and the immunocytochemical analysis appear to be useful for making this routine correction and for measuring the in vitro radiosensitivity of both tumour cells and fibroblasts from single tumour biopsies, which is of interest in future

  8. The role of myeloid cells in the promotion of tumour angiogenesis.

    Science.gov (United States)

    Murdoch, Craig; Muthana, Munitta; Coffelt, Seth B; Lewis, Claire E

    2008-08-01

    The use of various transgenic mouse models and analysis of human tumour biopsies has shown that bone marrow-derived myeloid cells, such as macrophages, neutrophils, eosinophils, mast cells and dendritic cells, have an important role in regulating the formation and maintenance of blood vessels in tumours. In this Review the evidence for each of these cell types driving tumour angiogenesis is outlined, along with the mechanisms regulating their recruitment and activation by the tumour microenvironment. We also discuss the therapeutic implications of recent findings that specific myeloid cell populations modulate the responses of tumours to agents such as chemotherapy and some anti-angiogenic therapies. PMID:18633355

  9. Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo.

    Directory of Open Access Journals (Sweden)

    Jason R Sutherland

    Full Text Available Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2, cytokines interleukin (IL -6, and -11 and vascular endothelial growth factor-A (VEGF-A. To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.

  10. MPLA incorporation into DC-targeting glycoliposomes favours anti-tumour T cell responses

    NARCIS (Netherlands)

    Boks, Martine A.; Ambrosini, Martino; Bruijns, Sven C.; Kalay, Hakan; Van Bloois, Louis; Storm, G; Garcia-Vallejo, Juan J.; Van Kooyk, Yvette

    2015-01-01

    Abstract Dendritic cells (DC) are attractive targets for cancer immunotherapy as they initiate strong and long-lived tumour-specific T cell responses. DC can be effectively targeted in vivo with tumour antigens by using nanocarriers such as liposomes. Cross-presentation of tumour antigens is enhance

  11. MPLA incorporation into DC-targeting glycoliposomes favours anti-tumour T cell responses

    NARCIS (Netherlands)

    Boks, M.A.; Ambrosini, Martino; Bruijns, Sven C.M.; Kalay, Hakan; Bloois, van Louis; Storm, G.; Garcia-Vallejo, Juan J.; Kooyk, van Y.

    2015-01-01

    Dendritic cells (DC) are attractive targets for cancer immunotherapy as they initiate strong and long-lived tumour-specific T cell responses. DC can be effectively targeted in vivo with tumour antigens by using nanocarriers such as liposomes. Cross-presentation of tumour antigens is enhanced with st

  12. Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells

    DEFF Research Database (Denmark)

    Cheng, Chang; Edin, Nina F Jeppesen; Lauritzen, Knut H;

    2012-01-01

    Tumour cells are characterized by aerobic glycolysis, which provides biomass for tumour proliferation and leads to extracellular acidification through efflux of lactate via monocarboxylate transporters (MCTs). Deficient and spasm-prone tumour vasculature causes variable hypoxia, which favours tum...... tumour cell survival and metastases. Brain metastases frequently occur in patients with advanced breast cancer.Effective treatment strategies are therefore needed against brain metastasis from breast carcinoma....

  13. Chromatin structure and epigenetics of tumour cells: A review

    Czech Academy of Sciences Publication Activity Database

    Bártová, Eva; Krejčí, Jana; Hájek, R.; Harničarová, Andrea; Kozubek, Stanislav

    2009-01-01

    Roč. 9, č. 1 (2009), s. 51-61. ISSN 1871-529X R&D Projects: GA AV ČR(CZ) 1QS500040508; GA ČR(CZ) GA204/06/0978 Grant ostatní: GA MŠk(CZ) LC06027; GA MŠk(CZ) LC535 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : tumour cells * chromatin * radiation Subject RIV: BO - Biophysics

  14. POMB/ACE chemotherapy for mediastinal germ cell tumours.

    Science.gov (United States)

    Bower, M; Brock, C; Holden, L; Nelstrop, A; Makey, A R; Rustin, G J; Newlands, E S

    1997-05-01

    Mediastinal germ cell tumours (MGCT) are rare and most published series reflect the experiences of individual institutions over many years. Since 1979, we have treated 16 men (12 non-seminomatous germ cell tumours and 4 seminomas) with newly diagnosed primary MGCT with POMB/ACE chemotherapy and elective surgical resection of residual masses. This approach yielded complete remissions in 15/16 (94%) patients. The median follow-up was 6.0 years and no relapses occurred more than 2 years after treatment. The 5 year overall survival in the non-seminomatous germ cell tumours (NSGCT) is 73% (95% confidence interval 43-90%). One patient with NSGCT developed drug-resistant disease and died without achieving remission and 2 patients died of relapsed disease. In addition, 4 patients with bulky and/or metastatic seminoma were treated with POMB/ACE. One died of treatment-related neutropenic sepsis in complete remission and one died of relapsed disease. Finally, 4 patients (2 NSGCT and 2 seminomas) referred at relapse were treated with POMB/ACE and one was successfully salvaged. The combination of POMB/ACE chemotherapy and surgery is effective management for MGCT producing high long-term survival rates. PMID:9291802

  15. Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines.

    OpenAIRE

    Liebmann, J. E.; Cook, J. A.; Lipschultz, C.; Teague, D.; Fisher, J; Mitchell, J B

    1993-01-01

    The cytotoxicity of paclitaxel against eight human tumour cell lines has been studied with in vitro clonogenic assays. The fraction of surviving cells fell sharply after exposure for 24 h to paclitaxel concentrations ranging from 2 to 20 nM; the paclitaxel IC50 was found to range between 2.5 and 7.5 nM. Increasing the paclitaxel concentration above 50 nM, however, resulted in no additional cytotoxicity after a 24 h drug exposure. Cells incubated in very high concentrations of paclitaxel (10,0...

  16. Complications of the post-chemotherapy resection of retroperitoneal residual tumour mass in patients with non-seminomatous testicular germ cell tumours

    NARCIS (Netherlands)

    Gels, ME; Nijboer, AP; Hoekstra, HJ; Sleijfer, DT; Molenaar, WM; Plukker, JT; Droste, JHJ; Schraffordt Koops, H.

    1997-01-01

    Objective To evaluate the resection of the retroperitoneal residual tumour mass (RRTM) for histological examination after chemotherapy in patients with disseminated non-seminomatous testicular germ cell tumours (NSTGCTs), with particular attention to surgical morbidity. Patients and methods From 197

  17. Efficient Monte Carlo modelling of individual tumour cell propagation for hypoxic head and neck cancer

    Science.gov (United States)

    Tuckwell, W.; Bezak, E.; Yeoh, E.; Marcu, L.

    2008-09-01

    A Monte Carlo tumour model has been developed to simulate tumour cell propagation for head and neck squamous cell carcinoma. The model aims to eventually provide a radiobiological tool for radiation oncology clinicians to plan patient treatment schedules based on properties of the individual tumour. The inclusion of an oxygen distribution amongst the tumour cells enables the model to incorporate hypoxia and other associated parameters, which affect tumour growth. The object oriented program FORTRAN 95 has been used to create the model algorithm, with Monte Carlo methods being employed to randomly assign many of the cell parameters from probability distributions. Hypoxia has been implemented through random assignment of partial oxygen pressure values to individual cells during tumour growth, based on in vivo Eppendorf probe experimental data. The accumulation of up to 10 million virtual tumour cells in 15 min of computer running time has been achieved. The stem cell percentage and the degree of hypoxia are the parameters which most influence the final tumour growth rate. For a tumour with a doubling time of 40 days, the final stem cell percentage is approximately 1% of the total cell population. The effect of hypoxia on the tumour growth rate is significant. Using a hypoxia induced cell quiescence limit which affects 50% of cells with and oxygen levels less than 1 mm Hg, the tumour doubling time increases to over 200 days and the time of tumour growth for a clinically detectable tumour (109 cells) increases from 3 to 8 years. A biologically plausible Monte Carlo model of hypoxic head and neck squamous cell carcinoma tumour growth has been developed for real time assessment of the effects of multiple biological parameters which impact upon the response of the individual patient to fractionated radiotherapy.

  18. Efficient Monte Carlo modelling of individual tumour cell propagation for hypoxic head and neck cancer

    International Nuclear Information System (INIS)

    A Monte Carlo tumour model has been developed to simulate tumour cell propagation for head and neck squamous cell carcinoma. The model aims to eventually provide a radiobiological tool for radiation oncology clinicians to plan patient treatment schedules based on properties of the individual tumour. The inclusion of an oxygen distribution amongst the tumour cells enables the model to incorporate hypoxia and other associated parameters, which affect tumour growth. The object oriented program FORTRAN 95 has been used to create the model algorithm, with Monte Carlo methods being employed to randomly assign many of the cell parameters from probability distributions. Hypoxia has been implemented through random assignment of partial oxygen pressure values to individual cells during tumour growth, based on in vivo Eppendorf probe experimental data. The accumulation of up to 10 million virtual tumour cells in 15 min of computer running time has been achieved. The stem cell percentage and the degree of hypoxia are the parameters which most influence the final tumour growth rate. For a tumour with a doubling time of 40 days, the final stem cell percentage is approximately 1% of the total cell population. The effect of hypoxia on the tumour growth rate is significant. Using a hypoxia induced cell quiescence limit which affects 50% of cells with and oxygen levels less than 1 mm Hg, the tumour doubling time increases to over 200 days and the time of tumour growth for a clinically detectable tumour (109 cells) increases from 3 to 8 years. A biologically plausible Monte Carlo model of hypoxic head and neck squamous cell carcinoma tumour growth has been developed for real time assessment of the effects of multiple biological parameters which impact upon the response of the individual patient to fractionated radiotherapy

  19. PDT and tumour infiltrating immune cells

    International Nuclear Information System (INIS)

    Mechanisms involved in tumor destruction following PhotoDynamic Therapy are still under investigation. Direct killing of tumor cells by phototoxic action is not the only mechanism responsible for tumor destruction. When Photofrin is used as a photosensitizer a majority of tumor cells is killed by secondary mechanisms, expressed only if tumor is left in situ for at least 6-12 hours after light treatment. The indirect mechanism of tumor destruction by PDT has been described as a massive necrosis of tumor tissue resulting from hypoxia induced by destruction of tumor vasculature. Earliest changes in tumor vasculature already occur during the course of light illumination. They include accumulation of polymorphonuclear leukocytes (neutrophils), platelet aggregation, vasoconstriction followed by vascular stasis and hemorrhage. Release of mediators of inflammation (e.g. prostaglandin E2, thromboxane), cytokines, proteolytic enzymes and other substances was also demonstrated. These events are typical for inflammatory response. Nature and significance of this response has, however, not been studied in detail. Initial results on host immune cell infiltration into PDT treated murine tumor are reported here. (author). 16 refs., 1 fig., 1 tab

  20. Retracing Circulating Tumour Cells for Biomarker Characterization after Enumeration

    Directory of Open Access Journals (Sweden)

    Anders S. Frandsen

    2015-06-01

    Mapping and retracing of CTCs enables downstream analysis of individual CTCs for existing and future cancer genotypic and phenotypic biomarkers. Future studies will uncover this potential of the novel retracing technology.

  1. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.

    Science.gov (United States)

    Le, Caroline P; Nowell, Cameron J; Kim-Fuchs, Corina; Botteri, Edoardo; Hiller, Jonathan G; Ismail, Hilmy; Pimentel, Matthew A; Chai, Ming G; Karnezis, Tara; Rotmensz, Nicole; Renne, Giuseppe; Gandini, Sara; Pouton, Colin W; Ferrari, Davide; Möller, Andreas; Stacker, Steven A; Sloan, Erica K

    2016-01-01

    Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. PMID:26925549

  2. Mixed germ cell tumour of testis: a case report with review of literature

    Directory of Open Access Journals (Sweden)

    S. V. Kumar

    2015-01-01

    Full Text Available Testicular tumours are rare neoplasm. Mixed germ cell tumour is the most common histological variant. Essentially, any admixture of the germ cell tumours as seen in pure form may be seen, one of the most common admixtures being embryonal carcinoma and teratoma. Unfortunately many of these patients present late usually with some complications. We present a rare case of mixed germ cell tumour with predominant embryonal carcinoma and yolk sac tumour in adolescent patient with multiple metastatic foci at the time of presentation. [Int J Res Med Sci 2015; 3(1.000: 327-330

  3. Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression

    Science.gov (United States)

    Zhang, Wen Cai; Chin, Tan Min; Yang, Henry; Nga, Min En; Lunny, Declan Patrick; Lim, Edwin Kok Hao; Sun, Li Li; Pang, Yin Huei; Leow, Yi Ning; Malusay, Shanneen Rossellini Y; Lim, Priscilla Xin Hui; Lee, Jeravan Zili; Tan, Benedict Jian Wei; Shyh-Chang, Ng; Lim, Elaine Hsuen; Lim, Wan Teck; Tan, Daniel Shao Weng; Tan, Eng Huat; Tai, Bee Choo; Soo, Ross Andrew; Tam, Wai Leong; Lim, Bing

    2016-01-01

    The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets. PMID:27325363

  4. Juvenile granulosa cell tumour: a rare clinical entity

    Directory of Open Access Journals (Sweden)

    Kaliki Hymavathi Reddy

    2014-08-01

    Full Text Available Ovarian cancer is the third most common neoplasm of the female genital tract. Based on the cell type of origin, primary ovarian malignancies are classified into surface epithelium, germ cell, and sex cord tumors. Sex cord tumors account for 1% to 2% of ovarian malignancies. They may contain granulosa cells, theca cells, sertoli cells, or fibroblasts of gonadal stromal origin. Granulosa Cell Tumours (GCTs account for approximately 2-5% of all ovarian tumors and can be divided into adult (95% and juvenile (5% types based on histologic findings. GCTs secrete estrogen thus resulting in menstrual irregularities in the affected individual. More serious estrogen effects can occur in various end organs such as uterus resulting in endometrial hyperplasia, endometrial adenocarcinomas and increased risk of breast cancers. Androgen production is also reported but rare and produces virilization in the affected women. Juvenile Granulosa Cell Tumours (JGCTs are clinically and histopathologically distinct from the GCTs. They are rarely encountered but mostly in youngsters. Surgery is the primary modality of treatment with chemotherapy being reserved for advanced or recurrent disease states. We herewith report an interesting case of JGCT in a young teenage girl. [Int J Reprod Contracept Obstet Gynecol 2014; 3(4.000: 1150-1154

  5. Primary Malignant Mixed Germ Cell Tumour with Squamous Cell Carcinoma of the Mandible; A Rare Entity

    OpenAIRE

    Kumar, Saurabh; Paul, Arun; Parmar, Harshad; Chacko, Rabin

    2015-01-01

    Germ cell Tumours (GCT) are neoplasm derived from germ cells. GCT usually occurs inside the gonads. Extragonadal GCT’s are rare. Most common GCT associated with head and neck region are the teratomas. Of the few teratomas found in the head and neck, malignant transformation of a teratomatous element is very uncommon, and primary bone involvement within the head and neck is even rare. We present a case of primary malignant mixed germ cell Tumour involving the mandible, the present case present...

  6. In situ and in vitro profiling of brain tumour initiating cells of high-grade gliomas

    OpenAIRE

    Leidgens, Verena Jeannine

    2016-01-01

    High-grade gliomas, especially glioblastomas, are highly complex and heterogeneous primary brain tumours. Glioblastoma (GBM) is one of the most aggressive cancers with poor overall survival prognosis. Fast and widespread invasion of the brain parenchyma by a subpopulation of progenitor tumour cells is a main pathophysiological feature of these tumours. Invasion renders localised therapies ineffective and is a primary cause of tumour recurrence as well as associated morbidity. Identification o...

  7. The epigenetics of tumour initiation: cancer stem cells and their chromatin.

    Science.gov (United States)

    Avgustinova, Alexandra; Benitah, Salvador Aznar

    2016-02-01

    Cancer stem cells (CSCs) have been identified in various tumours and are defined by their potential to initiate tumours upon transplantation, self-renew and reconstitute tumour heterogeneity. Modifications of the epigenome can favour tumour initiation by affecting genome integrity, DNA repair and tumour cell plasticity. Importantly, an in-depth understanding of the epigenomic alterations underlying neoplastic transformation may open new avenues for chromatin-targeted cancer treatment, as these epigenetic changes could be inherently more amenable to inhibition and reversal than hard-wired genomic alterations. Here we discuss how CSC function is affected by chromatin state and epigenomic instability. PMID:26874045

  8. Carcinoma in situ testis, the progenitor of testicular germ cell tumours

    DEFF Research Database (Denmark)

    Hoei-Hansen, C E; Rajpert-De Meyts, E; Daugaard, G;

    2005-01-01

    Testicular germ cell tumours (TGCT), including seminomas, embryonal carcinomas, teratomas and yolk sac tumours, have a common precursor, the carcinoma in situ (CIS) cell. Recent gene expression studies displaying close similarity of CIS cells to embryonic stem cells support the longstanding theory...

  9. Triple angiokinase inhibition, tumour hypoxia and radiation response of FaDu human squamous cell carcinomas

    International Nuclear Information System (INIS)

    Background and purpose: To test the effect of BIBF 1120, a novel small molecule inhibitor of multiple angiogenic receptor tyrosine kinases, on the hypoxia and radiation response of tumours. Materials and methods: Poorly differentiated human squamous cell carcinoma FaDu growing in nude mice was treated with BIBF 1120 and investigated by functional histology. To test the effect of BIBF 1120 on the radiobiological hypoxic fraction (rHF), the number and intrinsic radiation sensitivity of tumour stem cells and the outcome after fractionated irradiation, a series of local tumour control assays were performed. Results: BIBF 1120 significantly reduced the vessel area, vessel area with a perfusion signal and tumour growth rate but did not affect tumour hypoxia or the number and intrinsic radiation sensitivity of tumour stem cells. Concurrent BIBF 1120 had no effect on local tumour control after fractionated irradiation. Conclusion: Triple angiokinase inhibition resulted in a clear-cut decrease of angiogenesis, vessel area with a perfusion signal and tumour growth but did not change tumour hypoxia or radiation response of tumour stem cells. Further experiments into mechanisms of interaction between anti-angiogenic strategies and irradiation appear to be necessary to better define and exploit the potential of this strategy to improve local tumour control after fractionated radiotherapy.

  10. Effect of anti-glycolytic agents on tumour cells in vitro

    Science.gov (United States)

    Korshunov, D. A.; Kondakova, I. V.

    2016-08-01

    A metabolic change is one of the tumour hallmarks, which has recently attracted a great amount of attention. One of the main metabolic characteristics of tumour cells is a high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in a glycolysis pathway than that in a tricarboxylic acid cycle. The Warburg effect constitutes a fundamental adaptation of tumour cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumour glycolysis may become an attractive target for cancer therapy. Here, we research the effect of potential anticancer agents on tumour cells in vitro. In our study, we found a high sensitivity of tumour cells to anti-glycolityc drugs. In addition, tumour cells are more resistant to the agents studied in comparison with normal cells. We also observed an atypical cooperative interaction of tumour cells in the median lethal dose of drugs. They formed the specific morphological structure of the surviving cells. This behavior is not natural for the culture of tumour cells. Perhaps this is one of the mechanisms of cells' adaptation to the aggressive environment.

  11. Immunohistochemical identification of type I procollagen in tumour cells of scirrhous adenocarcinoma of the stomach.

    OpenAIRE

    Niitsu, Y; Ito, N.; Kohda, K; Owada, M.; Morita, K.; Sato, S.; Watanabe, N.; Kohgo, Y; Urushizaki, I.

    1988-01-01

    Human gastric carcinomas were tested for their immunohistochemical reactivity with anti-type I procollagen antiserum. In all specimens of scirrhous carcinomas, staining of the tumour cells was strongly positive, while in medullary carcinomas staining of the tumour cells was generally poor. These results suggest that the tumour cells in scirrhous carcinomas produce collagen in their stroma. Images Figure 1 Figure 4 Figure 3 Figure 5

  12. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models

    LENUS (Irish Health Repository)

    Donatello, Simona

    2011-04-26

    Abstract Background Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Methods Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. Results Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. Conclusions Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

  13. Galectin-3 coats the membrane of breast cells and makes a signature of tumours

    KAUST Repository

    Simone, Giuseppina

    2014-01-01

    Galectin-3, β-galactoside-binding lectin, coats the membrane of most cancer cells and is involved in metastasis and endothelium recognition as well as in evading immune surveillance through killing of activated T cells. To flag galectin as a biomarker of tumours and metastasis, it is pivotal to understand the role of this protein in different tumours and at different stages. Breast tumours have an anomalous behaviour of the galectin-3 compared to other tumour cells. Herein, FACS sorting and galactoside based assays were used to investigate the role of galectin-3 in metastasis and metastatisation of breast cancer cells. Breast galectin fingerprint at the FACS displayed a higher amount in healthy cells, compared to metastatic cells. The microfluidic assay was able to isolate tumour and metastatic cells more than healthy breast cells. Investigation was performed on samples from patients with breast tumours at stage I and stage III whilst MCF7 and EPH-4 cells were used to perform preliminary investigations. The readout of the conditioned medium (from culturing of stage I cells) fingerprint by FACS evidenced high expression of free galectin. Analysis of the results established that the galectin coating the membrane, by galactoside recognition of the breast cells, and engaged by the cells to form protein-carbohydrate complexes inside the microfluidic assay, resembled the tumour signature of tumours in breast cells whilst the galectin free is independent of those mechanisms. © 2014 The Royal Society of Chemistry.

  14. Role of metallothionein in cisplatin sensitivity of germ-cell tumours

    NARCIS (Netherlands)

    Meijer, C.; Timmer, A.; Vries, E.G.E.de; Groten, J.P.; Knol, A.; Zwart, N.; Dam, W.A.; Sleijfer, D.Th.; Mulder, N.H.

    2000-01-01

    Cisplatin (CDDP) is an extremely active drug in the treatment of germ- cell tumours. Earlier, we found an unexpected inverse correlation between the total amount of sulfhydryl groups and CDDP sensitivity in a panel of 3 human germ-cell tumour and 3 colon-carcinoma cell lines. Major components of the

  15. Stability of artemisinin in aqueous environments : Impact on its cytotoxic action to Ehrlich ascites tumour cells

    NARCIS (Netherlands)

    Beekman, AC; Woerdenbag, HJ; Van Uden, W; Pras, N; Konings, AWT; Wikstrom, HV

    1997-01-01

    We have recently shown artemisinin to be cytotoxic against Ehrlich ascites tumour cells. The aim of this study was to investigate the stability of this compound in the aqueous environment of the in-vitro Ehrlich ascites tumour cell system (RPMI 1640 cell culture medium supplemented with 10% foetal b

  16. Transport of calcium ions by Ehrlich ascites-tumour cells.

    Science.gov (United States)

    Landry, Y; Lehninger, A L

    1976-08-15

    Ehrlich ascites-tumour cells accumulate Ca2+ when incubated aerobically with succinate, phosphate and rotenone, as revealed by isotopic and atomic-absorption measurements. Ca2+ does not stimulate oxygen consumption by carefully prepared Ehrlich cells, but des so when the cells are placed in a hypo-osmotic medium. Neither glutamate nor malate support Ca2+ uptake in 'intact' Ehrlich cells, nor does the endogenous NAD-linked respiration. Ca2+ uptake is completely dependent on mitochondrial energy-coupling mechansims. It was an unexpected finding that maximal Ca2+ uptake supported by succinate requires rotenone, which blocks oxidation of enogenous NAD-linked substrates. Phosphate functions as co-anion for entry of Ca2+. Ca2+ uptake is also supported by extra-cellular ATP; no other nucleoside 5'-di- or tri-phosphate was active. The accumulation of Ca2+ apparently takes place in the mitochondria, since oligomycin and atractyloside inhibit ATP-supported Ca2+ uptake. Glycolysis does not support Ca2+ uptake. Neither free mitochondria released from disrupted cells nor permeability-damaged cells capable of absorbing Trypan Blue were responsible for any large fraction of the total observed energy-coupled Ca2+ uptake. The observations reported also indicate that electron flow through energy-conserving site 1 promotes Ca2+ release from Ehrlich cells and that extra-cellular ATP increase permeability of the cell membrane, allowing both ATP and Ca2+ to enter the cells more readily. PMID:988829

  17. The biology of circulating tumor cells.

    Science.gov (United States)

    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

  18. Tumour cell proliferation after failed ruthenium plaque radiotherapy for posterior uveal melanoma

    International Nuclear Information System (INIS)

    Enucleation following ruthenium plaque radiotherapy for posterior uveal melanoma indicates failure of treatment. This study focused on the histopathological findings and remaining tumour cell growth fraction in 42 of 46 patients with failed ruthenium plaque treatment (of 266 patients treated) for melanoma of the choroid or ciliary body. The cause for enucleation was clinically detected tumour regrowth in 27 (64%) patients, treatment-related ocular side effects in 12 (29%) cases and the patient's personal preference in three (7%) cases. The median time elapsing from plaque radiotherapy to enucleation was not significantly different for patients with recurrent tumour growth (23 months) compared to those enucleated without clinical signs of regrowth (19 months). While all tumours showed some regressive features by histopathological examination, only five melanomas were completely necrotic and viable-appearing tumours cells were present in all of the remaining 37 (88%) irradiated tumours. Microwave processed PC-10 immunostaining increased the sensitivity to detect cycling cells compared to the sole use of mitotic cell counts. By the former technique, proliferating tumour cells were detected in 17 or 23 (74%) studied melanomas of eyes enucleated for tumour regrowth following brachytherapy. Also, the number of cycling melanoma cells was similar to that of non-irradiated controls managed solely by enucleation. In contrast, the proliferative compartment of irradiated, but non-recurrent, posterior uveal melanomas were significantly reduced compared to those of matched controls. Still, cycling tumour cells were present in four of 13 (31%) irradiated melanomas, clinically assumed to be successfully treated. (au) 43 refs

  19. Radical Resection of a Late-Relapsed Testicular Germ Cell Tumour: Hepatectomy, Cavotomy, and Thrombectomy

    OpenAIRE

    C. Ní Leidhin; Redmond, C. E.; Cahalane, A. M.; Heneghan, H. M.; R. Motyer; Ryan, E. R.; Hoti, E.

    2014-01-01

    Up to 3.2% of patients with testicular germ cell tumours represent with late-relapsing disease. Aggressive surgical resection confers the greatest chance of cure in this patient group. We present the case of a late and extensively relapsed nonseminomatous germ cell tumour with thrombus present along the entire length of the inferior vena cava, as well as in the right hepatic vein. Techniques practised in liver transplantation were used to achieve complete resection of the tumour thrombus. Thi...

  20. Neutrophil-induced transmigration of tumour cells treated with tumour-conditioned medium is facilitated by granulocyte-macrophage colony-stimulating factor.

    LENUS (Irish Health Repository)

    Wu, Q D

    2012-02-03

    OBJECTIVE: To investigate the effect of different cytokines that are present in tumour-conditioned medium on human neutrophil (PMN)-induced tumour cell transmigration. DESIGN: Laboratory study. SETTING: University hospital, Ireland. MATERIAL: Isolated human PMN and cultured human breast tumour cell line, MDA-MB-231. Interventions: Human PMN treated with either tumour-conditioned medium or different media neutralised with monoclonal antibodies (MoAb), and MDA-MB-231 cells were plated on macrovascular and microvascular endothelial monolayers in collagen-coated transwells to assess migration of tumour cells. MAIN OUTCOME MEASURES: Cytokines present in tumour-conditioned medium, PMN cytocidal function and receptor expression, and tumour cell transmigration. RESULTS: tumour-conditioned medium contained high concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8), but not granulocyte colony-stimulating factor (G-CSF) and interleukin 3 (IL-3). Anti-GM-CSF MoAb significantly reduced PMN-induced transmigration of tumour cells treated with tumour-conditioned medium (p < 0.05), whereas anti-VEGF and anti-IL-8 MoAbs did not affect their migration. In addition, anti-GM-CSF MoAb, but not anti-VEGF or anti-IL-8 MoAb, reduced PMN CD11b and CD18 overexpression induced by tumour-conditioned medium (p < 0.05). CONCLUSION: These results indicate that the GM-CSF that is present in tumour-conditioned medium may be involved, at least in part, in alterations in PMN function mediated by the medium and subsequently PMN-induced transmigration of tumour cells.

  1. Spontaneous transformation of human granulosa cell tumours into an aggressive phenotype: a metastasis model cell line

    International Nuclear Information System (INIS)

    Granulosa cell tumours (GCTs) are frequently seen in menopausal women and are relatively indolent. Although the physiological properties of normal granulosa cells have been studied extensively, little is known about the molecular mechanism of GCT progression. Here, we characterise the unique behavioural properties of a granulosa tumour cell line, KGN cells, for the molecular analysis of GCT progression. Population doubling was carried out to examine the proliferation capacity of KGN cells. Moreover, the invasive capacity of these cells was determined using the in vitro invasion assay. The expression level of tumour markers in KGN cells at different passages was then determined by Western blot analysis. Finally, the growth and metastasis of KGN cells injected subcutaneously (s.c.) into nude mice was observed 3 months after injection. During in vitro culture, the advanced passage KGN cells grew 2-fold faster than the early passage cells, as determined by the population doubling assay. Moreover, we found that the advanced passage cells were 2-fold more invasive than the early passage cells. The expression pattern of tumour markers, such as p53, osteopontin, BAX and BAG-1, supported the notion that with passage, KGN cells became more aggressive. Strikingly, KGN cells at both early and advanced passages metastasized to the bowel when injected s.c. into nude mice. In addition, more tumour nodules were formed when the advanced passage cells were implanted. KGN cells cultured in vitro acquire an aggressive phenotype, which was confirmed by the analysis of cellular activities and the expression of biomarkers. Interestingly, KGN cells injected s.c. are metastatic with nodule formation occurring mostly in the bowel. Thus, this cell line is a good model for analysing GCT progression and the mechanism of metastasis in vivo

  2. Primary Malignant Mixed Germ Cell Tumour with Squamous Cell Carcinoma of the Mandible; A Rare Entity

    Science.gov (United States)

    Paul, Arun; Parmar, Harshad; Chacko, Rabin

    2015-01-01

    Germ cell Tumours (GCT) are neoplasm derived from germ cells. GCT usually occurs inside the gonads. Extragonadal GCT’s are rare. Most common GCT associated with head and neck region are the teratomas. Of the few teratomas found in the head and neck, malignant transformation of a teratomatous element is very uncommon, and primary bone involvement within the head and neck is even rare. We present a case of primary malignant mixed germ cell Tumour involving the mandible, the present case presented malignant transformation of the epithelial component showing foci of squamous cell carcinoma within the GCT. PMID:26266228

  3. Sodium hyaluronate enhances colorectal tumour cell metastatic potential in vitro and in vivo.

    LENUS (Irish Health Repository)

    Tan, B

    2012-02-03

    BACKGROUND: Sodium hyaluronate has been used intraperitoneally to prevent postoperative adhesions. However, the effect of sodium hyaluronate on tumour growth and metastasis in vitro and in vivo is still unknown. METHODS: Human colorectal tumour cell lines SW480, SW620 and SW707 were treated with sodium hyaluronate (10-500 microg\\/ml) and carboxymethylcellulose (0.125-1 per cent), and tumour cell proliferation and motility were determined in vitro. For the in vivo experiments male BD IX rats were randomized to a sodium hyaluronate group (n = 11; intraperitoneal administration of 0.5 x 10(6) DHD\\/K12 tumour cells and 5 ml 0.4 per cent sodium hyaluronate) or a phosphate-buffered saline group (n = 11; 0.5 x 10(6) DHD\\/K12 tumour cells and 5 ml phosphate-buffered saline intraperitoneally). Four weeks later the intraperitoneal tumour load was visualized directly. RESULTS: In vitro sodium hyaluronate increased tumour cell proliferation and motility significantly. Sodium hyaluronate-induced tumour cell motility appeared to be CD44 receptor dependent, whereas sodium hyaluronate-induced tumour cell proliferation was CD44 receptor independent. In vivo there was a significantly higher total tumour nodule count in the peritoneal cavity of the sodium hyaluronate-treated group compared with the control (P = 0.016). CONCLUSION: Sodium hyaluronate enhances tumour metastatic potential in vitro and in vivo, which suggests that use of sodium hyaluronate to prevent adhesions in colorectal cancer surgery may also potentiate intraperitoneal tumour growth. Presented to the Patey Prize Session of the Surgical Research Society and the annual scientific meeting of the Association of Surgeons of Great Britain and Ireland, Brighton, UK, 4-7 May 1999

  4. Mixed germ cell tumour of ovary presenting as pregnancy: a rare presentation

    Directory of Open Access Journals (Sweden)

    Kavita Mahadevappa

    2015-12-01

    Full Text Available Malignant mixed germ cell tumour of the ovary containing embryonal carcinoma and choriocarcinoma is a very rare entity. These tumours can present as precocious puberty or menstrual irregularities in adolescent girls. Here we report a case of 22 year old lady who presented as 5 months pregnancy in antenatal clinic. MRI Imaging and tumour markers revealed malignant ovarian tumour. Patient underwent surgicopathological staging and was found to have malignant mixed germ cell tumour stage IIIB, comprising of both choriocarcinoma and embryonal carcinoma components. Patient received one cycle of chemotherapy and was called for follow up. Mixed malignant germ cell tumour of the ovary is a highly aggressive neoplasm that can present in advanced stage. A high clinical suspicion is needed in patients presenting with pelvic mass associated with menstrual irregularity or amenorrhoea in adolescent and young women. [Int J Reprod Contracept Obstet Gynecol 2015; 4(6.000: 2084-2087

  5. Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres

    Science.gov (United States)

    Jain, Anjana; Betancur, Martha; Patel, Gaurangkumar D.; Valmikinathan, Chandra M.; Mukhatyar, Vivek J.; Vakharia, Ajit; Pai, S. Balakrishna; Brahma, Barunashish; MacDonald, Tobey J.; Bellamkonda, Ravi V.

    2014-03-01

    Glioblastoma multiforme is an aggressive, invasive brain tumour with a poor survival rate. Available treatments are ineffective and some tumours remain inoperable because of their size or location. The tumours are known to invade and migrate along white matter tracts and blood vessels. Here, we exploit this characteristic of glioblastoma multiforme by engineering aligned polycaprolactone (PCL)-based nanofibres for tumour cells to invade and, hence, guide cells away from the primary tumour site to an extracortical location. This extracortial sink is a cyclopamine drug-conjugated, collagen-based hydrogel. When aligned PCL-nanofibre films in a PCL/polyurethane carrier conduit were inserted in the vicinity of an intracortical human U87MG glioblastoma xenograft, a significant number of human glioblastoma cells migrated along the aligned nanofibre films and underwent apoptosis in the extracortical hydrogel. Tumour volume in the brain was significantly lower following insertion of aligned nanofibre implants compared with the application of smooth fibres or no implants.

  6. A single dividing cell population with imbalanced fate drives oesophageal tumour growth.

    Science.gov (United States)

    Frede, Julia; Greulich, Philip; Nagy, Tibor; Simons, Benjamin D; Jones, Philip H

    2016-09-01

    Understanding the cellular mechanisms of tumour growth is key for designing rational anticancer treatment. Here we used genetic lineage tracing to quantify cell behaviour during neoplastic transformation in a model of oesophageal carcinogenesis. We found that cell behaviour was convergent across premalignant tumours, which contained a single proliferating cell population. The rate of cell division was not significantly different in the lesions and the surrounding epithelium. However, dividing tumour cells had a uniform, small bias in cell fate so that, on average, slightly more dividing than non-dividing daughter cells were generated at each round of cell division. In invasive cancers induced by Kras(G12D) expression, dividing cell fate became more strongly biased towards producing dividing over non-dividing cells in a subset of clones. These observations argue that agents that restore the balance of cell fate may prove effective in checking tumour growth, whereas those targeting cycling cells may show little selectivity. PMID:27548914

  7. Rapid and quantitative discrimination of tumour cells on tissue slices.

    Science.gov (United States)

    Huang, Kai-Wen; Chieh, Jen-Jie; Liao, Shu-Hsien; Wei, Wen-Chun; Hsiao, Pei-Yi; Yang, Hong-Chang; Horng, Herng-Er

    2016-06-10

    After a needle biopsy, immunohistochemistry is generally used to stain tissue slices for clinically confirming tumours. Currently, tissue slices are immersed in a bioprobe-linked fluorescent reagent for several minutes, washed to remove the unbound reagent, and then observed using a fluorescence microscope. However, the observation must be performed by experienced pathologists, and producing a qualitative analysis is time consuming. Therefore, this study proposes a novel scanning superconducting quantum interference device biosusceptometry (SSB) method for avoiding these drawbacks. First, stain reagents were synthesised for the dual modalities of fluorescent and magnetic imaging by combining iron-oxide magnetic nanoparticles and the currently used fluorescent reagent. The reagent for the proposed approach was stained using the same procedure as that for the current fluorescent reagent, and tissue slices were rapidly imaged using the developed SSB for obtaining coregistered optical and magnetic images. Analysing the total intensity of magnetic spots in SSB images enables quantitatively determining the tumour cells of tissue slices. To confirm the magnetic imaging results, a traditional observation methodology entailing the use of a fluorescence microscope was also performed as the gold standard. This study determined high consistency between the fluorescent and magnetic spots in different regions of the tissue slices, demonstrating the feasibility of the proposed approach, which will benefit future clinical pathology. PMID:27138705

  8. Rapid and quantitative discrimination of tumour cells on tissue slices

    Science.gov (United States)

    Huang, Kai-Wen; Chieh, Jen-Jie; Liao, Shu-Hsien; Wei, Wen-Chun; Hsiao, Pei-Yi; Yang, Hong-Chang; Horng, Herng-Er

    2016-06-01

    After a needle biopsy, immunohistochemistry is generally used to stain tissue slices for clinically confirming tumours. Currently, tissue slices are immersed in a bioprobe-linked fluorescent reagent for several minutes, washed to remove the unbound reagent, and then observed using a fluorescence microscope. However, the observation must be performed by experienced pathologists, and producing a qualitative analysis is time consuming. Therefore, this study proposes a novel scanning superconducting quantum interference device biosusceptometry (SSB) method for avoiding these drawbacks. First, stain reagents were synthesised for the dual modalities of fluorescent and magnetic imaging by combining iron-oxide magnetic nanoparticles and the currently used fluorescent reagent. The reagent for the proposed approach was stained using the same procedure as that for the current fluorescent reagent, and tissue slices were rapidly imaged using the developed SSB for obtaining coregistered optical and magnetic images. Analysing the total intensity of magnetic spots in SSB images enables quantitatively determining the tumour cells of tissue slices. To confirm the magnetic imaging results, a traditional observation methodology entailing the use of a fluorescence microscope was also performed as the gold standard. This study determined high consistency between the fluorescent and magnetic spots in different regions of the tissue slices, demonstrating the feasibility of the proposed approach, which will benefit future clinical pathology.

  9. Circulating tumor cells: utopia or reality?

    Science.gov (United States)

    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

  10. Circulating Tumor Cells in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Brian [Institute of Urology, University of Southern California, 1441 Eastlake Avenue, Suite 7416, Los Angeles, CA 90033 (United States); Rochefort, Holly [Department of Surgery, University of Southern California, 1520 San Pablo Street, HCT 4300, Los Angeles, CA 90033 (United States); Goldkorn, Amir, E-mail: agoldkor@usc.edu [Department of Internal Medicine and Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Suite 3440, Los Angeles, CA 90033 (United States)

    2013-12-04

    Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management.

  11. Circulating Tumor Cells in Prostate Cancer

    International Nuclear Information System (INIS)

    Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management

  12. Circulating Tumor Cells in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Brian Hu

    2013-12-01

    Full Text Available Circulating tumor cells (CTCs can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management.

  13. FIBULA AND ILIAC BONE GRAFTING WITH INTERNAL FIXATION FOR GAINT CELL TUMOUR OF PROXIMAL TIBIA

    OpenAIRE

    Nishant Gaonkar; Takale; Kolekar; Vaibhav Koli; Jimit Shah

    2015-01-01

    Middle aged old female with swelling in left knee suggestive of giant cell tumour was treated with excisional biopsy with curettage, phenol cauterisation , bone graft and proximal tibia locking plate fixation. Sample sent for histopathology was consistent with diagnosis of giant cell tumour. No recurrence has been seen after 1 year of follow up.

  14. FIBULA AND ILIAC BONE GRAFTING WITH INTERNAL FIXATION FOR GAINT CELL TUMOUR OF PROXIMAL TIBIA

    Directory of Open Access Journals (Sweden)

    Nishant Gaonkar

    2015-02-01

    Full Text Available Middle aged old female with swelling in left knee suggestive of giant cell tumour was treated with excisional biopsy with curettage, phenol cauterisation , bone graft and proximal tibia locking plate fixation. Sample sent for histopathology was consistent with diagnosis of giant cell tumour. No recurrence has been seen after 1 year of follow up.

  15. Giant cell tumour of the tendon sheath of the hand: a pictorial essay

    International Nuclear Information System (INIS)

    Giant cell tumour of the tendon sheath is a soft tissue mass found occasionally in the hand. Its diagnosis can be readily made preoperatively if the characteristic MRI features are appreciated. This pictorial essay demonstrates and describes the imaging findings correlated with histopathological findings in a group of patients with proven giant cell tumour of the tendon sheath. Copyright (2001) Blackwell Science Pty Ltd

  16. L-lactate transport in Ehrlich ascites-tumour cells.

    Science.gov (United States)

    Spencer, T L; Lehninger, A L

    1976-02-15

    Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids. PMID:7237

  17. Radical resection of a late-relapsed testicular germ cell tumour: hepatectomy, cavotomy, and thrombectomy.

    Science.gov (United States)

    Ní Leidhin, C; Redmond, C E; Cahalane, A M; Heneghan, H M; Motyer, R; Ryan, E R; Hoti, E

    2014-01-01

    Up to 3.2% of patients with testicular germ cell tumours represent with late-relapsing disease. Aggressive surgical resection confers the greatest chance of cure in this patient group. We present the case of a late and extensively relapsed nonseminomatous germ cell tumour with thrombus present along the entire length of the inferior vena cava, as well as in the right hepatic vein. Techniques practised in liver transplantation were used to achieve complete resection of the tumour thrombus. This case illustrates the enhanced potential for tumour resection through a fusion of principles derived from surgical oncology and liver transplantation. PMID:25587480

  18. Radical Resection of a Late-Relapsed Testicular Germ Cell Tumour: Hepatectomy, Cavotomy, and Thrombectomy

    Directory of Open Access Journals (Sweden)

    C. Ní Leidhin

    2014-01-01

    Full Text Available Up to 3.2% of patients with testicular germ cell tumours represent with late-relapsing disease. Aggressive surgical resection confers the greatest chance of cure in this patient group. We present the case of a late and extensively relapsed nonseminomatous germ cell tumour with thrombus present along the entire length of the inferior vena cava, as well as in the right hepatic vein. Techniques practised in liver transplantation were used to achieve complete resection of the tumour thrombus. This case illustrates the enhanced potential for tumour resection through a fusion of principles derived from surgical oncology and liver transplantation.

  19. Circulating endothelial cells in cardiovascular disease.

    Science.gov (United States)

    Boos, Christopher J; Lip, Gregory Y H; Blann, Andrew D

    2006-10-17

    Quantification of circulating endothelial cells (CECs) in peripheral blood is developing as a novel and reproducible method of assessing endothelial damage/dysfunction. The CECs are thought to be mature cells that have detached from the intimal monolayer in response to endothelial injury and are a different cell population to endothelial progenitor cells (EPCs). The EPCs are nonleukocytes derived from the bone marrow that are believed to have proliferative potential and may be important in vascular regeneration. Currently accepted methods of CEC quantification include the use of immunomagnetic bead separation (with cell counting under fluorescence microscopy) and flow cytometry. Several recent studies have shown increased numbers of CECs in cardiovascular disease and its risk factors, such as unstable angina, acute myocardial infarction, stroke, diabetes mellitus, and critical limb ischemia, but no change in stable intermittent claudication, essential hypertension, or atrial fibrillation. Furthermore, CEC quantification at 48 h after acute myocardial infarction has been shown to be an accurate predictor of major adverse coronary events and death at both 1 month and 1 year. This article presents an overview of the pathophysiology of CECs in the setting of cardiovascular disease and a brief comparison with EPCs. PMID:17045885

  20. Tumour microenvironment and radiation response in sarcomas originating from tumourigenic human mesenchymal stem cells

    DEFF Research Database (Denmark)

    D'Andrea, Filippo Peder; Safwat, Akmal Ahmed; Burns, Jorge S.;

    2012-01-01

    to determine whether this heterogeneity persisted in tumours established from these clones, and whether the response to radiation treatment was principally governed by cell intrinsic qualities or by factors pertaining to the tumour microenvironment, such as the degree of hypoxia and vascularisation....... Methods: Immune deficient female mice were implanted on the backs with cells from one of the clones. The subsequent tumours were subjected to either radiation treatment or had the tumour microenvironment assayed, when they reached 400mm3. Radiation was given as a single fraction of 0 to 15 Gy and the...... degree of tumour control and time to three times the treatment volume were noted. Tumours used for the microenvironmental assay had intratumoral hypoxia measured by the Eppendorf oxygen electrode and Pimonidazole staining, and the extent of vascularisation determined by a microvasculature density assay...

  1. Epidermal Langerhans` cell induction of immunity against an ultraviolet-induced skin tumour

    Energy Technology Data Exchange (ETDEWEB)

    Cavanagh, L.L.; Sluyter, R.; Henderson, K.G.; Barnetson, R.St.C.; Halliday, G.M. [Royal Prince Alfred Hospital, Sydney, NSW (Australia). Dept. of Medicine (Dermatology)

    1996-03-01

    Lanerghans` cells (LC) have been shown experimentally to induce immune response against many antigens; however, their role in the initiation of anti-tumour immunity has received little attention. This study examined the ability of murine epidermal LC to induce immunity to an ultraviolet radiation (UV)-induced skin tumour. Freshly prepared epidermal cells (EC) were cultured for 2 or 20 hr with granulocyte-macrophage colony-stimulating factor (GM-CSF), pulsed with an extract of the UV-13-1 tumour, then used to immunize naive syngeneic mice. Delayed type hypersensitivity (DTH) was elicited 10 days after immunization by injection of UV-13-1 tumour cells into the ear pinna, and measured 24 hr later. EC cultured with GM-CSF for 2 hr induced anti-tumour DTH, as did EC cultured for 20 hr without GM-CSF. Conversely, EC cultured for 2 hr without GM-CSF, or EC cultured for 20 hr with GM-CSF were unable to induce a DTH. Induction of immunity required active presentation of tumour antigens by Ia{sup +} EC and was tumour specific. Thus Ia{sup +} epidermal cells are capable of inducing anti-tumour immunity to UV-induced skin tumours, but only when they contact antigen in particular states of maturation. (author).

  2. Epidermal Langerhans' cell induction of immunity against an ultraviolet-induced skin tumour

    International Nuclear Information System (INIS)

    Lanerghans' cells (LC) have been shown experimentally to induce immune response against many antigens; however, their role in the initiation of anti-tumour immunity has received little attention. This study examined the ability of murine epidermal LC to induce immunity to an ultraviolet radiation (UV)-induced skin tumour. Freshly prepared epidermal cells (EC) were cultured for 2 or 20 hr with granulocyte-macrophage colony-stimulating factor (GM-CSF), pulsed with an extract of the UV-13-1 tumour, then used to immunize naive syngeneic mice. Delayed type hypersensitivity (DTH) was elicited 10 days after immunization by injection of UV-13-1 tumour cells into the ear pinna, and measured 24 hr later. EC cultured with GM-CSF for 2 hr induced anti-tumour DTH, as did EC cultured for 20 hr without GM-CSF. Conversely, EC cultured for 2 hr without GM-CSF, or EC cultured for 20 hr with GM-CSF were unable to induce a DTH. Induction of immunity required active presentation of tumour antigens by Ia+ EC and was tumour specific. Thus Ia+ epidermal cells are capable of inducing anti-tumour immunity to UV-induced skin tumours, but only when they contact antigen in particular states of maturation. (author)

  3. Radiosensitization by cisplatin of RIF1 tumour cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Begg, A.C.; Kolk, P.J. van der; Dewit, L.; Bartelink, H.

    1986-11-01

    The ability of cis-diamminedichloroplatinum (II) (c-DDP) to enhance radiation-induced cell killing was tested on oxic RIF1 tumour cells in monolayer culture. Marked radiosensitization of the survivors of a 1 h drug treatment was found with all c-DDP doses tested, enhancement ratios increasing from 1.2 to 2.2 with increasing drug dose. Isobologram analyses showed that the interactions of c-DDP with X-rays were supra-additive. To test whether part of the enhancement was due to a selection of subpopulations, the diploid and tetraploid RIF1 cells, normally coexisting in culture, were separated by (a) unit gravity velocity sedimentation, and (b) by developing diploid and tetraploid clones. Both methods showed little difference in either drug sensitivity or radiation sensitivity between diploid and tetraploid cells. DNA histograms obtained by flow cytometry showed little or no cycle progression during the 1 h drug treatment. These data indicate that the radiosensitization was not the result of the drug exposure leaving cells in a radiosensitive phase. The observed radiosensitization, therefore, appears to have resulted from a true drug/X-ray interaction.

  4. Testicular germ cell tumours and parental occupational exposure to pesticides

    DEFF Research Database (Denmark)

    Le Cornet, Charlotte; Fervers, Béatrice; Oksbjerg Dalton, Susanne;

    2015-01-01

    controls per case were randomly selected from the general national populations, matched on year of birth. Information on parental occupation was collected through censuses or Pension Fund information and converted into a pesticide exposure index based on the Finnish National Job-Exposure Matrix. RESULTS......OBJECTIVES: A potential impact of exposure to endocrine disruptors, including pesticides, during intrauterine life, has been hypothesised in testicular germ cell tumour (TGCT) aetiology, but exposure assessment is challenging. This large-scale registry-based case-control study aimed to investigate...... the association between parental occupational exposure to pesticides and TGCT risk in their sons. METHODS: Cases born in 1960 or onwards, aged between 14 and 49 years, and diagnosed between 1978 and 2013 in Denmark, Finland, Norway or Sweden, were identified from the respective nationwide cancer registries. Four...

  5. Two cases report of a malignant germ cell tumour of ovary and a granulosa cell tumour:Interest of tumoral immunochemistry in the identification and management.

    Directory of Open Access Journals (Sweden)

    Jean eBouquet De Jolinière

    2014-05-01

    Full Text Available Abstract Objective: In this article, we present two case reports. The first case was a malignant germ cell tumor of the right ovary in a 23 year old female and a case of a bilateral undifferentiated granulosa cell tumor in a 71 year old female. The aim of these reports is to illustrate the interest of the immuno-histochemical analysis to define the correct diagnosis, to better classify these ovarian tumours and improve their management. Methods: This study we report two cases. The first case concern a 23 years old woman (A with a mixed germ cell tumour of the right ovary (dysgerminoma (75%, yolk sac tumour (20%, and a mature teratoma (5%, and the second case (B a bilateral non differentiated and necrotic granulosa cell tumour of both ovaries concerning a 71 year old patient. The staging system used was according to both classifications, the one of International Federation of Gynaecology and Obstetrics (FIGO 1987 for ovarian cancer, and the one of TNM code 2009. Results: The immunostaining establish the malignancy and the immunochemistry contribute to confirm effectively the right diagnosis (Table 2 and 3. Conclusion: An immuno-histochemical analysis is mandatory for the choice of chemotherapy to obtain the better response of the disease and improve the survival prognosis. The efficiency of the chemotherapy authorizes a conservative surgery including a unilateral salpingo-oophorectomy preserving fertility (A. Concerning the non-dysgerminoma tumour (B, and after a surgical staging and debulking, chemotherapy was recommended. The type of tumour and its histological feature conditioned the choice of treatment. The benefit of the immunohistological analysis in this case allowed the right adjuvant treatment. Key words: germ cell tumours, dysgerminoma, teratoma, yolk sac, ovarian cell tumour, and immunohistochemistry.

  6. Sticky and smelly issues: lessons on tumour cell and leucocyte trafficking, gene and immunotherapy of cancer.

    OpenAIRE

    Alexandroff, A B; McIntyre, C A; Porter, J. C.; Zeuthen, J; Vile, R. G.; Taub, D. D.

    1998-01-01

    The Second Meeting of the British Society for Immunology Tumour Immunology Affinity Group (TIAG) took place at King's College (London, UK) on 17-18 June 1997 and brought together over 100 tumour immunologists from the UK and abroad. In contrast to previous meetings the focus of the meeting was on the role of adhesion in immunosurveillance and tumour dissemination. In addition, recent achievements in the areas of chemokines, cytotoxic T-lymphocyte (CTL) and natural killer (NK) cells, co-stimul...

  7. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer

    OpenAIRE

    Goeppert, B; Frauenschuh, L; Zucknick, M; Stenzinger, A; Andrulis, M; Klauschen, F; Joehrens, K; Warth, A; Renner, M.; Mehrabi, A; Hafezi, M.; Thelen, A; Schirmacher, P; Weichert, W

    2013-01-01

    Background: Biliary tract cancers (BTC) are relatively rare malignant tumours with poor prognosis. It is known from other solid neoplasms that antitumour inflammatory response has an impact on tumour behaviour and patient outcome. The aim of this study was to provide a comprehensive characterisation of antitumour inflammatory response in human BTC. Methods: Tumour-infiltrating T lymphocytes (CD4+, CD8+, and Foxp3+), natural killer cells (perforin+), B lymphocytes (CD20+), macrophages (CD68+) ...

  8. Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells

    OpenAIRE

    Collins Hilary M; Abdelghany Magdy K; Messmer Marie; Yue Baigong; Deeves Sian E; Kindle Karin B; Mantelingu Kempegowda; Aslam Akhmed; Winkler G Sebastiaan; Kundu Tapas K; Heery David M

    2013-01-01

    Abstract Background Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on hi...

  9. Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Adriana J Michielsen

    Full Text Available Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5 could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.

  10. Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.

    LENUS (Irish Health Repository)

    Michielsen, Adriana J

    2011-01-01

    Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5) could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.

  11. Isolation of Circulating Tumor Cells by Dielectrophoresis

    Energy Technology Data Exchange (ETDEWEB)

    Gascoyne, Peter R. C., E-mail: pgascoyn@mdanderson.org [Department of Imaging Physics Research, The University of Texas M.D. Anderson Cancer Center Unit 951, 1515 Holcombe Boulevard, Houston, TX 77030 (United States); Shim, Sangjo [Department of Imaging Physics Research, The University of Texas M.D. Anderson Cancer Center Unit 951, 1515 Holcombe Boulevard, Houston, TX 77030 (United States); Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712 (United States); Present address: Micro & Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, 208 North Wright Street, Urbana, IL 61801 (United States)

    2014-03-12

    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.

  12. Isolation of Circulating Tumor Cells by Dielectrophoresis

    International Nuclear Information System (INIS)

    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

  13. Isolation of Circulating Tumor Cells by Dielectrophoresis

    Directory of Open Access Journals (Sweden)

    Peter R. C. Gascoyne

    2014-03-01

    Full Text Available 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.

  14. Detection and Characterization of Circulating Tumor Cells

    Science.gov (United States)

    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.

  15. Role of tumour initiating cells in the radiation resistance of osteosarcoma

    International Nuclear Information System (INIS)

    In the present study we confirm that mouse osteosarcoma (MOS) cells lines possess a subset of cells with Tumour Initiating Cells (TICs) properties. We found that isolated TICs are not inherently radioresistant compared to non-TICs. On the other hand, we found that the fraction of TICs correlates well with the radiosensitivity of MOS cell lines measured using clonogenic cell survival assay. We conclude from our study that the TICs contribute to the tumour radiation response due to their interaction with their tumour surrounding environmental (niche).

  16. Circulating Tumor Cells, Enumeration and Beyond

    Directory of Open Access Journals (Sweden)

    Jian-Mei Hou

    2010-06-01

    Full Text Available The detection and enumeration of circulating tumor cells (CTCs has shown significant clinical utility with respect to prognosis in breast, colorectal and prostate cancers. Emerging studies show that CTCs can provide pharmacodynamic information to aid therapy decision making. CTCs as a ‘virtual and real-time biopsy’ have clear potential to facilitate exploration of tumor biology, and in particular, the process of metastasis. The challenge of profiling CTC molecular characteristics and generating CTC signatures using current technologies is that they enrich rather than purify CTCs from whole blood; we face the problem of looking for the proverbial ‘needle in the haystack’. This review summarizes the current methods for CTC detection and enumeration, focuses on molecular characterization of CTCs, unveils some aspects of CTC heterogeneity, describes attempts to purify CTCs and scans the horizon for approaches leading to comprehensive dissection of CTC biology.

  17. Circulating Tumor Cells, Enumeration and Beyond

    International Nuclear Information System (INIS)

    The detection and enumeration of circulating tumor cells (CTCs) has shown significant clinical utility with respect to prognosis in breast, colorectal and prostate cancers. Emerging studies show that CTCs can provide pharmacodynamic information to aid therapy decision making. CTCs as a ‘virtual and real-time biopsy’ have clear potential to facilitate exploration of tumor biology, and in particular, the process of metastasis. The challenge of profiling CTC molecular characteristics and generating CTC signatures using current technologies is that they enrich rather than purify CTCs from whole blood; we face the problem of looking for the proverbial ‘needle in the haystack’. This review summarizes the current methods for CTC detection and enumeration, focuses on molecular characterization of CTCs, unveils some aspects of CTC heterogeneity, describes attempts to purify CTCs and scans the horizon for approaches leading to comprehensive dissection of CTC biology

  18. Circulating Tumor Cells, Enumeration and Beyond

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Jian-Mei [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); Krebs, Matthew [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); Christie Hospital Foundation NHS Trust, Manchester M20 4BX (United Kingdom); Ward, Tim; Morris, Karen; Sloane, Robert [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); Blackhall, Fiona [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); School of Cancer and Enabling Sciences, University of Manchester, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, Manchester M20 4BX (United Kingdom); Christie Hospital Foundation NHS Trust, Manchester M20 4BX (United Kingdom); Dive, Caroline, E-mail: cdive@picr.man.ac.uk [Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester M20 4BX (United Kingdom); School of Cancer and Enabling Sciences, University of Manchester, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, Manchester M20 4BX (United Kingdom)

    2010-06-09

    The detection and enumeration of circulating tumor cells (CTCs) has shown significant clinical utility with respect to prognosis in breast, colorectal and prostate cancers. Emerging studies show that CTCs can provide pharmacodynamic information to aid therapy decision making. CTCs as a ‘virtual and real-time biopsy’ have clear potential to facilitate exploration of tumor biology, and in particular, the process of metastasis. The challenge of profiling CTC molecular characteristics and generating CTC signatures using current technologies is that they enrich rather than purify CTCs from whole blood; we face the problem of looking for the proverbial ‘needle in the haystack’. This review summarizes the current methods for CTC detection and enumeration, focuses on molecular characterization of CTCs, unveils some aspects of CTC heterogeneity, describes attempts to purify CTCs and scans the horizon for approaches leading to comprehensive dissection of CTC biology.

  19. Polystyrene nanoparticles facilitate the internalization of impermeable biomolecules in non-tumour and tumour cells from colon epithelium

    International Nuclear Information System (INIS)

    Advanced colon cancer has a poor prognosis due to the limited effectiveness of current chemotherapies. Treatment failures may be avoided by the utilization of nanoparticles, which can enhance the effects of antitumor drugs, reduce their side effects and increase their directionality. Polystyrene nanoparticles have shown high biocompatibility and appropriate physicochemical properties and may represent a novel and more effective approach against colon cancer. In the present study, polystyrene nanoparticles were synthesized and fluorescently labelled, analyzing their cell internalization, intracellular localization and capacity to release transported molecules in tumour and non-tumour human colon cell lines (T84 and CCD-18). Flow cytometry and fluorescence microscopy studies demonstrated that polystyrene nanoparticles are an effective vehicle for the intracellular delivery of small molecules into colon epithelium cells. The percentage cell uptake was around 100 % in both T84 and CCD-18 cell lines after only 24 h of exposure and was cell confluence-independent. The polystyrene nanoparticles showed no cytotoxicity in either colon cell line. It was found that small molecules can be efficiently delivered into colon cells by using a disulphide bridge as release strategy. Analysis of the influence of the functionalization of the polystyrene nanoparticles surface on the internalization efficiency revealed some morphological changes in these cells. These results demonstrate that polystyrene nanoparticles may improve the transport of biomolecules into colon cells which could have a potential application in chemotherapeutic treatment against colon cancer

  20. Polystyrene nanoparticles facilitate the internalization of impermeable biomolecules in non-tumour and tumour cells from colon epithelium

    Energy Technology Data Exchange (ETDEWEB)

    Cabeza, Laura [University of Granada, Department of Human Anatomy and Embryology, Institute of Biopathology and Regenerative Medicine (IBIMER) (Spain); Cano-Cortés, Victoria; Rodríguez, María J. [University of Granada, Department of Pharmaceutical and Organic Chemistry (Spain); Vélez, Celia; Melguizo, Consolación, E-mail: melguizo@ugr.es [University of Granada, Department of Human Anatomy and Embryology, Institute of Biopathology and Regenerative Medicine (IBIMER) (Spain); Sánchez-Martín, Rosario M., E-mail: rmsanchez@ugr.es [University of Granada, Department of Pharmaceutical and Organic Chemistry (Spain); Prados, Jose [University of Granada, Department of Human Anatomy and Embryology, Institute of Biopathology and Regenerative Medicine (IBIMER) (Spain)

    2015-01-15

    Advanced colon cancer has a poor prognosis due to the limited effectiveness of current chemotherapies. Treatment failures may be avoided by the utilization of nanoparticles, which can enhance the effects of antitumor drugs, reduce their side effects and increase their directionality. Polystyrene nanoparticles have shown high biocompatibility and appropriate physicochemical properties and may represent a novel and more effective approach against colon cancer. In the present study, polystyrene nanoparticles were synthesized and fluorescently labelled, analyzing their cell internalization, intracellular localization and capacity to release transported molecules in tumour and non-tumour human colon cell lines (T84 and CCD-18). Flow cytometry and fluorescence microscopy studies demonstrated that polystyrene nanoparticles are an effective vehicle for the intracellular delivery of small molecules into colon epithelium cells. The percentage cell uptake was around 100 % in both T84 and CCD-18 cell lines after only 24 h of exposure and was cell confluence-independent. The polystyrene nanoparticles showed no cytotoxicity in either colon cell line. It was found that small molecules can be efficiently delivered into colon cells by using a disulphide bridge as release strategy. Analysis of the influence of the functionalization of the polystyrene nanoparticles surface on the internalization efficiency revealed some morphological changes in these cells. These results demonstrate that polystyrene nanoparticles may improve the transport of biomolecules into colon cells which could have a potential application in chemotherapeutic treatment against colon cancer.

  1. How does the metabolism of tumour cells differ from that of normal cells

    OpenAIRE

    Amoêdo, Nívea Dias; Valencia, Juan Perez; Rodrigues, Mariana Figueiredo; Galina, Antonio; Rumjanek, Franklin David

    2013-01-01

    Tumour cells thrive in environments that would be hostile to their normal cell counterparts. Survival depends on the selection of cell lines that harbour modifications of both, gene regulation that shifts the balance between the cell cycle and apoptosis and those that involve the plasticity of the metabolic machinery. With regards to metabolism, the selected phenotypes usually display enhanced anaerobic glycolysis even in the presence of oxygen, the so-called Warburg effect, and anabolic path...

  2. RM-06IN VITRO CLONAL EVOLUTION OF GLIOBLASTOMA (GBM) BRAIN TUMOUR INITIATING CELLS (BTIC) TO MODEL TUMOUR RECURRENCE

    OpenAIRE

    Qazi, Maleeha; Vora, Parvez; Venugopal, Chitra; McFarlane, Nicole; Hallett, Robin; Singh, Sheila

    2014-01-01

    Glioblastoma (GBM) is the most common and highly aggressive primary adult brain tumour. Despite multimodal therapy, patients on average experience relapse at 9 months and median survival rarely extends beyond 15 months. Targeting the cells that drive GBM formation as well as its inevitable and rapid recurrence has remained a major challenge, likely due to intra-tumoral heterogeneity. At the genetic level, this heterogeneity has prompted a molecular classification of GBM based on differential ...

  3. How does the metabolism of tumour cells differ from that of normal cells.

    Science.gov (United States)

    Amoêdo, Nívea Dias; Valencia, Juan Perez; Rodrigues, Mariana Figueiredo; Galina, Antonio; Rumjanek, Franklin David

    2013-01-01

    Tumour cells thrive in environments that would be hostile to their normal cell counterparts. Survival depends on the selection of cell lines that harbour modifications of both, gene regulation that shifts the balance between the cell cycle and apoptosis and those that involve the plasticity of the metabolic machinery. With regards to metabolism, the selected phenotypes usually display enhanced anaerobic glycolysis even in the presence of oxygen, the so-called Warburg effect, and anabolic pathways that provide precursors for the synthesis of lipids, proteins and DNA. The review will discuss the original ideas of Otto Warburg and how they initially led to the notion that mitochondria of tumour cells were dysfunctional. Data will be presented to show that not only the organelles are viable and respiring, but that they are key players in tumorigenesis and metastasis. Likewise, interconnecting pathways that stand out in the tumour phenotype and that require intact mitochondria such as glutaminolysis will be addressed. Furthermore, comments will be made as to how the peculiarities of the biochemistry of tumour cells renders them amenable to new forms of treatment by highlighting possible targets for inhibitors. In this respect, a case study describing the effect of a metabolite analogue, the alkylating agent 3BP (3-bromopyruvate), on glycolytic enzyme targets will be presented. PMID:24079832

  4. Early growth of tumour cells in lung tissue

    International Nuclear Information System (INIS)

    As the treatment of metastases is a very important problem in human and veterinary medicine (for instance osteosarcoma is notorious for its high deathrate due to this problem), proof was sought for the hypothesis that the doubling time of early metastases is shorter than that of tumor cells of an older age. This is of fundamental importance for the therapeutic problem: is a favourable effect to be expected from a limited dose of radiation on the lungs when metastases are still very small or even invisible. If the hypothesis holds true, it would be justified to treat patients, even though a small group of patients will be treated unnecessarily; clinical experience shows that some patients have not developed metastases without adjuvant treatment. The interest was directed at the very early (1-cell, 2-cell etc.) stages. Obviously these are not detectable in patients and therefore an experimental study with tumourcells in the lungs of mice was devised. The expectation is that the theoretical approach may produce an additional basis for the radiotherapeutic and chemotherapeutic treatment of patients, in whom the tumourload has been diminished by treatment of the primary tumour but where metastases, although frequently not detectable must be expected. (Auth.)

  5. Multi-level evidence that circulating CK18 is a biomarker of tumour burden in colorectal cancer

    OpenAIRE

    Greystoke, A; Dean, E; Saunders, M P; Cummings, J; Hughes, A; Ranson, M; Dive, C; Renehan, A G

    2012-01-01

    Background: Circulating total cytokeratin 18 (tCK18) and/or caspase cleaved cytokeratin 18 (cCK18) (measured by M65 and M30 enzyme-linked immunosorbent assays (ELISAs), respectively) are used as pharmacodynamic (PD) biomarkers of epithelial cell death in clinical trials. Having validated these ELISAs, we assessed their utility in colorectal cancer (CRC). Methods: We applied the assays in several settings: 53 controls; 97 patients undergoing surgery and 74 patients with metastatic CRC undergoi...

  6. Prediction of radiosensitivity in tumour cells: use of the alkaline comet assay to assess radiosensitivity in bladder and colorectal tumour cell lines

    International Nuclear Information System (INIS)

    Radiotherapy is the treatment of choice for a wide range of solid tumours yet it is impossible to predict which tumours will show a good response. We have investigated the radiosensitivity of a number of tumour cell lines (5 bladder and 4 colorectal) to verify whether the alkaline comet assay (ACA) can be used to predict tumour radiosensitivity. Preliminary studies showed that it is essential to carry out irradiations on cells pre-embedded in agarose to ensure that repair, prior to lysis, is kept to a minimum. Cells were embedded prior to irradiation, lysed and the comet tail moment analysed; this was compared to cell survival measured using a clonogenic assay. For all doses (0 - 6Gy) there was a good correlation between the two measures: r2 0.897 for bladder tumour cells and r2 = 0.929 for colorectal tumour cells. We also irradiated cells with 4Gy X-rays and measured initial damage, repair rate and residual damage. In both groups initial DNA damage and residual damage correlated with clonogenic survival; repair rate was very similar for the cell lines and was not predictive. One cell line (T24) had a pronounced shoulder on the radiation dose response curve such that there was a radioresistant response at 2 Gy and a radiosensitive response at 4 Gy. This change in response within the clinically relevant range emphasises that for a predictive test to have validity in the clinic it must be carried out in the clinically relevant range. The finding that initial damage varies between individual cell lines is consistent with some, but not all reports in the literature. We have also carried out nuclear texture analysis to measure phenotypic changes in DNA distribution and chromatin organisation. The results support the contention that organisation of nuclear chromatin is inherently different in different cell lines and may be significant in determining their response to radiation damage

  7. Chronic phase CML patients possess T cells capable of recognising autologous tumour cells.

    Science.gov (United States)

    Müller, Ludmila; Pawelec, Graham

    2002-05-01

    Much circumstantial evidence points to the immunogenicity of chronic myloid leukemia (CML) cells, most impressively the well-established T cell-dependent GvL effect seen in bone marrow transplantation. However, only a small number of shared antigens expressed by CML cells have been identified as potential targets for T cell-mediated immune responses which might be exploited for immunotherapy. It may be that unique antigens expressed by individual tumours are more potent rejection antigens if the patient's own T cells could be encouraged to react against them. Work is reviewed here which documents that in vitro mixed cultures between autologous T cells and dendritic cells of chronic-phase CML patients can give rise to sensitised T cells capable of recognising the patient's tumour cells. Additionally, mixed autologous tumour cell/lymphocyte cultures, modified by the addition of cytokine cocktails, may also result in the generation of similarly sensitised T cells. These results could be exploited for adoptive immunotherapy, and possibly, after identification of the antigens recognised, also for active immunotherapy, i.e. including therapeutic vaccination. PMID:12148904

  8. Nonlinear modelling of cancer: bridging the gap between cells and tumours

    International Nuclear Information System (INIS)

    Despite major scientific, medical and technological advances over the last few decades, a cure for cancer remains elusive. The disease initiation is complex, and including initiation and avascular growth, onset of hypoxia and acidosis due to accumulation of cells beyond normal physiological conditions, inducement of angiogenesis from the surrounding vasculature, tumour vascularization and further growth, and invasion of surrounding tissue and metastasis. Although the focus historically has been to study these events through experimental and clinical observations, mathematical modelling and simulation that enable analysis at multiple time and spatial scales have also complemented these efforts. Here, we provide an overview of this multiscale modelling focusing on the growth phase of tumours and bypassing the initial stage of tumourigenesis. While we briefly review discrete modelling, our focus is on the continuum approach. We limit the scope further by considering models of tumour progression that do not distinguish tumour cells by their age. We also do not consider immune system interactions nor do we describe models of therapy. We do discuss hybrid-modelling frameworks, where the tumour tissue is modelled using both discrete (cell-scale) and continuum (tumour-scale) elements, thus connecting the micrometre to the centimetre tumour scale. We review recent examples that incorporate experimental data into model parameters. We show that recent mathematical modelling predicts that transport limitations of cell nutrients, oxygen and growth factors may result in cell death that leads to morphological instability, providing a mechanism for invasion via tumour fingering and fragmentation. These conditions induce selection pressure for cell survivability, and may lead to additional genetic mutations. Mathematical modelling further shows that parameters that control the tumour mass shape also control its ability to invade. Thus, tumour morphology may serve as a predictor of

  9. Tumor heterogeneity and circulating tumor cells.

    Science.gov (United States)

    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

  10. Identifying cancer origin using circulating tumor cells.

    Science.gov (United States)

    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

  11. [{sup 18}F]FDG PET monitoring of tumour response to chemotherapy: does [{sup 18}F]FDG uptake correlate with the viable tumour cell fraction?

    Energy Technology Data Exchange (ETDEWEB)

    Spaepen, Karoline; Stroobants, Sigrid; Dupont, Patrick; Bormans, Guy; Mortelmans, Luc [Department of Nuclear Medicine, UZ Gasthuisberg, Herestraat 49, 3000, Leuven (Belgium); Balzarini, Jan [Rega Institute, Katholieke Universiteit, Leuven (Belgium); Verhoef, Gregor; Vandenberghe, Peter [Department of Hematology, UZ Gasthuisberg, Leuven (Belgium); De Wolf-Peeters, Christine [Department of Pathology, UZ Gasthuisberg, Leuven (Belgium)

    2003-05-01

    Because metabolic changes induced by chemotherapy precede the morphological changes, fluorine-18 fluorodeoxyglucose positron emission tomography ([{sup 18}F]FDG PET) is thought to predict response to therapy earlier and more accurately than other modalities. To be a reliable predictor of response, changes in tumour [{sup 18}F]FDG uptake should reflect changes in viable cell fraction, but little is known about the contribution of apoptotic and necrotic cancer cells and inflammatory tissue to the [{sup 18}F]FDG signal. In a tumour mouse model we investigated the relation between chemotherapy-induced changes in various tumoral components and tumour uptake and size. SCID mice were subcutaneously inoculated in the right thigh with 5 x 10{sup 6} Daudi cells. When the tumour measured 15-20 mm, Endoxan was given intravenously. At different time points [1-15 days (d1-d15) after the injection of Endoxan], ex vivo autoradiography and histopathology were performed in two mice and [{sup 18}F]FDG uptake in the tumour and tumour size were correlated with the different cell fractions measured with flow cytometry in five mice. At d1/d3, similar reductions in [{sup 18}F]FDG uptake and viable tumoral cell fraction were observed and these reductions preceded changes in tumour size. By d8/d10, [{sup 18}F]FDG uptake had stabilised despite a further reduction in viable tumoral cell fraction. At these time points a major inflammatory response was observed. At d15, an increase in viable tumour cells was again observed and this was accurately predicted by an increase in [{sup 18}F]FDG uptake, while the tumour volume remained unchanged. In contrast with variations in tumour volume, [{sup 18}F]FDG is a good marker for chemotherapy response monitoring. However, optimal timing seems crucial since a transient increase in stromal reaction may result in overestimation of the fraction of viable cells. (orig.)

  12. Non-invasive detection of genomic imbalances in Hodgkin/Reed-Sternberg cells in early and advanced stage Hodgkin's lymphoma by sequencing of circulating cell-free DNA: a technical proof-of-principle study

    OpenAIRE

    Vandenberghe, Peter; Wlodarska, Iwona; Tousseyn, Thomas; Dehaspe, Luc; Dierickx, Daan; Verheecke, Magali; Uyttebroeck, Anne; Bechter, Oliver; Delforge, Michel; Vandecaveye, Vincent; Brison, Nathalie; Verhoef, Gregor; Legius, Eric; Amant, Frédéric; Vermeesch, Joris

    2015-01-01

    Hodgkin's lymphoma is one of the most common lymphoid neoplasms in young adults, but the low abundance of neoplastic Hodgkin/Reed-Sternberg cells in the tumour hampers the elucidation of its pathogenesis, biology, and diversity. After an incidental observation that genomic aberrations known to occur in Hodgkin's lymphoma were detectable in circulating cell-free DNA, this study was undertaken to investigate whether circulating cell-free DNA can be informative about genomic imbalances in Hodgki...

  13. Host microenvironment in breast cancer development: Inflammatory and immune cells in tumour angiogenesis and arteriogenesis

    International Nuclear Information System (INIS)

    Breast cancer progression is associated with and dependent upon robust neovascularization. It is becoming clear that tumour-associated 'normal' cells, such as immune/inflammatory cells, endothelial cells and stromal cells, conspire with cancer cells in promoting this process. In particular, infiltrating immune/inflammatory cells secrete a diverse repertoire of growth factors and proteases that enable them to enhance tumour growth by stimulating angiogenesis and, as we suggest here, by promoting 'tumour arteriogenesis' – enlargement of feeding vessels supplying the expanding tumour capillary bed. Macrophages and their chemoattractants (e.g. macrophage chemoattractant protein-1) are critical for the arteriogenic process in ischaemia, and probably also in breast neoplasia. A better understanding of these various cellular and molecular constituents of breast cancer neovascularization may be useful in designing more effective therapies

  14. Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise Garm; Pallisgaard, Niels; Appelt, Ane Lindegaard;

    2015-01-01

    -house qPCR method. Results are presented according to REMARK. RESULTS: One-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas plasma KRAS...... an additional prognostic effect. CONCLUSION: The value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue....

  15. Tumour-initiating cells vs. cancer "stem" cells and CD133: What's in the name?

    Czech Academy of Sciences Publication Activity Database

    Neužil, Jiří; Stantic, M.; Zobalová, Renata; Chladová, Jaromíra; Wang, X. F.; Procházka, L.; Dong, L.; Anděra, Ladislav; Ralph, S.J.

    2007-01-01

    Roč. 255, č. 4 (2007), s. 855-859. ISSN 0006-291X Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : tumour-initiating cells * CD133 * resistance to treatment Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.749, year: 2007

  16. Genomic profiling of papillary renal cell tumours identifies small regions of DNA alterations: a possible role of HNF1B in tumour development

    NARCIS (Netherlands)

    Szponar, A.; Yusenko, M.V.; Kuiper, R.P.; Geurts van Kessel, A.H.M.; Kovacs, G.

    2011-01-01

    AIMS: Papillary renal cell tumours (RCT) are characterized by specific trisomies. The aim of this study was to identify small regions of duplication marking putative tumour genes. METHODS AND RESULTS: Full-tiling path bacterial artificial chromosome (BAC) array hybridization of 20 papillary RCTs con

  17. Diagnostic value of circulating tumor cells in cerebrospinal fluid

    OpenAIRE

    Ning Mu; Chunhua Ma; Rong Jiang; Yuan Lv; Jinduo Li; Bin Wang; Liwei Sun

    2016-01-01

    To assess circulating tumor cells in cerebrospinal fluid as a diagnostic approach to identify meningeal metastasis in patients with non-small cell lung cancer by using tumor marker immunostaining–fluorescence in situ hybridization (TM-iFISH).

  18. Circulating tumor cells in lung cancer.

    Science.gov (United States)

    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

  19. Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer.

    Science.gov (United States)

    Berntsson, Jonna; Nodin, Björn; Eberhard, Jakob; Micke, Patrick; Jirström, Karin

    2016-09-01

    Multiple studies have described associations between infiltrating immune cells and prognosis in cancer; however, the clinical relevance has most often been attributed to the T-cell linage. This study aimed to further investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in CRC. Immunohistochemical expression of CD20, CD138 and immunoglobulin kappa C (IGKC) was analysed in tissue microarrays with tumours from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of CD20, CD138 and IGKC expression on 5-year overall survival. Immune cell-specific CD20, CD138, and IGKC expression correlated significantly with lower T-stage (p stage, differentiation grade and vascular invasion (HR = 0.51; 95% CI 0.33-0.80). Immune cell-specific CD138 and IGKC expression correlated significantly with an improved OS in univariable Cox regression analysis; however, these associations did not remain significant in multivariable analysis. Finally, tumour cell-specific CD138 expression was found to be an independent factor of poor prognosis (HR 1.52; 95% CI 1.03-2.24). The results from the present study demonstrate that B cell infiltration in CRC has a significant impact on tumour progression and prognosis. These findings supplement and extend the current knowledge of the immune landscape in colorectal cancer, and merit further study. PMID:27074317

  20. Prospects for T cell immunotherapy of tumours by vaccination with immunodominant and subdominant peptides.

    Science.gov (United States)

    Melief, C J; Kast, W M

    1994-01-01

    Immunotherapy of tumours by adoptive transfer of cytotoxic T lymphocytes (CTL) is now feasible in experimental murine systems. These CTL recognize peptide sequences of defined length presented by major histocompatibility complex (MHC) class I molecules. Effective eradication of large tumour masses requires co-administration of interleukin 2. Tumour escape strategies are numerous but in various instances can be counteracted by defined measures. Initiation of CTL responses against poorly immunogenic virally induced tumours and other tumours requires novel strategies to overcome T cell inertia. We propose a strategy in which CTL are raised against target molecules of choice including differentiation antigens of restricted tissue distribution (autoantigens) or mutated/overexpressed oncogene products. The steps proposed include: (1) identification of target molecules of choice. (2) Identification in these target molecules of peptides fitting MHC allele-specific peptide motifs involved in peptide binding to MHC molecules. (3) Evaluation of actual binding of such peptides to specific MHC class I molecules. (4) In vitro CTL response induction by such peptides, presented by highly efficient antigen-presenting cells such as antigen processing-defective cells carrying empty MHC class I molecules loaded with a single peptide or dendritic cells. Both types of cells are capable of primary CTL response induction in vitro. (5) Evaluation of proper processing by the demonstration of tumour cell lysis by these CTL. (6) Adoptive transfer of tumour-specific CTL generated in vitro or vaccination with peptides. These various steps have now been taken for several viruses, virally induced tumours and other types of tumours and the first indications that this strategy is useful have been obtained. PMID:7796678

  1. Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine.

    Science.gov (United States)

    Bhutia, Yangzom D; Babu, Ellappan; Ganapathy, Vadivel

    2016-06-01

    Tumour cell metabolism is very different from normal cell metabolism; cancer cells re-programme the metabolic pathways that occur in normal cells in such a manner that it optimizes their proliferation, growth and survival. Although this metabolic re-programming obviously operates to the advantage of the tumour, it also offers unique opportunities for effective cancer therapy. Molecules that target the tumour cell-specific metabolic pathways have potential as novel anti-cancer drugs. Lonidamine belongs to this group of molecules and is already in use in some countries for cancer treatment. It has been known for a long time that lonidamine interferes with energy production in tumour cells by inhibiting hexokinase II (HKII), a glycolytic enzyme. However, subsequent studies have uncovered additional pharmacological targets for the drug, which include the electron transport chain and the mitochondrial permeability transition pore, thus expanding the pharmacological effects of the drug on tumour cell metabolism. A study by Nancolas et al. in a recent issue of the Biochemical Journal identifies two additional new targets for lonidamine: the pyruvate transporter in the mitochondria and the H(+)-coupled monocarboxylate transporters in the plasma membrane (PM). It is thus becoming increasingly apparent that the anti-cancer effects of lonidamine do not occur through a single target; the drug works at multiple sites. Irrespective of the molecular targets, what lonidamine does in the end is to undo what the tumour cells have done in terms of re-programming cellular metabolism and mitochondrial function. PMID:27234586

  2. Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Nardou Katya

    2008-06-01

    Full Text Available Abstract Background Histone deacetylase inhibitors (HDACi are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. Results We show here that the HDACi Sodium Butyrate (NaB, suberoylanilide hydroxamic acid (SAHA and Trichostatin A (TSA strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. Conclusion HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.

  3. Langerhans' cell histiocytosis: possible association with malignant germ cell tumour.

    OpenAIRE

    Ng, W K; Lam, K Y; Ng, I O

    1995-01-01

    A rare case of adult onset Langerhans' cell histiocytosis associated with dysgerminoma in a 35 year old Chinese woman is reported. The patient had a history of dysgerminoma of left ovary 15 years previously and had undergone surgery followed by radiotherapy and an uneventful recovery. She presented again in March 1994, this time with a left clavicular mass, which was shown histologically to be Langerhans' cell histiocytosis. The report illustrates the probable association between the two lesi...

  4. Tumour cell–derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth

    Directory of Open Access Journals (Sweden)

    Hiroaki Haga

    2015-01-01

    Full Text Available The contributions of mesenchymal stem cells (MSCs to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs. We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell–derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell–derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell–derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can “educate” MSCs to induce local microenvironmental changes that enhance tumour cell growth.

  5. Mixed germ cell tumour complicated by pulmonary thromboembolism: a case report

    Directory of Open Access Journals (Sweden)

    Hema Priya Kukreja

    2016-04-01

    Full Text Available Malignant ovarian germ cell tumours (MOGCTs are a heterogeneous group of tumours that have several histological different types derived from primordial germ cells of the embryonic gonad. They account for less than 5% of all ovarian malignancies, and are seen in the second and third decade of life. The majority of germ cell tumours are diagnosed in the early stages. Histology, FIGO stage and residual tumour after surgery are the most important prognostic factors. Recent multimodality therapy with staging laparotomy and conservative surgery, followed by platinum based chemotherapy, is associated with survival rates of 60 - 80%, even in patients with advanced disease. Mixed germ cell tumours are extremely rare and the prognosis depends on the size of each component of the tumour. The exact incidence of thrombo embolic events in patients with malignancy is difficult to determine. However ovarian malignancy is strongly associated with venous thrombo embolism. We report a case of a fourteen year old girl with a mixed GCT, with elements of yolk sac tumour and embryonal carcinoma, who succumbed to pulmonary thromboembolism. [Int J Reprod Contracept Obstet Gynecol 2016; 5(4.000: 1242-1244

  6. Tumour T1 changes in vivo are highly predictive of response to chemotherapy and reflect the number of viable tumour cells – a preclinical MR study in mice

    International Nuclear Information System (INIS)

    Effective chemotherapy rapidly reduces the spin–lattice relaxation of water protons (T1) in solid tumours and this change (ΔT1) often precedes and strongly correlates with the eventual change in tumour volume (TVol). To understand the biological nature of ΔT1, we have performed studies in vivo and ex vivo with the allosteric mTOR inhibitor, everolimus. Mice bearing RIF-1 tumours were studied by magnetic resonance imaging (MRI) to determine TVol and T1, and MR spectroscopy (MRS) to determine levels of the proliferation marker choline and levels of lipid apoptosis markers, prior to and 5 days (endpoint) after daily treatment with vehicle or everolimus (10 mg/kg). At the endpoint, tumours were ablated and an entire section analysed for cellular and necrotic quantification and staining for the proliferation antigen Ki67 and cleaved-caspase-3 as a measure of apoptosis. The number of blood-vessels (BV) was evaluated by CD31 staining. Mice bearing B16/BL6 melanoma tumours were studied by MRI to determine T1 under similar everolimus treatment. At the endpoint, cell bioluminescence of the tumours was measured ex vivo. Everolimus blocked RIF-1 tumour growth and significantly reduced tumour T1 and total choline (Cho) levels, and increased polyunsaturated fatty-acids which are markers of apoptosis. Immunohistochemistry showed that everolimus reduced the %Ki67+ cells but did not affect caspase-3 apoptosis, necrosis, BV-number or cell density. The change in T1 (ΔT1) correlated strongly with the changes in TVol and Cho and %Ki67+. In B16/BL6 tumours, everolimus also decreased T1 and this correlated with cell bioluminescence; another marker of cell viability. Receiver-operating-characteristic curves (ROC) for everolimus on RIF-1 tumours showed that ΔT1 had very high levels of sensitivity and specificity (ROCAUC = 0.84) and this was confirmed for the cytotoxic patupilone in the same tumour model (ROCAUC = 0.97). These studies suggest that ΔT1 is not a measure of cell density

  7. Ultrastructural proof of polyomavirus in Merkel cell carcinoma tumour cells and its absence in small cell carcinoma of the lung.

    Directory of Open Access Journals (Sweden)

    Charlotte T A H Wetzels

    Full Text Available BACKGROUND: A new virus called the Merkel Cell Polyomavirus (MCPyV has recently been found in Merkel Cell Carcinoma (MCC. MCC is a rare aggressive small cell neuroendocrine carcinoma primarily derived from the skin, morphologically indistinguishable from small cell lung carcinoma (SCLC. So far the actual presence of the virus in MCC tumour cells on a morphological level has not been demonstrated, and the presence of MCPyV in other small cell neuroendocrine carcinomas has not been studied yet. METHODOLOGY/PRINCIPAL FINDINGS: We investigated MCC tissue samples from five patients and SCLCs from ten patients for the presence of MCPyV-DNA by PCR and sequencing. Electron microscopy was used to search ultrastructurally for morphological presence of the virus in MCPyV-DNA positive samples. MCPyV was detected in two out of five primary MCCs. In one MCC patient MCPyV-DNA was detected in the primary tumour as well as in the metastasis, strongly suggesting integration of MCPyV in the cellular DNA of the tumour in this patient. In the primary MCC of another patient viral particles in tumour cell nuclei and cytoplasm were identified by electron microscopy, indicating active viral replication in the tumour cells. In none of the SCLCs MCPyV-DNA was detected. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest that MCPyV is an oncogenic polyomavirus in humans, and is potentially causally related to the development of MCC but not to the morphological similar SCLC.

  8. Non-germ cell tumours arising in germ cell tumours (teratoma with malignant transformation) in men: CT and MR findings

    Energy Technology Data Exchange (ETDEWEB)

    Athanasiou, A. [Department of Radiology, Institut Gustave-Roussy, Villejuif (France); Department of Radiology, Institut Curie, Paris (France)], E-mail: alexandra.athanasiou@curie.net; Vanel, D. [Department of Radiology, Institut Gustave-Roussy, Villejuif (France); Department of Radiology, Istituti Ortopedici Rizzoli, Bologna (Italy); El Mesbahi, O. [Department of Medicine, Institut Gustave-Roussy, Villejuif (France); Theodore, C. [Department of Medicine, Institut Gustave-Roussy, Villejuif (France); Department of Oncology, Hopital Foch, Suresnes (France); Fizazi, K. [Department of Medicine, Institut Gustave-Roussy, Villejuif (France)

    2009-02-15

    Purpose: To describe the imaging findings of germ cell tumours (GCT) containing non-germ cell malignant components (also designated teratoma with malignant transformation or TMT). Patients and methods: The records of 14 male patients with GCT and a non-germ cell histological component TMT were retrospectively reviewed. All patients had computed tomography (CT) and/or magnetic resonance (MR) studies before and after initial surgery and chemotherapy, as well as during follow-up. Imaging findings were correlated with the response to treatment and with overall survival. Pathological evaluation, immunohistochemistry, serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) were also taken into consideration. Sarcoma was identified in 10 out of 14 patients, with rhabdomyosarcoma ranking first (n = 4), followed by osteosarcoma (n = 2), fusiform cell sarcoma (n = 1), undifferentiated sarcoma (n = 1), neurosarcoma (n = 1) and myxoid sarcoma (n = 1). Other histological types of malignant transformation included adenocarcinoma (n = 3) and bronchoalveolar carcinoma (n = 1). Overall, 9 patients relapsed at a median time of 84 months (range 60-168). Results: Non-GCT malignant transformation was identified in the retroperitoneum (5), testis (3), mediastinum (3), peritoneum (2) and lungs (1). The CT and MR imaging findings before treatment and after relapse were evaluated with emphasis on imaging features that could possibly imply the presence of malignant transformation (heterogeneously enhancing soft-tissue masses, ossified masses with calcified lymph nodes, diffuse epiploic thickening associated with ascites and peritoneal nodules, pulmonary alveolar infiltration with septal thickening). All but 1 patient with TMT presented with nodal and distant metastases. The prognosis was poor: within a median follow-up of 59 months (range 3-180), 4 out of 14 patients were alive. Conclusion: TMT is rare and associated with poorer survival compared to GCT. Imaging can be useful

  9. Non-germ cell tumours arising in germ cell tumours (teratoma with malignant transformation) in men: CT and MR findings

    International Nuclear Information System (INIS)

    Purpose: To describe the imaging findings of germ cell tumours (GCT) containing non-germ cell malignant components (also designated teratoma with malignant transformation or TMT). Patients and methods: The records of 14 male patients with GCT and a non-germ cell histological component TMT were retrospectively reviewed. All patients had computed tomography (CT) and/or magnetic resonance (MR) studies before and after initial surgery and chemotherapy, as well as during follow-up. Imaging findings were correlated with the response to treatment and with overall survival. Pathological evaluation, immunohistochemistry, serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) were also taken into consideration. Sarcoma was identified in 10 out of 14 patients, with rhabdomyosarcoma ranking first (n = 4), followed by osteosarcoma (n = 2), fusiform cell sarcoma (n = 1), undifferentiated sarcoma (n = 1), neurosarcoma (n = 1) and myxoid sarcoma (n = 1). Other histological types of malignant transformation included adenocarcinoma (n = 3) and bronchoalveolar carcinoma (n = 1). Overall, 9 patients relapsed at a median time of 84 months (range 60-168). Results: Non-GCT malignant transformation was identified in the retroperitoneum (5), testis (3), mediastinum (3), peritoneum (2) and lungs (1). The CT and MR imaging findings before treatment and after relapse were evaluated with emphasis on imaging features that could possibly imply the presence of malignant transformation (heterogeneously enhancing soft-tissue masses, ossified masses with calcified lymph nodes, diffuse epiploic thickening associated with ascites and peritoneal nodules, pulmonary alveolar infiltration with septal thickening). All but 1 patient with TMT presented with nodal and distant metastases. The prognosis was poor: within a median follow-up of 59 months (range 3-180), 4 out of 14 patients were alive. Conclusion: TMT is rare and associated with poorer survival compared to GCT. Imaging can be useful

  10. Mitogen-activated Tasmanian devil blood mononuclear cells kill devil facial tumour disease cells.

    Science.gov (United States)

    Brown, Gabriella K; Tovar, Cesar; Cooray, Anne A; Kreiss, Alexandre; Darby, Jocelyn; Murphy, James M; Corcoran, Lynn M; Bettiol, Silvana S; Lyons, A Bruce; Woods, Gregory M

    2016-08-01

    Devil facial tumour disease (DFTD) is a transmissible cancer that has brought the host species, the Tasmanian devil, to the brink of extinction. The cancer cells avoid allogeneic immune recognition by downregulating cell surface major histocompatibility complex (MHC) I expression. This should prevent CD8(+) T cell, but not natural killer (NK) cell, cytotoxicity. The reason why NK cells, normally reactive to MHC-negative cells, are not activated to kill DFTD cells has not been determined. The immune response of wild devils to DFTD, if it occurs, is uncharacterised. To investigate this, we tested 12 wild devils with DFTD, and found suggestive evidence of low levels of antibodies against DFTD cells in one devil. Eight of these devils were also analysed for cytotoxicity, however, none showed evidence for cytotoxicity against cultured DFTD cells. To establish whether mimicking activation of antitumour responses could induce cytotoxic activity against DFTD, Tasmanian devil peripheral blood mononuclear cells (PBMCs) were treated with either the mitogen Concanavalin A, the Toll-like receptor agonist polyinosinic:polycytidylic acid or recombinant Tasmanian devil IL-2. All induced the PBMC cells to kill cultured DFTD cells, suggesting that activation does not occur after encounter with DFTD cells in vivo, but can be induced. The identification of agents that activate cytotoxicity against DFTD target cells is critical for developing strategies to protect against DFTD. Such agents could function as adjuvants to induce functional immune responses capable of targeting DFTD cells and tumours in vivo. PMID:27089941

  11. The effect of trocar composition on tumour cell adherence: and in vivo model

    International Nuclear Information System (INIS)

    Full text: Port site recurrence of tumour is a recognised complication of laparoscopic surgery for cancer. It has previously been shown that an increased number of tumour cells adhere to metal rather than plastic trocars and sites through which metal trocars had passed. In an extension of this study, adherence of such cells to trocars and trocar sites was investigated in an in vivo porcine model. 99mTc-HMPAO labelled LIM 1215 tumour cells were injected under direct laparoscopic vision into the pelvises of pigs, and then metal and plastic trocars were inserted through the anterior abdominal wall. Trocar type, removal and replacement, as well as site, were all examined for the presence of 99mTc-tumour cells by counting samples in a large volume counter. Greater contamination occurred with metal rather than plastic trocars, and after increased manipulation of the trocars. Copyright (2003) The Australian and New Zealand Society of Nuclear Medicine Inc

  12. M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma.

    Science.gov (United States)

    Shen, Long; Li, Honghao; Shi, Yuzhi; Wang, Dekun; Gong, Junbo; Xun, Jing; Zhou, Sifan; Xiang, Rong; Tan, Xiaoyue

    2016-01-01

    Effects of M2 tumour-associated macrophages on the pathogenesis of diffuse large B cell lymphoma (DLBCL) are still controversial. Our data showed that the number of CD163-positive M2 macrophages correlated negatively with DLBCL prognosis. Macrophage depletion by clodronate liposomes significantly suppressed tumour growth in a xenograft mouse model of DLBCL using OCI-Ly3 cells. Moreover, M2 polarization of macrophages induced legumain expression in U937 cells. Exogenous legumain promoted degradation of fibronectin and collagen I, which was abolished by administration of a legumain inhibitor RR-11a. Overexpression of legumain in Raw 264.7 cells also induced tube formation of endothelial cells in matrigel. In the xenograft mouse model of DLBCL, decreased fibronectin and collagen I, as well as increased legumain expression and angiogenesis were found at the late stage tumours compared with early stage tumours. Co-localization of legumain and fibronectin was observed in the extracellular matrix of tumour tissues. Administration of the legumain inhibitor to the xenograft DLBCL model suppressed tumour growth, angiogenesis and collagen deposition compared with the control. Taken together, our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL. PMID:27464733

  13. Radiation-Sensitising Effects of Antennapedia Proteins (ANTP-SmacN7 on Tumour Cells

    Directory of Open Access Journals (Sweden)

    Li Qing Du

    2013-12-01

    Full Text Available The objective of this study was to investigate the underlying mechanisms behind the radiation-sensitising effects of the antennapedia proteins (ANTP-smacN7 fusion protein on tumour cells. ANTP-SmacN7 fusion proteins were synthesised, and the ability of this fusion protein to penetrate cells was observed. Effects of radiation on the expression of X-linked inhibitor of apoptosis protein (XIAP were detected by western blotting. The radiation-sensitising effects of ANTP-SmacN7 fusion proteins were observed by a clonogenic assay. The effects of drugs and radiation on tumour cell apoptosis were determined using Annexin V/FITC double staining. Changes in caspase-8, caspase-9 and caspase-3 were detected by western blot before and after ANTP-SmacN7 inhibition of XIAP. The ANTP-SmacN7 fusion protein could enter and accumulate in cells; in vitro XIAP expression of radiation-induced tumour cells was negatively correlated with tumour radiosensitivity. The ANTP-SmacN7 fusion protein promoted tumour cell apoptosis through the activation of caspase3. ANTP-SmacN7 fusion protein may reduce tumour cell radioresistance by inducing caspase3 activation.

  14. Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis

    International Nuclear Information System (INIS)

    TRAIL (tumor necrosis factor related apoptosis inducing ligand) is an apoptosis inducing ligand with high specificity for malignant cell systems. Combined treatment modalities using TRAIL and cytotoxic drugs revealed highly additive effects in different tumour cell lines. Little is known about the efficacy and underlying mechanistic effects of a combined therapy using TRAIL and ionising radiation in solid tumour cell systems. Additionally, little is known about the effect of TRAIL combined with radiation on normal tissues. Tumour cell systems derived from breast- (MDA MB231), lung- (NCI H460) colorectal- (Colo 205, HCT-15) and head and neck cancer (FaDu, SCC-4) were treated with a combination of TRAIL and irradiation using two different time schedules. Normal tissue cultures from breast, prostate, renal and bronchial epithelia, small muscle cells, endothelial cells, hepatocytes and fibroblasts were tested accordingly. Apoptosis was determined by fluorescence microscopy and western blot determination of PARP processing. Upregulation of death receptors was quantified by flow cytometry. The combined treatment of TRAIL with irradiation strongly increased apoptosis induction in all treated tumour cell lines compared to treatment with TRAIL or irradiation alone. The synergistic effect was most prominent after sequential application of TRAIL after irradiation. Upregulation of TRAIL receptor DR5 after irradiation was observed in four of six tumour cell lines but did not correlate to tumour cell sensitisation to TRAIL. TRAIL did not show toxicity in normal tissue cell systems. In addition, pre-irradiation did not sensitise all nine tested human normal tissue cell cultures to TRAIL. Based on the in vitro data, TRAIL represents a very promising candidate for combination with radiotherapy. Sequential application of ionising radiation followed by TRAIL is associated with an synergistic induction of cell death in a large panel of solid tumour cell lines. However, TRAIL receptor

  15. Giant cell tumour in the foot of a skeletally immature girl: a case report.

    LENUS (Irish Health Repository)

    Baker, Joseph F

    2009-08-01

    We present a case of delayed diagnosis of a benign giant cell tumour (GCT) of the third metatarsal in a skeletally immature girl. The patient underwent en bloc excision of the tumour. The tumour had replaced the third metatarsal and had infiltrated the surrounding soft tissue and the second and fourth metatarsal bases. Deep, lateral and medial margins were all involved. A high index of suspicion is needed when evaluating any tumours of the foot, because the compact structure of the foot may delay diagnosis. Early detection is important for avoiding amputation, as the hindfoot and midfoot are classified as one compartment and radical resection is impossible to achieve. Tumours grow faster in the foot than in other bones. GCT in this location and age-group are rare and should be considered in the differential diagnosis of a destructive bony lesion in skeletally immature patients.

  16. Complementation of two related tumour cell classes during experimental metastasis tagged with different histochemical marker genes.

    OpenAIRE

    Lin, W.C.; O'Connor, K. L.; Culp, L. A.

    1993-01-01

    Intercellular complementation during tumour development and metastasis was analysed for two different oncogene (ras or sis) transformants of Balb/c 3T3 cells, tagged with different histochemical marker genes (lacZ or ALP to generate LZEJ or APSI cells, respectively), by localising them after their co-injection with specific double-staining protocols. This model evaluates whether limited progression of each tumour class can be facilitated reciprocally during co-localisation and co-growth in nu...

  17. Aspects of Tumour Targeting : Preclinical Studies on Human Malignant Cells in vitro

    OpenAIRE

    Dahlström Wester, Maria

    2009-01-01

    Exclusive eradication of tumour cells causing minimal damage to healthy tissue, a concept referred to as targeting, is an interesting approach to improve the outcome for patients afflicted with cancer. The general aim of this thesis was to highlighten aspects that could be of importance in developing novel treatment regimens based on specific targeting of tumour cells. Two variants of targeting strategies, boron neutron capture therapy (BNCT) and platelet-derived growth factor receptor (PDGFR...

  18. Tumour stromal cells derived from paediatric malignancies display MSC-like properties and impair NK cell cytotoxicity

    International Nuclear Information System (INIS)

    Tumour growth and metastatic infiltration are favoured by several components of the tumour microenvironment. Bone marrow-derived multipotent mesenchymal stromal cells (MSC) are known to contribute to the tumour stroma. When isolated from healthy bone marrow, MSC exert potent antiproliferative effects on immune effector cells. Due to phenotypic and morphological similarities of MSC and tumour stromal cells (TStrC), we speculated that immunotherapeutic approaches may be hampered if TStrC may still exhibit immunomodulatory properties of MSC. In order to compare immunomodulatory properties of MSC and tumour stromal cells (TStrC), we established and analyzed TStrC cultures from eleven paediatric tumours and MSC preparations from bone marrow aspirates. Immunophenotyping, proliferation assays and NK cell cytotoxicity assays were employed to address the issue. While TStrC differed from MSC in terms of plasticity, they shared surface expression of CD105, CD73 and other markers used for MSC characterization. Furthermore, TStrC displayed a strong antiproliferative effect on peripheral blood mononuclear cells (PBMC) in coculture experiments similar to MSC. NK cell cytotoxicity was significantly impaired after co-culture with TStrC and expression of the activating NK cell receptors NKp44 and NKp46 was reduced. Our data show that TStrC and MSC share important phenotypic and functional characteristics. The inhibitory effect of TStrC on PBMC and especially on NK cells may facilitate the immune evasion of paediatric tumours

  19. Formation of germline chimera Gaok chicken used circulation primordial germ cells (circulation PGCs fresh and thawed

    Directory of Open Access Journals (Sweden)

    Kostaman T

    2014-03-01

    Full Text Available Formation of germline chimeras by transfer of chicken primordial germ cells (PGCs is one of the effective techniques for preservation and regeneration of genetic resources in chickens. This study attempted to form germline chimeras of Gaok chicken buy purifying circulated PGCs of donor embryo before it is transferred to the recipient (White Leghorn chickens=WL and studied the ability of recipient embryo on survival in incubators, and hatchability. This study used 200 fertile eggs of Gaok and 90 fertile WL breed all of the eggs was incubated at 380C and 60% humidity in a portable incubator. PGCs-circulation of the blood collected Gaok embryos at stage 14-16 were taken from the dorsal aorta, and then purified by centrifugation method using nycodenz. PGCs-circulation results further purification frozen in liquid nitrogen before being transferred to the recipient embryo. The results showed that for the development of embryos transferred to the fresh circulation of PGCs-circulation as many as 25 cells can survive up to day 14, while one of the transferred of 50 and 100 cells into recipient embryos was hatched (10%. On the contrari recipient embryos that are transferred to the frozen PGCs-circulation the embryos development was shorter, and only survived until day 10th (treatment 25 cells, day 14th (treatment of 50 cells and day 17th (treatment of 100 cells. It is concluded that the amount of PGCs-circulation embryos transferred to the recipient is one factor that influence the success of the development germline chimeras.

  20. Tumours and tumourous diseases

    International Nuclear Information System (INIS)

    This book on tumours and tumourous diseases comprises two parts: 1. Bone tumours and tumourous lesions. 2. Soft tissue tumours and tumourous lesions. Details are presented on pathology, diagnosis, conservative and perioperative therapy, surgical therapy, complications after resection, indicators for amputation, recommendations for follow-up treatment, radiotherapy, radionuclide therapy, alternative therapies, therapy concepts in case of metastases, tissue engineering and plastic surgery. (uke)

  1. Feline cutaneous neuroendocrine carcinoma (Merkel cell tumour): clinical and pathological findings.

    Science.gov (United States)

    Bagnasco, Giorgio; Properzi, Roberto; Porto, Roberto; Nardini, Vincenzo; Poli, Alessandro; Abramo, Francesca

    2003-04-01

    A case of a feline Merkel cell tumour is described. An 8-year-old, female cat developed a round, alopecic, reddish mass on the nose. Wide excisional surgery was performed with cartilage resection. Histologically the mass was composed of solid islands of mostly basophilic densely packed cells with a scant cytoplasm, which was suggestive of a neuroendocrine origin. Results of immunohistochemical studies using antibodies against neurone-specific enolase, chromogranin, synaptophysin and pan-cytokeratin allowed classification of the lesion as a Merkel cell tumour. Ultrastructurally, dense core granules were identified in the cytoplasm. In a 2-year follow-up no relapses or metastases were observed. The clinical course recorded is in contrast with the malignant nature of a Merkel cell tumour recently described in a cat and of the human Merkel cell tumour, but is similar to the course of the canine Merkel cell tumour which is often benign. Early diagnosis along with the use of wide surgical excision might be considered an important factor in preventing relapse of this tumour. PMID:12662269

  2. Mast cells and eosinophils in rat mammary gland tumours induced by N-Nitroso-N-methylurea

    Directory of Open Access Journals (Sweden)

    Kissová Viktória

    2015-09-01

    Full Text Available The aim of the study was to evaluate the distribution and number of mast cells and eosinophils in rat mammary gland tumours induced by N-Nitroso-N-methylurea. The highest density of mast cells was found in cystic papillary adenocarcinomas of grade II. Eosinophils were detected only in the cystic papillary adenocarcinoma of grades I and II, in non-invasive cribriform adenocarcinoma and comedo-type carcinoma. Mast cell populations were observed perivascularly in the tumour stroma, in the host tumour interface, as well as in necrotic areas of neoplasms. Mast cells were observed to be intact according to their morphological changes, collectively referred to as degranulation. The obtained results indicate that mast cells and eosinophils play an important role in tumour micro-environment formation. The increased density of these cells in experimentally-induced rat mammary gland tumours suggests a poor prognosis in these cancers. Our results also confirmed that rat mammary gland tumours are good models for the study of breast cancers.

  3. In vivo acoustic and photoacoustic focusing of circulating cells

    Science.gov (United States)

    Galanzha, Ekaterina I.; Viegas, Mark G.; Malinsky, Taras I.; Melerzanov, Alexander V.; Juratli, Mazen A.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A.; Zharov, Vladimir P.

    2016-03-01

    In vivo flow cytometry using vessels as natural tubes with native cell flows has revolutionized the study of rare circulating tumor cells in a complex blood background. However, the presence of many blood cells in the detection volume makes it difficult to count each cell in this volume. We introduce method for manipulation of circulating cells in vivo with the use of gradient acoustic forces induced by ultrasound and photoacoustic waves. In a murine model, we demonstrated cell trapping, redirecting and focusing in blood and lymph flow into a tight stream, noninvasive wall-free transportation of blood, and the potential for photoacoustic detection of sickle cells without labeling and of leukocytes targeted by functionalized nanoparticles. Integration of cell focusing with intravital imaging methods may provide a versatile biological tool for single-cell analysis in circulation, with a focus on in vivo needleless blood tests, and preclinical studies of human diseases in animal models.

  4. In vivo acoustic and photoacoustic focusing of circulating cells

    Science.gov (United States)

    Galanzha, Ekaterina I.; Viegas, Mark G.; Malinsky, Taras I.; Melerzanov, Alexander V.; Juratli, Mazen A.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A.; Zharov, Vladimir P.

    2016-01-01

    In vivo flow cytometry using vessels as natural tubes with native cell flows has revolutionized the study of rare circulating tumor cells in a complex blood background. However, the presence of many blood cells in the detection volume makes it difficult to count each cell in this volume. We introduce method for manipulation of circulating cells in vivo with the use of gradient acoustic forces induced by ultrasound and photoacoustic waves. In a murine model, we demonstrated cell trapping, redirecting and focusing in blood and lymph flow into a tight stream, noninvasive wall-free transportation of blood, and the potential for photoacoustic detection of sickle cells without labeling and of leukocytes targeted by functionalized nanoparticles. Integration of cell focusing with intravital imaging methods may provide a versatile biological tool for single-cell analysis in circulation, with a focus on in vivo needleless blood tests, and preclinical studies of human diseases in animal models. PMID:26979811

  5. Computed tomography evaluation of mast cell tumours; Avaliacao por tomografia computadorizada dos mastocitomas

    Energy Technology Data Exchange (ETDEWEB)

    Lorigados, Carla Aparecida Batista; Matera, Julia Maria; Macedo, Thais; Pinto, Ana Carolina Brandao Fonseca, E-mail: clorigados@usp.br [Universidade de Sao Paulo (USP), SP (Brazil). Faculdade de Medicina Veterinaria e Zootecnia. Dept. de Cirurgia

    2012-07-01

    The mast cell tumours are common tumours of the canine skin. Computed tomography (CT) has assumed an important role in tumours evaluation and staging. The aim of this study was to evaluate the role of CT as a method of assessing characteristics of mast cell tumors. Ten dogs with mast cell tumor were evaluated. CT was performed before and after the intravenous injection of hydro soluble ionic iodine. Attenuation, contrast enhancement, cleavage with adjacent tissues and the unidimensional measurement of each lesion was determined in it maximum diameter, in transversal plane. Concerning the attenuation characteristic, 50% were homogeneous and 50% heterogeneous. The contrast enhancement was homogeneous in 50% of cases, heterogeneous in 40% and peripheral in 10%. Fifty percent of the tumours showed loss of plane of cleavage and 30% partial loss. This information can help in directing the patients that will be undergoing chemotherapy or surgery. (author)

  6. New approaches to targeted drug delivery to tumour cells

    Science.gov (United States)

    Severin, E. S.

    2015-01-01

    Basic approaches to the design of targeted drugs for the treatment of human malignant tumours have been considered. The stages of the development of these approaches have been described in detail and theoretically substantiated, and basic experimental results have been reported. Considerable attention is paid to the general characteristic of nanopharmacological drugs and to the description of mechanisms of cellular interactions with nanodrugs. The potentialities and limitations of application of nanodrugs for cancer therapy and treatment of other diseases have been considered. The use of nanodrugs conjugated with vector molecules seems to be the most promising trend of targeted therapy of malignant tumours. The bibliography includes 122 references.

  7. New approaches to targeted drug delivery to tumour cells

    International Nuclear Information System (INIS)

    Basic approaches to the design of targeted drugs for the treatment of human malignant tumours have been considered. The stages of the development of these approaches have been described in detail and theoretically substantiated, and basic experimental results have been reported. Considerable attention is paid to the general characteristic of nanopharmacological drugs and to the description of mechanisms of cellular interactions with nanodrugs. The potentialities and limitations of application of nanodrugs for cancer therapy and treatment of other diseases have been considered. The use of nanodrugs conjugated with vector molecules seems to be the most promising trend of targeted therapy of malignant tumours. The bibliography includes 122 references

  8. Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo

    International Nuclear Information System (INIS)

    Delivery of small interfering RNA (siRNA) to tumours remains a major obstacle for the development of RNA interference (RNAi)-based therapeutics. Following the promising pre-clinical and clinical results with the oncolytic herpes simplex virus (HSV) OncoVEXGM-CSF, we aimed to express RNAi triggers from oncolytic HSV, which although has the potential to improve treatment by silencing tumour-related genes, was not considered possible due to the highly oncolytic properties of HSV. To evaluate RNAi-mediated silencing from an oncolytic HSV backbone, we developed novel replicating HSV vectors expressing short-hairpin RNA (shRNA) or artificial microRNA (miRNA) against the reporter genes green fluorescent protein (eGFP) and β-galactosidase (lacZ). These vectors were tested in non-tumour cell lines in vitro and tumour cells that are moderately susceptible to HSV infection both in vitro and in mice xenografts in vivo. Silencing was assessed at the protein level by fluorescent microscopy, x-gal staining, enzyme activity assay, and western blotting. Our results demonstrate that it is possible to express shRNA and artificial miRNA from an oncolytic HSV backbone, which had not been previously investigated. Furthermore, oncolytic HSV-mediated delivery of RNAi triggers resulted in effective and specific silencing of targeted genes in tumour cells in vitro and tumours in vivo, with the viruses expressing artificial miRNA being comprehensibly more effective. This preliminary data provide the first demonstration of oncolytic HSV-mediated expression of shRNA or artificial miRNA and silencing of targeted genes in tumour cells in vitro and in vivo. The vectors developed in this study are being adapted to silence tumour-related genes in an ongoing study that aims to improve the effectiveness of oncolytic HSV treatment in tumours that are moderately susceptible to HSV infection and thus, potentially improve response rates seen in human clinical trials

  9. Adenomyoepithelial tumours and myoepithelial carcinomas of the breast – a spectrum of monophasic and biphasic tumours dominated by immature myoepithelial cells

    Directory of Open Access Journals (Sweden)

    Herbst Hermann

    2005-07-01

    Full Text Available Abstract Background Adenomyoepithelial tumours and myoepithelial carcinomas of the breast are primarily defined by the presence of neoplastic cells with a myoepithelial immunophenotype. Current classification schemes are based on purely descriptive features and an assessment of individual prognosis is still problematic. Methods A series of 27 adenomyoepithelial tumours of the breast was analysed immunohistochemically with antibodies directed against various cytokeratins, p63, smooth muscle alpha-actin (SMA and vimentin. Additionally, double immunofluorescence and comparative genomic hybridisation (CGH was performed. Results Immunohistochemically, all the tumours showed a constant expression of high molecular weight cytokeratins (Ck Ck5 and Ck14, p63, SMA and vimentin. With exception of one case diagnosed as myoepithelial carcinoma, all tested tumours expressed low molecular weight cytokeratin Ck18 in variable proportions of cells. Even in monophasic tumours lacking obvious glandular differentiation in conventional staining, a number of neoplastic cells still expressed those cytokeratins. Double immunofluorescence revealed tumour cells exclusively staining for Ck5/Ck14 in the presence of other cell populations that co-expressed high molecular weight Ck5/Ck14 as well as either low molecular weight Ck8/18 or SMA. Based on morphology, we assigned the series to three categories, benign, borderline and malignant. This classification was supported by a stepwise increase in cytogenetic alterations on CGH. Conclusion Adenomyoepithelial tumours comprise a spectrum of neoplasms consisting of an admixture of glandular and myoepithelial differentiation patterns. As a key component SMA-positive cells co-expressing cytokeratins could be identified. Although categorisation of adenomyoepithelial tumours in benign, borderline and malignant was supported by results of CGH, any assessment of prognosis requires to be firmly based on morphological grounds. At present

  10. Effects of tumour mass and circulating antigen on the biodistribution of 111In-labelled F(ab')2 fragments of human prostatic acid phosphatase monoclonal antibody in nude mice bearing PC-82 human prostatic tumor xenografts

    International Nuclear Information System (INIS)

    We have evaluated the effects of tumour mass and circulating antigen (prostatic acid phosphatase, PAP) on the biodistribution and the incorporation of 111In-labelled F(ab')2 monoclonal antibody (MoAb) fragments directed against human PAP into human prostatic tumours (PC-82; 0.1-8.9 g) growing in nude mice. The radioactivities in the blood, liver, spleen, kidney and tumour were compared at 1, 3, 4 and 6 days after the intravenous administration of the antibody fragments. There was a significant correlation between the tumour size and the serum PAP concentration in the model employed. Even tissue of a small tumour (111In-labelled F(ab')2 fragments. This relationship had levelled off by 72 h and most likely reflected a better vascularisation of the smaller tumours. Our results show that the increase in tumour size and in the concentration of circulating antigen in the blood led to decreased tumour-to-blood ratios, since there was a tendency for higher blood activities in mice with larger tumours and higher serum PAP concentrations. There was no correlation between tumour size and label uptake by the liver during the follow-up over 144 h, although serum PAP concentrations ranged from 3.1 μg/l to 352 μg/l. On the other hand, when compared with our previous data obtained with non-tumour-bearing mice, there was a significant increase in the uptake by the liver and spleen. These results indicate that even a small concentration of circulating antigen was able to trigger an abnormal change in the biodistribution of MoAbs. (orig.)

  11. Sensitivity of locally recurrent rat mammary tumour cell lines to syngeneic polymorphonuclear cell, macrophage and natural killer cell cytolysis.

    OpenAIRE

    Aeed, P. A.; Welch, D. R.

    1988-01-01

    Using a recently developed model for studying the biology of locally recurrent (LR) mammary tumours in the 13762NF rat mammary adenocarcinoma system, we examined the sensitivity to polymorphonuclear cell, macrophage and natural killer cell cytolysis. The parental MTF7(T20) cell line; the 'primary' tumours which arose following subcutaneous inoculation into the mammary fat pad, sc1 and sc3; and the local recurrences (following surgical excision) LR1 and LR1a from sc1, and LR3 from sc3 were all...

  12. Circulating tumor cells in oral squamous cell carcinoma: An insight

    Directory of Open Access Journals (Sweden)

    B V Prakruthi

    2015-01-01

    Full Text Available Circulating tumor cells (CTCs are those cells present in the blood and have antigenic and/or genetic characteristics of a specific tumor type. CTCs can be detected in the peripheral blood of cancer patients. Various techniques are available for detection of CTCs, which provide evidence for future metastasis. CTCs may provide new insight into the biology of cancer and process of metastasis in oral squamous cell carcinoma (OSCC. The detection of CTCs may represent a new diagnostic tool for predicting the occurrence of metastatic disease in OSCC and endow with the treatment strategies to efficiently treat and prevent cancer metastasis. This review gives an insight into the significance of CTCs and different techniques for detection of CTCs.

  13. Lessons from T cell responses to virus induced tumours for cancer eradication in general.

    Science.gov (United States)

    Melief, C J; Kast, W M

    1992-01-01

    Immunotherapy of virus induced tumours by adoptive transfer of virus specific cytotoxic T cells (CTL) is now feasible in experimental murine systems. These CTL recognize viral peptide sequences of defined length presented in the groove of MHC class I molecules. Effective eradication of large tumour masses requires coadministration of IL-2. In essence, T cell immunity against virus induced tumours does not differ from anti-viral T cell immunity in general. Tumour escape strategies are numerous but, in various instances, can be counteracted by defined measures. Initiation of CTL responses against poorly immunogenic non-virus induced tumours (the majority of human cancer) requires novel strategies to overcome T cell inertia. Rather than waiting to see whether tumour specific CTL (against unknown antigens) can be cultured from TIL, we propose an alternative strategy in which CTL are raised against target molecules of choice, including differentiation antigens of restricted tissue distribution (autoantigens) or mutated/overexpressed oncogene products. The various steps proposed include: (a) identification of target molecules of choice; (b) identification in these target molecules of MHC allele specific peptide motifs involved in peptide binding to MHC molecules; (c) evaluation of actual binding of such peptides to specific MHC class I molecules; (d) in vitro CTL response induction by such peptides, presented either by highly efficient antigen presenting cells (such as processing defective cells, which carry empty MHC class I molecules) loaded with a single peptide or by dendritic cells, both cell types being capable of primary CTL response induction in vitro and (e) adoptive transfer of tumour specific CTL generated in vivo or, more conveniently, vaccination with immunodominant peptides. The latter possibility seems to be feasible because peptide vaccination with a single immunodominant viral peptide can install CTL memory and confer protection against lethal virus

  14. Human germ cell tumours: expression of γ-glutamyl transpeptidase and sensitivity to cisplatin

    OpenAIRE

    Hanigan, M H; Frierson, H F; Abeler, V. M.; Kaern, J; Taylor, P T

    1999-01-01

    Previous studies have shown that the enzyme γ-glutamyl transpeptidase (GGT) is essential for the nephrotoxicity of cisplatin. This study was designed to determine whether GGT activity is necessary for the therapeutic effect of the drug. The relationship between GGT expression and clinical response to platinum-based chemotherapy was examined in 41 human germ cell tumours. Sections of formalin-fixed, paraffin-embedded tumours were immunohistochemically stained with an antibody directed against ...

  15. Circulating cancer stem cells: the importance to select.

    Science.gov (United States)

    Yang, Ming-Hsin; Imrali, Ahmet; Heeschen, Christopher

    2015-10-01

    It has been demonstrated that even localized tumors without clinically apparent metastasis give rise to circulating tumor cells (CTCs). A growing number of technically diverse platforms are being developed for detecting/isolating CTCs in the circulating blood. Despite the technical challenges of isolating rare CTCs from blood, recent studies have already shown the predictive value of CTCs enumeration. Thus, it is becoming increasingly accepted that CTC numbers are linked to patients' outcome and may also be used to monitor treatment response and disease relapse, respectively. Further CTCs provide a non-invasive source for tumor material, 'liquid biopsy', which is particularly important for patients, where no biopsy material can be obtained or where serial biopsies of the tumor, e.g., following treatment, are practically impossible. On the other hand the molecular and biological characterization of CTCs has still remained at a rather experimental stage. Future studies are necessary to define CTC heterogeneity to establish the crucial role of circulating cancer stem cells for driving metastasis, which represent a distinct subpopulation of CTCs that bear metastasis-initiating capabilities based on their stemness properties and invasiveness and thus are critical for the patients' clinical outcome. As compared to non-tumorigenic/metastatic bulk CTCs, circulating cancer stem cells may not only be capable of evading from the primary tumor, but also escape from immune surveillance, survive in the circulating blood and subsequently form metastases in distant organs. Thus, circulating cancer stem cells represent a subset of exclusively tumorigenic cancer stem cells characterized by their invasive characteristics and are potential therapeutic targets for preventing disease progression. To date, only a few original reports and reviews have been published focusing on circulating cancer stem cells. This review discusses the potential importance of isolating and characterizing

  16. Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: quantification of tumour hypoxia, metabolism and perfusion

    Energy Technology Data Exchange (ETDEWEB)

    Elmpt, Wouter van; Zegers, Catharina M.L.; Reymen, Bart; Even, Aniek J.G.; Oellers, Michel; Troost, Esther G.C.; Lambin, Philippe [Maastricht University Medical Centre, Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); Dingemans, Anne-Marie C. [Maastricht University Medical Centre, Department of Pulmonology, GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); Wildberger, Joachim E.; Das, Marco [Maastricht University Medical Centre, Department of Radiology, GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); Mottaghy, Felix M. [Maastricht University Medical Centre, Department of Nuclear Medicine, GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); University Hospital RWTH Aachen University, Department of Nuclear Medicine, Aachen (Germany)

    2016-02-15

    Multiple imaging techniques are nowadays available for clinical in-vivo visualization of tumour biology. FDG PET/CT identifies increased tumour metabolism, hypoxia PET visualizes tumour oxygenation and dynamic contrast-enhanced (DCE) CT characterizes vasculature and morphology. We explored the relationships among these biological features in patients with non-small-cell lung cancer (NSCLC) at both the patient level and the tumour subvolume level. A group of 14 NSCLC patients from two ongoing clinical trials (NCT01024829 and NCT01210378) were scanned using FDG PET/CT, HX4 PET/CT and DCE CT prior to chemoradiotherapy. Standardized uptake values (SUV) in the primary tumour were calculated for the FDG and hypoxia HX4 PET/CT scans. For hypoxia imaging, the hypoxic volume, fraction and tumour-to-blood ratio (TBR) were also defined. Blood flow and blood volume were obtained from DCE CT imaging. A tumour subvolume analysis was used to quantify the spatial overlap between subvolumes. At the patient level, negative correlations were observed between blood flow and the hypoxia parameters (TBR >1.2): hypoxic volume (-0.65, p = 0.014), hypoxic fraction (-0.60, p = 0.025) and TBR (-0.56, p = 0.042). At the tumour subvolume level, hypoxic and metabolically active subvolumes showed an overlap of 53 ± 36 %. Overlap between hypoxic sub-volumes and those with high blood flow and blood volume was smaller: 15 ± 17 % and 28 ± 28 %, respectively. Half of the patients showed a spatial mismatch (overlap <5 %) between increased blood flow and hypoxia. The biological imaging features defined in NSCLC tumours showed large interpatient and intratumour variability. There was overlap between hypoxic and metabolically active subvolumes in the majority of tumours, there was spatial mismatch between regions with high blood flow and those with increased hypoxia. (orig.)

  17. Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: quantification of tumour hypoxia, metabolism and perfusion

    International Nuclear Information System (INIS)

    Multiple imaging techniques are nowadays available for clinical in-vivo visualization of tumour biology. FDG PET/CT identifies increased tumour metabolism, hypoxia PET visualizes tumour oxygenation and dynamic contrast-enhanced (DCE) CT characterizes vasculature and morphology. We explored the relationships among these biological features in patients with non-small-cell lung cancer (NSCLC) at both the patient level and the tumour subvolume level. A group of 14 NSCLC patients from two ongoing clinical trials (NCT01024829 and NCT01210378) were scanned using FDG PET/CT, HX4 PET/CT and DCE CT prior to chemoradiotherapy. Standardized uptake values (SUV) in the primary tumour were calculated for the FDG and hypoxia HX4 PET/CT scans. For hypoxia imaging, the hypoxic volume, fraction and tumour-to-blood ratio (TBR) were also defined. Blood flow and blood volume were obtained from DCE CT imaging. A tumour subvolume analysis was used to quantify the spatial overlap between subvolumes. At the patient level, negative correlations were observed between blood flow and the hypoxia parameters (TBR >1.2): hypoxic volume (-0.65, p = 0.014), hypoxic fraction (-0.60, p = 0.025) and TBR (-0.56, p = 0.042). At the tumour subvolume level, hypoxic and metabolically active subvolumes showed an overlap of 53 ± 36 %. Overlap between hypoxic sub-volumes and those with high blood flow and blood volume was smaller: 15 ± 17 % and 28 ± 28 %, respectively. Half of the patients showed a spatial mismatch (overlap <5 %) between increased blood flow and hypoxia. The biological imaging features defined in NSCLC tumours showed large interpatient and intratumour variability. There was overlap between hypoxic and metabolically active subvolumes in the majority of tumours, there was spatial mismatch between regions with high blood flow and those with increased hypoxia. (orig.)

  18. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression

    Directory of Open Access Journals (Sweden)

    Johannsen Manfred

    2008-06-01

    Full Text Available Abstract Background A Disintegrin And Metalloprotease (ADAM 9 has been implicated in tumour progression of various solid tumours, however, little is known about its role in renal cell carcinoma. We evaluated the expression of ADAM9 on protein and transcript level in a clinico-pathologically characterized renal cell cancer cohort. Methods 108 renal cancer cases were immunostained for ADAM9 on a tissue-micro-array. For 30 additional cases, ADAM9 mRNA of microdissected tumour and normal tissue was analyzed via quantitative RT-PCR. SPSS 14.0 was used to apply crosstables (Fisher's exact test and χ2-test, correlations and univariate as well as multivariate survival analyses. Results ADAM9 was significantly up-regulated in renal cancer in comparison to the adjacent normal tissue on mRNA level. On protein level, ADAM9 was significantly associated with higher tumour grade, positive nodal status and distant metastasis. Furthermore, ADAM9 protein expression was significantly associated with shortened patient survival in the univariate analysis. Conclusion ADAM9 is strongly expressed in a large proportion of renal cell cancers, concordant with findings in other tumour entities. Additionally, ADAM9 expression is significantly associated with markers of unfavourable prognosis. Whether the demonstrated prognostic value of ADAM9 is independent from other tumour parameters will have to be verified in larger study cohorts.

  19. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression

    International Nuclear Information System (INIS)

    A Disintegrin And Metalloprotease (ADAM) 9 has been implicated in tumour progression of various solid tumours, however, little is known about its role in renal cell carcinoma. We evaluated the expression of ADAM9 on protein and transcript level in a clinico-pathologically characterized renal cell cancer cohort. 108 renal cancer cases were immunostained for ADAM9 on a tissue-micro-array. For 30 additional cases, ADAM9 mRNA of microdissected tumour and normal tissue was analyzed via quantitative RT-PCR. SPSS 14.0 was used to apply crosstables (Fisher's exact test and χ2-test), correlations and univariate as well as multivariate survival analyses. ADAM9 was significantly up-regulated in renal cancer in comparison to the adjacent normal tissue on mRNA level. On protein level, ADAM9 was significantly associated with higher tumour grade, positive nodal status and distant metastasis. Furthermore, ADAM9 protein expression was significantly associated with shortened patient survival in the univariate analysis. ADAM9 is strongly expressed in a large proportion of renal cell cancers, concordant with findings in other tumour entities. Additionally, ADAM9 expression is significantly associated with markers of unfavourable prognosis. Whether the demonstrated prognostic value of ADAM9 is independent from other tumour parameters will have to be verified in larger study cohorts

  20. Evidence of distinct tumour-propagating cell populations with different properties in primary human hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Federico Colombo

    Full Text Available BACKGROUND AND AIMS: Increasing evidence that a number of malignancies are characterised by tumour cell heterogeneity has recently been published, but there is still a lack of data concerning liver cancers. The aim of this study was to investigate and characterise tumour-propagating cell (TPC compartments within human hepatocellular carcinoma (HCC. METHODS: After long-term culture, we identified three morphologically different tumour cell populations in a single HCC specimen, and extensively characterised them by means of flow cytometry, fluorescence microscopy, karyotyping and microarray analyses, single cell cloning, and xenotransplantation in NOD/SCID/IL2Rγ/⁻ mice. RESULTS: The primary cell populations (hcc-1, -2 and -3 and two clones generated by means of limiting dilutions from hcc-1 (clone-1/7 and -1/8 differently expressed a number of tumour-associated stem cell markers, including EpCAM, CD49f, CD44, CD133, CD56, Thy-1, ALDH and CK19, and also showed different doubling times, drug resistance and tumorigenic potential. Moreover, we found that ALDH expression, in combination with CD44 or Thy-1 negativity or CD56 positivity identified subpopulations with a higher clonogenic potential within hcc-1, hcc-2 and hcc-3 primary cell populations, respectively. Karyotyping revealed the clonal evolution of the cell populations and clones within the primary tumour. Importantly, the primary tumour cell population with the greatest tumorigenic potential and drug resistance showed more chromosomal alterations than the others and contained clones with epithelial and mesenchymal features. CONCLUSIONS: Individual HCCs can harbor different self-renewing tumorigenic cell types expressing a variety of morphological and phenotypical markers, karyotypic evolution and different gene expression profiles. This suggests that the models of hepatic carcinogenesis should take into account TPC heterogeneity due to intratumour clonal evolution.

  1. Studies into characteristics of cancer stem cells and their role in the origin of epithelial tumours.

    OpenAIRE

    Burkert, J.

    2008-01-01

    Tumours are organised in a cellular hierarchy, originating in and maintained by a minority of cells with stem cell characteristics, so-called 'cancer stem cells'. The Side Population (SP) phenotype, distinguished by its ability to efflux the nucleic acid dye Hoechst 33342, as well as surface markers CD44 and CD133 were evaluated as potential cancer stem cell markers in human colorectal cancer cell lines and primary adenocarcinomas by testing sorted cell fractions for phenotypical and behaviou...

  2. Circulating mesenchymal stem cells and their clinical implications

    Directory of Open Access Journals (Sweden)

    Liangliang Xu

    2014-01-01

    Full Text Available Circulating mesenchymal stem cells (MSCs is a new cell source for tissue regeneration and tissue engineering. The characteristics of circulating MSCs are similar to those of bone marrow-derived MSCs (BM-MSCs, but they exist at a very low level in healthy individuals. It has been demonstrated that MSCs are able to migrate to the sites of injury and that they have some distinct genetic profiles compared to BM-MSCs. The current review summaries the basic knowledge of circulating MSCs and their potential clinical applications, such as mobilizing the BM-MSCs into circulation for therapy. The application of MSCs to cure a broad spectrum of diseases is promising, such as spinal cord injury, cardiovascular repair, bone and cartilage repair. The current review also discusses the issues of using of allogeneic MSCs for clinical therapy.

  3. Influence of tumours on protective anti-tumour immunity and the effects of irradiation

    Directory of Open Access Journals (Sweden)

    Gemma Ann Foulds

    2013-02-01

    Full Text Available Innate and adaptive immunity play important roles in the development and progression of cancer and it is becoming apparent that tumours can influence the induction of potentially protective responses in a number of ways. The prevalence of immunoregulatory T cell populations in the circulation and tumours of patients with cancer is increased, and the presence of these cells appears to present a major barrier to the induction of tumour immunity. One aspect of tumour-mediated immunoregulation which has received comparatively little attention is that which is directed towards natural killer (NK cells, although evidence that the phenotype and function of NK cell populations are modified in patients with cancer is accumulating.Although the precise mechanisms underlying these localised and systemic immunoregulatory effects remain unclear, tumour-derived factors appear, in part at least, to be involved. The effects could be manifested by an altered function and/or via an influence on the migratory properties of individual cell subsets. A better insight into endogenous immunoregulatory mechanisms and the capacity of tumours to modify the phenotype and function of innate and adaptive immune cells might assist the development of new immunotherapeutic approaches and improve the management of patients with cancer.This article reviews current knowledge relating to the influence of tumours on protective anti-tumour immunity and considers the potential influence that radiation-induced effects might have on the prevalence, phenotype and function of innate and adaptive immune cells in patients with cancer.

  4. Tumour dose uniformity in radiotherapy: experimental evidence for cell response to non-uniform irradiation

    International Nuclear Information System (INIS)

    A common goal of radiotherapy is the application of uniform radiation dose to the tumour volume. Such a goal has been formalized by the ICRU (ICRU 50, 1993), based on the assumption that cells respond independently and any under-dosed region represents an area with a higher probability to act as a recurrence site. However, dose distributions provided by intensity-modulated radiotherapy (IMRT) and other techniques offer opportunities to escalate tumour doses and greatly reduce normal tissue doses, with these effects enhanced further if dose non-uniformity is allowed in the tumour. A study of the response of several tumour cell lines has suggested an averaging effect if those cells are exposed to a gradient rather then a uniform dose. A study was performed with cell cultures exposed in a 6 MV X-ray beam in full equilibrium conditions with the beam modulated by a wedge filter. With cell communication channels open, cells exposed at the lower or higher dose ends of the wedge responded as if irradiated to mean dose levels, with the severity of this effect dependent on cell type. A possible explanation for this effect is cellular communication. When cells are irradiated with communication channels physically blocked, the normal dose response experienced under uniform irradiation conditions results. There are significant implications of this result for radiotherapy treatment and prescription, dependent primarily on translation of the results to the clinical setting. The ability to deliver largely non-uniform doses to tumours would greatly facilitate normal tissue avoidance and enhance our ability to escalate doses to tumours. This result can also be used to explain some recent observations regarding dose-response extracted from clinical trial data

  5. Infrared laser pulse triggers increased singlet oxygen production in tumour cells

    Science.gov (United States)

    Sokolovski, S. G.; Zolotovskaya, S. A.; Goltsov, A.; Pourreyron, C.; South, A. P.; Rafailov, E. U.

    2013-12-01

    Photodynamic therapy (PDT) is a technique developed to treat the ever-increasing global incidence of cancer. This technique utilises singlet oxygen (1O2) generation via a laser excited photosensitiser (PS) to kill cancer cells. However, prolonged sensitivity to intensive light (6-8 weeks for lung cancer), relatively low tissue penetration by activating light (630 nm up to 4 mm), and the cost of PS administration can limit progressive PDT applications. The development of quantum-dot laser diodes emitting in the highest absorption region (1268 nm) of triplet oxygen (3O2) presents the possibility of inducing apoptosis in tumour cells through direct 3O2 --> 1O2 transition. Here we demonstrate that a single laser pulse triggers dose-dependent 1O2 generation in both normal keratinocytes and tumour cells and show that tumour cells yield the highest 1O2 far beyond the initial laser pulse exposure. Our modelling and experimental results support the development of direct infrared (IR) laser-induced tumour treatment as a promising approach in tumour PDT.

  6. CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment.

    Science.gov (United States)

    Zhang, Tao; Tseng, Chieh; Zhang, Yan; Sirin, Olga; Corn, Paul G; Li-Ning-Tapia, Elsa M; Troncoso, Patricia; Davis, John; Pettaway, Curtis; Ward, John; Frazier, Marsha L; Logothetis, Christopher; Kolonin, Mikhail G

    2016-01-01

    White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that αSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression. PMID:27241286

  7. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting

    Directory of Open Access Journals (Sweden)

    Sander A. A. Kooijmans

    2016-03-01

    Full Text Available Background: Extracellular vesicles (EVs are attractive candidate drug delivery systems due to their ability to functionally transport biological cargo to recipient cells. However, the apparent lack of target cell specificity of exogenously administered EVs limits their therapeutic applicability. In this study, we propose a novel method to equip EVs with targeting properties, in order to improve their interaction with tumour cells. Methods: EV producing cells were transfected with vectors encoding for anti-epidermal growth factor receptor (EGFR nanobodies, which served as targeting ligands for tumour cells, fused to glycosylphosphatidylinositol (GPI anchor signal peptides derived from decay-accelerating factor (DAF. EVs were isolated using ultrafiltration/size-exclusion liquid chromatography and characterized using western blotting, Nanoparticle Tracking Analysis, and electron microscopy. EV–tumour cell interactions were analyzed under static conditions using flow cytometry and under flow conditions using a live-cell fluorescence microscopy-coupled perfusion system. Results: V analysis showed that GPI-linked nanobodies were successfully displayed on EV surfaces and were highly enriched in EVs compared with parent cells. Display of GPI-linked nanobodies on EVs did not alter general EV characteristics (i.e. morphology, size distribution and protein marker expression, but greatly improved EV binding to tumour cells dependent on EGFR density under static conditions. Moreover, nanobody-displaying EVs showed a significantly improved cell association to EGFR-expressing tumour cells under flow conditions. Conclusions: We show that nanobodies can be anchored on the surface of EVs via GPI, which alters their cell targeting behaviour. Furthermore, this study highlights GPI-anchoring as a new tool in the EV toolbox, which may be applied for EV display of a variety of proteins, such as antibodies, reporter proteins and signaling molecules.

  8. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models.

    LENUS (Irish Health Repository)

    Donatello, Simona

    2011-01-01

    Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression.

  9. Tumour-infiltrating lymphocytes mediate lysis of autologous squamous cell carcinomas of the head and neck

    DEFF Research Database (Denmark)

    Hald, Jeppe; Rasmussen, N; Claesson, Mogens Helweg

    1995-01-01

    , the cancer cells either overexpressed the tumour-suppressor gene product p53 or harboured human papilloma virus 16/18 (HPV). The TIL were expanded in vitro in the presence of interleukin-2, immobilised anti-CD3 mAb and soluble anti-CD28 mAb. Expanded TIL cultures contained both CD4+ and CD8+ T cells...

  10. Expression of core clock genes in colorectal tumour cells compared with normal mucosa

    DEFF Research Database (Denmark)

    Fonnes, S; Donatsky, A M; Gögenur, I

    2015-01-01

    AIM: Experimental studies have shown that some circadian core clock genes may act as tumour suppressors and have an important role in the response to oncological treatment. This study investigated the evidence regarding modified expression of core clock genes in colorectal cancer and its...... expression of colorectal cancer cells compared with healthy mucosa cells from specimens analysed by real-time or quantitative real-time polymer chain reaction. The expression of the core clock genes Period, Cryptochrome, Bmal1 and Clock in colorectal tumours were compared with healthy mucosa and correlated...... of Clock. Other core clock genes did not appear to be differentially expressed. Decreased Period gene expression was correlated to some clinicopathological features. CONCLUSION: The Period genes seemed to be modified in colorectal tumour cells compared with normal mucosa. Core clock genes might be...

  11. Tumour thrombus consistency has no impact on survival in patients with renal cell carcinoma.

    Science.gov (United States)

    Gołąbek, T; Przydacz, M; Okoń, K; Kopczyński, J; Bukowczan, J; Sobczyński, R; Curyło, Ł; Gołąbek, K; Curyło, Ł; Chłosta, P

    2016-06-01

    The prognosis of renal cell carcinoma (RCC) with venous tumour thrombus (VTT) is variable and not always possible to predict. The prognostic impact and independence of tumour thrombus-related factors including the recently introduced tumour thrombus consistency (TTC) on overall survival remain controversial. The aim of this study was to investigate the prognostic role of TTC in patients' survival. We determined the tumour thrombus consistency (solid vs. friable) in a cohort of 84 patients with RCC and VTT who underwent nephrectomy with thrombectomy, and performed a retrospective evaluation of the patients' data from the prospectively maintained database. A total of 45% of patients had solid thrombus (sTT) and 55% had friable thrombus (fTT). The venous tumour thrombus consistency was not predictive of overall survival. Further studies, preferably prospective and with a larger number of patients, are needed to validate the obtained results, as well as to evaluate the usefulness of tumour thrombus consistency in clinical practice for stratifying the risk of recurrence and planning further follow-up. PMID:27543869

  12. Effects of D2O on biochemical parameters of normal cells and tumour cells

    International Nuclear Information System (INIS)

    The influence of high temperatures (Hyperthermia) on normal tissue and Ehrlich-Ascites tumour cells ('ATZ') was examined under several conditions with regard to the application of deuterium oxide as a stabilising factor. It was proven that the DNA-synthesis of normal tissue (liver, mouse) is not sensitive to temperature. This effect of hyperthermia only occurs when the tissue is damaged, e.g. by trypsinising. The influence of hyperthermia on several biochemical parameters and on morphological changes of the Ascites cells was examined. The findings show that deuterium oxide (D2O) is able to reduce both the thermal and the ureal denaturation of enzymes. Thus tests were carried out to find out if D2O also reduces toxic influence in complicated biological systems. The assumption of high D2O concentrations to prevent several reactions was confirmed. When the Ascites tumour cells in the H2O-buffer were exposed to the damaging influence of hyperthermia, the high degree of damage was seen with the decreasing DNA synthesis, reduced aerobic glycose capacity, a drop in the ATP values and breakdown of the permeability of the membrane. Deuterium oxide was able under high temperature (from appr. 440C on) to reduce the degree of damage to DNA synthesis, while auto-effects (inhibition of synthesis) of D2O predominate in the lower region. Aerobic glycolysis was damaged in both cases to the same degree, however. In D2O after hyperthermia the ATP-level dropped faster than in H2O. D2O not only reduces the thermal denaturation of the Ascites tumour cells, but it also eliminates the toxic influence of the zytostaticum TRENIMONsup(R) (under 380 or 460C incubation). (orig./AJ)

  13. Small round blue cell tumours: diagnostic and prognostic usefulness of the expression of B7-H3 surface molecule

    OpenAIRE

    Gregorio, A.; Corrias, M V; R. Castriconi; Dondero, A; Mosconi, M.; Gambini, C; Moretta, A; Moretta, L; Bottino, C

    2008-01-01

    Aims: To assess whether the expression of B7-H3 surface molecule could improve differential diagnosis of small cell round tumours. Methods and results: One hundred and one well-characterized paraffin-embedded small round cell tumours, stored in the pathology archive of the Gaslini Institute, were immunohistochemically analysed with the 5B14 monoclonal antibody, which recognizes the surface molecule B7-H3. All lymphoblastic lymphomas and the blastematous component of Wilms’ tumours were comple...

  14. Steroid hormones affect binding of the sigma ligand {sup 11}C-SA4503 in tumour cells and tumour-bearing rats

    Energy Technology Data Exchange (ETDEWEB)

    Rybczynska, Anna A.; Elsinga, Philip H.; Sijbesma, Jurgen W.; Jong, Johan R. de; Vries, Erik F. de; Dierckx, Rudi A.; Waarde, Aren van [University of Groningen, Nuclear Medicine and Molecular Imaging, University of Groningen Medical Center, Groningen (Netherlands); Ishiwata, Kiichi [Tokyo Metropolitan Institute of Gerontology, Positron Medical Center, Tokyo (Japan)

    2009-07-15

    Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist {sup 11}C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. {sup 11}C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Binding of {sup 11}C-SA4503 to C6 cells was increased ({proportional_to}50%) upon removal and decreased ({proportional_to}60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC{sub 50} progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of {sup 11}C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. The binding of {sup 11}C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids. (orig.)

  15. Steroid hormones affect binding of the sigma ligand 11C-SA4503 in tumour cells and tumour-bearing rats

    International Nuclear Information System (INIS)

    Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist 11C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. 11C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Binding of 11C-SA4503 to C6 cells was increased (∝50%) upon removal and decreased (∝60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC50 progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of 11C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. The binding of 11C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids. (orig.)

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

    KAUST Repository

    Cima, Igor

    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.

  17. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting

    OpenAIRE

    Sander A. A. Kooijmans; Gómez Aleza, Clara; Roffler, Steve R; van Solinge, Wouter W.; Vader, Pieter; Schiffelers, Raymond M.

    2016-01-01

    Background: Extracellular vesicles (EVs) are attractive candidate drug delivery systems due to their ability to functionally transport biological cargo to recipient cells. However, the apparent lack of target cell specificity of exogenously administered EVs limits their therapeutic applicability. In this study, we propose a novel method to equip EVs with targeting properties, in order to improve their interaction with tumour cells.Methods: EV producing cells were transfected with vectors enco...

  18. Diagnostic Efficacy of Radiology in the Diagnosis of Giant Cell Tumour of Bone

    OpenAIRE

    Afia Akhter; Mohammad Serajus Saleheen; Nadira Majid; Syed Salahuddin; Kwazi Dil Afroz; Md Rezwanur Rahman; Syed Makarram Ali

    2014-01-01

    Background: Giant cell tumour (GCT) is an aggressive and potentially malignant lesion. Microscopic feature reveals osteoclast like giant cells in a mononuclear stromal cells background. The mononuclear stromal cell is interpreted as neoplastic. Objective: As radiological diagnosis is non invasive and cost effective in comparison to histopathological diagnosis, considering the patients’ compliance, the aim of the study was to observe the diagnostic efficacy of radiology in diagnosis of GCT...

  19. Circulating Tumor Cell Composition in Renal Cell Carcinoma

    Science.gov (United States)

    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

  20. Modelling tumour cell proliferation from vascular structure using tissue decomposition into avascular elements.

    Science.gov (United States)

    Besenhard, Maximilian O; Jarzabek, Monika; O'Farrell, Alice C; Callanan, John J; Prehn, Jochen Hm; Byrne, Annette T; Huber, Heinrich J

    2016-08-01

    Computer models allow the mechanistically detailed study of tumour proliferation and its dependency on nutrients. However, the computational study of large vascular tumours requires detailed information on the 3-dimensional vessel network and rather high computation times due to complex geometries. This study puts forward the idea of partitioning vascularised tissue into connected avascular elements that can exchange cells and nutrients between each other. Our method is able to rapidly calculate the evolution of proliferating as well as dead and quiescent cells, and hence a proliferative index, from a given amount and distribution of vascularisation of arbitrary complexity. Applying our model, we found that a heterogeneous vessel distribution provoked a higher proliferative index, suggesting increased malignancy, and increased the amount of dead cells compared to a more static tumour environment when a homogenous vessel distribution was assumed. We subsequently demonstrated that under certain amounts of vascularisation, cell proliferation may even increase when vessel density decreases, followed by a subsequent decrease of proliferation. This effect was due to a trade-off between an increase in compensatory proliferation for replacing dead cells and a decrease of cell population due to lack of oxygen supply in lowly vascularised tumours. Findings were illustrated by an ectopic colorectal cancer mouse xenograft model. Our presented approach can be in the future applied to study the effect of cytostatic, cytotoxic and anti-angiogenic chemotherapy and is ideally suited for translational systems biology, where rapid interaction between theory and experiment is essential. PMID:27155046

  1. Interferon regulatory factor-8 modulates the development of tumour-induced CD11b+Gr-1+ myeloid cells.

    Science.gov (United States)

    Stewart, Trina J; Greeneltch, Kristy M; Reid, Julia E; Liewehr, David J; Steinberg, Seth M; Liu, Kebin; Abrams, Scott I

    2009-09-01

    Tumour-induced myeloid-derived suppressor cells (MDSC) promote immune suppression and mediate tumour progression. However, the molecular basis for the generation of MDSC, which in mice co-express the CD11b(+) and Gr-1(+) cell surface markers remains unclear. Because CD11b(+)Gr-1(+) cells expand during progressive tumour growth, this suggests that tumour-induced events alter signalling pathways that affect normal myeloid cell development. Interferon regulatory factor-8 (IRF-8), a member of the IFN-gamma regulatory factor family, is essential for normal myelopoiesis. We therefore examined whether IRF-8 modulated tumour-induced CD11b(+)Gr-1(+) cell development or accumulation using both implantable (4T1) and transgenic (MMTV-PyMT) mouse models of mammary tumour growth. In the 4T1 model, both splenic and bone marrow-derived CD11b(+)Gr-1(+) cells of tumour-bearing mice displayed a marked reduction in IRF-8 expression compared to control populations. A causal link between IRF-8 expression and the emergence of tumour-induced CD11b(+)Gr-1(+) cells was explored in vivo using a double transgenic (dTg) mouse model designed to express transgenes for both IRF-8 and mammary carcinoma development. Despite the fact that tumour growth was unaffected, splenomegaly, as well as the frequencies and absolute numbers of CD11b(+)Gr-1(+) cells were significantly lower in dTg mice when compared with single transgenic tumour-bearing mice. Overall, these data reveal that IRF-8 plays an important role in tumour-induced development and/or accumulation of CD11b(+)Gr-1(+) cells, and establishes a molecular basis for the potential manipulation of these myeloid populations for cancer therapy. PMID:20196788

  2. An evolutionary-game model of tumour-cell interactions: possible relevance to gene therapy

    DEFF Research Database (Denmark)

    Bach, Lars Arve; Bentzen, Søren; Alsner, Jan;

    2001-01-01

    interpretations of gene therapy. Two prototypical strategies for gene therapy are suggested, both of them leading to extinction of the malignant phenotype: one approach would be to reduce the relative proportion of the cooperating malignant cell type below a certain critical value. Another approach would be to......Evolutionary games have been applied as simple mathematical models of populations where interactions between individuals control the dynamics. Recently, it has been proposed to use this type of model to describe the evolution of tumour cell populations with interactions between cells. We extent the...... analysis to allow for synergistic effects between cells. A mathematical model of a tumour cell population is presented in which population-level synergy is assumed to originate through the interaction of triplets of cells. A threshold of two cooperating cells is assumed to be required to produce a...

  3. The evolution of carrying capacity in constrained and expanding tumour cell populations

    Science.gov (United States)

    Gerlee, Philip; Anderson, Alexander R. A.

    2015-10-01

    Cancer cells are known to modify their micro-environment such that it can sustain a larger population, or, in ecological terms, they construct a niche which increases the carrying capacity of the population. It has however been argued that niche construction, which benefits all cells in the tumour, would be selected against since cheaters could reap the benefits without paying the cost. We have investigated the impact of niche specificity on tumour evolution using an individual based model of breast tumour growth, in which the carrying capacity of each cell consists of two components: an intrinsic, subclone-specific part and a contribution from all neighbouring cells. Analysis of the model shows that the ability of a mutant to invade a resident population depends strongly on the specificity. When specificity is low selection is mostly on growth rate, while high specificity shifts selection towards increased carrying capacity. Further, we show that the long-term evolution of the system can be predicted using adaptive dynamics. By comparing the results from a spatially structured versus well-mixed population we show that spatial structure restores selection for carrying capacity even at zero specificity, which poses a solution to the niche construction dilemma. Lastly, we show that an expanding population exhibits spatially variable selection pressure, where cells at the leading edge exhibit higher growth rate and lower carrying capacity than those at the centre of the tumour.

  4. Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours

    DEFF Research Database (Denmark)

    Hoei-Hansen, C E; Almstrup, K; Nielsen, J E;

    2005-01-01

    AIMS: NANOG is a key regulator of embryonic stem cell (ESC) self-renewal and pluripotency. Our recent genome-wide gene expression profiling study of the precursor of testicular germ cell tumours, carcinoma in situ testis (CIS), showed close similarity between ESC and CIS, including high NANOG...... expression. In the present study we analysed the protein expression of NANOG during normal development of human testis and in a large series of neoplastic/dysgenetic specimens. METHODS AND RESULTS: We detected abundant expression of NANOG in CIS and in CIS-derived testicular tumours with marked differences...... earlier than for OCT-4. We detected no expression at the protein level in normal testis. CONCLUSIONS: NANOG is a new marker for testicular CIS and germ cell tumours and the high level of NANOG along with OCT-4 are determinants of the stem cell-like pluripotency of the preinvasive CIS cell. Timing of NANOG...

  5. Semiquantitative determination of circulating islet cell surface antibodies in diabetes

    International Nuclear Information System (INIS)

    Circulating pancreatic islet cell antibodies have been demonstrated in patients with insulin-dependent diabetes (IDD). The islet cell surface antibodies (ICSA) were determined by an indirect immunofluorescence test using a suspension of viable islet cells, and similar cytoplasmic antibodies which require the use of group O human pancreas were also found in the serum of some patients. A strong association exists between the presence of islet cell antibodies and the onset of insulin-dependent diabetes. The quantitative determination of circulating ICSA using 125I-protein A, which binds to IgG attached to the islet cell surface, was essentially as described by Lernmark et al. In the present study, we determined the circulating ICSA in diabetes, especially in IDD. The ICSA were estimated in various sera from both indirect immunofluorescence and 125I-protein A. Controls bound 125I-protein A. Sera from 4 IDD patients with circulating ICSA demonstrated by immunofluorescence showed >3,000 cpm 125I-protein A binding activity, and that from 5 patients without ICSA bound <2,000 cpm. Sera from newly-diagnosed diabetics who had severe hyperglycemia showed <2,000 cpm, with or without ICSA. (author)

  6. Sex determination by SRY PCR and sequencing of Tasmanian devil facial tumour cell lines reveals non-allograft transmission.

    Science.gov (United States)

    Cui, Xianlan; Wang, Yunfeng; Hua, Bobby; Miller, Webb; Zhao, Yan; Cui, Hongyu; Kong, Xiangang

    2016-05-20

    Devil facial tumour disease (DFTD) is an infectious tumour disease and was hypothesised to be transmitted by allograft during biting based on two cytogenetic findings of DFTD tumours in 2006. It was then believed that DFTD tumours were originally from a female devil. In this study the devil sex-determining region Y (SRY) gene was PCR amplified and sequenced, and six pairs of devil SRY PCR primers were used for detection of devil SRY gene fragments in purified DFTD tumour cell lines. Using three pairs of devil SRY PCR primers, devil SRY gene sequence was detected by PCR and sequencing in genomic DNA of DFTD tumour cell lines from six male devils, but not from six female devils. Four out of six DFTD tumour cell lines from male devils contained nucleotides 288-482 of the devil SRY gene, and another two DFTD tumour cell lines contained nucleotides 381-577 and 493-708 of the gene, respectively. These results indicate that the different portions of the SRY gene in the DFTD tumours of the male devils were originally from the male hosts, rejecting the currently believed DFTD allograft transmission theory. The reasons why DFTD transmission was incorrectly defined as allograft are discussed. PMID:27084454

  7. MPLA incorporation into DC-targeting glycoliposomes favours anti-tumour T cell responses.

    Science.gov (United States)

    Boks, Martine A; Ambrosini, Martino; Bruijns, Sven C; Kalay, Hakan; van Bloois, Louis; Storm, Gert; Garcia-Vallejo, Juan J; van Kooyk, Yvette

    2015-10-28

    Dendritic cells (DC) are attractive targets for cancer immunotherapy as they initiate strong and long-lived tumour-specific T cell responses. DC can be effectively targeted in vivo with tumour antigens by using nanocarriers such as liposomes. Cross-presentation of tumour antigens is enhanced with strong adjuvants such as TLR ligands. However, often these adjuvants have off-target effects, and would benefit from a DC-specific targeting strategy, similar to the tumour antigen. The goal of this study was to develop a strategy for specifically targeting DC with tumour antigen and adjuvant by using glycoliposomes. We have generated liposomes containing the glycan Lewis(Le)(X) which is highly specific for the C-type lectin receptor DC-SIGN expressed by DC. Le(X)-modified liposomes were taken up by human monocyte-derived DC in a DC-SIGN-specific manner. As adjuvants we incorporated the TLR ligands Pam3CySK4, Poly I:C, MPLA and R848 into liposomes and compared their adjuvant capacity on DC. Incorporation of the TLR4 ligand MPLA into glycoliposomes induced DC maturation and production of pro-inflammatory cytokines, in a DC-SIGN-specific manner, and DC activation was comparable to administration of soluble MPLA. Incorporation of MPLA into glycoliposomes significantly enhanced antigen cross-presentation of the melanoma tumour antigen gp100280-288 peptide to CD8(+) T cells compared to non-glycosylated MPLA liposomes. Importantly, antigen cross-presentation of the gp100280-288 peptide was significantly higher using MPLA glycoliposomes compared to the co-administration of soluble MPLA with glycoliposomes. Taken together, our data demonstrates that specific targeting of a gp100 tumour antigen and the adjuvant MPLA to DC-SIGN-expressing DC enhances the uptake of peptide-containing liposomes, the activation of DC, and induces tumour antigen-specific CD8(+) T cell responses. These data demonstrate that adjuvant-containing glycoliposome-based vaccines targeting DC-SIGN(+) DC

  8. The evaluation of in vitro effect of daunorubicin and tamoxifen in ehrlich ascites tumour (EAT) cells

    International Nuclear Information System (INIS)

    In the most countries, breast cancer is still the most important cancer among women. It is known that Ehrlich Ascites Tumour is experimental breast cancer model in animal. The cells used in the study are hyper diploid line of Ehrlich Ascites Tumour (EAT) cells, initially provided to us from Institute of Pathology, Koln University. In the present study, an hyper diploid line which is estrogen receptor positive was used. An anthracycline-derived antibiotic, Daunorubicin (DNR, Cerubidine) is one of the clinically used anticancer drugs. DNR has been used alone or in combination with other cytotoxic agents against a variety of animal and human tumours. In vitro cell culture studies show that DNR enters the cell nuclei, inhibits nucleic acid synthesis, and arrest cell division. Tamoxifen (TAM, Nolvadex) is a semi-synthetical estrogen antagonist, used in the management of pre and post menopausal breast cancer. This drug bind to intracellular estrogen receptors, and prevents endogenous estrogens from binding to their own receptors. It is known that Ehrlich Ascites Tumour is experimental breast cancer model in animal. The cells used in the study are hyper diploid line of EAT cells initially provided to us from Institute of Pathology, Koln University. In the present study, an hyper diploid line which is Estrogen Receptor (+) was used. Estrogen Receptor levels were studied by the methods of Lippman and Huff and Raynaud et al. with minor modifications. Estrogen Receptor activity as demonstrated by dextran-coated charcoal technique is closely correlated with the clinical ability of Tamoxifen to inhibit tumour growth

  9. Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo

    Directory of Open Access Journals (Sweden)

    Anesti Anna-Maria

    2010-09-01

    Full Text Available Abstract Background Delivery of small interfering RNA (siRNA to tumours remains a major obstacle for the development of RNA interference (RNAi-based therapeutics. Following the promising pre-clinical and clinical results with the oncolytic herpes simplex virus (HSV OncoVEXGM-CSF, we aimed to express RNAi triggers from oncolytic HSV, which although has the potential to improve treatment by silencing tumour-related genes, was not considered possible due to the highly oncolytic properties of HSV. Methods To evaluate RNAi-mediated silencing from an oncolytic HSV backbone, we developed novel replicating HSV vectors expressing short-hairpin RNA (shRNA or artificial microRNA (miRNA against the reporter genes green fluorescent protein (eGFP and β-galactosidase (lacZ. These vectors were tested in non-tumour cell lines in vitro and tumour cells that are moderately susceptible to HSV infection both in vitro and in mice xenografts in vivo. Silencing was assessed at the protein level by fluorescent microscopy, x-gal staining, enzyme activity assay, and western blotting. Results Our results demonstrate that it is possible to express shRNA and artificial miRNA from an oncolytic HSV backbone, which had not been previously investigated. Furthermore, oncolytic HSV-mediated delivery of RNAi triggers resulted in effective and specific silencing of targeted genes in tumour cells in vitro and tumours in vivo, with the viruses expressing artificial miRNA being comprehensibly more effective. Conclusions This preliminary data provide the first demonstration of oncolytic HSV-mediated expression of shRNA or artificial miRNA and silencing of targeted genes in tumour cells in vitro and in vivo. The vectors developed in this study are being adapted to silence tumour-related genes in an ongoing study that aims to improve the effectiveness of oncolytic HSV treatment in tumours that are moderately susceptible to HSV infection and thus, potentially improve response rates seen

  10. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours

    International Nuclear Information System (INIS)

    Oxygen deficient hypoxic cells, which are resistant to sparsely ionising radiation, have now been identified in most animal and some human solid tumours and will influence the response of those tumours to radiation treatment. This hypoxia can be either chronic, arising from an oxygen diffusion limitation, or acute, resulting from transient stoppages in microregional blood flow. Extensive experimental studies, especially in the last decade, have shown that nicotinamide and structurally related analogs can effectively sensitize murine tumours to both single and fractionated radiation treatments and that they do so in preference to the effects seen in mouse normal tissues. The earliest studies suggested that this enhancement of radiation damage was the result of an inhibition of the repair mechanisms. However, recent studies in mouse tumours have shown that these drugs prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia. This novel discovery led to the suggestion that the potential role of these agents as radiosensitizers would be when combined with treatments that overcame chronic hypoxia. The combined nicotinamide with hyperthermia proved that the enhancement of radiation damage by both agents together was greater than that seen with each agent alone. Similar results were later seen for nicotinamide combined with a perfluorochemical emulsion, carbogen breathing, and pentoxifylline, and in all these studies the effects in tumours were always greater than those seen in appropriate normal tissues. Of all the analogs, it is nicotinamide itself which has been the most extensively studied as a radiosensitizer in vivo and the one that shows the greatest effect in animal tumours. It is also an agent that has been well established clinically, with daily doses of up to 6 g, associated with a low incidence of side effects. This human dose is equivalent to 100-200 mg/kg in mice and such doses will maximally sensitize murine tumours to

  11. Cancer Stem Cells, Epithelial to Mesenchymal Markers, and Circulating Tumor Cells in Small Cell Lung Cancer

    NARCIS (Netherlands)

    Pore, Milind; Meijer, Coby; de Bock, Geertruida H; Boersma-van Ek, Wytske; Terstappen, Leon W M M; Groen, Harry J M; Timens, Wim; Kruyt, Frank A E; Hiltermann, T Jeroen N

    2016-01-01

    BACKGROUND: Small cell lung cancer (SCLC) has a poor prognosis, and even with localized (limited) disease, the 5-year survival has only been around 20%. Elevated levels of circulating tumor cells (CTCs) have been associated with a worse prognosis, and markers of cancer stem cells (CSCs) and epitheli

  12. Tumour cell growth inhibitory potential of mushroom extracts from the genus Suillus

    OpenAIRE

    Vaz, Josiana A.; Santos, Tiago; Tavares, Catarina; Almeida, Gabriela M.; Ferreira, Isabel C. F. R.; Vasconcelos, M. Helena

    2012-01-01

    Mushrooms are a source of compounds with promising antitumour activity [1]. We have been working on the identification of wild mushrooms with promising antitumour activity and a Clitocybe alexandri extract which induces cell cycle arrest and apoptosis in a lung cancer cell line has been previously identified by part of the team [2]. The objective of this work was to continue the identification of mushrooms from the Northeast of Portugal with tumour cell growth inhibitory potential. Thirty...

  13. The contribution of drug resistant cancer stem cells to paediatric brain tumours

    OpenAIRE

    Punjaruk, Wiyada

    2010-01-01

    Introduction: Recent studies have revealed that cancer stem cells (CSCs) exist in malignant disease. Additionally, it is proposed that these cells may survive following chemotherapy, and hence contribute to tumour relapse. A significant mechanism of drug resistance in CSCs is believed to be the expression of ATP-binding cassette (ABC) transporters that efflux cytotoxic agents out of cells. The objective of this study was to study the existence of CSCs in a panel of primary paediatric brain tu...

  14. Treatment with IL-2 and IL-12 inhibits tumour cell division in SL2 lymphoma

    NARCIS (Netherlands)

    Masztalerz, A; Van Luyn, M; Werner, N; Molema, G; Everse, LA; Den Otter, W

    2004-01-01

    We examined which mechanism plays a dominant role in the rejection of solid SL2 lymphoma treated with locally applied IL-2 and /or IL-12. This treatment resulted in about 80% cures. There was a moderate influx of leukocytes in the tissue surrounding tumours; yet these cells failed to invade the soli

  15. Tumour resistance in induced pluripotent stem cells derived from naked mole-rats

    Science.gov (United States)

    Miyawaki, Shingo; Kawamura, Yoshimi; Oiwa, Yuki; Shimizu, Atsushi; Hachiya, Tsuyoshi; Bono, Hidemasa; Koya, Ikuko; Okada, Yohei; Kimura, Tokuhiro; Tsuchiya, Yoshihiro; Suzuki, Sadafumi; Onishi, Nobuyuki; Kuzumaki, Naoko; Matsuzaki, Yumi; Narita, Minoru; Ikeda, Eiji; Okanoya, Kazuo; Seino, Ken-ichiro; Saya, Hideyuki; Okano, Hideyuki; Miura, Kyoko

    2016-01-01

    The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype—ARF suppression-induced senescence (ASIS)—that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR. PMID:27161380

  16. Human papillomavirus and Epstein-Barr virus in the etiology of testicular germ cell tumours

    DEFF Research Database (Denmark)

    Rajpert-De Meyts, E; Hørding, U; Nielsen, H W;

    1994-01-01

    Epidemiological features suggest that the risk of testicular cancer may be related to exposure to unknown infectious agents, including viruses. Therefore a series of twenty specimens of testicular germ cell tumours, including preinvasive carcinoma in-situ, were tested for the presence of DNA sequ...

  17. Two cases report of a malignant germ cell tumour of ovary and a granulosa cell tumour:Interest of tumoral immunochemistry in the identification and management.

    OpenAIRE

    Jean eBouquet De Jolinière

    2014-01-01

    Abstract Objective: In this article, we present two case reports. The first case was a malignant germ cell tumor of the right ovary in a 23 year old female and a case of a bilateral undifferentiated granulosa cell tumor in a 71 year old female. The aim of these reports is to illustrate the interest of the immuno-histochemical analysis to define the correct diagnosis, to better classify these ovarian tumours and improve their management. Methods: This study we report two cases. The first case...

  18. Synchronous Multicentric Giant Cell Tumour of Distal Radius and Sacrum with Pulmonary Metastases.

    Science.gov (United States)

    Tandra, Varun Sharma; Kotha, Krishna Mohan Reddy; Satyanarayana, Moorthy Gadisetti Venkata; Vadlamani, Kali Varaprasad; Yerravalli, Vyjayanthi

    2015-01-01

    Giant cell tumour (GCT) is an uncommon primary bone tumour, and its multicentric presentation is exceedingly rare. We report a case of a 45-year-old female who presented to us with GCT of left distal radius. On the skeletal survey, osteolytic lesion was noted in her right sacral ala. Biopsy confirmed both lesions as GCT. Pulmonary metastasis was also present. Resection-reconstruction arthroplasty for distal radius and thorough curettage and bone grafting of the sacral lesion were done. Multicentric GCT involving distal radius and sacrum with primary sacral involvement is not reported so far to our knowledge. PMID:26106496

  19. Synchronous Multicentric Giant Cell Tumour of Distal Radius and Sacrum with Pulmonary Metastases

    Directory of Open Access Journals (Sweden)

    Varun Sharma Tandra

    2015-01-01

    Full Text Available Giant cell tumour (GCT is an uncommon primary bone tumour, and its multicentric presentation is exceedingly rare. We report a case of a 45-year-old female who presented to us with GCT of left distal radius. On the skeletal survey, osteolytic lesion was noted in her right sacral ala. Biopsy confirmed both lesions as GCT. Pulmonary metastasis was also present. Resection-reconstruction arthroplasty for distal radius and thorough curettage and bone grafting of the sacral lesion were done. Multicentric GCT involving distal radius and sacrum with primary sacral involvement is not reported so far to our knowledge.

  20. Expression profiling of circulating tumor cells in metastatic breast cancer

    Czech Academy of Sciences Publication Activity Database

    Lang, J.; Scott, J.H.; Wolf, D.M.; Novák, Petr; Punj, V.; Magbanua, M.J.M.; Zhu, W.Z.; Mineyev, N.; Haqq, CH.; Crothers, J.

    2015-01-01

    Roč. 149, č. 1 (2015), s. 121-131. ISSN 0167-6806 Institutional support: RVO:60077344 Keywords : Circulating tumor cells * Micrometastases * Breast cancer * EpCAM Subject RIV: FD - Oncology ; Hematology Impact factor: 3.940, year: 2014

  1. Cryopreservation of Circulating Tumor Cells for Enumeration and Characterization

    DEFF Research Database (Denmark)

    Nejlund, Sarah; Smith, Julie; Kraan, Jaco;

    2016-01-01

    BACKGROUND: A blood sample containing circulating tumor cells (CTCs) may serve as a surrogate for metastasis in invasive cancer. Cryopreservation will provide new opportunities in management of clinical samples in the laboratory and allow collection of samples over time for future analysis of exi...

  2. Aromatase inhibitors - a viable option for recurrent granulosa cell tumour of ovary: overview and case report

    International Nuclear Information System (INIS)

    Granulosa cell tumour of the ovary in adults is a rare tumour of low malignant potential affecting middle aged peri or post menopausal patients. These tumours are often diagnosed at an early stage, due to their hormonally active nature. They, however, have unique distinguishing histologic features and behaviour of frequent and late local or systemic relapses. The diagnosis can be challenging with unusual presentations. There is high association of endometrial carcinoma. Surgery is the mainstay of management in early low risk disease, while radiotherapy and systemic platinum based chemotherapy are employed in higher stage with poor prognostic indices. Survival is good in early stage disease. Recurrent, progressive, and treatment refractory disease is not infrequent and poses management challenge. Endocrine manipulation and hormone treatment are employed in few cases with equivocal results, as reported in literature. We present a case of recurrent and treatment refractory GCT in a postmenopausal patient, managed by aromatase inhibitor Anastrozole with reasonable efficacy. (author)

  3. The relationship of DNA double-strand break induction to radiosensitivity in human tumour cell lines

    International Nuclear Information System (INIS)

    Recent data suggest that differences in radiosensitivity between cell lines can be related to differences in dsb induction (Radford 1986). The current authors set out to assess the extent to which differences in radiation survival between nine human tumour cell lines could be attributed to differences in dsb induction. The lines varied widely in sensitivity, ranging from a sensitive neuroblastoma (surviving fraction at 2 Gy, SF2 = 0.13) to a resistant bladder carcinoma (SF2 = 0.62). Dsb induction was found to vary between the cell lines, such that resistant cells generally suffered less damage than sensitive ones. The data suggest that, in human tumour cell lines, differences in radiosensitivity may at least in part be due to different levels of damage induction, but that some lines may vary in their tolerance of damage due to differences in biological characteristics such as repair capacity. (author)

  4. Cytomorphology of Circulating Colorectal Tumor Cells: A Small Case Series

    Directory of Open Access Journals (Sweden)

    Dena Marrinucci

    2010-01-01

    Full Text Available Several methodologies exist to enumerate circulating tumor cells (CTCs from the blood of cancer patients; however, most methodologies lack high-resolution imaging, and thus, little is known about the cytomorphologic features of these cells. In this study of metastatic colorectal cancer patients, we used immunofluorescent staining with fiber-optic array scanning technology to identify CTCs, with subsequent Wright-Giemsa and Papanicolau staining. The CTCs were compared to the corresponding primary and metastatic tumors. The colorectal CTCs showed marked intrapatient pleomorphism. In comparison to the corresponding tissue biopsies, cells from all sites showed similar pleomorphism, demonstrating that colorectal CTCs retain the pleomorphism present in regions of solid growth. They also often retain particular cytomorphologic features present in the patient's primary and/or metastatic tumor tissue. This study provides an initial analysis of the cytomorphologic features of circulating colon cancer cells, providing a foundation for further investigation into the significance and metastatic potential of CTCs.

  5. Exosomal Heat Shock Proteins as New Players in Tumour Cell-to-cell Communication

    Directory of Open Access Journals (Sweden)

    Claudia Campanella

    2014-06-01

    Full Text Available Exosomes have recently been proposed as novel elements in the study of intercellular communication in normal and pathological conditions. The biomolecular composition of exosomes reflects the specialized functions of the original cells. Heat shock proteins (Hsps are a group of chaperone proteins with diverse biological roles. In recent years, many studies have focused on the extracellular roles played by Hsps that appear to be involved in cancer development and immune system stimulation. Hsps localized on the surface of exosomes, secreted by normal and tumour cells, could be key players in intercellular cross-talk, particularly during the course of different diseases, such as cancer. Exosomal Hsps offer significant opportunities for clinical applications, including their use as potential novel biomarkers for the diagnoses or prognoses of different diseases, or for therapeutic applications and drug delivery.

  6. Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system.

    Science.gov (United States)

    Papaevangelou, Efthymia; Whitley, Guy S; Johnstone, Alan P; Robinson, Simon P; Howe, Franklyn A

    2016-06-01

    Nitric oxide (NO) is a free radical signalling molecule involved in various physiological and pathological processes, including cancer. Both tumouricidal and tumour promoting effects have been attributed to NO, making its role in cancer biology controversial and unclear. To investigate the specific role of tumour-derived NO in vascular development, C6 glioma cells were genetically modified to include a doxycycline regulated gene expression system that controls the expression of an antisense RNA to inducible nitric oxide synthase (iNOS) to manipulate endogenous iNOS expression. Xenografts of these cells were propagated in the presence or absence of doxycycline. Susceptibility magnetic resonance imaging (MRI), initially with a carbogen (95% O2 /5% CO2 ) breathing challenge and subsequently an intravascular blood pool contrast agent, was used to assess haemodynamic vasculature (ΔR2 *) and fractional blood volume (fBV), and correlated with histopathological assessment of tumour vascular density, maturation and function. Inhibition of NO production in C6 gliomas led to significant growth delay and inhibition of vessel maturation. Parametric fBV maps were used to identify vascularised regions from which the carbogen-induced ΔR2 * was measured and found to be positively correlated with vessel maturation, quantified ex vivo using fluorescence microscopy for endothelial and perivascular cell staining. These data suggest that tumour-derived iNOS is an important mediator of tumour growth and vessel maturation, hence a promising target for anti-vascular cancer therapies. The combination of ΔR2 * response to carbogen and fBV MRI can provide a marker of tumour vessel maturation that could be applied to non-invasively monitor treatment response to iNOS inhibitors. PMID:26756734

  7. Computer simulation of tumour control probabilities after irradiation for varying intrinsic radio-sensitivity using a single cell based model

    International Nuclear Information System (INIS)

    Background. Currently, optimisation of the dose distribution and clinical acceptance are almost entirely based on the physical dose distribution and tumour control probability modelling is far from being routinely used as objective in treatment planning. For future individualised radiotherapeutic strategies, a reliable patient specific simulation model, taking into account customised tumour features, is needed to predict and improve treatment outcome. Materials and methods. To approach these demands, a single cell and Monte-Carlo based model was developed, which enables three-dimensional tumour growth and radiation response simulation. Tumour cells were characterised by cell-associated features such as age, intrinsic radio-sensitivity, proliferation ability, and oxygenation status, while capillary cells were considered as sources of a radial-dependent oxygen profile. Response to radiation was simulated by the linear-quadratic model, taking into account the lower radio-sensitivity of poorly oxygenated tumour cells. Results. The present study shows the influence of the model components and demonstrates the impact of the intra- and inter-tumoural radio-sensitivity heterogeneity on the treatment response. Conclusion. The simulation model adequately delineates the importance of the above described selected parameters on tumour control probability, providing an insight into the interplay of different physical and biological parameters, and its relevance for an individual tumour response

  8. Differentiation of tumour and inflammation: characterisation of [methyl-3H]methionine (MET) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) uptake in human tumour and inflammatory cells

    International Nuclear Information System (INIS)

    Previous studies suggest that radiolabelled amino acids could be superior to FDG in differentiating tumour and inflammation. Therefore the aim of this study was to investigate the uptake of FET and MET in human tumour and inflammatory cells and to investigate their uptake kinetics. For uptake studies, cells were incubated with 370 kBq FET or 3.7 kBq MET for 15 min. Kinetic studies were performed at variable concentrations of FET and MET. Competitive inhibition studies were done with BCH, MeAIB and L-serine. All inflammatory cells incorporated more MET than the tumour cells. The uptake of FET, in contrast, was significantly lower in all inflammatory cells than in the tumour cells. In tumour cells the uptake of MET was about five times the uptake of FET. The competitive inhibitors reduced uptake of both tracers to 20-40% in tumour cells and to 70% in inflammatory cells. Kinetic studies showed that MET and FET transport was saturable in all cells except macrophages and followed a Michaelis-Menten kinetic. Highest capacity (Vmax) and affinity (Km) for the uptake of MET was observed in granulocytes. Capacity and affinity for FET uptake were highest in the DHL-4 cells. In contrast to MET, FET accumulated to a significantly greater extent in tumour cells than in inflammatory cells. The marked differences between tumour and inflammatory cells concerning FET and MET uptake suggest that FET and MET are substrates of different subtypes of the L system. (orig.)

  9. Steroid hormones affect binding of the sigma ligand C-11-SA4503 in tumour cells and tumour-bearing rats

    NARCIS (Netherlands)

    Rybczynska, Anna A.; Elsinga, Philip H.; Sijbesma, Jurgen W.; Ishiwata, Kiichi; de Jong, Johan R.; de Vries, Erik F.; Dierckx, Rudi A.; van Waarde, Aren

    2009-01-01

    Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined change

  10. Urothelial atypia and survival rate of 500 unselected patients with primary transitional-cell tumour of the urinary bladder

    DEFF Research Database (Denmark)

    Rosenkilde Olsen, P; Wolf, H; Schroeder, T; Fischer, A; Højgaard, K

    1988-01-01

    In a consecutive series of 500 unselected patients with primary urinary bladder tumours the influence of urothelial atypia on the 5 years survival-rate was examined. All tumours were transitional-cell tumours categorized according to the T-classification. Mucosal biopsies from 7 pre-selected sites...... were taken at the initial cystoscopy in 391 patients (78%) to identify urothelial atypia. The over-all cumulative 5 years survival-rate was 48%. Submucosal and muscle invasion had major influence on survival, whereas tumour grade was less important. Patients with urothelial atypia fared significantly...

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

    OpenAIRE

    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 pres...

  12. Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment.

    Science.gov (United States)

    Rausch, Vanessa; Liu, Li; Apel, Anja; Rettig, Theresa; Gladkich, Jury; Labsch, Sabrina; Kallifatidis, Georgios; Kaczorowski, Adam; Groth, Ariane; Gross, Wolfgang; Gebhard, Martha M; Schemmer, Peter; Werner, Jens; Salnikov, Alexei V; Zentgraf, Hanswalter; Büchler, Markus W; Herr, Ingrid

    2012-07-01

    Involvement of dysregulated autophagy in cancer growth and progression has been shown in different tumour entities, including pancreatic ductal adenocarcinoma (PDA). PDA is an extremely aggressive tumour characterized by a small population of highly therapy-resistant cancer stem cells (CSCs) capable of self-renewal and migration. We examined whether autophagy might be involved in the survival of CSCs despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSCs and autophagy are co-expressed in patient-derived tissue of PDA. Hypoxia starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem-like properties (CSC(high)), while pancreatic tumour cells with fewer stem cell markers (CSC(low)) did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSC(high) cells, which exhibited higher expression of autophagy-related genes under normoxic conditions and relative to CSC(low) cells, as found by RT-PCR and western blot analysis. LC3 was already fully converted to the active LC3-II form in both cell lines, as evaluated by western blot and detection of accumulated GFP-LC3 protein by fluorescence microscopy. H/S increased formation of autophagic and acid vesicles, as well as expression of autophagy-related genes, to a higher extent in CSC(high) cells. Modulation of autophagy by inhibitors and activators resensitized CSC(high) to apoptosis and diminished clonogenicity, spheroid formation, expression of CSC-related genes, migratory activity and tumourigenicity in mice. Our data suggest that enhanced autophagy levels may enable survival of CSC(high) cells under H/S. Interference with autophagy-activating or -inhibiting drugs disturbs the fine-tuned physiological balance of enhanced autophagy in CSC and switches survival signalling to suicide. PMID:22262369

  13. Therapy of MHC Class I+ and Class I- HPV 16-Associated Tumours with Cytokines, Genetically Modified Tumour Vaccines and Dendritic Cells

    Czech Academy of Sciences Publication Activity Database

    Bubeník, Jan; Šímová, Jana; Mikyšková, Romana; Vonka, V.

    2004-01-01

    Roč. 27, č. 4 (2004), s. 161D. ISSN 0147-958X. [International Congress of Immunology /12./ and Annual Conference of FOCIS /4./. Montreal, 18.07.2004-23.07.2004] Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV 16 * tumour vaccines * dendritic cells Subject RIV: EC - Immunology Impact factor: 1.051, year: 2004

  14. Influence of femtosecond laser radiation on cells of the transplantable tumour Krebs-2

    Energy Technology Data Exchange (ETDEWEB)

    Meshalkin, Yu P; Popova, N A; Nikolin, V P; Kaledin, V I; Kirpichnikov, A V; Pestryakov, Efim V

    2012-06-30

    The influence of femtosecond radiation of a titaniumsapphire laser on cells of the transplantable ascitic tumour Krebs-2 was studied. After in vitro irradiation by the pulsed fundamentalharmonic radiation with the wavelength 800 nm, pulse duration 30 fs, repetition rate 1 kHz, mean power 100 and 300 mW and exposure time 3 min, as well as by the second-harmonic radiation (40 nm, 50 fs, 120 mW), all cells were diffusely stained by the vital stain trypan blue, which may be an evidence of their death or abnormalities of membrane permeability. However, implantation of such cells to experimental animals led to formation of tumours at the transplantation site with the kinetics slightly different from the control one. In the group of mice to which the cells were inoculated after irradiation with second harmonic pulses of titanium-sapphire laser the inhibition of tumour growth was observed due to partial death of cells under the action of UV spectral components. To explain the mechanism of the observed phenomenon the possibility of pore formation (photoporation) in the cell membrane, described earlier in the papers on foreign DNA transfection into cells, is considered.

  15. Influence of femtosecond laser radiation on cells of the transplantable tumour Krebs-2

    International Nuclear Information System (INIS)

    The influence of femtosecond radiation of a titaniumsapphire laser on cells of the transplantable ascitic tumour Krebs-2 was studied. After in vitro irradiation by the pulsed fundamentalharmonic radiation with the wavelength 800 nm, pulse duration 30 fs, repetition rate 1 kHz, mean power 100 and 300 mW and exposure time 3 min, as well as by the second-harmonic radiation (40 nm, 50 fs, 120 mW), all cells were diffusely stained by the vital stain trypan blue, which may be an evidence of their death or abnormalities of membrane permeability. However, implantation of such cells to experimental animals led to formation of tumours at the transplantation site with the kinetics slightly different from the control one. In the group of mice to which the cells were inoculated after irradiation with second harmonic pulses of titanium-sapphire laser the inhibition of tumour growth was observed due to partial death of cells under the action of UV spectral components. To explain the mechanism of the observed phenomenon the possibility of pore formation (photoporation) in the cell membrane, described earlier in the papers on foreign DNA transfection into cells, is considered.

  16. Efficient Capture and Isolation of Tumor-Related Circulating Cell-Free DNA from Cancer Patients Using Electroactive Conducting Polymer Nanowire Platforms

    OpenAIRE

    Jeon, SeungHyun; Lee, HyungJae; Bae, Kieun; Yoon, Kyong-Ah; Lee, Eun Sook; Cho, Youngnam

    2016-01-01

    Circulating cell-free DNA (cfDNA) is currently recognized as a key non-invasive biomarker for cancer diagnosis and progression and therapeutic efficacy monitoring. Because cfDNA has been detected in patients with diverse types of cancers, the use of efficient strategies to isolate cfDNA not only provides valuable insights into tumour biology, but also offers the potential for developing new cancer-specific targets. However, the challenges associated with conventional cfDNA extraction methods ...

  17. Giant cell tumour of tendon sheath with simultaneous two tendon involvement of the foot treated with excision of the tumour and reconstruction of the flexor retinaculum using tibialis posterior tendon in a paediatric patient: A rare case report.

    Science.gov (United States)

    Tiwari, Vivek; Ansari, Tahir; Mittal, Samarth; Sharma, Pankaj; Nalwa, Aasma

    2015-12-01

    Giant cell tumour of tendon sheath is a benign soft tissue tumour arising from the tendon sheath. The involvement of foot and ankle by such tumours is relatively rare. Children are not commonly afflicted by this condition. All such tumours are reported to arise either from a single tendon sheath or one joint. We report a case of giant cell tumour of tendon sheath in a 12-year-old child, arising simultaneously from the tendon sheaths of tibialis posterior and flexor digitorum longus tendons, as well as extending into the ankle joint. It was treated by complete excision of the mass along with the tendon sheaths with reconstruction of the flexor retinaculum. The location of the tumour, age of the patient, diffuse nature of the tumour and novel technique of reconstruction of the flexor retinaculum make this case extremely rare and the first to be reported in literature. PMID:26564735

  18. Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.

    Science.gov (United States)

    Whelan, M C; Casey, G; MacConmara, M; Lederer, J A; Soden, D; Collins, J K; Tangney, M; O'Sullivan, G C

    2010-07-01

    Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development. PMID:20186173

  19. Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.

    LENUS (Irish Health Repository)

    Whelan, M C

    2012-01-31

    Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.

  20. Sensing and enumerating rare circulating cells with diffuse light

    Science.gov (United States)

    Zettergren, Eric; Vickers, Dwayne; Niedre, Mark

    2011-02-01

    Detection and quantification of circulating cells in live animals is a challenging and important problem in many areas of biomedical research. Current methods involve extraction of blood samples and counting of cells ex-vivo. Since only small blood volumes are analyzed at specific time points, monitoring of changes in cell populations over time is difficult and rare cells often escape detection. The goal of this research is to develop a method for enumerating very rare circulating cells in the bloodstream non-invasively. This would have many applications in biomedical research, including monitoring of cancer metastasis and tracking of hematopoietic stem cells. In this work we describe the optical configuration of our instrument which allows fluorescence detection of single cells in diffusive media at the mesoscopic scale. Our instrument design consists of two continuous wave laser diode sources and an 8-channel fiber coupled multi-anode photon counting PMT. Fluorescence detector fibers were arranged circularly around the target in a miniaturized ring configuration. Cell-simulating fluorescent microspheres and fluorescently-labeled cells were passed through a limb mimicking phantom with similar optical properties and background fluorescence as a limb of a mouse. Our data shows that we are able to successfully detect and count these with high quantitative accuracy. Future work includes characterization of our instrument using fluorescently labeled cells in-vivo. If successful, this technique would allow several orders of magnitude in vivo detection sensitivity improvement versus current approaches.

  1. Enhanced thermal stability of lysosomal beta-D-galactosidase in parenchymal cells of tumour bearing mice.

    OpenAIRE

    Lenti, L; Lipari, M.; Lombardi, D; Zicari, A.; Dotta, A.; Pontieri, G. M.

    1986-01-01

    The thermal stability of the enzyme beta-D-galactosidase varies among different organs in normal C57Bl/6 mice, and increases in the same organs in mice with Lewis Lung carcinoma. Thermal stability of this enzyme is also increased by treatment of the mice with cell-free extracts of tumour cells or with inflammatory compounds such as carrageenan or orosomucoid. After desialylation, orosomucoid more effectively increases the heat stability of the enzyme. By contrast talc, which has no galactosyl...

  2. The effect of Translationally Controlled Tumour Protein (TCTP) on programmed cell death in plants

    OpenAIRE

    Hoepflinger, Marion Christine; Reitsamer, Johannes; Geretschlaeger, Anja Maria; Mehlmer, Norbert; Tenhaken, Raimund

    2013-01-01

    Background: Translationally controlled tumour protein (TCTP), a well known protein of the animal kingdom, was shown to be a Ca2+-binding protein with important functions in many different cellular processes (e.g. protection against stress and apoptosis, cell growth, cell cycle progression, and microtubule organization). However, only little is known about TCTP in plants. Transcript and protein levels of plant TCTPs were shown to be altered by various stress conditions (e.g. cold, salt, draugh...

  3. Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma

    OpenAIRE

    Morris, M.

    2008-01-01

    Promoter region hypermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many human cancers. Previously, to identify candidate epigenetically inactivated TSGs in renal cell carcinoma (RCC), we monitored changes in gene expression in four RCC cell lines after treatment with the demethylating agent 5-azacytidine. This enabled us to identify HAI-2/SPINT2 as a novel epigenetically inactivated candidate RCC TSG. To identify further candidat...

  4. Emerging roles of extracellular vesicles in the adaptive response of tumour cells to microenvironmental stress

    Directory of Open Access Journals (Sweden)

    Paulina Kucharzewska

    2013-03-01

    Full Text Available Cells are constantly subjected to various types of endogenous and exogenous stressful stimuli, which can cause serious and even permanent damage. The ability of a cell to sense and adapt to environmental alterations is thus vital to maintain tissue homeostasis during development and adult life. Here, we review some of the major phenotypic characteristics of the hostile tumour microenvironment and the emerging roles of extracellular vesicles in these events.

  5. Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases.

    NARCIS (Netherlands)

    Groot, J.W. de; Rikhof, B.; Doorn, J. van; Bilo, H.J.; Alleman, M.A.; Honkoop, A.H.; Graaf, W.T.A. van der

    2007-01-01

    This review focuses on the tumour types and symptoms associated with non-islet cell tumour-induced hypoglycaemia (NICTH) as well as the pathogenesis, diagnosis and treatment of this rare paraneoplastic phenomenon. In addition, we report two illustrative cases of patients suffering from NICTH caused

  6. Non-islet cell tumour-induced hypoglycaemia : a review of the literature including two new cases

    NARCIS (Netherlands)

    De Groot, Jan Willem B.; Rikhof, Bart; Van Doom, Jaap; Bilo, Henk J. G.; Alleman, Maarten A.; Honkoop, Aafke H.; Van der Graaf, Winette T. A.

    2007-01-01

    This review focuses on the tumour types and symptoms associated with non-islet cell tumour-induced hypoglycaemia (NICTH) as well as the pathogenesis, diagnosis and treatment of this rare paraneoplastic phenomenon. In addition, we report two illustrative cases of patients suffering from NICTH caused

  7. Lack of relationship between TIMP-1 tumour cell immunoreactivity, treatment efficacy and prognosis in patients with advanced epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Steffensen, Karina Dahl; Waldstrøm, Marianne; Christensen, Rikke Kølby;

    2010-01-01

    BACKGROUND: Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a natural inhibitor of the matrix metalloproteinases (MMPs) which are proteolytic enzymes involved in degradation of extracellular matrix thereby favoring tumour cell invasion and metastasis. TIMP-1 activity in tumour tissue may...

  8. Photoacoustic imaging of single circulating melanoma cells in vivo

    Science.gov (United States)

    Wang, Lidai; Yao, Junjie; Zhang, Ruiying; Xu, Song; Li, Guo; Zou, Jun; Wang, Lihong V.

    2015-03-01

    Melanoma, one of the most common types of skin cancer, has a high mortality rate, mainly due to a high propensity for tumor metastasis. The presence of circulating tumor cells (CTCs) is a potential predictor for metastasis. Label-free imaging of single circulating melanoma cells in vivo provides rich information on tumor progress. Here we present photoacoustic microscopy of single melanoma cells in living animals. We used a fast-scanning optical-resolution photoacoustic microscope to image the microvasculature in mouse ears. The imaging system has sub-cellular spatial resolution and works in reflection mode. A fast-scanning mirror allows the system to acquire fast volumetric images over a large field of view. A 500-kHz pulsed laser was used to image blood and CTCs. Single circulating melanoma cells were imaged in both capillaries and trunk vessels in living animals. These high-resolution images may be used in early detection of CTCs with potentially high sensitivity. In addition, this technique enables in vivo study of tumor cell extravasation from a primary tumor, which addresses an urgent pre-clinical need.

  9. Cybernetical investigations on the radiation effects on tumour cells

    International Nuclear Information System (INIS)

    The goal of this work was to find suitable conditions for the in-vitro investigations with these E.A.T. cells so that basic experiments carried out with yeast cells will also be possible. Systematic investigations on cell multiplication led to reliable and definite test conditions for these cells. For the evaluation of the data which had been measured with several sorts of radiation the cybernetic model was applied. (orig./MG)

  10. IMRT technique application in vertebra L3 giant cell tumour - a case report

    International Nuclear Information System (INIS)

    Giant cell tumour is a rare locally malignant neoplasm of the bone, which is characterised by a high risk of recurrence. The main management is surgery and, in the case of a nonradical operation, radiotherapy. The aim of the paper is to present the case of a 38-year old woman with a diagnosis of giant cell tumour localised in the 3rd vertebral body. For this rare localisation both surgery and radiotherapy are at high risk of neurological complications due to the close neighbourhood of critical organs (the spinal cone and cauda equina). The treatment of the patient consisted of a non radical operation and postoperative radiotherapy with a total dose of 54 Gy given in 27 fractions. In this case the intensity modulated radiotherapy (IMRT) technique seemed to be specially beneficial (a high dose gradient), enabling radiosensitive critical organs to be protected. After 3 months, in spite of the treatment, a recurrence was detected by CT and the patient was re operated on. The reason for the local regrowth of the tumour might be insufficient stabilization of the irradiated region. The literature reports only a few cases of IMRT usage for paraspinal tumour treatment. Immobilization body frames were used for these patients. Thus this modern radiotherapy technique requires not only a doctors experience but also improvement of ways of its application in new organ localizations. (authors)

  11. The Role of TG2 in Regulating S100A4-Mediated Mammary Tumour Cell Migration

    OpenAIRE

    Zhuo Wang; Martin Griffin

    2013-01-01

    The importance of S100A4, a Ca(2+)-binding protein, in mediating tumour cell migration, both intracellularly and extracellularly, is well documented. Tissue transglutaminase (TG2) a Ca(2+)-dependent protein crosslinking enzyme, has also been shown to enhance cell migration. Here by using the well characterised non-metastatic rat mammary R37 cells (transfected with empty vector) and highly metastatic KP1 cells (R37 cells transfected with S100A4), we demonstrate that inhibition of TG2 either by...

  12. Specific transfer of oncolytic adenoviruses by mesenchymal stem cells for the elimination of pancreatic tumour stem cells

    OpenAIRE

    KACZOROWSKI, ADAM

    2014-01-01

    Abstract Pancreatic adenocarcinoma has a very poor prognosis with currently existing therapies prolonging patient life for only a few weeks. Therefore novel therapy options are urgently needed. Present theories maintain that only a small fraction of tumour cells (the cancer stem cells (CSC)) are responsible for the highly aggressive behaviour of pancreatic cancer. These cells show a stem cell like phenotype and a high resistance to chemotherapy. Oncolytic viruses are promising candidat...

  13. Circulating tumor cell detection using photoacoustic spectral methods

    Science.gov (United States)

    Strohm, Eric M.; Berndl, Elizabeth S. L.; Kolios, Michael C.

    2014-03-01

    A method to detect and differentiate circulating melanoma tumor cells (CTCs) from blood cells using ultrasound and photoacoustic signals with frequencies over 100 MHz is presented. At these frequencies, the acoustic wavelength is similar to the dimensions of a cell, which results in unique features in the signal; periodically varying minima and maxima occur throughout the power spectrum. The spacing between minima depends on the ratio of the size to sound speed of the cell. Using a 532 nm pulsed laser and a 375 MHz center frequency wide-bandwidth transducer, the ultrasound and photoacoustic signals were measured from single cells. A total of 80 cells were measured, 20 melanoma cells, 20 white blood cells (WBCs) and 40 red blood cells (RBCs). The photoacoustic spectral spacing Δf between minima was 95 +/- 15 MHz for melanoma cells and greater than 230 MHz for RBCs. No photoacoustic signal was detected from WBCs. The ultrasonic spectral spacing between minima was 46 +/- 9 MHz for melanoma cells and 98 +/- 11 for WBCs. Both photoacoustic and ultrasound signals were detected from melanoma cells, while only ultrasound signals were detected from WBCs. RBCs showed distinct photoacoustic spectral variations in comparison to any other type of cell. Using the spectral spacing and signal amplitudes, each cell type could be grouped together to aid in cell identification. This method could be used for label-free counting and classifying cells in a sample.

  14. GIANT CELL TUMOUR OF THE TENDON SHEATH: A CASE REPORT

    OpenAIRE

    Ravikumar; Amit

    2014-01-01

    INTRODUCTION: The giant cell tumor of tendon sheath is among the more common soft tissue tumors of the hand. It is a slowly progressive, usually painless, rubbery mass predominating on the radial three digits of the hand and is typically identified adherent to the digital flexor tendon sheath of the hand. The histology is variable but the tumors consistently contain multinucleated giant cells and xanthoma cells. CASE PRESENTATION: A case report of a 57 years old female patient...

  15. Detection and isolation of circulating melanoma cells using photoacoustic flowmetry.

    Science.gov (United States)

    O'Brien, Christine M; Rood, Kyle; Sengupta, Shramik; Gupta, Sagar K; DeSouza, Thiago; Cook, Aaron; Viator, John A

    2011-01-01

    Circulating tumor cells (CTCs) are those cells that have separated from a macroscopic tumor and spread through the blood and lymph systems to seed secondary tumors(1,2,3). CTCs are indicators of metastatic disease and their detection in blood samples may be used to diagnose cancer and monitor a patient's response to therapy. Since CTCs are rare, comprising about one tumor cell among billions of normal blood cells in advanced cancer patients, their detection and enumeration is a difficult task. We exploit the presence of pigment in most melanoma cells to generate photoacoustic, or laser induced ultrasonic waves in a custom flow cytometer for detection of circulating melanoma cells (CMCs)(4,5). This process entails separating a whole blood sample using centrifugation and obtaining the white blood cell layer. If present in whole blood, CMCs will separate with the white blood cells due to similar density. These cells are resuspended in phosphate buffered saline (PBS) and introduced into the flowmeter. Rather than a continuous flow of the blood cell suspension, we induced two phase flow in order to capture these cells for further study. In two phase flow, two immiscible liquids in a microfluidic system meet at a junction and form alternating slugs of liquid(6,7). PBS suspended white blood cells and air form microliter slugs that are sequentially irradiated with laser light. The addition of a surfactant to the liquid phase allows uniform slug formation and the user can create different sized slugs by altering the flow rates of the two phases. Slugs of air and slugs of PBS with white blood cells contain no light absorbers and hence, do not produce photoacoustic waves. However, slugs of white blood cells that contain even single CMCs absorb laser light and produce high frequency acoustic waves. These slugs that generate photoacoustic waves are sequestered and collected for cytochemical staining for verification of CMCs. PMID:22143421

  16. Inactivation of the von Hippel-Lindau tumour suppressor gene induces Neuromedin U expression in renal cancer cells

    OpenAIRE

    Shukla Deepa; Esteban Miguel A; Harten Sarah K; Ashcroft Margaret; Maxwell Patrick H

    2011-01-01

    Abstract Background 209 000 new cases of renal carcinoma are diagnosed each year worldwide and new therapeutic targets are urgently required. The great majority of clear cell renal cancer involves inactivation of VHL, which acts as a gatekeeper tumour suppressor gene in renal epithelial cells. However how VHL exerts its tumour suppressor function remains unclear. A gene expression microarray comparing RCC10 renal cancer cells expressing either VHL or an empty vector was used to identify novel...

  17. Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells

    OpenAIRE

    Rong Fan; Travis Emery; Yongguo Zhang; Yuxuan Xia; Jun Sun; Jiandi Wan

    2016-01-01

    During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viabili...

  18. Circulating tumor cells in newly diagnosed inflammatory breast cancer

    OpenAIRE

    Mego, Michal; Giordano, Antonio; De Giorgi, Ugo; Masuda, Hiroko; Hsu, Limin; Giuliano, Mario; Fouad, Tamer M.; Dawood, Shaheenah; Ueno, Naoto T.; Valero, Vicente; Andreopoulou, Eleni; Alvarez, Ricardo H.; Wendy A Woodward; Hortobagyi, Gabriel N; Cristofanilli, Massimo

    2015-01-01

    Introduction Circulating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC. Methods This retrosp...

  19. Isolation and Molecular Characterization of Circulating Melanoma Cells

    OpenAIRE

    Xi Luo; Devarati Mitra; Ryan J. Sullivan; Ben S. Wittner; Anya M. Kimura; Shiwei Pan; Mai P. Hoang; Brian W. Brannigan; Donald P. Lawrence; Keith T. Flaherty; Lecia V. Sequist; Martin McMahon; Marcus W. Bosenberg; Shannon L. Stott; David T. Ting

    2014-01-01

    Melanoma is an invasive malignancy with a high frequency of blood-borne metastases, but circulating tumor cells (CTCs) have not been readily isolated. We adapted microfluidic CTC capture to a tamoxifen-driven B-RAF/PTEN mouse melanoma model. CTCs were detected in all tumor-bearing mice, rapidly declining after B-RAF inhibitor treatment. CTCs were shed early from localized tumors and a short course of B-RAF inhibition following surgical resection was sufficient to dramatically suppress distant...

  20. Anti tumor vaccination with hybrid dendritic-tumour cells

    International Nuclear Information System (INIS)

    Dendritic cells are the most potent antigen-presenting cells, and the possibility of their use for cancer vaccination has renewed the interest in this therapeutic modality. Nevertheless, the ideal immunization protocol with these cells has not been described yet. In this paper we describe the preliminary results of a protocol using autologous tumor and allogeneic dendritic hybrid cell vaccination every 6 weeks, for metastatic melanoma and renal cell carcinoma (RCC) patients. Thirty-five patients were enrolled between March 2001 and March 2003. Though all patients included presented with large tumor burdens and progressive diseases, 71% of them experienced stability after vaccination, with durations up to 19 months. Among RCC patients 3/22 (14%) presented objective responses. The median time to progression was 4 months for melanoma and 5.7 months for RCC patients; no significant untoward effects were noted. Furthermore, immune function, as evaluated by cutaneous delayed-type hypersensitivity reactions to recall antigens and by peripheral blood proliferative responses to tumor-specific and nonspecific stimuli, presented a clear tendency to recover in vaccinated patients. These data indicate that dendritic cell-tumor cell hybrid vaccination affects the natural history of advanced cancer and provide support for its study in less advanced patients, who should, more likely, benefit even more from this approach. (author)

  1. Isolation and characterization of circulating tumor cells in prostate cancer

    Directory of Open Access Journals (Sweden)

    Elan Shlomo Diamond

    2012-10-01

    Full Text Available Circulating tumor cells (CTCs are tumor cells found in the peripheral blood that originate from established sites of malignancy and likely have metastatic potential. Analysis of circulating tumor cells CTCs has shown great promise as a prognostic marker as well as a potential source of novel therapeutics. Isolation and characterization these cells for study, however, remain challenging due to their rarity in comparison with other cellular components of peripheral blood. Several techniques that exploit the unique biochemical properties of CTCs have been developed to facilitate isolation of these cells. Positive selection of CTCs is achieved using microfluidic surfaces coated with antibodies against epithelial cell markers or tumor specific antigens such as EpCAM or prostate specific membrane antigen (PSMA. Following isolation, characterization of CTCs may help guide clinical decision-making. For instance, molecular and genetic characterization may shed light on the development of chemotherapy resistance and mechanisms of metastasis without the need for tissue biopsy. This paper will review novel isolation techniques to capture CTCs from patients with advanced cancers, as well as efforts to characterize the CTCs. We will also review ways in which these analyses can assist in clinical decision-making,Conclusion: The study of CTCs provides insight into the molecular biology of their tumors of origin that will eventually guide the development tailored therapeutics. These advances are predicated on high yield and accurate isolation techniques that exploit the unique biochemical features of these cells.

  2. Clinical value of imaging using antibody to alpha fetoprotein in germ cell tumours

    International Nuclear Information System (INIS)

    Germ cell tumours (GCT) producing alpha fetoprotein (aFP) can be imaged by external scintigraphy after intraveneous administration of radiolabelled antibody directed against aFP. Antibody imaging (AI) by this method was used in an attempt to guide surgical resection of deposits of drug-resistant or recurrent GCT. 30 patients with GCT and raised aFP in whom site of tumour was not known were investigated by AI and conventional imaging methods. All but one were heavily pretreated. Where tumour appeared localised, resection was attempted. Tumour was found in all sites positive by both AI and conventional imaging. AI produced false-positive results in one of 30 patients and false-negative results in 9 patients. Computerised tomography was false-positive in one case and false-negative in three. In these patients, AI gave true-negative and true-positive results, respectively. Of 11 patients with positive AI in whom resection was attempted, 6 achieved sustained complete response with up to 5 years follow-up. We conclude AI and conventional imaging methods to be complementary in selection for surgery of patients with drug-resistant or recurrent GCT. (orig.)

  3. The relationship between induced chromosome aberrations and chromosome abnormality in tumour cells

    International Nuclear Information System (INIS)

    The occurrence of chromosome abnormalities in cancer cells and the induction of chromosome aberrations by many different carcinogenic agents are now well established facts and there are many detailed studies in both areas. It is known, however, whether or not there is any relationship between the induced aberrations and those seen in tumours. The purpose of this paper is to consider any evidence which might suggest that such a relationship does exist and the significance that this would have in the genesis of neoplasia. There are at least four chromosomal situations in human tumours: (a) cytogenetically normal, (b) clonal but unique, (c) clonal and specific for a particular neoplasm, (d) clonal and common to some tumours of different types. Any theory that we develop must take account of all four situations. A number of different suggestions have been made to try to explain the observation of chromosome abnormalities in human tumours. The one feature that does seem common to all situations is clonal evolution. A modified somatic mutation hypothesis to account for the chromosome changes occurring before and after malignant transformation is suggested

  4. First report of circulating microRNAs in tumour necrosis factor receptor-associated periodic syndrome (TRAPS.

    Directory of Open Access Journals (Sweden)

    Orso Maria Lucherini

    Full Text Available Tumor necrosis factor-receptor associated periodic syndrome (TRAPS is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1(st year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention.

  5. Raman spectroscopy of single human tumour cells exposed to ionizing radiation in vitro

    International Nuclear Information System (INIS)

    This work investigates the capability of Raman spectroscopy (RS) to study the effects of ionizing radiation on single human tumour cells. Prostate tumour cells (cell line DU145) are cultured in vitro and irradiated to doses between 15 and 50 Gy with single fractions of 6 MV photons. Single-cell Raman spectra are acquired from irradiated and unirradiated cultures up to 5 days post-irradiation. Principal component analysis is used to distinguish the uniquely radiation-induced spectral changes from inherent sources of spectral variability arising from cell cycle differences and other known factors. We observe uniquely radiation-induced spectral changes which are correlated with both the irradiated dose and the incubation time post-irradiation. The spectral changes induced by radiation arise from biochemical differences in lipids, nucleic acids, amino acids and conformational protein structures between irradiated and unirradiated cells. To our knowledge, this study is the first use of RS to observe radiation-induced biochemical differences in single cells, and is the first use of vibrational spectroscopy to observe uniquely radiation-induced biochemical differences in single cells independent of concurrent cell-cycle- or cell-death-related processes.

  6. Repopulation of tumour cells following irradiation with X-rays or low energy neutrons

    International Nuclear Information System (INIS)

    The repopulation of C3H mouse mammary carcinoma cells following X-ray or fast neutron irradiation was investigated in vivo using TCD50 as an endpoint. Tumours in the C3H mouse leg were irradiated in air with an X-ray dose of 9.6, 28.8 or 48.0 Gy, or a neutron dose of 2.6 or 5.2 Gy, and, various times thereafter, graded X-ray doses were given under hypoxic conditions to determine TCD50. A significant finding was that the tumour cells treated with a neutron dose, either 2.6 or 5.2 Gy, appeared to repopulate slightly more rapidly than those irradiated with X-rays, and the doubling times following two different neutron doses were not significantly different. (author)

  7. Bioreductive pharmaceuticals. Possible selective chemotherapics of solid tumours

    International Nuclear Information System (INIS)

    The surgical treatment and the radiotherapy allow to reduce the mass tumour in regions you specify from the susceptible body to extirpation or high dose of radiations. But none in the two ways is applicable to the destruction of cells very disseminated or circulating tumour that are present in most of the patients with cancer, for it is development the chemotherapy. Inside the agents used chemotherapy they are distinguished: 1) the biological agents, 2) the endocrine agents, 3) the medicine anti neoplasms

  8. Platinum Complexes And Their Anti-Tumour Activity Against Chronic Lymphocytic Leukaemia Cells

    OpenAIRE

    Silconi Žana Besser; Benazic Sasa; Milovanovic Jelena; Arsenijevic Aleksandar; Stojanovic Bojana; Milovanovic Marija; Kanjevac Tatjana

    2015-01-01

    Since the discovery of the antitumor activity of cisplatin by Rosenberg and co-workers, the use of metal complexes in cancer treatment has caused a huge interest. Today, platinum-based drugs are part of standard chemotherapy in the management of a variety of ca ncers, germ cell tumours, sarcomas, and lymphomas. Unfortunately, toxicity and drug resistance are major obstacles to wider clinical application of these drugs. Their use is greatly limited by severe side effects such as nephrotoxicity...

  9. Clinical evaluation of serum tumour marker CA 242 in non-small cell lung cancer.

    OpenAIRE

    Pujol, J L; Cooper, E H; Lehmann, M.; Purves, D. A.; Dan-Aouta, M.; Midander, J.; Godard, P.; Michel, F B

    1993-01-01

    CA 242, a novel tumour carbohydrate antigen present in serum (upper limit of normal values: 20.0 U ml-1), has been measured in a group of 102 pathologically confirmed non-small cell lung cancer patients. The aim of the present prospective study was to identify any relationship between pre-treatment serum CA 242 level and different features of lung cancer including prognosis. Serum CA 242 was measured using the delayed europium lanthanide fluoroimmunometric assay. Sensitivity and specificity w...

  10. HPV16-associated tumours: Therapy of surgical minimal residual disease with dendritic cell-based vaccines

    Czech Academy of Sciences Publication Activity Database

    Reiniš, Milan; Indrová, Marie; Mendoza, Luis; Mikyšková, Romana; Bieblová, Jana; Bubeník, Jan; Šímová, Jana

    2004-01-01

    Roč. 25, č. 4 (2004), s. 1165-1170. ISSN 1019-6439 R&D Projects: GA MZd NC7148; GA ČR GA301/04/0492; GA ČR GA301/01/0985; GA AV ČR IAA5052203 Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV16 * minimal residual tumour disease * dendritic cells Subject RIV: EC - Immunology Impact factor: 3.056, year: 2004

  11. Non-islet Cell Tumour Hypoglycaemia (NICTH) in Malignant Mesothelioma: Case Report

    OpenAIRE

    Wong, Wai Keat

    2015-01-01

    Non-islet cell tumour hypoglycaemia (NICTH) is an uncommon but important clinical condition. It can occur in a setting of known malignancy. Here, we report the case of a 56-year-old, non-diabetic, female patient with unresectable malignant pleural mesothelioma who presented with unexplained recurrent hypoglycaemia. Surreptitious use of insulin or other hypoglycaemic agents were ruled out. Investigations revealed markedly suppressed insulin-like growth factor-I, normal insulin-like growth fact...

  12. Expression profiling of genes regulated by TGF-beta: Differential regulation in normal and tumour cells

    Directory of Open Access Journals (Sweden)

    Takahashi Takashi

    2007-04-01

    Full Text Available Abstract Background TGF-beta is one of the key cytokines implicated in various disease processes including cancer. TGF-beta inhibits growth and promotes apoptosis in normal epithelial cells and in contrast, acts as a pro-tumour cytokine by promoting tumour angiogenesis, immune-escape and metastasis. It is not clear if various actions of TGF-beta on normal and tumour cells are due to differential gene regulations. Hence we studied the regulation of gene expression by TGF-beta in normal and cancer cells. Results Using human 19 K cDNA microarrays, we show that 1757 genes are exclusively regulated by TGF-beta in A549 cells in contrast to 733 genes exclusively regulated in HPL1D cells. In addition, 267 genes are commonly regulated in both the cell-lines. Semi-quantitative and real-time qRT-PCR analysis of some genes agrees with the microarray data. In order to identify the signalling pathways that influence TGF-beta mediated gene regulation, we used specific inhibitors of p38 MAP kinase, ERK kinase, JNK kinase and integrin signalling pathways. The data suggest that regulation of majority of the selected genes is dependent on at least one of these pathways and this dependence is cell-type specific. Interestingly, an integrin pathway inhibitor, RGD peptide, significantly affected TGF-beta regulation of Thrombospondin 1 in A549 cells. Conclusion These data suggest major differences with respect to TGF-beta mediated gene regulation in normal and transformed cells and significant role of non-canonical TGF-beta pathways in the regulation of many genes by TGF-beta.

  13. Circulating tumor cells: the substrate of personalized medicine?

    Directory of Open Access Journals (Sweden)

    BryanGreene

    2012-07-01

    Full Text Available Circulating tumor cells (CTCs are believed to be responsible for the development of metastatic disease. Over the last several years there has been a great interest in understanding the biology of CTCs to understand metastasis, as well as for the development of companion diagnostics to predict patient response to anti-cancer targeted therapies. Understanding CTC biology requires innovative technologies for the isolation of these rare cells. Here we review several methods for the detection, capture, and analysis of CTCs and also provide insight on improvements for CTC capture amenable to cellular therapy applications.

  14. Desmoplastic small round cell tumour: Cytological and immunocytochemical features

    Directory of Open Access Journals (Sweden)

    Filho Adhemar

    2005-01-01

    Full Text Available Abstract Background Desmoplastic small round cell tumor (DSRCT is a rare and highly aggressive neoplasm. The cytological diagnosis of these tumors can be difficult because they show morphological features quite similar to other small round blue cells tumors. We described four cases of DSRCT with cytological sampling: one obtained by fine needle aspiration biopsy (FNAB and three from serous effusions. The corresponding immunocytochemical panel was also reviewed. Methods Papanicolaou stained samples from FNAB and effusions were morphologically described. Immunoreaction with WT1 antibody was performed in all cytological samples. An immunohistochemical panel including the following antibodies was performed in the corresponding biopsies: 34BE12, AE1/AE3, Chromogranin A, CK20, CK7, CK8, Desmin, EMA, NSE, Vimentin and WT1. Results The smears showed high cellularity with minor size alteration. Nuclei were round to oval, some of them with inconspicuous nucleoli. Tumor cells are clustered, showing rosette-like feature. Tumor cells in effusions and FNA were positive to WT1 in 3 of 4 cytology specimens (2 out 3 effusions and one FNA. Immunohistochemical reactions for vimentin, NSE, AE1/AE3 and WT1 were positive in all cases in tissue sections. Conclusion The use of an adjunct immunocytochemical panel coupled with the cytomorphological characteristics allows the diagnosis of DSRCT in cytological specimens.

  15. High-dose chemotherapy in germ cell tumours: a large single centre experience.

    Science.gov (United States)

    Rick, O; Beyer, J; Kingreen, D; Schwella, N; Krusch, A; Schleicher, J; Kirsch, A; Huhn, D; Siegert, W

    1998-11-01

    High-dose chemotherapy (HDCT) has evolved as a strategy to improve the treatment outcome in patients with relapsed and/or refractory germ cell tumours. Between August 1989 and September 1995, 150 consecutive patients with relapsed and/or refractory germ cell tumours were treated with conventional-dose salvage chemotherapy followed by one cycle of HDCT with carboplatin 1500-2000 mg/m2, etoposide 1200-2400 mg/m2 and ifosfamide 0-10 g/m2 and were retrospectively analysed. With a median follow-up time of 55 months (range 21-88 months) 51/150 (34%) patients are alive and disease free. The projected event-free and overall survival are 29% (confidence interval 22-37%) and 39% (confidence interval 31-47%) respectively. The relevance of prognostic variables for long-term survival after HDCT were prospectively confirmed. Persisting toxicities occurred in approximately one third of the long-term survivors. Treatment intensification with HDCT resulted in a significant proportion of the long-term survivors in patients with relapsed and/or refractory germ cell tumours. Trials to prospectively evaluate HDCT as an early intervention in these patients seem justified. PMID:10023310

  16. Cell survival and growth delay in rat R-1 tumours after radiation and vinblastine treatment

    International Nuclear Information System (INIS)

    The rat R-1 rhabdomyosarcoma with a capacity for colony growth in vitro after excision of the tumour and dissociation by a trypsin method was used to investigate the effectiveness of radio-chemotherapy. Growth delay data were compared with data on survival of cells derived from tumours treated in situ. An excess in growth delay was observed when vinblastine (1.5 mg/kg) was given at intervals of 0.3 to 2 d after or 4 d before a dose of 20 Gy of X-rays. Cell survival data indicated that the maximum effectiveness of the drug treatment and the combined treatment (vinblastine and a dose of 10 Gy) can be assessed 2 to 3 d after treatment. The fractions of surviving cells determined after combined therapy at 0,1 and 2 d intervals were not significantly different from the fractions expected on the basis of simple multiplication of the fractions surviving individual treatments. The data suggested that the excess in tumour growth delay observed cannot be accounted for by co-operative interaction of the doses of radiation and drug. (author)

  17. Equine Cutaneous Mast Cell Tumours Exhibit Variable Differentiation, Proliferation Activity and KIT Expression.

    Science.gov (United States)

    Ressel, L; Ward, S; Kipar, A

    2015-11-01

    Equine cutaneous mast cell tumours (CMCTs) are generally considered to be benign skin lesions, although recurrent and multicentric tumours have been described. For canine CMCTs, grading and prognostic approaches are well established and aberrant KIT expression as well as high proliferation indices are associated with poor outcome. However, in the case of equine CMCTs, morphological features, proliferative activity and KIT expression pattern have not been assessed or related to biological behaviour, and there is discussion as to whether CMCTs are true neoplastic processes. The present study describes 45 equine CMCTs in terms of their morphology and KIT and PCNA expression by immunohistochemistry. KIT expression was classified as membranous (I), cytoplasmic and focally stippled (II) or diffuse cytoplasmic (III). A large proportion of the tumours were multinodular or diffuse dermal infiltrates of mast cells with mild anisokaryosis, a low proliferative rate and a dominance of KIT pattern I, representing well-differentiated CMCTs. In approximately one third of the cases, the mast cells exhibited more infiltrative growth, moderate to marked anisokaryosis and a higher degree of proliferation. These were classified as poorly differentiated CMCTs and exhibited only KIT patterns II and III. These findings indicate that there is a subgroup of poorly differentiated equine CMCTs, in which there is an association between aberrant KIT expression, high proliferative rate and potential aggressive behaviour, all features that confirm at least the poorly differentiated CMCT as a true neoplastic processes. PMID:26292768

  18. Adhesion receptors as therapeutic targets for circulating tumor cells

    Directory of Open Access Journals (Sweden)

    MichaelR.King

    2012-07-01

    Full Text Available Metastasis contributes to >90% of cancer-associated mortality. Though primary tumors can be removed by surgical resection or chemo/radiotherapy, metastatic disease is a great challenge to treatment due to its systemic nature. As metastatic “seeds”, circulating tumor cells (CTCs are believed to be responsible for dissemination from a primary tumor to anatomically distant organs. Despite the possibility of physical trapping of CTCs in microvessels, recent advances have provided insights into the involvement of a variety of adhesion molecules on CTCs. Such adhesion molecules facilitate direct interaction with the endothelium in specific tissues or indirectly through leukocytes. Importantly, significant progress has been made in understanding how these receptors confer enhanced invasion and survival advantage during hematogenous circulation of CTCs through recruitment of macrophages, neutrophils, platelets, and other cells. This review highlights the identification of novel adhesion molecules and how blocking their function can compromise successful seeding and colonization of CTCs in new microenvironment. Encouraged by existing diagnostic tools to identify and isolate CTCs, strategic targeting of these adhesion molecules to deliver conventional chemotherapeutics or novel apoptotic signals is discussed for the neutralization of CTCs in the circulation.

  19. Oncogenic extracellular vesicles in brain tumour progression

    Directory of Open Access Journals (Sweden)

    Esterina eD'Asti

    2012-07-01

    Full Text Available The brain is a frequent site of neoplastic growth, including both primary and metastatic tumours. The clinical intractability of many brain tumours and their distinct biology are implicitly linked to the unique microenvironment of the central nervous system (CNS and cellular interactions within. Among the most intriguing forms of cellular interactions is that mediated by membrane-derived extracellular vesicles (EVs. Their biogenesis (vesiculation and uptake by recipient cells serves as a unique mechanism of intercellular trafficking of complex biological messages including the exchange of molecules that cannot be released through classical secretory pathways, or that are prone to extracellular degradation. Tumour cells produce EVs containing molecular effectors of several cancer-related processes such as growth, invasion, drug resistance, angiogenesis, and coagulopathy. Notably, tumour-derived EVs (oncosomes also contain oncogenic proteins, transcripts, DNA and microRNA (miR. Uptake of this material may change properties of the recipient cells and impact the tumour microenvironment. Examples of transformation-related molecules found in the cargo of tumour-derived EVs include the oncogenic epidermal growth factor receptor (EGFRvIII, tumour suppressors (PTEN and oncomirs (miR-520g. It is postulated that EVs circulating in blood or cerebrospinal fluid (CSF of brain tumour patients may be used to decipher molecular features (mutations of the underlying malignancy, reflect responses to therapy or molecular subtypes of primary brain tumours (e.g. glioma or medulloblastoma. It is possible that metastases to the brain may also emit EVs with clinically relevant oncogenic signatures. Thus EVs emerge as a novel and functionally important vehicle of intercellular communication that can mediate multiple biological effects. In addition, they provide a unique platform to develop molecular biomarkers in brain malignancies.

  20. Cisplatinum dose dependent response in germ cell cancer evaluated by tumour marker modelling

    DEFF Research Database (Denmark)

    Carl, J; Christensen, T B; von der Maase, H

    1992-01-01

    This study presents an analysis on longitudinal tumour marker series in twenty-two patients with non-seminomatous germ cell cancers treated with cisplatinum (DDP) based combination chemotherapy. Series of alphafoetoprotein (AFP), human chorionic gonadotrophin (HCG) and lactate dehydrogenase (LDH...... faster than AFP producing cells, and were 3-5-fold more sensitive to the chemotherapy given than AFP producing cells. Treatment response versus DDP dose appeared to be bi-phasic, but with no significant change in treatment efficiency within the given range of DDP doses....

  1. Inhibition of p38 MAPK sensitizes tumour cells to cisplatin-induced apoptosis mediated by reactive oxygen species and JNK

    OpenAIRE

    Pereira, Lorena; Igea, Ana; Canovas, Begoña; Dolado, Ignacio; Nebreda, Angel R

    2013-01-01

    The p38 MAPK pathway is an important regulator of many cellular responses. It is well established that p38 MAPK signalling negatively regulates epithelial cell transformation, but enhanced p38 MAPK activity has been also correlated with bad clinical prognosis in some tumour types. Here, we provide genetic and pharmacological evidence showing that p38 MAPK inhibition cooperates with the chemotherapeutic agent cisplatin to kill tumour cells. We show that p38 MAPK inhibition results in ROS upreg...

  2. Imaging and radiation effects of gold nanoparticles in tumour cells

    Science.gov (United States)

    McQuaid, Harold N.; Muir, Mark F.; Taggart, Laura E.; McMahon, Stephen J.; Coulter, Jonathan A.; Hyland, Wendy B.; Jain, Suneil; Butterworth, Karl T.; Schettino, Giuseppe; Prise, Kevin M.; Hirst, David G.; Botchway, Stanley W.; Currell, Fred J.

    2016-01-01

    Gold nanoparticle radiosensitization represents a novel technique in enhancement of ionising radiation dose and its effect on biological systems. Variation between theoretical predictions and experimental measurement is significant enough that the mechanism leading to an increase in cell killing and DNA damage is still not clear. We present the first experimental results that take into account both the measured biodistribution of gold nanoparticles at the cellular level and the range of the product electrons responsible for energy deposition. Combining synchrotron-generated monoenergetic X-rays, intracellular gold particle imaging and DNA damage assays, has enabled a DNA damage model to be generated that includes the production of intermediate electrons. We can therefore show for the first time good agreement between the prediction of biological outcomes from both the Local Effect Model and a DNA damage model with experimentally observed cell killing and DNA damage induction via the combination of X-rays and GNPs. However, the requirement of two distinct models as indicated by this mechanistic study, one for short-term DNA damage and another for cell survival, indicates that, at least for nanoparticle enhancement, it is not safe to equate the lethal lesions invoked in the local effect model with DNA damage events.

  3. Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells

    Directory of Open Access Journals (Sweden)

    Collins Hilary M

    2013-01-01

    Full Text Available Abstract Background Post-translational modifications (PTMs of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7. Methods Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR. Results Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as γH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2

  4. Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells

    International Nuclear Information System (INIS)

    Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7. Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR. Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as γH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2. In

  5. Comparison of CT scan and colour flow doppler ultrasound in detecting venous tumour thrombous in renal cell carcinoma

    International Nuclear Information System (INIS)

    Renal cell carcinoma has marked tendency to spread into renal vein, inferior vena cava and right side of heart. Extension of tumour thrombus into these veins will alter the surgical approach. We have compared the CT scan with Colour flow Doppler ultrasound in detecting venous tumour thrombus in renal vein and inferior vena cava. This cross-sectional study included 30 adult patients presenting with renal tumour. Patients of either gender were included in the study. Non probability convenience sampling was used. All patients underwent colour flow Doppler ultrasound and CT scan with contrast to asses the renal vein and inferior vena cava. The results were confirmed by intra operative findings and histopathology. The data was analyzed using SPSS version 12. Out of 30 patients, 20 (66%) were males and 10 (34%) female. The tumour was predominantly on the right side (60%), as was renal venous tumour thrombus (44%). Inferior vena cava was involved in 4 cases predominantly due to right sided tumours. The sensitivity of Doppler ultrasound in detecting renal venous tumour thrombus (88% on right and 100% on left side) was higher than CT scan (63% on right and 60% on left side). Doppler ultrasound was also superior to CT scan in detecting vena caval thrombus. The overall sensitivity of Doppler sonography was higher than CT scan in detecting tumour extension into renal veins and inferior vena cava. Therefore, it can be used as a complementary tool in equivocal cases. (author)

  6. EGFR-TK inhibition before radiotherapy reduces tumour volume but does not improve local control: Differential response of cancer stem cells and nontumourigenic cells?

    International Nuclear Information System (INIS)

    Background and purpose: Waiting times before radiotherapy may reduce tumour control probability due to proliferation of tumour cells. The aim of the experiment was to test whether the growth inhibiting effect of epidermal growth factor receptor (EGFR)-inhibitors after surgery or tumour transplantation results in a lower tumour mass at time of irradiation and can thereby improve local tumour control. Materials and methods: The EGFR-tyrosine kinase inhibitor BIBX1382BS was applied over 14 days starting from microscopically non-in-sano-resection of FaDu tumours or from tumour transplantation, followed by irradiation (5f/5d). Endpoint was local tumour control. In addition, vital tumour areas, pimonidazole hypoxic fraction, BrdU labelling index, and colony forming ability in vitro were tested in control tumours and after BIBX1382BS treatment (starting from transplantation). Results: The tumour volume at start of irradiation was significantly lower in the BIBX1382BS treated tumours as compared to the control groups by factors of 11 (post-surgery setting) and 2.7 (transplantation setting). However, the reduced volume did not translate into improved local control after irradiation. The TCD50 values after surgery were 25.4 Gy [95% CI 18; 33 Gy] in the control group and 30.5 Gy [24; 37] in the BIBX1382BS group (p = 0.25). Treatment after transplantation resulted in TCD50 values of 41.1 Gy [35; 47] in the control group and 41.1 Gy [33; 49] in the BIBX1382BS group (p = 1). While the proportion of S-phase cells decreased after BIBX1382BS treatment, no differences were observed between the pimonidazole hypoxic fractions and in vitro colony forming ability. Conclusions: EGFR-TK inhibition with BIBX1382BS over 14 days between macroscopically complete tumour resection or tumour transplantation and start of radiotherapy significantly reduced tumour volume but did not improve local tumour control. One possible explanation is that the EGFR-TK inhibitor has a higher activity in

  7. HPV 16-associated tumours: IL-12 can repair the absence of cytotoxic and proliferative responses of tumour infiltrating cells after chemotherapy

    Czech Academy of Sciences Publication Activity Database

    Indrová, Marie; Bieblová, Jana; Rossowska, J.; Kuropka, P.; Pajtasz-Piasecka, E.; Bubeník, Jan; Reiniš, Milan

    2009-01-01

    Roč. 34, č. 1 (2009), s. 173-180. ISSN 1019-6439 R&D Projects: GA ČR GA301/06/0774 EU Projects: European Commission(XE) 18933 - CLINIGENE Grant ostatní: Polish Ministry of Science and Higher Education(PL) N401 235334 Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV 16 * vaccines * tumour-infiltrating cells Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.447, year: 2009

  8. Filtration parameters influencing circulating tumor cell enrichment from whole blood.

    Directory of Open Access Journals (Sweden)

    Frank A W Coumans

    Full Text Available Filtration can achieve circulating tumor cell (CTC enrichment from blood. Key parameters such as flow-rate, applied pressure, and fixation, vary largely between assays and their influence is not well understood. Here, we used a filtration system, to monitor these parameters and determine their relationships. Whole blood, or its components, with and without spiked tumor cells were filtered through track-etched filters. We characterize cells passing through filter pores by their apparent viscosity; the viscosity of a fluid that would pass with the same flow. We measured a ratio of 5·10(4∶10(2∶1 for the apparent viscosities of 15 µm diameter MDA-231 cells, 10 µm white cells and 90 fl red cells passing through a 5 µm pore. Fixation increases the pressure needed to pass cells through 8 µm pores 25-fold and halves the recovery of spiked tumor cells. Filtration should be performed on unfixed samples at a pressure of ∼10 mbar for a 1 cm(2 track-etched filter with 5 µm pores. At this pressure MDA-231 cells move through the filter in 1 hour. If fixation is needed for sample preservation, a gentle fixative should be selected. The difference in apparent viscosity between CTC and blood cells is key in optimizing recovery of CTC.

  9. Bisphosphonate treatment of aggressive primary, recurrent and metastatic Giant Cell Tumour of Bone

    International Nuclear Information System (INIS)

    Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour which contains numerous osteoclast-like giant cells. GCTB frequently recurs and can produce metastatic lesions in the lungs. Bisphosphonates are anti-resorptive drugs which act mainly on osteoclasts. In this study, we have examined clinical and radiological outcomes of treatment with aminobisphosphonates on 25 cases of aggressive primary, recurrent and metastatic GCTB derived from four European centres. We also analysed in vitro the inhibitory effect of zoledronic acid on osteoclasts isolated from GCTBs. Treatment protocols differed with several different aminobisphosphonates being employed, but stabilisation of disease was achieved in most of these cases which were refractory to conventional treatment. Most inoperable sacral/pelvic tumours did not increase in size and no further recurrence was seen in GCTBs that had repeatedly recurred in bone and soft tissues. Lung metastases did not increase in size or number following treatment. Zoledronic acid markedly inhibited lacunar resorption by GCTB-derived osteoclasts in vitro. Our findings suggest that bisphosphonates may be useful in controlling disease progression in GCTB and that these agents directly inhibit GCTB - derived osteoclast resorption. These studies highlight the need for the establishment of standardised protocols to assess the efficacy of bisphosphonate treatment of GCTB

  10. Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity

    OpenAIRE

    Ilett, EJ; Prestwich, RJ; Kottke, T; Errington, F; Thompson, JM; Harrington, KJ; Pandha, HS; Coffey, M; Selby, PJ; Vile, RG; Melcher, AA

    2009-01-01

    Reovirus is a naturally occurring oncolytic virus currently in early clinical trials. However, the rapid induction of neutralizing antibodies represents a major obstacle to successful systemic delivery. This study addresses, for the first time, the ability of cellular carriers in the form of T cells and dendritic cells (DC) to protect reovirus from systemic neutralization. In addition, the ability of these cellular carriers to manipulate the subsequent balance of anti-viral versus anti-tumour...

  11. The histogenesis of giant cell tumour of bone: a model of interaction between neoplastic cells and osteoclasts

    OpenAIRE

    Zheng, M H; ROBBINS, P; Xu, J.; Huang, Liping; Wood, D. J.; Papadimitriou, J M

    2001-01-01

    Giant cell tumour of bone (GCT) is a benign primary neoplasm of a bone characterised by distinctive clinical, radiological and pathological features. Females are slightly more often affected than males, and the majority of patients present between the ages of 20 and 50. GCT is locally aggressive and produces expansive and lytic lesions, most commonly in the epiphyses of long tubular bones. Histologically, it is composed of oval and spindle mononuclear cells, un...

  12. Cytoreductive surgery in disseminated non-seminomatous germ cell tumours of testis.

    Science.gov (United States)

    Kulkarni, R P; Reynolds, K W; Newlands, E S; Dawson, P M; Makey, A R; Theodorou, N A; Bradley, J; Begent, R H; Rustin, G J; Bagshawe, K D

    1991-02-01

    Between 1977 and 1988, 67 patients underwent surgical removal of residual metastatic deposits following an aggressive chemotherapy regimen (cisplatin, vincristine, methotrexate and bleomycin alternating with etoposide, actinomycin D and cyclophosphamide) for disseminated germ cell tumours of the testis (stage IIB or above). Ninety-one surgical procedures were performed. There were 63 (69 per cent) retroperitoneal lymph node dissections, 16 (18 per cent) thoracotomies, three (3 per cent) hepatic resections, three (3 per cent) craniotomies, five (5 per cent) delayed orchidectomies and one anterolateral decompression of the vertebral column. Nine (13 per cent) patients required a repeat retroperitoneal node dissection and one patient needed a repeat thoracotomy to remove recurrent metastatic deposits during the period of follow-up. Multivisceral resections and vascular reconstruction procedures were required in 20 (30 per cent) patients undergoing retroperitoneal node dissection. Fifty-five (82 per cent) patients remain in complete remission with a mean follow-up period of 49.6 months (range 2-121 months). Nine (13 per cent) patients died with metastatic disease between 2 months to 4 years after operation. There were three deaths in the perioperative period (4 per cent). The histology of the resected metastases revealed undifferentiated active tumour in 20 (30 per cent) patients, differentiated mature teratoma in 29 (43 per cent) patients and fibrosis/necrosis in 18 (27 per cent) patients. Twelve (60 per cent) patients with undifferentiated elements and 15 patients (60 per cent) with raised preoperative tumour markers (poor prognostic categories) are in complete remission. Cytoreductive surgery in patients with metastatic germ cell tumours offers the best chance of remission following chemotherapy even in poor prognostic group categories. PMID:1707715

  13. Modeling and simulation of circulating tumor cells in flow

    Science.gov (United States)

    Lee, Angela Meeyoun

    In this thesis, we mathematically model and computationally simulate several aspects associated with the dynamics of circulating tumor cells in the bloodstream. We focus on physical processes that initiate cancer metastasis, such as intravasation and the subsequent diffusion of thrombin by the expression of tissue factor (TF) on the surface of the circulating tumor cells that are of epithelial origin. In Part I, we develop a low-dimensional parametric deformation model of a cancer cell under shear flow. The surface deformation of MDA-MB-213 cells is imaged using DIC microscopy imaging techniques until the cell releases into the flow. We post-process the time sequence of images using an Active Shape Model (ASM) to obtain the principal components of deformation, which are then used as parameters in an empirical constitutive equation to model the cell deformations as a function of the fluid normal and shear forces imparted. The cell surface is modeled as a 2D Gaussian interface with three active parameters: height, x-width, and y-width. Fluid forces are calculated on the cell surface by discretizing the surface with regularized Stokeslets, and the flow is driven by a stochastically fluctuating pressure gradient. The Stokeslet strengths are obtained so that viscous boundary conditions are enforced on the surface of the cell and the surrounding plate. We show that the low-dimensional model is able to capture the principal deformations of the cell reasonably well and argue that Active Shape Models can be exploited further as a useful tool to bridge the gap between experiments, models, and numerical simulations in this biological setting. In Part II, we describe a mathematical and computational model for diffusion-limited procoagulant circulating tumor cells (CTCs) in flow. We first build a model based on an exact formulation of Green's function solutions for domains with a blood vessel wall and for closed domains. Time-dependent gradient trackers are used to highlight

  14. Effects of a cloned cell line with NK activity on bone marrow transplants, tumour development and metastasis in vivo

    Science.gov (United States)

    Warner, John F.; Dennert, Gunther

    1982-11-01

    Natural killer (NK) cells cloned in vitro have been transferred into NK-deficient hosts. These cells have been shown to have a role in the rejection of allogeneic bone marrow grafts, resistance to both radiation-induced thymic leukaemia and challenge with melanoma tumour cells. It appears that NK cells have an important role in immune surveillance.

  15. Gene expression profiling of circulating tumor cells and peripheral blood mononuclear cells from breast cancer patients

    Czech Academy of Sciences Publication Activity Database

    Hensler, M.; Vancurova, I.; Becht, E.; Palata, O.; Strnad, P.; Tesarova, P.; Cabinakova, M.; Švec, David; Kubista, Mikael; Bartunkova, J.; Spisek, R.; Sojka, L.

    2016-01-01

    Roč. 5, č. 4 (2016), e1102827. ISSN 2162-402X Institutional support: RVO:86652036 Keywords : Breast cancer * gene expression profiling * circulating tumor cells Subject RIV: FD - Oncology ; Hematology

  16. Genetic modification of cancer cells using non-viral, episomal S/MAR vectors for in vivo tumour modelling.

    Directory of Open Access Journals (Sweden)

    Orestis Argyros

    Full Text Available The development of genetically marked animal tumour xenografts is an area of ongoing research to enable easier and more reliable testing of cancer therapies. Genetically marked tumour models have a number of advantages over conventional tumour models, including the easy longitudinal monitoring of therapies and the reduced number of animals needed for trials. Several different methods have been used in previous studies to mark tumours genetically, however all have limitations, such as genotoxicity and other artifacts related to the usage of integrating viral vectors. Recently, we have generated an episomally maintained plasmid DNA (pDNA expression system based on Scaffold/Matrix Attachment Region (S/MAR, which permits long-term luciferase transgene expression in the mouse liver. Here we describe a further usage of this pDNA vector with the human Ubiquitin C promoter to create stably transfected human hepatoma (Huh7 and human Pancreatic Carcinoma (MIA-PaCa2 cell lines, which were delivered into "immune deficient" mice and monitored longitudinally over time using a bioluminometer. Both cell lines revealed sustained episomal long-term luciferase expression and formation of a tumour showing the pathological characteristics of hepatocellular carcinoma (HCC and pancreatic carcinoma (PaCa, respectively. This is the first demonstration that a pDNA vector can confer sustained episomal luciferase transgene expression in various mouse tumour models and can thus be readily utilised to follow tumour formation without interfering with the cellular genome.

  17. Tumour-specific metabolic adaptation to acidosis is coupled to epigenetic stability in osteosarcoma cells.

    Science.gov (United States)

    Chano, Tokuhiro; Avnet, Sofia; Kusuzaki, Katsuyuki; Bonuccelli, Gloria; Sonveaux, Pierre; Rotili, Dante; Mai, Antonello; Baldini, Nicola

    2016-01-01

    The glycolytic-based metabolism of cancers promotes an acidic microenvironment that is responsible for increased aggressiveness. However, the effects of acidosis on tumour metabolism have been almost unexplored. By using capillary electrophoresis with time-of-flight mass spectrometry, we observed a significant metabolic difference associated with glycolysis repression (dihydroxyacetone phosphate), increase of amino acid catabolism (phosphocreatine and glutamate) and urea cycle enhancement (arginino succinic acid) in osteosarcoma (OS) cells compared with normal fibroblasts. Noteworthy, metabolites associated with chromatin modification, like UDP-glucose and N(8)-acetylspermidine, decreased more in OS cells than in fibroblasts. COBRA assay and acetyl-H3 immunoblotting indicated an epigenetic stability in OS cells than in normal cells, and OS cells were more sensitive to an HDAC inhibitor under acidosis than under neutral pH. Since our data suggest that acidosis promotes a metabolic reprogramming that can contribute to the epigenetic maintenance under acidosis only in tumour cells, the acidic microenvironment should be considered for future therapies. PMID:27186436

  18. Tumour-specific metabolic adaptation to acidosis is coupled to epigenetic stability in osteosarcoma cells

    Science.gov (United States)

    Chano, Tokuhiro; Avnet, Sofia; Kusuzaki, Katsuyuki; Bonuccelli, Gloria; Sonveaux, Pierre; Rotili, Dante; Mai, Antonello; Baldini, Nicola

    2016-01-01

    The glycolytic-based metabolism of cancers promotes an acidic microenvironment that is responsible for increased aggressiveness. However, the effects of acidosis on tumour metabolism have been almost unexplored. By using capillary electrophoresis with time-of-flight mass spectrometry, we observed a significant metabolic difference associated with glycolysis repression (dihydroxyacetone phosphate), increase of amino acid catabolism (phosphocreatine and glutamate) and urea cycle enhancement (arginino succinic acid) in osteosarcoma (OS) cells compared with normal fibroblasts. Noteworthy, metabolites associated with chromatin modification, like UDP-glucose and N8-acetylspermidine, decreased more in OS cells than in fibroblasts. COBRA assay and acetyl-H3 immunoblotting indicated an epigenetic stability in OS cells than in normal cells, and OS cells were more sensitive to an HDAC inhibitor under acidosis than under neutral pH. Since our data suggest that acidosis promotes a metabolic reprogramming that can contribute to the epigenetic maintenance under acidosis only in tumour cells, the acidic microenvironment should be considered for future therapies. PMID:27186436

  19. Genetic engineering of platelets to neutralize circulating tumor cells.

    Science.gov (United States)

    Li, Jiahe; Sharkey, Charles C; Wun, Brittany; Liesveld, Jane L; King, Michael R

    2016-04-28

    Mounting experimental evidence demonstrates that platelets support cancer metastasis. Within the circulatory system, platelets guard circulating tumor cells (CTCs) from immune elimination and promote their arrest at the endothelium, supporting CTC extravasation into secondary sites. Neutralization of CTCs in blood circulation can potentially attenuate metastases to distant organs. Therefore, extensive studies have explored the blockade of platelet-CTC interactions as an anti-metastatic strategy. Such an intervention approach, however, may cause bleeding disorders since the platelet-CTC interactions inherently rely on the blood coagulation cascade including platelet activation. On the other hand, platelets have been genetically engineered to correct inherited bleeding disorders in both animal models and human clinical trials. In this study, inspired by the physical association between platelets and CTCs, platelets were genetically modified to express surface-bound tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine known to induce apoptosis specifically in tumor cells. The TRAIL-expressing platelets were demonstrated to kill cancer cells in vitro and significantly reduce metastases in a mouse model of prostate cancer metastasis. Our results suggest that using platelets to produce and deliver cancer-specific therapeutics can provide a Trojan-horse strategy of neutralizing CTCs to attenuate metastasis. PMID:26921521

  20. Characterization of DNA Methylation in Circulating Tumor Cells

    Directory of Open Access Journals (Sweden)

    Constantin F. Pixberg

    2015-10-01

    Full Text Available Epigenetics contributes to molecular mechanisms leading to tumor cell transformation and systemic progression of cancer. However, the dynamics of epigenetic remodeling during metastasis remains unexplored. In this context, circulating tumor cells (CTCs might enable a direct insight into epigenetic mechanisms relevant for metastasis by providing direct access to systemic cancer. CTCs can be used as prognostic markers in cancer patients and are regarded as potential metastatic precursor cells. However, despite substantial technical progress, the detection and molecular characterization of CTCs remain challenging, in particular the analysis of DNA methylation. As recent studies have started to address the epigenetic state of CTCs, we discuss here the potential of such investigations to elucidate mechanisms of metastasis and to develop tumor biomarkers.

  1. Nanostructured Substrates for Capturing Circulating Tumor Cells in Whole Blood

    Science.gov (United States)

    Tseng, Hsian-Rong

    2009-03-01

    Over the past decade, circulating tumor cells (CTCs) has become an emerging ``biomarker'' for detecting early-stage cancer metastasis, predicting patient prognosis, as well as monitoring disease progression and therapeutic outcomes. However, isolation of CTCs has been technically challenging due to the extremely low abundance (a few to hundreds per ml) of CTCs among a high number of hematologic cells (109 per mL) in the blood. Our joint research team at UCLA has developed a new cell capture technology for quantification of CTCs in whole blood samples. Similar to most of the existing approaches, epithelial cell adhesion molecule antibody (anti-EpCAM) was grafted onto the surfaces to distinguish CTCs from the surrounding hematologic cells. The uniqueness of our technology is the use of nanostructured surfaces, which facilitates local topographical interactions between CTCs and substrates at the very first cell/substrate contacting time point. We demonstrated the ability of these nanostructured substrates to capture CTCs in whole blood samples with significantly improved efficiency and selectivity. The successful demonstration of this cell capture technology using brain, breast and prostate cancer cell lines encouraged us to test this approach in clinical setting. We have been able to bond our first validation study with a commercialized technology based on the use of immunomagnetic nanoparticles. A group of clinically well-characterized prostate cancer patients at UCLA hospital have been recruited and tested in parallel by these two technologies.

  2. Circulation times of cancer cells by in vivo flow cytometry

    Science.gov (United States)

    Zhang, Li; Li, Yan; Gu, Zhengqin; Chen, Tong; Wang, Cheng; Wei, Xunbin

    2012-03-01

    Liver cancer is one of the most common malignancies in the world, with approximately 1,000,000 cases reported every year. Hepatocellular carcinoma may metastasize to lung, bones, kidney, and many other organs. Surgical resection, liver transplantation, chemotherapy and radiation therapy are the foundation of current HCC therapies. However the outcomes are poor: the survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed. A recently developed "in vivo flow cytometer" combined with real-time confocal fluorescence imaging are used to assess spreading and the circulation kinetics of liver tumor cells. The in vivo flow cytometer has the capability to detect and quantify continuously the number and flow characteristics of fluorescently labeled cells in vivo in real time without extracting blood sample. We have measured the depletion kinetics of two related human HCC cell lines, high-metastatic HCCLM3 cells and low-metastatic HepG2 cells, which were from the same origin and obtained by repetitive screenings in mice. >60% HCCLM3 cells are depleted within the first hour. Interestingly, the low-metastatic HepG2 cells possess noticeably slower depletion kinetics. In comparison, <40% HepG2 cells are depleted within the first hour. The differences in depletion kinetics might provide insights into early metastasis processes.

  3. Microchip-based immunomagnetic detection of circulating tumor cells.

    Science.gov (United States)

    Hoshino, Kazunori; Huang, Yu-Yen; Lane, Nancy; Huebschman, Michael; Uhr, Jonathan W; Frenkel, Eugene P; Zhang, Xiaojing

    2011-10-21

    Screening for circulating tumor cells (CTCs) in blood has been an object of interest for evidence of progressive disease, status of disease activity, recognition of clonal evolution of molecular changes and for possible early diagnosis of cancer. We describe a new method of microchip-based immunomagnetic CTC detection, in which the benefits of both immunomagnetic assay and the microfluidic device are combined. As the blood sample flows through the microchannel closely above arrayed magnets, cancer cells labeled with magnetic nanoparticles are separated from blood flow and deposited at the bottom wall of the glass coverslip, which allows direct observation of captured cells with a fluorescence microscope. A polydimethylsiloxane (PDMS)-based microchannel fixed on a glass coverslip was used to screen blood samples. The thin, flat dimensions of the microchannel, combined with the sharp magnetic field gradient in the vicinity of arrayed magnets with alternate polarities, lead to an effective capture of labeled cells. Compared to the commercially available CellSearch™ system, fewer (25%) magnetic particles are required to achieve a comparable capture rate, while the screening speed (at an optimal blood flow rate of 10 mL h(-1)) is more than five times faster than those reported previously with a microchannel-based assay. For the screening experiment, blood drawn from healthy subjects into CellSave™ tubes was spiked with cultured cancer cell lines of COLO205 and SKBR3. The blood was then kept at room temperature for 48 hours before the screening, emulating the actual clinical cases of blood screening. Customized Fe(3)O(4) magnetic nanoparticles (Veridex Ferrofluid™) conjugated to anti-epithelial cell adhesion molecule (EpCAM) antibodies were introduced into the blood samples to label cancer cells, and the blood was then run through the microchip device to capture the labelled cells. After capture, the cells were stained with fluorescent labelled anti

  4. Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model

    International Nuclear Information System (INIS)

    Aberrant regulation of cell migration drives progression of many diseases, including cancer cell invasion and metastasis formation. Analysis of tumour invasion and metastasis in living organisms to date is cumbersome and involves difficult and time consuming investigative techniques. For primary human tumours we establish here a simple, fast, sensitive and cost-effective in vivo model to analyse tumour invasion and metastatic behaviour. We fluorescently labelled small explants from gastrointestinal human tumours and investigated their metastatic behaviour after transplantation into zebrafish embryos and larvae. The transparency of the zebrafish embryos allows to follow invasion, migration and micrometastasis formation in real-time. High resolution imaging was achieved through laser scanning confocal microscopy of live zebrafish. In the transparent zebrafish embryos invasion, circulation of tumour cells in blood vessels, migration and micrometastasis formation can be followed in real-time. Xenografts of primary human tumours showed invasiveness and micrometastasis formation within 24 hours after transplantation, which was absent when non-tumour tissue was implanted. Furthermore, primary human tumour cells, when organotopically implanted in the zebrafish liver, demonstrated invasiveness and metastatic behaviour, whereas primary control cells remained in the liver. Pancreatic tumour cells showed no metastatic behaviour when injected into cloche mutant embryos, which lack a functional vasculature. Our results show that the zebrafish is a useful in vivo animal model for rapid analysis of invasion and metastatic behaviour of primary human tumour specimen

  5. Electrical Detection Method for Circulating Tumor Cells Using Graphene Nanoplates.

    Science.gov (United States)

    Han, Song-I; Han, Ki-Ho

    2015-10-20

    This paper presents a microfluidic device for electrical discrimination of circulating tumor cells (CTCs) using graphene nanoplates (GNPs) as a highly conductive material bound to the cell surface. For two-step cascade discrimination, the microfluidic device is composed of a CTC-enrichment device and an impedance cytometry. Using lateral magnetophoresis, the CTC-enrichment device enriches rare CTCs from millions of background blood cells. Then, the impedance cytometry electrically identifies CTCs from the enriched sample, containing CTCs and persistent residual blood cells, based on the electrical impedance of CTCs modified by the GNPs. GNPs were used as a highly conductive material for modifying surface conductivity of CTCs, thereby improving the accuracy of electrical discrimination. The experimental results showed that a colorectal cancer cell line (DLD-1) spiked into peripheral blood was enriched by nearly 500-fold by the CTC-enrichment device. The phase of the electrical signal measured from DLD-1 cells covered by GNPs shifted by about 100° in comparison with that from normal blood cells, which allows the impedance cytometry to identify CTCs at a rate of 94% from the enriched samples. PMID:26402053

  6. Occult leydig cell tumour and androgen-receptor positive breast cancer in a woman with severe hyperandrogenism

    OpenAIRE

    Saraceno, Giovanna; Barresi, Valeria; Trimarchi, Francesco; Cannavo, Salvatore

    2013-01-01

    Leydig cell tumours represent more than 75% of all testosterone-secreting ovarian masses. These benign tumours are frequently occult or very small, but cause dramatic virilization. Chronic hyperandrogenism can also induce systemic complications, which increase morbidity and mortality risk. One of the most obvious effects of increased testosterone levels is polycythemia, a complication which induces dermatologic, osteoarticular and gastrointestinal manifestations and is associated with increas...

  7. O 6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

    OpenAIRE

    Clemons, M.; Kelly, J.; Watson, A.J.; Howell, A.; McElhinney, R S; McMurry, T B H; Margison, G P

    2005-01-01

    Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O 6-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O 6-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O 6-(4-bromothenyl)guanine (PaTrin-2, Patrin™, Lomeguatrib) on MGMT activity and cell or xenograft tumour gr...

  8. Photo(chemotherapy reduces circulating Th17 cells and restores circulating regulatory T cells in psoriasis.

    Directory of Open Access Journals (Sweden)

    Takuya Furuhashi

    Full Text Available BACKGROUND: Photo(chemotherapy is widely used to treat psoriasis, the pathogenesis of which might be caused by an imbalance of Th17 cells/regulatory T cells (Treg. In the present study, we evaluated the effects of photo(chemotherapy on the Th17/Treg balance and Treg function. METHODS: Peripheral blood was obtained from psoriasis patients treated with bath-psoralen ultraviolet A (UVA, n = 50 or narrowband ultraviolet B (UVB, n = 18, and age-matched healthy volunteers (n = 20. CD3(+CD4(+IL-17A(+ or CD4(+CD25(+Foxp3(+cells were analyzed to estimate Th17 or Treg number by fluorescence-activated cell sorting. Moreover, CD4(+ CD25(- T cells from patients treated with PUVA(n = 14 were incubated in CFSE and activated with or without CD4(+ CD25(+T cells, and the suppressive function of CD4(+ CD25(+T cells were analyzed. RESULTS: Photo(chemotherapy significantly reduced Th17 levels from 5.66 ± 3.15% to 2.96 ± 2.89% in patients with increased Th17 (Th17/CD4>3.01% [mean+SD of controls]. In contrast, photo(chemotherapy significantly increased Treg levels from 2.77 ± 0.75 to 3.40 ± 1.88% in patients with less than 4.07% Treg level, defined as the mean of controls. Furthermore, while Treg suppressed the CD4(+CD25(- T cell proliferation to a greater extent in controls (Treg Functional Ratio 94.4 ± 4.28% than in patients (70.3±25.1%, PUVA significantly increased Treg Functional Ratio to 88.1 ± 6.47%. Th17 levels in severe patients (>30 PASI were significantly higher as compared to controls. Th17 levels that were left after treatment in the patients not achieving PASI 50 (3.78 ± 4.18% were significantly higher than those in the patients achieving PASI 75 (1.83±1.87%. Treg levels in patients achieving PASI 90 (4.89 ± 1.70% were significantly higher than those in the patients not achieving PASI 90 (3.90 ± 1.66%. Treg levels prior to treatment with Th17 high decreased group (5.16 ± 2.20% was significantly higher than that with Th17 high increased group

  9. Differentiation of tumour and inflammation: characterisation of [methyl-{sup 3}H]methionine (MET) and O-(2-[{sup 18}F]fluoroethyl)-L-tyrosine (FET) uptake in human tumour and inflammatory cells

    Energy Technology Data Exchange (ETDEWEB)

    Stoeber, Barbara; Tanase, Ursula; Herz, Michael; Seidl, Christof; Schwaiger, Markus; Senekowitsch-Schmidtke, Reingard [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum Rechts der Isar, Munich (Germany)

    2006-08-15

    Previous studies suggest that radiolabelled amino acids could be superior to FDG in differentiating tumour and inflammation. Therefore the aim of this study was to investigate the uptake of FET and MET in human tumour and inflammatory cells and to investigate their uptake kinetics. For uptake studies, cells were incubated with 370 kBq FET or 3.7 kBq MET for 15 min. Kinetic studies were performed at variable concentrations of FET and MET. Competitive inhibition studies were done with BCH, MeAIB and L-serine. All inflammatory cells incorporated more MET than the tumour cells. The uptake of FET, in contrast, was significantly lower in all inflammatory cells than in the tumour cells. In tumour cells the uptake of MET was about five times the uptake of FET. The competitive inhibitors reduced uptake of both tracers to 20-40% in tumour cells and to 70% in inflammatory cells. Kinetic studies showed that MET and FET transport was saturable in all cells except macrophages and followed a Michaelis-Menten kinetic. Highest capacity (V{sub max}) and affinity (K{sub m}) for the uptake of MET was observed in granulocytes. Capacity and affinity for FET uptake were highest in the DHL-4 cells. In contrast to MET, FET accumulated to a significantly greater extent in tumour cells than in inflammatory cells. The marked differences between tumour and inflammatory cells concerning FET and MET uptake suggest that FET and MET are substrates of different subtypes of the L system. (orig.)

  10. Oestrogen receptors and small nuclear ring finger protein 4 (RNF4) in malignant ovarian germ cell tumours.

    Science.gov (United States)

    Salonen, Jonna; Butzow, Ralf; Palvimo, Jorma J; Heikinheimo, Markku; Heikinheimo, Oskari

    2009-08-13

    The peak incidence of malignant ovarian germ cell tumours occurs soon after puberty. Thus, gonadal steroids may play a role in their development. Oestrogen receptors (ERalpha and ERbeta) and their co-regulators, including small nuclear ring finger protein 4 (SNURF/RNF4) mediate oestrogen actions. While ERbeta and SNURF are down-regulated in testicular germ cell tumours, their role in the ovarian germ cell tumours remains unknown. We herein studied the different subtypes of malignant ovarian germ cell tumours, and found that they all express ERalpha, ERbeta, and SNURF. Stimulation with oestradiol (E2), ERalpha, ERbeta and SNURF significantly up-regulated mRNA expression in the human germinoma derived NCC-IT cells. Further, the effects of E2 were counteracted by an anti-oestrogen (ICI 182,780). Neither E2 nor ICI 182,780 had an effect on the proliferation of NCC-IT cells as assessed by flow cytometric analysis. Our results suggest that oestrogen signalling has a role in malignant ovarian germ cell tumours. PMID:19524139

  11. Proving tumour cells by acute nutritional/energy deprivation as a survival threat: a task for microscopy

    Czech Academy of Sciences Publication Activity Database

    Janečková, H.; Veselý, Pavel; Chmelík, R.

    2009-01-01

    Roč. 29, č. 6 (2009), s. 2339-2345. ISSN 0250-7005 Institutional research plan: CEZ:AV0Z50520514 Keywords : tumour cell * nutritional deprivation * energy deprivation * cell survival * cell death * digital holographic microscopy * dynamic phase difference Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.428, year: 2009

  12. Prognostic value of circulating VEGFR2+ bone marrow-derived progenitor cells in patients with advanced cancer.

    Science.gov (United States)

    Massard, Christophe; Borget, Isabelle; Le Deley, Marie Cécile; Taylor, Melissa; Gomez-Roca, Carlos; Soria, Jean Charles; Farace, Françoise

    2012-06-01

    We hypothesised that host-related markers, possibly reflecting tumour aggressiveness, such as circulating endothelial cells (CEC) and circulating VEGFR2(+) bone marrow-derived (BMD) progenitor cells, could have prognostic value in patients with advanced cancer enrolled in early anticancer drug development trials. Baseline CECs (CD45(-)CD31(+)CD146(+)7AAD(-) cells) and circulating VEGFR2(+)-BMD progenitor cells (defined as CD45(dim)CD34(+)VEGFR2(+)7AAD(-) cells) were measured by flow-cytometry in 71 and 58 patients included in phase 1 trials testing novel anti-vascular or anti-angiogenic agents. Correlations between levels of CECs, circulating VEGFR2(+)-BMD progenitor cells, clinical and biological prognostic factors (i.e. the Royal Marsden Hospital (RMH) score), and overall survival (OS) were studied. The median value of CECs was 12 CEC/ml (range 0-154/ml). The median level of VEGFR2(+)-BMD progenitor cells was 1.3% (range 0-32.5%) of circulating BMD-CD34(+) progenitors. While OS was not correlated with CEC levels, it was significantly worse in patients with high VEGFR2(+)-BMD progenitor levels (>1%) (median OS 9.0 versus 17.0 months), and with a RMH prognostic score >0 (median OS 9.0 versus 24.2 months). The prognostic value of VEGFR2(+)-BMD progenitor levels remained significant (hazard ratio (HR) = 2.3, 95% confidence interval (CI), 1.1-4.6, p = 0.02) after multivariate analysis. A composite VEGFR2(+)-BMD progenitor level/RHM score ≥ 2 was significantly associated with an increased risk of death compared to scores of 0 or 1 (median OS 9.0 versus 18.4 months, HR = 2.6 (95%CI, 1.2-5.8, p = 0.02)). High circulating VEGFR2(+)-BMD progenitor levels are associated with poor prognostics and when combined to classical clinical and biological parameters could provide a new tool for patient selection in early anticancer drug trials. PMID:22370181

  13. Variation in sensitizing effect of caffeine in human tumour cell lines after γ-irradiation

    International Nuclear Information System (INIS)

    We have investigated whether the protective role of the G2 checkpoint has increasing importance when the p53-dependent G1 checkpoint is inactivated. We have studied the differential effect of caffeine by clonogenic assays and flow cytometry in three human tumour cell lines with different functionality of p53 protein. The radiosensitizing effect of caffeine (2 mM) expressed itself as a significant decrease in surviving fraction at 2 Gy and a significant increase in α-values in RT112 and TE671, both with non-functional p53. However, no radiosensitizing effect was seen in cells with a normal p53 function (MCF-7 BUS). Two millimoles of caffeine also caused important changes in the cell cycle progression after irradiation. MCF-7 BUS showed a G1 arrest after irradiation and an early G2 arrest but those cells that reached the second G2 did not arrest significantly. In contrast, TE671 exhibited radiosensitization by caffeine, no G1 arrest, a G2 arrest in those cells irradiated in G2, no significant accumulation in the second G2 but an overall delay in release from the first cell cycle, which could be abrogated by caffeine. RT112 was similar to TE671 except that the emphasis in a G2 arrest was shifted from the block in cells irradiated in G2 to those irradiated at other cell cycle phases. The data presented confirm that p53 status can be a significant determinant of the efficacy of caffeine as radiosensitizer in these tumour cell lines, and document the importance of the G2 checkpoint in this effect. (author)

  14. In vitro activity of bortezomib in cultures of patient tumour cells--potential utility in haematological malignancies.

    Science.gov (United States)

    Wiberg, Kristina; Carlson, Kristina; Aleskog, Anna; Larsson, Rolf; Nygren, Peter; Lindhagen, Elin

    2009-01-01

    Bortezomib represents a new class of anti-cancer drugs, the proteasome inhibitors. We evaluated the in vitro activity of bortezomib with regard to tumour-type specificity and possible mechanisms of drug resistance in 115 samples of tumour cells from patients and in a cell-line panel, using the short-term fluorometric microculture cytotoxicity assay. Bortezomib generally showed dose-response curves with a steep slope. In patient cells, bortezomib was more active in haematological than in solid tumour samples. Myeloma and chronic myeloid leukaemia were the most sensitive tumour types although with great variability in drug response between the individual samples. Colorectal and kidney cancer samples were the least sensitive. In the cell-line panel, only small differences in response were seen between the different cell lines, and the proteasome inhibitors, lactacystin and MG 262, showed an activity pattern similar to that of bortezomib. The cell-line data suggest that resistance to bortezomib was not mediated by MRP-, PgP, GSH-; tubulin and topo II-associated MDR. Combination experiments indicated synergy between bortezomib and arsenic trioxide or irinotecan. The data support the current use of bortezomib but also points to its potential utility in other tumour types and in combination with cytotoxic drugs. PMID:19016012

  15. Expression pattern of clinically relevant markers in paediatric germ cell- and sex-cord stromal tumours is similar to adult testicular tumours

    DEFF Research Database (Denmark)

    Mosbech, Christiane Hammershaimb; Svingen, Terje; Nielsen, John Erik;

    2014-01-01

    , elaborate on clinical-pathological associations and better understand their developmental divergence. The tumours were screened for expression of stemness-related factors (OCT4, AP-2γ, SOX2), classical yolk sac tumours (YSTs; AFP, SALL4), GCTs (HCG, PLAP, PDPN/D2-40), as well as markers for sex-cord stromal...... tumour (PDPN, GATA4). All YSTs expressed AFP and SALL4, with GATA4 present in 13/14. The majority of teratomas expressed SOX2 and PDPN, whereas SALL4 was found in 8/13 immature teratomas. Adult seminoma markers AP-2γ, OCT4, SALL4 and PDPN were all expressed in dysgerminoma. We further report a previously...... unrecognised pathogenetic relationship between AFP and SALL4 in YST in that different populations of YST cells express either SALL4 or AFP, which suggests variable differentiation status. We also show that AP-2γ is expressed in the granulosa layer of ovarian follicles and weakly expressed in immature but not...

  16. Efficient Capture and Isolation of Tumor-Related Circulating Cell-Free DNA from Cancer Patients Using Electroactive Conducting Polymer Nanowire Platforms

    Science.gov (United States)

    Jeon, SeungHyun; Lee, HyungJae; Bae, Kieun; Yoon, Kyong-Ah; Lee, Eun Sook; Cho, Youngnam

    2016-01-01

    Circulating cell-free DNA (cfDNA) is currently recognized as a key non-invasive biomarker for cancer diagnosis and progression and therapeutic efficacy monitoring. Because cfDNA has been detected in patients with diverse types of cancers, the use of efficient strategies to isolate cfDNA not only provides valuable insights into tumour biology, but also offers the potential for developing new cancer-specific targets. However, the challenges associated with conventional cfDNA extraction methods prevent their further clinical applications. Here, we developed a nanostructured conductive polymer platform for the efficient capture and release of circulating cfDNA and demonstrated its potential clinical utility using unprocessed plasma samples from patients with breast and lung cancers. Our results confirmed that the platform's enhanced efficiency allows tumor-specific circulating cfDNA to be recovered at high yield and purity. PMID:27162553

  17. Circulating endothelial progenitor cells in kidney transplant patients.

    Directory of Open Access Journals (Sweden)

    Giovana S Di Marco

    Full Text Available BACKGROUND: Kidney transplantation (RTx leads to amelioration of endothelial function in patients with advanced renal failure. Endothelial progenitor cells (EPCs may play a key role in this repair process. The aim of this study was to determine the impact of RTx and immunosuppressive therapy on the number of circulating EPCs. METHODS: We analyzed 52 RTx patients (58±13 years; 33 males, mean ± SD and 16 age- and gender-matched subjects with normal kidney function (57±17; 10 males. RTx patients received a calcineurin inhibitor (CNI-based (65% or a CNI-free therapy (35% and steroids. EPC number was determined by double positive staining for CD133/VEGFR2 and CD34/VEGFR2 by flow cytometry. Stromal cell-derived factor 1 alpha (SDF-1 levels were assessed by ELISA. Experimentally, to dissociate the impact of RTx from the impact of immunosuppressants, we used the 5/6 nephrectomy model. The animals were treated with a CNI-based or a CNI-free therapy, and EPCs (Sca+cKit+ and CD26+ cells were determined by flow cytometry. RESULTS: Compared to controls, circulating number of CD34+/VEGFR2+ and CD133+/VEGFR2+ EPCs increased in RTx patients. There were no correlations between EPC levels and statin, erythropoietin or use of renin angiotensin system blockers in our study. Indeed, multivariate analysis showed that SDF-1--a cytokine responsible for EPC mobilization--is independently associated with the EPC number. 5/6 rats presented decreased EPC counts in comparison to control animals. Immunosuppressive therapy was able to restore normal EPC values in 5/6 rats. These effects on EPC number were associated with reduced number of CD26+ cells, which might be related to consequent accumulation of SDF-1. CONCLUSIONS: We conclude that kidney transplantation and its associated use of immunosuppressive drugs increases the number of circulating EPCs via the manipulation of the CD26/SDF-1 axis. Increased EPC count may be associated to endothelial repair and function in

  18. DNA double strand breaks in Ehrlich ascites tumour cells at low doses of X-rays

    International Nuclear Information System (INIS)

    DNA double strand breaks (dsb) were determined in Ehrlich ascites tumour cells at doses down to 5 Gy. Sedimentation profiles were analysed using a computer program and the number of dsb was determined by simulation of random breaks in the mass distribution of the control sample and by comparison of this simulated profile with that of the irradiated one. The number of dsb formed was proportional to X-ray dose in the range of 5 to 2000 Gy. The induction per dose was found to be nmsub(r)-1 D-1=(11.7+-2) x 10-12 Gy-1. (author)

  19. Prognosis after salvage treatment for unselected male patients with germ cell tumours.

    OpenAIRE

    Gerl, A; Clemm, C.; Schmeller, N.; Hartenstein, R.; Lamerz, R.; Wilmanns, W.

    1995-01-01

    Long-term outcome of salvage treatment was reviewed in 67 unselected male patients relapsing during or after their primary cisplatin-based chemotherapy for metastatic germ cell tumours. Seven patients underwent only surgery and/or radiotherapy as curatively intended salvage treatment. Thirty-five patients (52%) had a complete or partial response to salvage treatment, 20 (57%) of whom relapsed again. With a median follow-up of 90 months (range 3-143 months) 20 patients (30%) are alive with no ...

  20. Dendritic cell-based vaccines for therapy of HPV16-induced tumours

    Czech Academy of Sciences Publication Activity Database

    Bubeník, Jan; Šímová, Jana; Vonka, V.; Šmahel, M.; Mikyšková, Romana; Mendoza, Luis

    2001-01-01

    Roč. 495, - (2001), s. 359-363. ISSN 0065-2598 R&D Projects: GA MZd NC5526; GA ČR GA312/98/0826; GA ČR GA312/99/0542; GA ČR GA301/00/0114; GA ČR GA301/01/0985; GA AV ČR IAA7052002 Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV16 * dendritic cells * tumour vaccines Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.513, year: 2000

  1. Pharmacological characterization of β2-adrenoceptor in PGT-β mouse pineal gland tumour cells

    OpenAIRE

    Suh, Byung-Chang; Chae, Hee-Don; Chung, Joo-Ho; Kim, Kyong-Tai

    1999-01-01

    The adrenoceptor in a mouse pineal gland tumour cell line (PGT-β) was identified and characterized using pharmacological and physiological approaches.Adrenaline and noradrenaline, adrenoceptor agonists, stimulated cyclic AMP generation in a concentration-dependent manner, but had no effect on inositol 1,4,5-trisphosphate production. Adrenaline was a more potent activator of cyclic AMP generation than noradrenaline, with half maximal-effective concentrations (EC50) seen at 175±22 nM and 18±2 μ...

  2. Spermatogonial Nature of the Germ Cell Component of Canine Testicular Mixed Germ Cell-Sex Cord Stromal Tumours.

    Science.gov (United States)

    Mizukami, S; Murakami, T; Tanaka, T; Machida, N; Nomura, K; Yoshida, T; Shibutani, M

    2016-07-01

    The present study has characterized the germ cell component of canine testicular mixed germ cell-sex cord stromal tumours (MGSCTs) by examining the histological nature and histochemical and immunohistochemical features using gonocytic and spermatogonial cellular markers, c-Kit, placental alkaline phosphatase (PLAP), protein gene product 9.5 (PGP9.5), Sal-like protein 4 (SALL4), and the periodic acid-Schiff (PAS) reaction. Histologically, all 45 examples of MGSCTs were classified as spermatocytic seminomas (SSs) and Sertoli cell tumours in combination. The germ cell component of all MGSCTs was negative by PAS staining. Immunohistochemically, PLAP immunoreactivity was lacking in the germ cell component of all MGSCTs, which is not consistent with a gonocytic origin. The germ cell component was positive for PGP9.5 and SALL4 in all MGSCTs and positive for c-Kit in 53% of MGSCTs, which is consistent with the phenotype of spermatogonia. Furthermore, the germ cell component in 71% of MGSCTs had moderate immunoreactivity for SALL4, which is suggestive of a spermatogonial phenotype. Conversely, 29% of cases had a minor population of germ cells showing strong SALL4 immunoreactivity, suggesting a phenotype similar to prespermatogonia. The results suggest that the germ cell component of canine MGSCTs is morphologically classified as SS, with the majority of cases showing the spermatogonial phenotype and some cases containing a small population of prespermatogonia. PMID:27241073

  3. Whole-body FDG-PET in patients with stage I non-seminomatous germ cell tumours

    DEFF Research Database (Denmark)

    Lassen, U; Daugaard, G; Eigtved, A; Højgaard, L; Nielsen, Knud Damsgaard; Rørth, M

    2003-01-01

    negative and no false positive PET scans. The sensitivity, specificity and accuracy of PET were 70%, 100% and 93%, respectively. The sensitivity of detecting small retroperitoneal metastases was 88%. The negative and positive predictive values were 92% and 100%, respectively, whereas the negative......Relapse occurs in 30% of patients with stage I non-seminomatous germ cell tumours (NSGCT) within 1 year after orchiectomy. Whole-body positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) may detect small metastases when standard staging with computed tomography (CT) and tumour...... markers is negative. In this study, 46 patients underwent FDG-PET after staging with normal CT and tumour markers. To exclude diagnostic test bias and workup bias, all patients had routine follow-up with repeated CT and tumour marker evaluation, even though the initial FDG-PET was positive. Thirty...

  4. New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation

    Directory of Open Access Journals (Sweden)

    Branka Zorc

    2012-01-01

    Full Text Available Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a–e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1, 4-chloro-pyridine-2-carboxamides 2a–e, 4-(4-aminophenoxy-pyridine-2-carboxamides 3a–e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethylphenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a–e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a–e (IC50 = 1-4.3 μmol·L−1. Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.

  5. Fetal Microchimeric Cells Participate in Tumour Angiogenesis in Melanomas Occurring during Pregnancy

    OpenAIRE

    Nguyen Huu, Sau; Oster, Michèle; Avril, Marie-Françoise; Boitier, Françoise; Mortier, Laurent; Richard, Marie-Aleth; Kerob, Delphine; Maubec, Eve; Souteyrand, Pierre; Moguelet, Philippe; Khosrotehrani, Kiarash; Aractingi, Selim

    2009-01-01

    Melanoma is a major malignancy in younger individuals that accounts for 8% of all neoplasias associated with gestation. During pregnancy, a small number of fetal cells enter the maternal circulation. These cells persist and then migrate to various maternal tissues where they may engraft and differentiate, particularly if there is organ damage, adopting the phenotype of the host organ. To understand the relationship between melanoma and pregnancy, we analyzed these tumors in both humans and mi...

  6. Juvenile granulosa cell tumour of the ovary presenting with hyperprolactinaemic amenorrhoea and galactorrhoea

    Science.gov (United States)

    Iqbal, Ahmed; Lubina-Solomon, Alexandra; Kew, Fiona M; Webster, Jonathan

    2016-01-01

    Summary Secondary amenorrhoea and galactorrhoea represent a common endocrine presentation. We report a case of an oestrogen-producing juvenile granulosa cell tumour (JGCT) of the ovary in a 16-year-old post-pubertal woman with hyperprolactinaemia amenorrhoea and galactorrhoea which resolved following surgical resection of the tumour. This patient presented with a 9-month history of secondary amenorrhoea and a 2-month history of galactorrhoea. Elevated serum prolactin at 7081 mIU/l and suppressed gonadotropins (LH <0.1 U/l; FSH <0.1 U/l) were detected. Serum oestradiol was significantly elevated at 7442 pmol/l with undetectable β-human chorionic gonadotropin. MRI showed a bulky pituitary with no visible adenoma. MRI of the abdomen showed a 4.8 cm mass arising from the right ovary with no evidence of metastatic disease. Serum inhibin B was elevated at 2735 ng/l. A right salpingo-oophorectomy was performed, and histology confirmed the diagnosis of a JGCT, stage International Federation of Gynaecology and Obstetrics 1A. Immunohistochemical staining for prolactin was negative. Post-operatively, oestrogen and prolactin levels were normalised, and she subsequently had a successful pregnancy. In summary, we present a case of an oestrogen-secreting JGCT with hyperprolactinaemia manifesting clinically with galactorrhoea and secondary amenorrhoea. We postulate that observed hyperprolactinaemia was caused by oestrogenic stimulation of pituitary lactotroph cells, a biochemical state analogous to pregnancy. To the best of our knowledge, this is the first report of hyperprolactinaemia as a result of excessive oestrogen production in the context of a JGCT. Learning points Hyperprolactinaemia with bilateral galactorrhoea and secondary amenorrhoea has a wide differential diagnosis and is not always caused by a prolactin secreting pituitary adenoma.Significantly elevated serum oestradiol levels in the range seen in this case, in the absence of pregnancy, are indicative

  7. The genomic landscape of testicular germ cell tumours: from susceptibility to treatment.

    Science.gov (United States)

    Litchfield, Kevin; Levy, Max; Huddart, Robert A; Shipley, Janet; Turnbull, Clare

    2016-07-01

    The genomic landscape of testicular germ cell tumour (TGCT) can be summarized using four overarching hypotheses. Firstly, TGCT risk is dominated by inherited genetic factors, which determine nearly half of all disease risk and are highly polygenic in nature. Secondly KIT-KITLG signalling is currently the major pathway that is implicated in TGCT formation, both as a predisposition risk factor and a somatic driver event. Results from genome-wide association studies have also consistently suggested that other closely related pathways involved in male germ cell development and sex determination are associated with TGCT risk. Thirdly, the method of disease formation is unique, with tumours universally stemming from a noninvasive precursor lesion, probably of fetal origin, which lies dormant through childhood into adolescence and then eventually begins malignant growth in early adulthood. Formation of a 12p isochromosome, a hallmark of TGCT observed in nearly all tumours, is likely to be a key triggering event for malignant transformation. Finally, TGCT have been shown to have a distinctive somatic mutational profile, with a low rate of point mutations contrasted with frequent large-scale chromosomal gains. These four hypotheses by no means constitute a complete model that explains TGCT tumorigenesis, but advances in genomic technologies have enabled considerable progress in describing and understanding the disease. Further advancing our understanding of the genomic basis of TGCT offers a clear opportunity for clinical benefit in terms of preventing invasive cancer arising in young men, decreasing the burden of chemotherapy-related survivorship issues and reducing mortality in the minority of patients who have treatment-refractory disease. PMID:27296647

  8. Immunology of naturally transmissible tumours

    OpenAIRE

    Siddle, Hannah V; Kaufman, Jim

    2014-01-01

    Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonise a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, Canine Transmissible Venereal Tumour (CTVT) that spreads among dogs and Devil Facial Tumour Disease (D...

  9. Wild mushrooms Clitocybe alexandri and Lepista inversa: in vitro antioxidant activity and growth inhibition of human tumour cell lines.

    Science.gov (United States)

    Vaz, Josiana A; Heleno, Sandrina A; Martins, Anabela; Almeida, Gabriela M; Vasconcelos, M Helena; Ferreira, Isabel C F R

    2010-10-01

    The in vitro antioxidant and growth inhibitory activity of extracts obtained from two Portuguese wild mushrooms (Clitocybe alexandri and Lepista inversa) was studied in human tumour cell lines. The extracts were phenolic (methanolic and ethanolic) and polysaccharidic (boiling water). The antioxidant activity assays included evaluation of radical-scavenging capacity, reducing power and inhibition of lipid peroxidation measured in liposome solutions. Extract-induced cell growth inhibition was measured in four different tumour cell lines (lung, breast, colon and gastric cancer) using the SRB assay. The polysaccharidic extract of L. inversa was the most potent as antioxidant (EC(50)mushrooms are promising sources of bioactive compounds. PMID:20647028

  10. Recent Advances in the Molecular Characterization of Circulating Tumor Cells

    Energy Technology Data Exchange (ETDEWEB)

    Lowes, Lori E. [London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 4L6 (Canada); Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1 (Canada); Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 4L6 (Canada); Allan, Alison L., E-mail: alison.allan@lhsc.on.ca [London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 4L6 (Canada); Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1 (Canada); Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 4L6 (Canada); Lawson Health Research Institute, London, ON N6C 2R5 (Canada)

    2014-03-13

    Although circulating tumor cells (CTCs) were first observed over a century ago, lack of sensitive methodology precluded detailed study of these cells until recently. However, technological advances have now facilitated the identification, enumeration, and characterization of CTCs using a variety of methods. The majority of evidence supporting the use of CTCs in clinical decision-making has been related to enumeration using the CellSearch{sup ®} system and correlation with prognosis. Growing evidence also suggests that CTC monitoring can provide an early indication of patient treatment response based on comparison of CTC levels before and after therapy. However, perhaps the greatest potential that CTCs hold for oncology lies at the level of molecular characterization. Clinical treatment decisions may be more effective if they are based on molecular characteristics of metastatic cells rather than on those of the primary tumor alone. Molecular characterization of CTCs (which can be repeatedly isolated in a minimally invasive fashion) provides the opportunity for a “real-time liquid biopsy” that allows assessment of genetic drift, investigation of molecular disease evolution, and identification of actionable genomic characteristics. This review focuses on recent advances in this area, including approaches involving immunophenotyping, fluorescence in situ hybridization (FISH), multiplex RT-PCR, microarray, and genomic sequencing.

  11. Transport Mechanisms of Circulating Tumor Cells in Microfluidic Devices

    Science.gov (United States)

    Rangharajan, Kaushik; Conlisk, A. T.; Prakash, Shaurya

    2014-11-01

    Lab-on-a-chip (LoC) devices are becoming an essential tool for several emerging point-of-care healthcare needs and applications. Among the plethora of challenging problems in the personalized healthcare domain, early detection of cancer continues to be a challenge. For instance, identification of most tumors occurs by the time the tumor comprises approximately 1 billion cells, with poor prognosis for metastatic disease. The key obstacle in identifying and subsequent capture of circulating tumor cells (CTCs) is that the amount of CTCs in the blood stream is ~1 in 109 cells. The fundamental challenge in design and fabrication of microfluidic devices arises due to lack of information on suitable sorting needed for sample preparation before any labeling or capture scheme can be employed. Moreover, the ability to study these low concentration cells relies on knowledge of their physical and chemical properties, of which the physical properties are poorly understood. Also, nearly all existing microfluidic mixers were developed for aqueous electrolyte solutions to enhance mixing in traditional low Re flows. However, no systematic studies have developed design rules for particle mixing. Therefore, we present a numerical model to discuss design rules for microscale mixers and sorters for particle sorting for high efficiency antibody labeling of CTCs along with presenting a pathway for a device to capture CTCs without the need for labeling based on particle electrical properties. NSF Nanoscale Science and Engineering Center (NSEC) for the Affordable Nanoengineering of Polymeric Biomedical Devices EEC-0914790.

  12. Recent Advances in the Molecular Characterization of Circulating Tumor Cells

    Directory of Open Access Journals (Sweden)

    Lori E. Lowes

    2014-03-01

    Full Text Available Although circulating tumor cells (CTCs were first observed over a century ago, lack of sensitive methodology precluded detailed study of these cells until recently. However, technological advances have now facilitated the identification, enumeration, and characterization of CTCs using a variety of methods. The majority of evidence supporting the use of CTCs in clinical decision-making has been related to enumeration using the CellSearch® system and correlation with prognosis. Growing evidence also suggests that CTC monitoring can provide an early indication of patient treatment response based on comparison of CTC levels before and after therapy. However, perhaps the greatest potential that CTCs hold for oncology lies at the level of molecular characterization. Clinical treatment decisions may be more effective if they are based on molecular characteristics of metastatic cells rather than on those of the primary tumor alone. Molecular characterization of CTCs (which can be repeatedly isolated in a minimally invasive fashion provides the opportunity for a “real-time liquid biopsy” that allows assessment of genetic drift, investigation of molecular disease evolution, and identification of actionable genomic characteristics. This review focuses on recent advances in this area, including approaches involving immunophenotyping, fluorescence in situ hybridization (FISH, multiplex RT-PCR, microarray, and genomic sequencing.

  13. Expression of the PLS3 Gene in Circulating Cells in Patients with Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Kujawski Ryszard

    2015-02-01

    Full Text Available Circulating tumor cells (CTC are cells in circulating blood that have the antigen and gene features of tumor cells of a specific type. Since they can be potentially used in diagnostics and monitoring of treatment of many tumors, they have been attracting attention of researchers worldwide. Plastin-3 (PL S3 is one of such markers of CTC.

  14. 21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

    Science.gov (United States)

    2010-04-01

    ... cancer cells in a prepared sample of whole blood. This device is intended for adjunctive use in... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection...

  15. Isolation and Molecular Characterization of Circulating Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Xi Luo

    2014-05-01

    Full Text Available Melanoma is an invasive malignancy with a high frequency of blood-borne metastases, but circulating tumor cells (CTCs have not been readily isolated. We adapted microfluidic CTC capture to a tamoxifen-driven B-RAF/PTEN mouse melanoma model. CTCs were detected in all tumor-bearing mice and rapidly declined after B-RAF inhibitor treatment. CTCs were shed early from localized tumors, and a short course of B-RAF inhibition following surgical resection was sufficient to dramatically suppress distant metastases. The large number of CTCs in melanoma-bearing mice enabled a comparison of RNA-sequencing profiles with matched primary tumors. A mouse melanoma CTC-derived signature correlated with invasiveness and cellular motility in human melanoma. CTCs were detected in smaller numbers in patients with metastatic melanoma and declined with successful B-RAF-targeted therapy. Together, the capture and molecular characterization of CTCs provide insight into the hematogenous spread of melanoma.

  16. Advances in Research on Circulating Tumor Cells in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yingjian SONG

    2012-10-01

    Full Text Available Metastatic and recurrent tumors have been identified as the leading attribute to the lung cancer deaths. Cancer research has demonstrated the critical role circulating tumor cells (CTCs play in the metastatic spread of carcinomas and the recurrence of lung cancer. The rapid advancement of technology in targeted therapy resolves the embarrassing situation for those late-stage patients whose tumor tissues cannot be obtained. CTCs, as a substitute for the tumor tissues, represent a decisive tool to the cancer treatment strategy. Thus, CTCs exert a fundamental role in the early detection of micro-metastasis, assisting in diagnosis, prognosis and monitoring of the recurrent tumors, and subsequently choosing an individualized approach for the therapeutic treatment. This article will review the advances, which have been made in the research area of CTCs with the aid of its applications in cancer therapy.

  17. Advanced Research on Circulating Tumor Cells in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Hui LI

    2012-11-01

    Full Text Available Lung cancer is the malignant disease with the highest rate in terms of incidence and mortality in China. Early diagnosis and timely monitoring tumor recurrence and metastasis are extremely important for improving 5-year survival rate of lung cancer patients. Circulating tumor cells (CTCs, as a "liquid biopsy specimens” for the primary tumor, provide the possibility to perform real-time, non-invasive histological identification for lung cancer patients. The detection of CTCs contributes to early diagnosis, surveillance of tumor recurrence and metastasis, and prediction of therapeutic efficacy and prognosis. Furthermore, CTCs-dependent detection emerges as a new approach for molecularly pathologic examination, study of molecular mechanisms involved in drug resistance, and resolution for tumor heterogeneity. This study reviewed the recent progress of CTCs in lung cancer research field.

  18. The role of meiotic cohesin REC8 in chromosome segregation in {gamma} irradiation-induced endopolyploid tumour cells

    Energy Technology Data Exchange (ETDEWEB)

    Erenpreisa, Jekaterina [Latvian Biomedicine Research and Study Centre, Riga, LV-1067 (Latvia); Cragg, Mark S. [Tenovus Laboratory, Cancer Sciences Division, Southampton University School of Medicine, General Hospital, Southampton SO16 6YD (United Kingdom); Salmina, Kristine [Latvian Biomedicine Research and Study Centre, Riga, LV-1067 (Latvia); Hausmann, Michael [Kirchhoff Inst. fuer Physik, Univ. of Heidelberg, D-69120 Heidelberg (Germany); Scherthan, Harry, E-mail: scherth@web.de [Inst. fuer Radiobiologie der Bundeswehr in Verbindung mit der Univ. Ulm, D-80937 Munich (Germany); MPI for Molec. Genetics, 14195 Berlin (Germany)

    2009-09-10

    Escape from mitotic catastrophe and generation of endopolyploid tumour cells (ETCs) represents a potential survival strategy of tumour cells in response to genotoxic treatments. ETCs that resume the mitotic cell cycle have reduced ploidy and are often resistant to these treatments. In search for a mechanism for genome reduction, we previously observed that ETCs express meiotic proteins among which REC8 (a meiotic cohesin component) is of particular interest, since it favours reductional cell division in meiosis. In the present investigation, we induced endopolyploidy in p53-dysfunctional human tumour cell lines (Namalwa, WI-L2-NS, HeLa) by gamma irradiation, and analysed the sub-cellular localisation of REC8 in the resulting ETCs. We observed by RT-PCR and Western blot that REC8 is constitutively expressed in these tumour cells, along with SGOL1 and SGOL2, and that REC8 becomes modified after irradiation. REC8 localised to paired sister centromeres in ETCs, the former co-segregating to opposite poles. Furthermore, REC8 localised to the centrosome of interphase ETCs and to the astral poles in anaphase cells where it colocalised with the microtubule-associated protein NuMA. Altogether, our observations indicate that radiation-induced ETCs express features of meiotic cell divisions and that these may facilitate chromosome segregation and genome reduction.

  19. Effector memory T-cell frequencies in relation to tumour stage, location and HPV status in HNSCC patients

    NARCIS (Netherlands)

    A.W. Turksma; H.J. Bontkes; H. van den Heuvel; T.D. de Gruijl; B.M.E. von Blomberg; B.J.M. Braakhuis; C.R. Leemans; E. Bloemena; C.J.L.M. Meijer; E. Hooijberg

    2013-01-01

    Background The immune system plays an important role in tumour immune surveillance. Head and neck squamous cell carcinoma patients are often immune compromised. Objective To chart the baseline levels of T-cell subpopulation frequencies in patients with cancer prior to treatment. Subjects and methods

  20. Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells

    International Nuclear Information System (INIS)

    We have previously documented that transient polyploidy is a potential cell survival strategy underlying the clonogenic re-growth of tumour cells after genotoxic treatment. In an attempt to better define this mechanism, we recently documented the key role of meiotic genes in regulating the DNA repair and return of the endopolyploid tumour cells (ETC) to diploidy through reduction divisions after irradiation. Here, we studied the role of the pluripotency and self-renewal stem cell genes NANOG, OCT4 and SOX2 in this polyploidy-dependent survival mechanism. In irradiation-resistant p53-mutated lymphoma cell-lines (Namalwa and WI-L2-NS) but not sensitive p53 wild-type counterparts (TK6), low background expression of OCT4 and NANOG was up-regulated by ionising radiation with protein accumulation evident in ETC as detected by OCT4/DNA flow cytometry and immunofluorescence (IF). IF analysis also showed that the ETC generate PML bodies that appear to concentrate OCT4, NANOG and SOX2 proteins, which extend into complex nuclear networks. These polyploid tumour cells resist apoptosis, overcome cellular senescence and undergo bi- and multi-polar divisions transmitting the up-regulated OCT4, NANOG and SOX2 self-renewal cassette to their descendents. Altogether, our observations indicate that irradiation-induced ETC up-regulate key components of germ-line cells, which potentially facilitate survival and propagation of the tumour cell population.

  1. A three-dimensional engineered tumour for spatial snapshot analysis of cell metabolism and phenotype in hypoxic gradients

    Science.gov (United States)

    Rodenhizer, Darren; Gaude, Edoardo; Cojocari, Dan; Mahadevan, Radhakrishnan; Frezza, Christian; Wouters, Bradly G.; McGuigan, Alison P.

    2016-02-01

    The profound metabolic reprogramming that occurs in cancer cells has been investigated primarily in two-dimensional cell cultures, which fail to recapitulate spatial aspects of cell-to-cell interactions as well as tissue gradients present in three-dimensional tumours. Here, we describe an engineered model to assemble three-dimensional tumours by rolling a scaffold-tumour composite strip. By unrolling the strip, the model can be rapidly disassembled for snapshot analysis, allowing spatial mapping of cell metabolism in concert with cell phenotype. We also show that the establishment of oxygen gradients within samples that are shaped by oxygen-dependent signalling pathways, as well as the consequential variations in cell growth, response to hypoxic gradients extending from normoxia to severe hypoxia, and therapy responsiveness, are consistent with those of tumours in vivo. Moreover, by using liquid chromatography tandem mass spectrometry, we mapped cellular metabolism and identified spatially defined metabolic signatures of cancer cells to reveal both known and novel metabolic responses to hypoxia.

  2. The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis

    International Nuclear Information System (INIS)

    Protein-bound polysaccharide (PSK) is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated. The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells. PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G0/G1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation. These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells

  3. The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis

    Directory of Open Access Journals (Sweden)

    Garrido Federico

    2008-03-01

    Full Text Available Abstract Background Protein-bound polysaccharide (PSK is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated. Methods The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells. Results PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G0/G1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation. Conclusion These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells.

  4. Oncological and functional results following operation for giant cell tumour of bone

    Institute of Scientific and Technical Information of China (English)

    Yongzhong Wei; Eugene T.H. Ek; Lipeng Yu; Guoyong Yin

    2008-01-01

    Objective:Giant cell tumours(GCT) represent one of the most common benign turnouts of bone. However, despite its benign nature they are aggressive lesions that have a tendency to recur. This study aims to report experience with the treatment of GCTs, and reviews the relationship between surgical management and clinical outcome. Methods:A retrospective review was performed with 70 patients (32 males and 38 females) who presented to our institution between 1991 and 2001 with GCT of bone. An evaluation of the oncological and functional results was conducted and patients were divided into three groups according to the treatment method; Group Ⅰ:(46 patients) intralesional curettage and adjuvant therapy and packing with filling materials. Group Ⅱ:(18 patients) en-bloc resection and arthrodesis or reconstruction. Group Ⅲ:(6 patients) amputation. Results:The mean follow-up period was 10 years (range, 5-15 years). The overall rate of local recurrence was 14%, 22% in Group Ⅰ, and only 4% in Group Ⅱ and Group Ⅲ According to the Musculoskeletal Tumour Society(MSTS) score for functional outcome, the mean overall score for Group Ⅰ was 27.9 (out of 30), 15.9 for Group Ⅱ. Of note, the 9 patients within Group Ⅱ who received endoprosthetic reconstruction, the mean overall MSTS functional score was 25.5. Conclusion:Intralesional curettage with adjuvant therapies and filling agents is often associated with a relatively high recurrence rate, however joint function is well preserved. Patients with more extensive, biologically aggressive, and/or recurrent tumours are best treated with en-bloc resection.

  5. Lack of relationship between TIMP-1 tumour cell immunoreactivity, treatment efficacy and prognosis in patients with advanced epithelial ovarian cancer

    International Nuclear Information System (INIS)

    Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a natural inhibitor of the matrix metalloproteinases (MMPs) which are proteolytic enzymes involved in degradation of extracellular matrix thereby favoring tumour cell invasion and metastasis. TIMP-1 activity in tumour tissue may therefore play an essential role in the progression of a malignant tumour. The primary aim of the present study was to evaluate TIMP-1 protein immunoreactivity in tissue from primary ovarian cancer patients and associate these findings with the course of the disease including response to treatment in the individual patient. TIMP-1 was assessed by immunohistochemistry (in tissue micro arrays) in a total of 163 ovarian cancer specimens obtained from primary debulking surgery during 1991-1994 as part of a randomized clinical protocol. Positive TIMP-1 immunoreactivity was found in 12.3% of the tumours. The median survival time for the 143 patients with TIMP-1 negative tumours was 23.7 months [19.0-29.4] 95% CI, while the median survival time for the 20 patients with TIMP-1 positive tumours was 15.9 months [12.3-27.4] 95% CI. Although a difference of 7.8 months in median overall survival in favor of the TIMP-1 tumour negative patients was found, this difference did not reach statistical significance (p = 0.28, Kaplan-Meier, log-rank test). Moreover, TIMP-1 immunoreactivity was not associated with CA125 response (p = 0.53) or response at second look surgery (p = 0.72). TIMP-1 immunoreactivity in tumour tissue from patients with primary epithelial ovarian cancer did not correlate with patient survival or response to combination platinum/cyclophosphamide therapy

  6. A cryogenic circulating advective multi-pass absorption cell

    International Nuclear Information System (INIS)

    A novel absorption cell has been developed to enable a spectroscopic survey of a broad range of polycyclic aromatic hydrocarbons (PAH) under astrophysically relevant conditions and utilizing a synchrotron radiation continuum to test the still controversial hypothesis that these molecules or their ions could be carriers of the diffuse interstellar bands. The cryogenic circulating advective multi-pass absorption cell resembles a wind tunnel; molecules evaporated from a crucible or injected using a custom gas feedthrough are entrained in a laminar flow of cryogenically cooled buffer gas and advected into the path of the synchrotron beam. This system includes a multi-pass optical White cell enabling absorption path lengths of hundreds of meters and a detection sensitivity to molecular densities on the order of 107 cm-3. A capacitively coupled radio frequency dielectric barrier discharge provides ionized and metastable buffer gas atoms for ionizing the candidate molecules via charge exchange and the Penning effect. Stronger than expected clustering of PAH molecules has slowed efforts to record gas phase PAH spectra at cryogenic temperatures, though such clusters may play a role in other interstellar phenomena.

  7. A cryogenic circulating advective multi-pass absorption cell

    Energy Technology Data Exchange (ETDEWEB)

    Stockett, M. H.; Lawler, J. E. [Department of Physics, University of Wisconsin, 1150 University Avenue, Madison, Wisconsin 53706 (United States)

    2012-03-15

    A novel absorption cell has been developed to enable a spectroscopic survey of a broad range of polycyclic aromatic hydrocarbons (PAH) under astrophysically relevant conditions and utilizing a synchrotron radiation continuum to test the still controversial hypothesis that these molecules or their ions could be carriers of the diffuse interstellar bands. The cryogenic circulating advective multi-pass absorption cell resembles a wind tunnel; molecules evaporated from a crucible or injected using a custom gas feedthrough are entrained in a laminar flow of cryogenically cooled buffer gas and advected into the path of the synchrotron beam. This system includes a multi-pass optical White cell enabling absorption path lengths of hundreds of meters and a detection sensitivity to molecular densities on the order of 10{sup 7} cm{sup -3}. A capacitively coupled radio frequency dielectric barrier discharge provides ionized and metastable buffer gas atoms for ionizing the candidate molecules via charge exchange and the Penning effect. Stronger than expected clustering of PAH molecules has slowed efforts to record gas phase PAH spectra at cryogenic temperatures, though such clusters may play a role in other interstellar phenomena.

  8. Photoacoustic monitoring of circulating tumor cells released during medical procedures

    Science.gov (United States)

    Juratli, Mazen A.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A.; Galanzha, Ekaterina; Suen, James Y.; Zharov, Vladimir P.

    2013-03-01

    Many cancer deaths are related to metastasis to distant organs due to dissemination of circulating tumor cells (CTCs) shed from the primary tumor. For many years, oncologists believed some medical procedures may provoke metastasis; however, no direct evidence has been reported. We have developed a new, noninvasive technology called in vivo photoacoustic (PA) flow cytometry (PAFC), which provides ultrasensitive detection of CTCs. When CTCs with strongly light-absorbing intrinsic melanin pass through a laser beam aimed at a peripheral blood vessel, laser-induced acoustic waves from CTCs were detected using an ultrasound transducer. We focused on melanoma as it is one of the most metastatically aggressive malignancies. The goal of this research was to determine whether melanoma manipulation, like compression, incisional biopsy, or tumor excision, could enhance penetration of cancer cells from the primary tumor into the circulatory system. The ears of nude mice were inoculated with melanoma cells. Blood vessels were monitored for the presence of CTCs using in vivo PAFC. We discovered some medical procedures, like compression of the tumor, biopsy, and surgery may either initiate CTC release in the blood which previously contained no CTCs, or dramatically increased (10-30-fold) CTC counts above the initial level. Our results warn oncologists to use caution during physical examination, and surgery. A preventive anti-CTC therapy during or immediately after surgery, by intravenous drug administration could serve as an option to treat the resulting release of CTCs.

  9. Tumour Cell Membrane Poration and Ablation by Pulsed Low-Intensity Electric Field with Carbon Nanotubes

    Directory of Open Access Journals (Sweden)

    Lijun Wang

    2015-03-01

    Full Text Available Electroporation is a physical method to increase permeabilization of cell membrane by electrical pulses. Carbon nanotubes (CNTs can potentially act like “lighting rods” or exhibit direct physical force on cell membrane under alternating electromagnetic fields thus reducing the required field strength. A cell poration/ablation system was built for exploring these effects of CNTs in which two-electrode sets were constructed and two perpendicular electric fields could be generated sequentially. By applying this system to breast cancer cells in the presence of multi-walled CNTs (MWCNTs, the effective pulse amplitude was reduced to 50 V/cm (main field/15 V/cm (alignment field at the optimized pulse frequency (5 Hz of 500 pulses. Under these conditions instant cell membrane permeabilization was increased to 38.62%, 2.77-fold higher than that without CNTs. Moreover, we also observed irreversible electroporation occurred under these conditions, such that only 39.23% of the cells were viable 24 h post treatment, in contrast to 87.01% cell viability without presence of CNTs. These results indicate that CNT-enhanced electroporation has the potential for tumour cell ablation by significantly lower electric fields than that in conventional electroporation therapy thus avoiding potential risks associated with the use of high intensity electric pulses.

  10. The role of TG2 in regulating S100A4-mediated mammary tumour cell migration.

    Directory of Open Access Journals (Sweden)

    Zhuo Wang

    Full Text Available The importance of S100A4, a Ca(2+-binding protein, in mediating tumour cell migration, both intracellularly and extracellularly, is well documented. Tissue transglutaminase (TG2 a Ca(2+-dependent protein crosslinking enzyme, has also been shown to enhance cell migration. Here by using the well characterised non-metastatic rat mammary R37 cells (transfected with empty vector and highly metastatic KP1 cells (R37 cells transfected with S100A4, we demonstrate that inhibition of TG2 either by TG2 inhibitors or transfection of cells with TG2 shRNA block S100A4-accelerated cell migration in the KP1cells and in R37 cells treated with exogenous S100A4. Cell migration was also blocked by the treatment with the non-cell permeabilizing TG2 inhibitor R294, in the human breast cancer cell line MDA-MB-231 (Clone 16, which has a high level of TG2 expression. Inhibition was paralleled by a decrease in S100A4 polymer formation. In vitro co-immunoprecipitation and Far Western blotting assays and cross-linking assays showed not only the direct interaction between TG2 and S100A4, but also confirmed S100A4 as a substrate for TG2. Using specific functional blocking antibodies, a targeting peptide and a recombinant protein as a competitive treatment, we revealed the involvement of syndecan-4 and α5β1 integrin co-signalling pathways linked by activation of PKCα in this TG2 and S100A4-mediated cell migration. We propose a mechanism for TG2-regulated S100A4-related mediated cell migration, which is dependent on TG2 crosslinking.

  11. Circulating angiogenic cell dysfunction in patients with hereditary hemorrhagic telangiectasia.

    Directory of Open Access Journals (Sweden)

    Liana Zucco

    Full Text Available Hereditary hemorrhagic telangiectasia (HHT is an autosomal dominant vascular disorder. Circulating angiogenic cells (CACs play an important role in vascular repair and regeneration. This study was designed to examine the function of CACs derived from patients with HHT. Peripheral blood mononuclear cells (PBMNCs isolated from patients with HHT and age- and gender-matched healthy volunteers were assessed for expression of CD34, CD133 and VEGF receptor 2 by flow cytometry. PBMNCs were cultured to procure early outgrowth CACs. Development of endothelial cell (EC phenotype in CACs was analyzed by fluorescence microscopy. CAC apoptosis was assayed with Annexin V staining, and CAC migration assessed by a modified Boyden chamber assay. mRNA expression of endoglin (ENG, activin receptor-like kinase-1 (ACVLR1 or ALK1 and endothelial nitric oxide synthase (eNOS in CACs was measured by real time RT-PCR. The percentage of CD34+ cells in PBMNCs from HHT patients was significantly higher than in PBMNCs of healthy controls. CACs derived from patients with HHT not only showed a significant reduction in EC-selective surface markers following 7-day culture, but also a significant increase in the rate of basal apoptosis and blunted migration in response to vascular endothelial growth factor and stromal cell-derived factor-1. CACs from HHT patients expressed significantly lower levels of ENG, ALK1 and eNOS mRNAs. In conclusion, CACs from patients with HHT exhibited various functional impairments, suggesting a reduced regenerative capacity of CACs to repair the vascular lesions seen in HHT patients.

  12. Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib

    OpenAIRE

    Wong, Andrea Li Ann; Lim, Joline Si Jing; Sinha, Arvind; Gopinathan, Anil; Lim, Robert; Tan, Chee-Seng; Soh, Thomas; Venkatesh, Sudhakar; Titin, Christina; Sapari, Nur Sabrina; Lee, Soo-Chin; Yong, Wei-Peng; Tan, David Shao Ping; Pang, Brendan; Wang, Ting-Ting

    2015-01-01

    Background Regorafenib, a multi-kinase inhibitor, is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy. However, this benefit was limited to 1.4 months improvement in overall survival, with more than half of patients experiencing grade 3 to 4 adverse events. We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit. Methods Patients with met...

  13. Platinum Complexes And Their Anti-Tumour Activity Against Chronic Lymphocytic Leukaemia Cells

    Directory of Open Access Journals (Sweden)

    Silconi Žana Besser

    2015-09-01

    Full Text Available Since the discovery of the antitumor activity of cisplatin by Rosenberg and co-workers, the use of metal complexes in cancer treatment has caused a huge interest. Today, platinum-based drugs are part of standard chemotherapy in the management of a variety of ca ncers, germ cell tumours, sarcomas, and lymphomas. Unfortunately, toxicity and drug resistance are major obstacles to wider clinical application of these drugs. Their use is greatly limited by severe side effects such as nephrotoxicity, ototoxicity, and neurotoxicity. Although cisplatin is one of the most successful anticancer drugs to date, its biochemical mechanism of action is still unclear. Cisplatin is generally accepted as having the ability to interact with the purine bases on the DNA, causing DNA damage, interfering with DNA repair mechanisms, and subsequently inducing apoptosis in cancer cells.

  14. The sensitivity of human tumour cells to quinone bioreductive drugs: what role for DT-diaphorase?

    Science.gov (United States)

    Robertson, N; Stratford, I J; Houlbrook, S; Carmichael, J; Adams, G E

    1992-08-01

    15 human tumour cell lines (lung, breast and colon) have been evaluated for their sensitivity to the quinone based anti-cancer drugs Mitomycin C, Porfiromycin, and EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-(IH-indole-4,7-dione)prop-beta- en-alpha-ol). Sensitivity has been compared with the intra-cellular levels of DT-diaphorase, an enzyme thought to be important in the reductive activation of these quinones. No correlation exists between levels of DT-diaphorase and sensitivity to Mitomycin C or Porfiromycin. However, for EO9 those cell lines showing highest levels of DT-diaphorase activity tend to be the most sensitive. PMID:1510692

  15. Abundance of DLK1, differential expression of CYP11B1, CYP21A2 and MC2R, and lack of INSL3 distinguish testicular adrenal rest tumours from Leydig cell tumours

    DEFF Research Database (Denmark)

    Poulsen, Grete Lottrup; Nielsen, John E; Skakkebæk, Niels E; Juul, Anders; Rajpert-De Meyts, Ewa

    2015-01-01

    cells (LCs), and masses consisting of such cells are occasionally misclassified as malignant testicular tumours, which may lead to erroneous orchiectomy in these patients. DESIGN: In this study, we aimed to investigate the potential of LC developmental markers and adrenal steroidogenic markers in the......OBJECTIVE: Testicular adrenal rest tumours (TARTs) are a common finding in patients with congenital adrenal hyperplasia (CAH). These tumours constitute a diagnostic and management conundrum and may lead to infertility. TART cells share many functional and morphological similarities with Leydig...... differential diagnosis of TARTs and malignant LC tumours (LCTs). METHODS: We investigated mRNA and protein expression of testicular steroidogenic enzymes; CYP11A1 and HSD3B1/2, markers of adrenal steroidogenesis; CYP11B1, CYP21A2 and ACTH receptor/melanocortin 2 receptor (MC2R), and markers of LC maturation...

  16. HER2-positive circulating tumor cells in breast cancer.

    Directory of Open Access Journals (Sweden)

    Michail Ignatiadis

    Full Text Available PURPOSE: Circulating Tumor Cells (CTCs detection and phenotyping are currently evaluated in Breast Cancer (BC. Tumor cell dissemination has been suggested to occur early in BC progression. To interrogate dissemination in BC, we studied CTCs and HER2 expression on CTCs across the spectrum of BC staging. METHODS: Spiking experiments with 6 BC cell lines were performed and blood samples from healthy women and women with BC were analyzed for HER2-positive CTCs using the CellSearch®. RESULTS: Based on BC cell lines experiments, HER2-positive CTCs were defined as CTCs with HER2 immunofluorescence intensity that was at least 2.5 times higher than the background. No HER2-positive CTC was detected in 42 women without BC (95% confidence interval (CI 0-8.4% whereas 4.1% (95%CI 1.4-11.4% of 73 patients with ductal/lobular carcinoma in situ (DCIS/LCIS had 1 HER2-positive CTC/22.5 mL, 7.9%, (95%CI 4.1-14.9% of 101 women with non metastatic (M0 BC had ≥1 HER2-positive CTC/22.5 mL (median 1 cell, range 1-3 cells and 35.9% (95%CI 22.7-51.9% of 39 patients with metastatic BC had ≥1 HER2-positive CTC/7.5 mL (median 1.5 cells, range 1-42 cells. In CTC-positive women with DCIS/LCIS or M0 BC, HER2-positive CTCs were more commonly detected in HER2-positive (5 of 5 women than HER2-negative BC (5 of 12 women (p = 0.03. CONCLUSION: HER2-positive CTCs were detected in DCIS/LCIS or M0 BC irrespective of the primary tumor HER2 status. Nevertheless, their presence was more common in women with HER2-positive disease. Monitoring of HER2 expression on CTCs might be useful in trials with anti-HER2 therapies.

  17. Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines.

    LENUS (Irish Health Repository)

    Anoopkumar-Dukie, S

    2009-10-01

    Oxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax\\/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.

  18. Game theory in the death galaxy: interaction of cancer and stromal cells in tumour microenvironment.

    Science.gov (United States)

    Wu, Amy; Liao, David; Tlsty, Thea D; Sturm, James C; Austin, Robert H

    2014-08-01

    Preventing relapse is the major challenge to effective therapy in cancer. Within the tumour, stromal (ST) cells play an important role in cancer progression and the emergence of drug resistance. During cancer treatment, the fitness of cancer cells can be enhanced by ST cells because their molecular signalling interaction delays the drug-induced apoptosis of cancer cells. On the other hand, competition among cancer and ST cells for space or resources should not be ignored. We explore the population dynamics of multiple myeloma (MM) versus bone marrow ST cells by using an experimental microecology that we call the death galaxy, with a stable drug gradient and connected microhabitats. Evolutionary game theory is a quantitative way to capture the frequency-dependent nature of interactive populations. Therefore, we use evolutionary game theory to model the populations in the death galaxy with the gradients of pay-offs and successfully predict the future densities of MM and ST cells. We discuss the possible clinical use of such analysis for predicting cancer progression. PMID:25097749

  19. Profiling of Sox4-dependent transcriptome in skin links tumour suppression and adult stem cell activation

    Directory of Open Access Journals (Sweden)

    Miguel Foronda

    2015-12-01

    Full Text Available Adult stem cells (ASCs reside in specific niches in a quiescent state in adult mammals. Upon specific cues they become activated and respond by self-renewing and differentiating into newly generated specialised cells that ensure appropriate tissue fitness. ASC quiescence also serves as a tumour suppression mechanism by hampering cellular transformation and expansion (White AC et al., 2014. Some genes restricted to early embryonic development and adult stem cell niches are often potent modulators of stem cell quiescence, and derailed expression of these is commonly associated to cancer (Vervoort SJ et al., 2013. Among them, it has been shown that recommissioned Sox4 expression facilitates proliferation, survival and migration of malignant cells. By generating a conditional Knockout mouse model in stratified epithelia (Sox4cKO mice, we demonstrated a delayed plucking-induced Anagen in the absence of Sox4. Skin global transcriptome analysis revealed a prominent defect in the induction of transcriptional networks that control hair follicle stem cell (HFSC activation such as those regulated by Wnt/Ctnnb1, Shh, Myc or Sox9, cell cycle and DNA damage response-associated pathways. Besides, Sox4cKO mice are resistant to skin carcinogenesis, thus linking Sox4 to both normal and pathological HFSC activation (Foronda M et al., 2014. Here we provide additional details on the analysis of Sox4-regulated transcriptome in Telogen and Anagen skin. The raw and processed microarray data is deposited in GEO under GSE58155.

  20. Profiling of Sox4-dependent transcriptome in skin links tumour suppression and adult stem cell activation.

    Science.gov (United States)

    Foronda, Miguel; Morgado-Palacin, Lucia; Gómez-López, Gonzalo; Domínguez, Orlando; Pisano, David G; Blasco, Maria A

    2015-12-01

    Adult stem cells (ASCs) reside in specific niches in a quiescent state in adult mammals. Upon specific cues they become activated and respond by self-renewing and differentiating into newly generated specialised cells that ensure appropriate tissue fitness. ASC quiescence also serves as a tumour suppression mechanism by hampering cellular transformation and expansion (White AC et al., 2014). Some genes restricted to early embryonic development and adult stem cell niches are often potent modulators of stem cell quiescence, and derailed expression of these is commonly associated to cancer (Vervoort SJ et al., 2013). Among them, it has been shown that recommissioned Sox4 expression facilitates proliferation, survival and migration of malignant cells. By generating a conditional Knockout mouse model in stratified epithelia (Sox4 (cKO) mice), we demonstrated a delayed plucking-induced Anagen in the absence of Sox4. Skin global transcriptome analysis revealed a prominent defect in the induction of transcriptional networks that control hair follicle stem cell (HFSC) activation such as those regulated by Wnt/Ctnnb1, Shh, Myc or Sox9, cell cycle and DNA damage response-associated pathways. Besides, Sox4 (cKO) mice are resistant to skin carcinogenesis, thus linking Sox4 to both normal and pathological HFSC activation (Foronda M et al., 2014). Here we provide additional details on the analysis of Sox4-regulated transcriptome in Telogen and Anagen skin. The raw and processed microarray data is deposited in GEO under GSE58155. PMID:26697322

  1. Circulating tumor cells in breast cancer at the diagnosis are associated with lymph node involvement, tumor size and negative ER status

    Directory of Open Access Journals (Sweden)

    P. Ferro

    2011-01-01

    Full Text Available We investigated the association of circulating tumor cells (CTC with poor prognostic markers in breast cancer (BC at time of diagnosis. Peripheral blood (PB samples from 190 patients with invasive BC, 12 patients with in situ BC, before theraphy and/or surgery, and 330 from patients without BC were tested for CTCs by RT-PCR for human mammaglobin (hMAM. hMAM was expressed only in PB of invasive BC (9.5% and a significant correlation was found between CTCs with lymph node involvement, tumour size and negative ER. We conclude that CTC detention in invasive BC may be an additional poor prognostic indicator.

  2. Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

    International Nuclear Information System (INIS)

    Circulating tumor cells (CTCs) are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0–54 CTCs per 5 min). These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients

  3. Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

    Energy Technology Data Exchange (ETDEWEB)

    Juratli, Mazen A.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A. [Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Melerzanov, Alexander V. [Moscow Institute of Physics and Technology (MIPT), Moscow Region, 141700 (Russian Federation); Zharov, Vladimir P. [Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Moscow Institute of Physics and Technology (MIPT), Moscow Region, 141700 (Russian Federation); Galanzha, Ekaterina I., E-mail: egalanzha@uams.edu [Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

    2014-01-15

    Circulating tumor cells (CTCs) are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0–54 CTCs per 5 min). These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients.

  4. Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

    Directory of Open Access Journals (Sweden)

    Mazen A. Juratli

    2014-01-01

    Full Text Available Circulating tumor cells (CTCs are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0–54 CTCs per 5 min. These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients.

  5. Nanotechnology for the detection and kill of circulating tumor cells

    Science.gov (United States)

    Gao, Yang; Yuan, Zhou

    2014-09-01

    Circulating tumor cells (CTCs) represent a surrogate biomarker of hematogenous metastases and thus could be considered as a `liquid biopsy' which reveals metastasis in action. But it is absolutely a challenge to detect CTCs due to their extreme rarity. At present, the most common principle is to take advantage of the epithelial surface markers of CTCs which attach to a specific antibody. Antibody-magnetic nanobeads combine with the epithelial surface markers, and then the compound is processed by washing, separation, and detection. However, a proportion of CTC antigen expressions are down-regulated or lost in the process of epithelial-mesenchymal transition (EMT), and thus, this part of CTCs cannot be detected by classical detection methods such as CellSearch. To resolve this problem, some multiple-marker CTC detections have been developed rapidly. Additionally, nanotechnology is a promising approach to kill CTCs with high efficiency. Implantable nanotubes coated with apoptosis-promoting molecules improve the disease-free survival and overall survival. The review introduces some novel CTC detection techniques and therapeutic methods by virtue of nanotechnology to provide a better knowledge of the progress about CTC study.

  6. Opportunities and Challenges for Pancreatic Circulating Tumor Cells.

    Science.gov (United States)

    Nagrath, Sunitha; Jack, Rhonda M; Sahai, Vaibhav; Simeone, Diane M

    2016-09-01

    Sensitive and reproducible platforms have been developed for detection, isolation, and enrichment of circulating tumor cells (CTCs)-rare cells that enter the blood from solid tumors, including those of the breast, prostate gland, lung, pancreas, and colon. These might be used as biomarkers in diagnosis or determination of prognosis. CTCs are no longer simply detected and quantified; they are now used in ex vivo studies of anticancer agents and early detection. We review what we have recently learned about CTCs from pancreatic tumors, describing advances in their isolation and analysis and challenges to their clinical utility. We summarize technologies used to isolate CTCs from blood samples of patients with pancreatic cancer, including immunoaffinity and label-free physical attribute-based capture. We explain methods of CTC analysis and how findings from these studies might be used to detect cancer at earlier stages, monitor disease progression, and determine prognosis. We review studies that have expanded CTCs for testing of anticancer agents and how these approaches might be used to personalize treatment. Advances in the detection, isolation, and analysis of CTCs have increased our understanding of the dissemination and progression of pancreatic cancer. However, standardization of methodologies and prospective studies are needed for this emerging technology to have a significant effect on clinical care. PMID:27339829

  7. Lab-on-chip platform for circulating tumor cells isolation

    Science.gov (United States)

    Maurya, D. K.; Fooladvand, M.; Gray, E.; Ziman, M.; Alameh, K.

    2015-12-01

    We design, develop and demonstrate the principle of a continuous, non-intrusive, low power microfluidics-based lab-ona- chip (LOC) structure for Circulating Tumor Cell (CTC) separation. Cell separation is achieved through 80 cascaded contraction and expansion microchannels of widths 60 μm and 300 μm, respectively, and depth 60 μm, which enable momentum-change-induced inertial forces to be exerted on the cells, thus routing them to desired destinations. The total length of the developed LOC is 72 mm. The LOC structure is simulated using the COMSOL multiphysics software, which enables the optimization of the dimensions of the various components of the LOC structure, namely the three inlets, three filters, three contraction and expansion microchannel segments and five outlets. Simulation results show that the LOC can isolate CTCs of sizes ranging from 15 to 30 μm with a recovery rate in excess of 90%. Fluorescent microparticles of two different sizes (5 μm and 15 μm), emulating blood and CTC cells, respectively, are used to demonstrate the principle of the developed LOC. A mixture of these microparticles is injected into the primary LOC inlet via an electronically-controlled syringe pump, and the large-size particles are routed to the primary LOC outlet through the contraction and expansion microchannels. Experimental results demonstrate the ability of the developed LOC to isolate particles by size exclusion with an accuracy of 80%. Ongoing research is focusing on the LOC design improvement for better separation efficiency and testing of biological samples for isolation of CTCs.

  8. Increased exosome production from tumour cell cultures using the Integra CELLine Culture System.

    Science.gov (United States)

    Mitchell, J Paul; Court, Jacqueline; Mason, Malcolm David; Tabi, Zsuzsanna; Clayton, Aled

    2008-06-01

    Exosomes are nanometer-sized vesicles, secreted from most cell types, with documented immune-modulatory functions. Exosomes can be purified from cultured cells but to do so effectively, requires maintenance of cells at high density in order to obtain sufficient accumulation of exosomes in the culture medium, prior to purification. Whilst high density cultures can be achieved with cells in suspension, this remains difficult with adherent cells, resulting in low quantity of exosomes for subsequent study. We have used the Integra CELLine culture system, originally designed for hybridoma cultures, to achieve a significant increase in obtainable exosomes from adherent and non-adherent tumour cells. Traditional cultures of mesothelioma cells (cultured in 75 cm(2) flasks) gave an average yield of 0.78 microg+/-0.14 microg exosome/ml of conditioned medium. The CELLine Adhere 1000 (CLAD1000) flask, housing the same cell line, increased exosome yield approximately 12 fold to 10.06 microg+/-0.97 microg/ml. The morphology, phenotype and immune function of these exosomes were compared, and found to be identical in all respects. Similarly an 8 fold increase in exosome production was obtained from NKL cells (a suspension cell line) using a CELLine 1000 (CL1000) flask. The CELLine system also incurred ~5.5 fold less cost and reduced labour for cell maintenance. This simple culture system is a cost effective, useful method for significantly increasing the quantity of exosomes available from cultured cells, without detrimental effects. This tool should prove advantageous in future studies of exosome-immune modulation in cancer and other settings. PMID:18423480

  9. Inhibitory effect of STAT3 gene combined with CDDP on growth of human Wilms tumour SK-NEP-1 cells.

    Science.gov (United States)

    Wang, Junrong; Zhang, Nina; Qu, Haijiang; You, Guangxian; Yuan, Junhui; Chen, Caie; Li, Wenyi; Pan, Feng

    2016-07-01

    To investigate the effects of signal transducer and activator of transcription 3 (STAT3) combined with cisplatin (CDDP) on the growth of human Wilms tumour (WT) SK-NEP-1 cell subcutaneous xenografts in nude mice and the possible mechanisms. Human WT SK-NEP-1 cells were subcutaneously transplanted to establish the BALB/c nude mice xenograft model. Mice were randomly divided into five groups: blank control group, adenovirus control group (NC group), STAT3 group, CDDP group and STAT3 plus CDDP group (combination group). Tumour volume and tumour weight were observed during the therapeutic process. The expression levels of STAT3, glucose regulatory protein 78 (GRP78) and BCL2-associated X protein (BAX) were evaluated by immunohistochemical analysis. Compared with the STAT3 group or CDDP group, the tumour weight and volume was significantly reduced in the combination group (Pstatistical significance was found in NC group compared with the blank control group (P > 0.05). Immunohistochemical analysis showed that STAT3, GRP78 and BAX protein levels in the combination group were significantly higher than those in STAT3 group and CDDP group (P<0.05). Exogenous STAT3 and CDDP may synergistically inhibit the xenograft tumour growth through up-regulation of BAX protein via GRP78. PMID:27129294

  10. Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells

    Science.gov (United States)

    Fan, Rong; Emery, Travis; Zhang, Yongguo; Xia, Yuxuan; Sun, Jun; Wan, Jiandi

    2016-06-01

    During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viability decreased with the increase of circulating time, but increased with the magnitude of wall shear stress. Proliferation of cells survived from circulation could be maintained when physiologically relevant wall shear stresses were applied. High wall shear stress (60.5 dyne/cm2), however, led to decreased cell proliferation at long circulating time (1 h). We further showed that the expression levels of β-catenin and c-myc, proliferation regulators, were significantly enhanced by increasing wall shear stress. The presented study provides a new insight to the roles of circulatory shear stress in cellular responses of circulating tumor cells in a physiologically relevant model, and thus will be of interest for the study of cancer cell mechanosensing and cancer metastasis.

  11. Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells

    Science.gov (United States)

    Fan, Rong; Emery, Travis; Zhang, Yongguo; Xia, Yuxuan; Sun, Jun; Wan, Jiandi

    2016-01-01

    During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viability decreased with the increase of circulating time, but increased with the magnitude of wall shear stress. Proliferation of cells survived from circulation could be maintained when physiologically relevant wall shear stresses were applied. High wall shear stress (60.5 dyne/cm2), however, led to decreased cell proliferation at long circulating time (1 h). We further showed that the expression levels of β-catenin and c-myc, proliferation regulators, were significantly enhanced by increasing wall shear stress. The presented study provides a new insight to the roles of circulatory shear stress in cellular responses of circulating tumor cells in a physiologically relevant model, and thus will be of interest for the study of cancer cell mechanosensing and cancer metastasis. PMID:27255403

  12. Light-oxygen effect in cells and its potential applications in tumour therapy (review)

    International Nuclear Information System (INIS)

    The light-oxygen effect (POE) represents damage (and at low optical doses, activation) of cells by photogeneration of molecular singlet oxygen from O2 dissolved in cells, in accordance with the reaction: 3O2+hν→1O2→ biological effect. The phases of evolution of the LOE are similar to the phases, observed in cell experiments, of the photodynamic effect (PDE) the mechanism of which is the basis of the familiar method of photodynamic cancer therapy. The reported proofs of the occurrence of the LOE are in the form of detailed spectra of the biological action of optical radiation on cells recorded in four spectral intervals with the aid of tunable lasers. Allowances are made for the relationships governing a new type of cell excitation, associated with reversible structural transitions in the biomembrane. A demonstration is reported of the same efficiency of cw and pulsed irradiation. An analysis is made of the reasons why the optical doses initiating the PDE and the LOE are comparable. The results are given of the first experimental applications of the LOE in tumour therapy. Identification of the primary photoacceptor (O2) in cell biostimulation and photodestruction provides a scientific basis for the development of low-intensity laser light-oxygen cancer therapy methods. (lasers in medicine)

  13. A case of Sertoli-Leydig cell tumour of the ovary with a multilocular cystic appearance on CT and MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Azuma, Asako [Kyoto University, Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto (Japan); Kameda Medical Center, Department of Radiology, Kamogawa (Japan); Koyama, Takashi [Kyoto University Hospital, Department of Radiology, Kyoto (Japan); Mikami, Yoshiki [Kyoto University Hospital, Laboratory of Anatomic Pathology, Kyoto (Japan); Tamai, Ken; Fujimoto, Koji; Morisawa, Nobuko; Togashi, Kaori [Kyoto University, Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto (Japan); Nagano, Fusaka; Yoshioka, Shinya [Graduate School of Medicine, Kyoto University Hospital, Department of Gynecology and Obstetrics, Kyoto (Japan)

    2008-08-15

    We present a case of Sertoli-Leydig cell tumour of the ovary in a 14-year-old girl who presented with abdominal distension. Ultrasonography showed a multilocular cystic lesion filled with finely echogenic fluid. Contrast-enhanced CT demonstrated a huge multilocular cystic mass with thickened septa. At MR imaging, the capsule of the cyst was focally thickened, showing intermediate signal intensity on T2-W images. Although extensive cyst formation of Sertoli-Leydig cell tumour is rare, this tumour should be considered in the differential diagnosis of a multilocular cystic ovarian tumour in a young female. (orig.)

  14. A case of Sertoli-Leydig cell tumour of the ovary with a multilocular cystic appearance on CT and MR imaging

    International Nuclear Information System (INIS)

    We present a case of Sertoli-Leydig cell tumour of the ovary in a 14-year-old girl who presented with abdominal distension. Ultrasonography showed a multilocular cystic lesion filled with finely echogenic fluid. Contrast-enhanced CT demonstrated a huge multilocular cystic mass with thickened septa. At MR imaging, the capsule of the cyst was focally thickened, showing intermediate signal intensity on T2-W images. Although extensive cyst formation of Sertoli-Leydig cell tumour is rare, this tumour should be considered in the differential diagnosis of a multilocular cystic ovarian tumour in a young female. (orig.)

  15. YOLK SAC TUMOUR IN A PREMENARCHAL GIRL : A CASE REPORT

    OpenAIRE

    Sourav; Avishek; Pallab Kumar; Bandana; Mrinmoyee

    2015-01-01

    Yolk sac tumour, otherwise known as endodermal sinus tumour, is a rare and highly malignant germ cell tumour accounting for approximately 10% of malignant germ cell tumours. The tumour usually presents as a rapidly growing mass in young women. Here we present a case of a young premenarchal girl with a huge ovarian tumour which pro...

  16. Immunotherapeutic efficacy of vaccines generated by fusion of dendritic cells and HPV16-associated tumour cells

    Czech Academy of Sciences Publication Activity Database

    Šímová, Jana; Bubeník, Jan; Bieblová, Jana; Indrová, Marie; Jandlová, Táňa

    2005-01-01

    Roč. 51, č. 1 (2005), s. 19-24. ISSN 0015-5500 R&D Projects: GA AV ČR(CZ) IAA5052203; GA ČR(CZ) GA301/04/0492 Grant ostatní: Liga proti rakovině, Praha(CZ) - Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV16 * DC-tumour hybrids * immunotherapy Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.719, year: 2005

  17. Serial measurement of the circulating levels of tumour necrosis factor and its soluble receptors 1 and 2 for monitoring leprosy patients during multidrug treatment

    Directory of Open Access Journals (Sweden)

    Rosane Dias Costa

    2013-12-01

    Full Text Available Leprosy is an infectious and contagious spectral disease accompanied by a series of immunological events triggered by the host response to the aetiologic agent, Mycobacterium leprae . The induction and maintenance of the immune/inflammatory response in leprosy are linked to multiple cell interactions and soluble factors, primarily through the action of cytokines. The purpose of the present study was to evaluate the serum levels of tumour necrosis factor (TNF-α and its soluble receptors (sTNF-R1 and sTNF-R2 in leprosy patients at different stages of multidrug treatment (MDT in comparison with non-infected individuals and to determine their role as putative biomarkers of the severity of leprosy or the treatment response. ELISA was used to measure the levels of these molecules in 30 healthy controls and 37 leprosy patients at the time of diagnosis and during and after MDT. Our results showed increases in the serum levels of TNF-α and sTNF-R2 in infected individuals in comparison with controls. The levels of TNF-α, but not sTNF-R2, decreased with treatment. The current results corroborate previous reports of elevated serum levels of TNF-α in leprosy and suggest a role for sTNF-R2 in the control of this cytokine during MDT.

  18. Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141(+)XCR1+ dendritic cells.

    Science.gov (United States)

    Silk, K M; Silk, J D; Ichiryu, N; Davies, T J; Nolan, K F; Leishman, A J; Carpenter, L; Watt, S M; Cerundolo, V; Fairchild, P J

    2012-10-01

    Monocyte-derived dendritic cells (moDC) have been widely used in cancer immunotherapy but show significant donor-to-donor variability and low capacity for the cross-presentation of tumour-associated antigens (TAA) to CD8(+) T cells, greatly limiting the success of this approach. Given recent developments in induced pluripotency and the relative ease with which induced pluripotent stem (iPS) cell lines may be generated from individuals, we have succeeded in differentiating dendritic cells (DC) from human leukocyte antigen (HLA)-A(*)0201(+) iPS cells (iPS cell-derived DC (ipDC)), using protocols compliant with their subsequent clinical application. Unlike moDC, a subset of ipDC was found to coexpress CD141 and XCR1 that have been shown previously to define the human equivalent of mouse CD8α(+) DC, in which the capacity for cross-presentation has been shown to reside. Accordingly, ipDC were able to cross-present the TAA, Melan A, to a CD8(+) T-cell clone and stimulate primary Melan A-specific responses among naïve T cells from an HLA-A(*)0201(+) donor. Given that CD141(+)XCR1(+) DC are present in peripheral blood in trace numbers that preclude their clinical application, the ability to generate a potentially unlimited source from iPS cells offers the possibility of harnessing their capacity for cross-priming of cytotoxic T lymphocytes for the induction of tumour-specific immune responses. PMID:22071967

  19. Isolation and number of circulated primordial germ cells (circulated-PGCs on stages of embryonic development of Gaok chicken

    Directory of Open Access Journals (Sweden)

    Kostaman T

    2013-03-01

    Full Text Available Avian primordial germ cell (PGCs show a unique migration pathway during early development. During the early embryonic development, as soon as the formation of blood vessels, PGCs enter the circulatory system and migrate to the gonadal primordial. The aim of this study was to examine the number of circulated-PGCs from Gaok chicken at different developmental stages of embryo. One hundred fertile eggs were divided into 5 groups and incubated in a portable incubator at 38oC and humidity 60%. Hatching was set according to the embryonic development stage between 14-18. The blood collection was done through the dorsal aorta using micropipette under microscope. The collected blood was grouped based on the embryonic stages and placed on a 1.5 ml eppendorf tube which had been filled with 1.000 µl of Calcium and Magnesium-free phosphate buffered saline (PBS -. The PGCs were then purified using nycodenz density gradient centrifugation. The results showed that the average number of circulated-PGCs per embryo from Gaok chicken were significantly affected by the stage of embryonic development (P < 0.05. The number of circulated-PGCs at stages 14, 15, 16, 17 and 18 were 42.8 ± 8.9, 51.0 ± 5.8, 37.6 ± 5.9, 32.8 ± 3.6 and 32.6 ± 3.2, respectively. However, the number of circulated-PGCs was no different between stage of 17 and 18. At Gaok chicken, the number of circulated-PGCs reach the peak at stage 15, it is recommended that collection of PGCs embryonic chicken from blood circulation was the best on stage 15. This information is useful in efficiency production of germline chimera and to preserve PGCs of other Indonesian native chicken.

  20. Genetic mutations in accordance with a low malignant potential tumour are not demonstrated in clear cell papillary renal cell carcinoma.

    Science.gov (United States)

    Raspollini, Maria Rosaria; Castiglione, Francesca; Cheng, Liang; Montironi, Rodolfo; Lopez-Beltran, Antonio

    2016-06-01

    Clear cell papillary renal cell carcinoma (CCPRCC) cases were evaluated for mutations on the following genes: KRAS, NRAS, BRAF, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET and EGFR. Four male and three female patients of age 42-74 years were evaluated. All cases were incidentally detected by ultrasound and ranged 1.8-3.5 cm. Microscopic examination showed variably tubulopapillary, tubular acinar, cystic architecture and the characteristic linear arrangement of nuclei. The cells were reactive with CK7 (strong), CA IX (cup-shape) and 34 β E12. CD10, AMACR/RACEMASE and GATA3 were negative. There were no mutations on any of the investigated genes. This preliminary observation supports the concept that CCPRCC might be indeed an indolent tumour worth it to be named as clear cell papillary neoplasm of low potential. PMID:26941183

  1. Microimaging FT-IR of oral cavity tumours. Part III: Cells, inoculated tissues and human tissues

    Science.gov (United States)

    Conti, C.; Ferraris, P.; Giorgini, E.; Pieramici, T.; Possati, L.; Rocchetti, R.; Rubini, C.; Sabbatini, S.; Tosi, G.; Mariggiò, M. A.; Lo Muzio, L.

    2007-05-01

    The biochemistry of healthy and tumour cell cultures, inoculated tissues and oral cavity tissues have been studied by FT-IR Microscopy with the aim to relate spectral patterns with microbiological and histopathological findings. 'Supervised' and 'unsupervised' procedures of data handling afforded a satisfactory degree of accordance between spectroscopic and the other two techniques. In particular, changes in frequency and intensity of proteins, connective and nucleic acids vibrational modes as well as the visualization of biochemical single wave number or band ratio images, allowed an evaluation of the pathological changes. The spectroscopic patterns of inoculated tissues resulted quite similar to human tissues; differences of both types of sections with cellular lines could be explained by the influence of the environment.

  2. A Rare Case of Metastatic Desmoplastic Small Round Cell Tumour: Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Shahzaib Nabi

    2015-01-01

    Full Text Available A 26-year-old male without any significant past medical history presented to the hospital with shortness of breath, cough, pleuritic chest pain, and weight loss for the past 3 months. On chest CT, he was found to have extensive mediastinal and hilar lymphadenopathy and multiple pulmonary nodules. On physical examination, a right groin mass was noted which had been slowly growing for the past 2 years. Ultrasound of the groin showed complex solid mass with internal vascular channels. CT guided biopsy of the mass showed desmoplastic small round cell tumour. His hospital course was complicated by hypoxic respiratory failure requiring emergent intubation and ICU admission where he completed one cycle of vincristine, cyclophosphamide, and doxorubicin with subsequent improvement, followed by extubation. His condition continued to improve after second cycle of chemotherapy and he was ultimately discharged in a stable condition to continue outpatient chemotherapy after a 2-month inpatient stay.

  3. Effect of reconstituted basement membrane components on the growth of a panel of human tumour cell lines in nude mice.

    OpenAIRE

    Topley, P.; Jenkins, D C; Jessup, E. A.; Stables, J. N.

    1993-01-01

    Previous reports have indicated that reconstituted basement membrane (matrigel), when co-injected with either established or primary human tumour cells, can improve the growth of subcutaneous xenografts in nude mice. The human adenocarcinoma cell lines A549, SW480, and WiDr, and the human fibrosarcoma cell line HT1080scc2 exhibit varying degrees of tumourigenicity in nude mice. All these lines showed increased tumorigenicity and/or growth rate, together with a change towards a more differenti...

  4. Radiation damage, repopulation and cell recovery analysis of in vitro tumour cell megacolony culture data using a non-Poissonian cell repopulation TCP model

    International Nuclear Information System (INIS)

    The effects of radiation damage, tumour repopulation and cell sublethal damage repair and the possibility of extracting information about the model parameters describing them are investigated in this work. Previously published data on two different cultured cell lines were analysed with the help of a tumour control probability (TCP) model that describes tumour cell dynamics properly. Different versions of a TCP model representing the cases of full or partial cell recovery between fractions of radiation, accompanied by repopulation or no repopulation were used to fit the data and were ranked according to statistical criteria. The data analysis shows the importance of the linear-quadratic mechanism of cell damage for the description of the in vitro cell dynamics. In a previous work where in vivo data were analysed, the employment of the single hit model of cell kill and cell repopulation produced the best fit, while ignoring the quadratic term of cell damage in the current analysis leads to poor fits. It is also concluded that more experiments using different fractionation regimes producing diverse data are needed to help model analysis and better ranking of the models

  5. Simultaneous removal of a tumour of the right atrium and inferior vena cava and coronary bypass-grafting in a patient with recurrent clear renal cell carcinoma

    Science.gov (United States)

    Pietrzyk, Edward; Głuszek, Stanisław; Michta, Kamil; Kot, Marta; Wożakowska-Kapłon, Beata

    2015-01-01

    Metastatic cardiac tumours are the most common malignant cardiac tumours. In the early stages they are usually asymptomatic, but their consequences can be very serious, and the prognosis is poor. We present a patient with recurrent renal cell carcinoma as a tumour of the right atrium and the vena cava inferior in whom cancerous masses were removed with simultaneously coronary artery bypass-grafting. PMID:26855653

  6. Histone H1x is highly expressed in human neuroendocrine cells and tumours

    International Nuclear Information System (INIS)

    Histone H1x is a ubiquitously expressed member of the H1 histone family. H1 histones, also called linker histones, stabilize compact, higher order structures of chromatin. In addition to their role as structural proteins, they actively regulate gene expression and participate in chromatin-based processes like DNA replication and repair. The epigenetic contribution of H1 histones to these mechanisms makes it conceivable that they also take part in malignant transformation. Based on results of a Blast data base search which revealed an accumulation of expressed sequence tags (ESTs) of H1x in libraries from neuroendocrine tumours (NETs), we evaluated the expression of H1x in NETs from lung and the gastrointestinal tract using immunohistochemisty. Relative protein and mRNA levels of H1x were analysed by Western blot analysis and quantitative real-time RT-PCR, respectively. Since several reports describe a change of the expression level of the replacement subtype H1.0 during tumourigenesis, the analysis of this subtype was included in this study. We found an increased expression of H1x but not of H1.0 in NET tissues in comparison to corresponding normal tissues. Even though the analysed NETs were heterogenous regarding their grade of malignancy, all except one showed a considerably higher protein amount of H1x compared with corresponding non-neoplastic tissue. Furthermore, double-labelling of H1x and chromogranin A in sections of pancreas and small intestine revealed that H1x is highly expressed in neuroendocrine cells of these tissues. We conclude that the high expression of histone H1x in NETs is probably due to the abundance of this protein in the cells from which these tumours originate

  7. Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner

    Czech Academy of Sciences Publication Activity Database

    Yan, B.; Stantic, M.; Zobalová, Renata; Bezawork-Geleta, A.; Stapelberg, M.; Stursa, J.; Prokopová, Kateřina; Dong, L.; Neužil, Jiří

    2015-01-01

    Roč. 15, č. 401 (2015). ISSN 1471-2407 R&D Projects: GA MZd NT14078; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Tumour-initiating cells * Mitochondrially targeted vitamin E succinate * Complex II Subject RIV: FD - Oncology ; Hematology Impact factor: 3.362, year: 2014

  8. Over-expression of tumour suppressor gene p53 in laryngeal squamous cell carcinomas and its prognostic significance.

    Science.gov (United States)

    Salam, M A; Crocker, J; Morris, A

    1995-02-01

    p53 is a nuclear phosphoprotein which acts as a tumour suppressor factor, regulating cell growth and division. Mutations in the p53 gene appear to be the most common genetic alterations in human cancer. The aim of this study was to investigate p53 expression in laryngeal squamous cell carcinomas and to assess its role as a marker of prognostic significance. Using immunohistochemical staining techniques, a series of laryngeal carcinomas (n = 87) were examined for expression of the mutant form of p53 phosphoprotein using the monoclonal antibody PAB 1801. p53 over-expression was noted in 50 biopsies of laryngeal carcinomas (57.5%) but not in any of the non-neoplastic laryngeal mucosa which were used as the control. There was no statistical correlation between p53 immunoreactivity and the clinicopathological parameters of the cancers including: site of tumour, TNM staging, differentiation grading and tumour recurrence. These findings indicate that p53 expression is strongly associated with carcinoma cells and not with normal cells in the larynx. However, p53 expression is probably unrelated to the biological aggressiveness of these tumours. PMID:7788934

  9. Histological characteristics of human papilloma-virus-positive and -negative invasive and in situ squamous cell tumours of the penis

    DEFF Research Database (Denmark)

    Krustrup, Dorrit; Jensen, Helle Lone; van den Brule, Adriaan J C;

    2009-01-01

    A high prevalence of cervical cancer associated high-risk types of human papillomavirus (hrHPV) has been demonstrated in premalignant and invasive squamous cell lesions of the penis, but large studies correlating histological characteristics with HPV status are few in number. Tumour tissues from ...

  10. Circulating Cell Free DNA in the Diagnosis of Trophoblastic Tumors

    Directory of Open Access Journals (Sweden)

    Mark R. Openshaw

    2016-02-01

    Full Text Available Gestational trophoblastic neoplasia (GTN represents a group of diseases characterized by production of human chorionic gonadotropin (hCG. Since non-gestational tumors may occasionally secrete hCG, histopathological diagnosis is important for appropriate clinical management. However, a histopathological diagnosis is not always available. We therefore investigated the feasibility of extracting cell free DNA (cfDNA from the plasma of women with GTN for use as a “liquid biopsy” in patients without histopathological diagnosis. cfDNA was prepared from the plasma of 20 women with a diagnosis of GTN and five with hCG-secreting tumors of unknown origin. Genotyping of cfDNA from the patient, genomic DNA from her and her partner and DNA from the tumor tissue identified circulating tumor DNA (ctDNA (from 9% to 53% of total cfDNA in 12 of 20 patients with GTN. In one case without a tissue diagnosis, ctDNA enabled a diagnosis of GTN originating in a non-molar conception and in another a diagnosis of non-gestational tumor, based on the high degree of allelic instability and loss of heterozygosity in the ctDNA. In summary ctDNA can be detected in the plasma of women with GTN and can facilitate the diagnosis of both gestational and non-gestational trophoblastic tumors in cases without histopathological diagnosis.

  11. Cell-free circulating tumor DNA in cancer.

    Science.gov (United States)

    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

  12. Pre-treatment number of clonogenic cells and their radiosensitivity are major determinants of local tumour control after fractionated irradiation

    International Nuclear Information System (INIS)

    Objective: The response of tumours to fractionated radiotherapy is determined by many factors including repopulation, reoxygenation, the number of clonogenic cells, and their intrinsic radiosensitivity. However, after single radiation doses given under conditions of clamp hypoxia, the dose to control a tumour locally is dependent only on the number of clonogenic cells and their cellular radiosensitivity. Therefore, these parameters were investigated using local control after single doses given under hypoxia, to predict the outcome of fractionated irradiation. Materials and methods: Ten hSCC cell lines (FaDu, UT-SCC-15, UT-SCC-14, XF354, UT-SCC-5, UT-SCC-45, SAS, CAL-33, UT-SCC-8, and HSC-4) were transplanted subcutaneously into the right hind-leg of NMRI nude mice. At 7 mm in diameter, tumours were irradiated either with graded single doses under clamp blood flow conditions (n = 873) or with 30 graded fractions within 6 weeks (n = 905) under ambient conditions. Local tumour control was determined 120 days after irradiation. Radiation response was quantified in terms of TCD50, i.e. the dose required to control 50% of tumours locally. Results: Ten tumour lines investigated showed a pronounced heterogeneity in both TCD50(30fx/6w) after fractionated irradiation and TCD50(SDclamp) after single dose irradiation. TCD50(30fx/6w) varied between 45 Gy for UT-SCC-45 and 127 Gy for SAS; TCD50(SDclamp) varied between 42 Gy for UT-SCC-14 and 66 Gy for CAL-33. Two tumours were excluded from further analysis due to immunogenicity or non-defined TCD50. Linear regression analysis revealed a significant positive correlation between TCD50(SDclamp) and TCD50(30fx/6w) (R 2 = 0.82, p = 0.002). Conclusions: Significant association between TCD50(SDclamp) and TCD50(30fx/6w) suggests that the pre-treatment number of clonogenic tumour cells and their cellular radiosensitivity have a major impact on local control after fractionated radiotherapy

  13. Tumour heterogeneity in non-small cell lung carcinoma assessed by CT texture analysis: a potential marker of survival

    Energy Technology Data Exchange (ETDEWEB)

    Ganeshan, Balaji; Miles, Ken [Brighton and Sussex Medical School, Clinical Imaging Sciences Centre, Division of Clinical and Laboratory Investigation, Brighton, East Sussex (United Kingdom); Panayiotou, Elleny; Burnand, Kate [Brighton and Sussex University Hospitals NHS Trust, Brighton (United Kingdom); Dizdarevic, Sabina [Brighton and Sussex University Hospitals NHS Trust, Department of Nuclear Medicine, Royal Sussex County Hospital, Brighton (United Kingdom)

    2012-04-15

    To establish the potential for tumour heterogeneity in non-small cell lung cancer (NSCLC) as assessed by CT texture analysis (CTTA) to provide an independent marker of survival for patients with NSCLC. Tumour heterogeneity was assessed by CTTA of unenhanced images of primary pulmonary lesions from 54 patients undergoing {sup 18}F-fluorodeoxyglucose (FDG) PET-CT for staging of NSCLC. CTTA comprised image filtration to extract fine, medium and coarse features with quantification of the distribution of pixel values (uniformity) within the filtered images. Receiver operating characteristics identified thresholds for PET and CTTA parameters that were related to patient survival using Kaplan-Meier analysis. The median (range) survival was 29.5 (1-38) months. 24, 10, 14 and 6 patients had tumour stages I, II, III and IV respectively. PET stage and tumour heterogeneity assessed by CTTA were significant independent predictors of survival (PET stage: Odds ratio 3.85, 95% confidence limits 0.9-8.09, P = 0.002; CTTA: Odds ratio 56.4, 95% confidence limits 4.79-666, p = 0.001). SUV was not a significantly associated with survival. Assessment of tumour heterogeneity by CTTA of non-contrast enhanced images has the potential for to provide a novel, independent predictor of survival for patients with NSCLC. (orig.)

  14. Location of tumour cells in colon tissue by Texas red labelled pentosan polysulphate, an inhibitor of a cell surface protease.

    Science.gov (United States)

    Anees, M

    1996-01-01

    Pentosan polysulphate (PPS), a highly negatively charged polysaccharide, is a significant inhibitor of an isoenzymic form of a cell surface protease referred to as guanidinobenzoatase GB, associated with colonic carcinoma tissues in frozen sections and free GB in solution, in a concentration-dependent manner. However PPS failed to recognise and bind to the isoenzymic form of GB associated with normal colon epithelial cell surfaces. Texas red labelled PPS (TR-PPS) binds to the tumour cell surfaces of colonic carcinoma and colonic polyps and these cells fluoresce red, whilst the normal colon cell surfaces failed to bind the TR-PPS, and hence lacked red fluorescence. Polysulphonated suramin also selectively recognised and inhibited the colonic carcinoma GB isoenzyme. The kinetic data indicated that this inhibition was not caused by a mere polyanionic effect, since highly sulphated heparin failed to show a significant inhibition of colonic carcinoma GB, however trypan blue did show 50% inhibition. Kinetic studies have also shown that PPS is a non-competitive, reversible inhibitor of colonic carcinoma GB, with an apparent Km 6.8 x 10(-7) M. Gel analysis has shown that PPS binds to another site, distinct from the active centre, and after binding PPS changed the conformation of GB. These studies suggest that TR-PPS is a potent inhibitor of colonic carcinoma GB, and can be used as a novel fluorescent probe for the location of tumour cells in frozen sections of human colon tissues. PSS could also have potential as a vehicle for the transport of cytotoxic compounds to carcinoma cells of the colon. PMID:8835946

  15. Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects

    OpenAIRE

    Taylor, D D; Gerçel-Taylor, C

    2005-01-01

    Dendritic and lymphoid ‘exosomes' regulate immune activation. Tumours release membranous material mimicking these ‘exosomes,' resulting in deletion of reactive lymphocytes. Tumour-derived ‘exosomes' have recently been explored as vaccines, without analysis of their immunologic consequences. This investigation examines the composition of tumour-derived ‘exosomes' and their effects on T lymphocytes. Membranous materials were isolated from ascites of ovarian cancer patients (n=6) and Western imm...

  16. Radiosensitization by misonidazole, pimonidazole and azomycin and intracellular uptake in human tumour cell lines

    International Nuclear Information System (INIS)

    Radiosensitization of two human tumour cell lines, HT-1080 and LoVo was compared with Chinese hamster line V73-379A. Although the two human lines were more radiosensitive than V79, enhancement ratios for misonidazole, pimonidazole and azomycin were similar for all three. In all cells uptake of misonidazole and azomycin was very rapid; that of pimonidazole was initially much slower before reaching a plateau. The ratios of intracellular concentration of radiosensitizer to extracellular concentration (Ci to Ce)for misonidazole were 0.8 (HT-1080) and 0.7 (LoVo and V79); for azomycin 0.9 (HT-1080 and LoVo) and 0.8 (V79). CiCe for pimonidazole varied with cell line [1.8 (LoVo), 2.6 (HT-1080) and 3.3 (V79)]. When average cell volume was taken into consideration, concentrations of non-protein sulphydryl were very similar [4.2 (HT-1080), 5.6 (LoVo), 5.7 (V79) m mol dm-3]. MPSH levels expressed as n mol/mg protein were also similar. (author)

  17. The bromine enhancement ratio in mammalian cells in vitro and experimental mouse tumours

    International Nuclear Information System (INIS)

    Human kidney cells in culture and cells of mouse sarcoma-180 were allowed to incorporate bromine into their DNA. Cultured cells with and without incorporated BUdR were irradiated with electromagnetic radiations ranging in energy from 12 keV X-rays to 60Co γ-rays to find out whether or not there exists any energy dependence of the bromine dose enhancement ratio BER. Such a dependence should show in the immediate neighbourhood of the K-absorption edge of bromine (13.5 keV). Any influence of the Auger effect triggered in bromine by external irradiation should show by a significant increase of the BER for energies rising from slightly below to slight above the bromine K-edge. Values of D37, D0 and the extrapolation numbers of the cell survival curves served as biological endpoints. Measured values of BER ranged from 1.12-2.00 without any significant dependence on energy. A weakly pronounced peak was found for 50 kV X-rays of 26 keV mean energy. Sarcoma-180 were irradiated with 14 keV X-rays and 60C γ-rays. BUdR was administered i.v., i.p. and directly into the tumours in quantities of up to 1 ml of a 10-3M solution. (Auth.)

  18. Glucocorticoid regulation of SLIT/ROBO tumour suppressor genes in the ovarian surface epithelium and ovarian cancer cells.

    Directory of Open Access Journals (Sweden)

    Rachel E Dickinson

    Full Text Available The three SLIT ligands and their four ROBO receptors have fundamental roles in mammalian development by promoting apoptosis and repulsing aberrant cell migration. SLITs and ROBOs have emerged as candidate tumour suppressor genes whose expression is inhibited in a variety of epithelial tumours. We demonstrated that their expression could be negatively regulated by cortisol in normal ovarian luteal cells. We hypothesised that after ovulation the locally produced cortisol would inhibit SLIT/ROBO expression in the ovarian surface epithelium (OSE to facilitate its repair and that this regulatory pathway was still present, and could be manipulated, in ovarian epithelial cancer cells. Here we examined the expression and regulation of the SLIT/ROBO pathway in OSE, ovarian cancer epithelial cells and ovarian tumour cell lines. Basal SLIT2, SLIT3, ROBO1, ROBO2 and ROBO4 expression was lower in primary cultures of ovarian cancer epithelial cells when compared to normal OSE (P<0.05 and in poorly differentiated SKOV-3 cells compared to the more differentiated PEO-14 cells (P<0.05. Cortisol reduced the expression of certain SLITs and ROBOs in normal OSE and PEO-14 cells (P<0.05. Furthermore blocking SLIT/ROBO activity reduced apoptosis in both PEO-14 and SKOV-3 tumour cells (P<0.05. Interestingly SLIT/ROBO expression could be increased by reducing the expression of the glucocorticoid receptor using siRNA (P<0.05. Overall our findings indicate that in the post-ovulatory phase one role of cortisol may be to temporarily inhibit SLIT/ROBO expression to facilitate regeneration of the OSE. Therefore this pathway may be a target to develop strategies to manipulate the SLIT/ROBO system in ovarian cancer.

  19. Is a deep one-cell meridional circulation essential for the flux transport Solar Dynamo?

    OpenAIRE

    Hazra, Gopal; Karak, Bidya Binay; Choudhuri, Arnab Rai

    2013-01-01

    The solar activity cycle is successfully modeled by the flux transport dynamo, in which the meridional circulation of the Sun plays an important role. Most of the kinematic dynamo simulations assume a one-cell structure of the meridional circulation within the convection zone, with the equatorward return flow at its bottom. In view of the recent claims that the return flow occurs at a much shallower depth, we explore whether a meridional circulation with such a shallow return flow can still r...

  20. Circulating tumor cells in oral squamous cell carcinoma-an enigma or reality?

    Directory of Open Access Journals (Sweden)

    N Anitha

    2015-01-01

    Full Text Available Oral squamous cell carcinoma (OSCC is ranking 1 st among males and 4 th among females in India. In spite of major advances in diagnosis and treatment of OSCC, survival rates, have remained poor. Circulating tumor cells (CTCs in the blood stream, play an important role in establishing metastases. It is important to identify patients suffering from nonlocalized tumor with "circulating" tumor cells to determine the tailor made, systemic therapy in addition to local resection and irradiation. Thus, detecting metastases at an early stage are needed for better prognosis and survival. CTCs as new prognostic marker to detect the metastatic potential will provide a novel insight into tumor burden and efficacy of therapy. The recent advances and its application in OSCC will be reviewed.

  1. Discovery of a Metastatic Immune Escape Mechanism Initiated by the Loss of Expression of the Tumour Biomarker Interleukin-33.

    Science.gov (United States)

    Saranchova, Iryna; Han, Jeffrey; Huang, Hui; Fenninger, Franz; Choi, Kyung Bok; Munro, Lonna; Pfeifer, Cheryl; Welch, Ian; Wyatt, Alexander W; Fazli, Ladan; Gleave, Martin E; Jefferies, Wilfred A

    2016-01-01

    A new paradigm for understanding immune-surveillance and immune escape in cancer is described here. Metastatic carcinomas express reduced levels of IL-33 and diminished levels of antigen processing machinery (APM), compared to syngeneic primary tumours. Complementation of IL-33 expression in metastatic tumours upregulates APM expression and functionality of major histocompatibility complex (MHC)-molecules, resulting in reduced tumour growth rates and a lower frequency of circulating tumour cells. Parallel studies in humans demonstrate that low tumour expression of IL-33 is an immune biomarker associated with recurrent prostate and kidney renal clear cell carcinomas. Thus, IL-33 has a significant role in cancer immune-surveillance against primary tumours, which is lost during the metastatic transition that actuates immune escape in cancer. PMID:27619158

  2. Treatment of transplanted CT26 tumour with dendritic cell vaccine in combination with blockade of vascular endothelial growth factor receptor 2 and CTLA-4

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Buus, S; Claesson, M H

    2005-01-01

    We investigated the anti CT26 tumour effect of dendritic cell based vaccination with the MuLV gp70 envelope protein-derived peptides AH1 and p320-333. Vaccination lead to generation of AH1 specific cytotoxic lymphocytes (CTL) and some decrease in tumour growth of simultaneously inoculated CT26 ce...... of mice with already established tumours was only obtained after combination of vaccination, DC101 and 9H10 treatment in which setting 80% of the mice rejected their tumours....

  3. Fluorodeoxyglucose positron emission tomography in the initial staging of germ cell tumours

    Energy Technology Data Exchange (ETDEWEB)

    Hain, S.F.; O' Doherty, M.J. [Clinical PET Centre, Guy' s and St Thomas' Hospitals, London (United Kingdom); Timothy, A.R.; Leslie, M.D.; Partridge, S.E. [Dept. of Clinical Oncology, Guy' s and St Thomas' Hospitals, London (United Kingdom); Huddart, R.A. [Dept. of Radiotherapy and Oncology, Royal Marsden, Surrey (United Kingdom)

    2000-05-01

    Testicular cancer is a rare tumour with the potential for cure at diagnosis. It is important, however, to identify those patients with metastases at presentation so as to ensure that the optimum treatment strategy is employed. Many criteria have been used to try to place patients into high- or low-risk groups, with variable success. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has the potential to identify active disease and thereby influence further management. Here we report on a retrospective study of the use of FDG-PET in the detection of metastatic testicular carcinoma at diagnosis. Thirty-one patients [13 with seminoma and 18 with non-seminomatous germ cell tumours (13 teratomas, 5 mixed)] were staged by FDG-PET scanning. The imaging was performed using a Siemens ECAT 951 scanner. All results were assessed on the basis of histology or clinical follow-up. FDG-PET scan identified metastatic disease in ten and was negative in 16; there were no false-positives and five false-negatives. There were six patients in whom FDG-PET was negative and computed tomography was regarded as suspicious but follow-up was inconclusive. The positive predictive value was 100%. The negative predictive value was 76% or 91%, depending on whether the aforementioned six cases were regarded as true-negatives or false-negatives. It may be concluded that FDG-PET is capable of detecting metastatic disease at diagnosis that is not identified by other imaging techniques. These preliminary results are sufficient to suggest that a large prospective study should be performed to evaluate the role of FDG-PET in primary staging of disease. (orig.)

  4. Chromatin H3K27me3/H3K4me3 histone marks define gene sets in high-grade serous ovarian cancer that distinguish malignant, tumour-sustaining and chemo-resistant ovarian tumour cells.

    Science.gov (United States)

    Chapman-Rothe, N; Curry, E; Zeller, C; Liber, D; Stronach, E; Gabra, H; Ghaem-Maghami, S; Brown, R

    2013-09-19

    In embryonic stem (ES) cells, bivalent chromatin domains containing H3K4me3 and H3K27me3 marks silence developmental genes, while keeping them poised for activation following differentiation. We have identified gene sets associated with H3K27me3 and H3K4me3 marks at transcription start sites in a high-grade ovarian serous tumour and examined their association with epigenetic silencing and malignant progression. This revealed novel silenced bivalent marked genes, not described previously for ES cells, which are significantly enriched for the PI3K (P<10(-7)) and TGF-β signalling pathways (P<10(-5)). We matched histone marked gene sets to gene expression sets of eight normal fallopian tubes and 499 high-grade serous malignant ovarian samples. This revealed a significant decrease in gene expression for the H3K27me3 and bivalent gene sets in malignant tissue. We then correlated H3K27me3 and bivalent gene sets to gene expression data of ovarian tumour 'stem cell-like' sustaining cells versus non-sustaining cells. This showed a significantly lower expression for the H3K27me3 and bivalent gene sets in the tumour-sustaining cells. Similarly, comparison of matched chemo-sensitive and chemo-resistant ovarian cell lines showed a significantly lower expression of H3K27me3/bivalent marked genes in the chemo-resistant compared with the chemo-sensitive cell line. Our analysis supports the hypothesis that bivalent marks are associated with epigenetic silencing in ovarian cancer. However it also suggests that additional tumour specific bivalent marks, to those known in ES cells, are present in tumours and may potentially influence the subsequent development of drug resistance and tumour progression. PMID:23128397

  5. Expression of FGFR3 during human testis development and in germ cell-derived tumours of young adults

    DEFF Research Database (Denmark)

    Ewen, Katherine A; Olesen, Inge A; Winge, Sofia B;

    2013-01-01

    development and to ascertain whether FGFR3 signalling is linked to germ cell proliferation and the pathogenesis of testicular germ cell tumours (TGCTs) of young adult men. Using RT-PCR, immunohistochemistry and Western blotting, we examined 58 specimens of human testes throughout development for FGFR3...... expression, and then compared expression of FGFR3 with proliferation markers (PCNA or Ki67). We also analysed for FGFR3 expression 30 TGCTs and 28 testes containing the tumour precursor cell, carcinoma in situ (CIS). Fetal and adult testes expressed exclusively the FGFR3IIIc isoform. FGFR3 protein expression......Observations in patients with an activating mutation of fibroblast growth factor receptor 3 (FGFR3) suggest a role for FGFR3 signalling in promoting proliferation or survival of germ cells. In this study, we aimed to identify the FGFR3 subtype and the ontogeny of expression during human testis...

  6. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice

    Directory of Open Access Journals (Sweden)

    Debajit Bhowmick

    2016-01-01

    Full Text Available Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP, generation of reactive oxygen species (ROS, and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma.

  7. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice.

    Science.gov (United States)

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  8. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice

    Science.gov (United States)

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K.; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  9. Batf3-Dependent Dendritic Cells in the Renal Lymph Node Induce Tolerance against Circulating Antigens

    OpenAIRE

    Gottschalk, Catherine; Damuzzo, Vera; Gotot, Janine; Kroczek, Richard A.; Yagita, Hideo; Murphy, Kenneth M.; Knolle, Percy A.; Ludwig-Portugall, Isis; Kurts, Christian

    2013-01-01

    Although the spleen is a major site where immune tolerance to circulating innocuous antigens occurs, the kidney also contributes. Circulating antigens smaller than albumin are constitutively filtered and concentrated in the kidney and reach the renal lymph node by lymphatic drainage, where resident dendritic cells (DCs) capture them and induce tolerance of specific cytotoxic T cells through unknown mechanisms. Here, we found that the coinhibitory cell surface receptor programmed death 1 (PD-1...

  10. Modeling and simulation of procoagulant circulating tumor cells in flow

    Directory of Open Access Journals (Sweden)

    PaulKennethNewton

    2012-09-01

    Full Text Available We describe a mathematical/computational model for thrombin concentration gradients generated by procoagulant circulating tumor cells (CTCs in flow. We examine how CTCs enhance blood coagulation as they diffuse tissue factor (TF-dependent coagulation enzymes in a flow environment with vessel walls. Concentration fields of various enzymes, such as prothrombin and thrombin, diffuse to and from CTCs, respectively, as they propagate through the bloodstream. The diffusion-dependent generation of these enzymes sets up complex time-dependent concentration fields. The CTCs are modeled as diffusing point particles in an incompressible fluid, and we exploit exact analytical solutions based on three-dimensional Green’s functions for unbounded domains with one wall for high-resolution numerical simulations. Time-dependent gradient trackers are used to highlight that concentration fields build up (i near boundaries (vessel walls, (ii in regions surrounding the diffusing particles, and (iii in complex time-dependent regions of the flow where fields associated with different particles overlap. Two flow conditions are modeled: no flow, and unidirectional constant flow. Our results indicate that the CTC-generated thrombin diffuses to and persists at the blood vessel wall, and that the spatial distribution of CTCs in flow determines local thrombin concentration. The magnitude of the diffusion gradient and local thrombin concentration is dependent upon bulk solution concentrations of coagulation factors within normal reported concentration ranges. Therefore, our model highlights the potential to determine patient-specific risks for CTC-induced hypercoagulability as a function of CTC number and individual patient concentration of coagulation factors.

  11. Expression of the c-kit protein product in carcinoma-in-situ and invasive testicular germ cell tumours

    DEFF Research Database (Denmark)

    Rajpert-De Meyts, E; Skakkebaek, N E

    1994-01-01

    , CIS and overtly invasive human male germ cell tumours were analysed immunohistochemically for expression of the c-kit proto-oncogene protein product. Testicular tissue samples from 36 patients with various types of testicular germ cell neoplasia and 19 control specimens were stained using an indirect...... addition, we propose that the c-kit protein product is a new marker for carcinoma-in-situ of the testis....

  12. In vitro growth inhibitory activity of the Portuguese wild mushroom Clitocybe alexandri in human tumour cell lines

    OpenAIRE

    Vaz, Josiana A.; Almeida, Gabriela M.; Martins, Anabela; Vasconcelos, M. Helena; Ferreira, Isabel C. F. R.

    2010-01-01

    Some mushrooms are a powerful source of bioactive compounds. lndeed, many pre-clinical studies have been conducted in human tumour cell lines and in some cases a number of compounds extracted from mushrooms have entered clinical trials [1]. Our previous results showed that phenolic (methanolic and ethanolic) and polissacharidic extracts from Clitocybe alexandri inhibited the growth of four human cell lines (lung, breast, colon and gastric cancer) [2]. The aim of the present wor...

  13. Inactivation of the von Hippel-Lindau tumour suppressor gene induces Neuromedin U expression in renal cancer cells

    Directory of Open Access Journals (Sweden)

    Shukla Deepa

    2011-07-01

    Full Text Available Abstract Background 209 000 new cases of renal carcinoma are diagnosed each year worldwide and new therapeutic targets are urgently required. The great majority of clear cell renal cancer involves inactivation of VHL, which acts as a gatekeeper tumour suppressor gene in renal epithelial cells. However how VHL exerts its tumour suppressor function remains unclear. A gene expression microarray comparing RCC10 renal cancer cells expressing either VHL or an empty vector was used to identify novel VHL regulated genes. Findings NMU (Neuromedin U is a neuropeptide that has been implicated in energy homeostasis and tumour progression. Here we show for the first time that VHL loss-of-function results in dramatic upregulation of NMU expression in renal cancer cells. The effect of VHL inactivation was found to be mediated via activation of Hypoxia Inducible Factor (HIF. Exposure of VHL expressing RCC cells to either hypoxia or dimethyloxalylglycine resulted in HIF activation and increased NMU expression. Conversely, suppression of HIF in VHL defective RCC cells via siRNA of HIF-α subunits or expression of Type 2C mutant VHLs reduced NMU expression levels. We also show that renal cancer cells express a functional NMU receptor (NMUR1, and that NMU stimulates migration of renal cancer cells. Conclusions These findings suggest that NMU may act in an autocrine fashion, promoting progression of kidney cancer. Hypoxia and HIF expression are frequently observed in many non-renal cancers and are associated with a poor prognosis. Our study raises the possibility that HIF may also drive NMU expression in non-renal tumours.

  14. Sporadic diffuse segmental interstitial cell of Cajal hyperplasia harbouring two gastric gastrointestinal stromal tumours (GIST) mimicking hereditary GIST syndromes

    OpenAIRE

    Mafalda Costa Neves; Gordon Stamp; Satvinder Mudan

    2015-01-01

    Introduction: Gastrointestinal stromal tumours (GISTs) are thought to derive from or differentiate towards the interstitial cells of Cajal (ICC) as most demonstrate a similar immunoprofile: CD117+, CD34+ and DOG1+. ICC hyperplasia refers to KIT-expressing microscopic spindle cell proliferations involving the myenteric plexus. Case report: 74 year-old male presented with a 5-year history of heartburn and dysphagia. Imaging revealed a 4 cm GIST in the gastric fundus. Pathology of the resecte...

  15. Circulating endothelial cells in coronary artery disease and acute coronary syndrome

    NARCIS (Netherlands)

    Schmidt, David E; Manca, Marco; Höfer, Imo E

    2015-01-01

    Circulating endothelial cells (CECs) have been put forward as a promising biomarker for diagnosis and prognosis of coronary artery disease and acute coronary syndromes. This review entails current insights into the physiology and pathobiology of CECs, including their relationship with circulating en

  16. The Clinical Utilization of Circulating Cell Free DNA (CCFDNA in Blood of Cancer Patients

    Directory of Open Access Journals (Sweden)

    Yanyuan Wu

    2013-09-01

    Full Text Available Qualitative and quantitative testing of circulating cell free DNA (CCFDNA can be applied for the management of malignant and benign neoplasms. Detecting circulating DNA in cancer patients may help develop a DNA profile for early stage diagnosis in malignancies. The technical issues of obtaining, using, and analyzing CCFDNA from blood will be discussed.

  17. In silico modelling of a cancer stem cell-targeting agent and its effects on tumour control during radiotherapy

    Science.gov (United States)

    Marcu, Loredana G.; Marcu, David

    2016-01-01

    Head and neck cancers (HNC), like most solid tumours, contain a subpopulation of cancer stem cells (CSC) that are commonly responsible for treatment failure. Conventional therapies are unsuccessful in controlling CSCs, thus novel, targeting therapies are needed. A promising agent is ATRA (All-trans-retinoic acid) that was shown to induce CSC differentiation, cell cycle redistribution and CSCs radiosensitisation. To add to the limited data, this work simulated the effects of ATRA on a virtual HNC and evaluated tumour response to radiotherapy. A Monte Carlo technique was employed to grow a HNC consisting of all lineages of cancer cells. The biologically realistic input parameters led to a pre-treatment CSC population of 5.9%. The Linear Quadratic model was employed to simulate radiotherapy. ATRA-induced differentiation, cell arrest and apoptosis were modelled, based on literature data. While the effect of differentiation was marginal, the strongest influence on CSC subpopulation was displayed by ATRA’s cell arrest effect via an exponential behaviour of the dose-response curve. The apoptotic effect induced by ATRA shows linear correlation between the percentage of apoptotic cells and dose required to eradicate CSCs. In conclusion, ATRA is a potent CSC-targeting agent with viable impact on tumour control when combined with radiotherapy. PMID:27573059

  18. Energy metabolism and ATP turnover time during the cell cycle in roentgen irradiated Ehrlich ascites tumour cells

    International Nuclear Information System (INIS)

    The cell-cycle related energy metabolism after roentgen irradiation of in vivo growing Ehrlich ascites tumour cells was investigated in cell fractions obtained by elutriator centrifuging. The oxygen consumption and the lactate and pyruvate production, measured in vitro after 4.5, 5 and 9 Gy up to 24 h, were undisturbed, while the decrease in the in vivo ATP content was dose-independent in all parts of the cell cycle. On the basis of these data the ATP turnover time was found to be decreased. The decrease in the ATP content is considered to be less likely to be due to membrane leakage or increased ATP consumption than to reduced ATP production. Since in vitro incubation normalizes the ATP content, it is suggested that environmental factors in the ascites liquid after irradiation cause a decrease in the ATP production. Low ATP contents of the cells do not appear to influence the irradiation-induced changes in the cell flow through the cell cycle. (Auth.)

  19. Perivascular epithelioid cell tumour of the vagina in an 8 year old girl.

    Science.gov (United States)

    Ong, Lin Yin; Hwang, Wei Sek; Wong, Adelina; Chan, Mei Yoke; Chui, Chan Hon

    2007-03-01

    Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor with an unpredictable natural history. We present the first reported case of PEComa of the vagina diagnosed in an 8-year-old girl. This was initially diagnosed on biopsy as an embryonal rhabdomyosarcoma, and the patient underwent 3 cycles of chemotherapy according to the Mesenchymal Malignant Tumour 1989 protocol. A repeat scan, however, revealed an increase in tumor size. Total resection was achieved via a transvaginal (vertical sleeve) partial vaginectomy. The resected tumor had the typical appearance of a PEComa. Immunostains showed positive staining of tumor cells for HMB45, neuron-specific enolase, and calponin but were negative for S100 protein, melaninA, chromogranin, smooth muscle actin, desmin, caldesmon, epithelial membrane antigen, AE1/3, and synaptophysin. Six months after surgery, she remains free of tumor and is on follow-up with regular local examinations under anesthesia and computed tomography scans. Our case highlights the importance of an accurate initial diagnosis, and we stress the importance of regular surveillance over a significant period. PMID:17336201

  20. Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus

    International Nuclear Information System (INIS)

    A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV) was discovered as the causative agent of MCC. It is found clonally integrated into the majority of MCC tumours, which require MCPyV oncoproteins to survive. Since its discovery, research has begun to reveal the molecular virology of MCPyV, as well as how it induces tumourigenesis. It is thought to be a common skin commensal, found at low levels in healthy individuals. Upon loss of immunosurveillance, MCPyV reactivates, and a heavy viral load is associated with MCC pathogenesis. Although MCPyV is in many ways similar to classical oncogenic polyomaviruses, such as SV40, subtle differences are beginning to emerge. These unique features highlight the singular position MCPyV has as the only human oncogenic polyomavirus, and open up new avenues for therapies against MCC

  1. Merkel cell polyomavirus: molecular insights into the most recently discovered human tumour virus.

    Science.gov (United States)

    Stakaitytė, Gabrielė; Wood, Jennifer J; Knight, Laura M; Abdul-Sada, Hussein; Adzahar, Noor Suhana; Nwogu, Nnenna; Macdonald, Andrew; Whitehouse, Adrian

    2014-01-01

    A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV) was discovered as the causative agent of MCC. It is found clonally integrated into the majority of MCC tumours, which require MCPyV oncoproteins to survive. Since its discovery, research has begun to reveal the molecular virology of MCPyV, as well as how it induces tumourigenesis. It is thought to be a common skin commensal, found at low levels in healthy individuals. Upon loss of immunosurveillance, MCPyV reactivates, and a heavy viral load is associated with MCC pathogenesis. Although MCPyV is in many ways similar to classical oncogenic polyomaviruses, such as SV40, subtle differences are beginning to emerge. These unique features highlight the singular position MCPyV has as the only human oncogenic polyomavirus, and open up new avenues for therapies against MCC. PMID:24978434

  2. Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus

    Directory of Open Access Journals (Sweden)

    Gabrielė Stakaitytė

    2014-06-01

    Full Text Available A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC, a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV was discovered as the causative agent of MCC. It is found clonally integrated into the majority of MCC tumours, which require MCPyV oncoproteins to survive. Since its discovery, research has begun to reveal the molecular virology of MCPyV, as well as how it induces tumourigenesis. It is thought to be a common skin commensal, found at low levels in healthy individuals. Upon loss of immunosurveillance, MCPyV reactivates, and a heavy viral load is associated with MCC pathogenesis. Although MCPyV is in many ways similar to classical oncogenic polyomaviruses, such as SV40, subtle differences are beginning to emerge. These unique features highlight the singular position MCPyV has as the only human oncogenic polyomavirus, and open up new avenues for therapies against MCC.

  3. Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis.

    Science.gov (United States)

    Hyde, C A C; Missailidis, S

    2009-06-01

    Arachidonic acid (AA) and its metabolites have recently generated a heightened interest due to growing evidence of their significant role in cancer biology. Thus, inhibitors of the AA cascade, first and foremost COX inhibitors, which have originally been of interest in the treatment of inflammatory conditions and certain types of cardiovascular disease, are now attracting attention as an arsenal against cancer. An increasing number of investigations support their role in cancer chemoprevention, although the precise molecular mechanisms that link levels of AA, and its metabolites, with cancer progression have still to be elucidated. This article provides an overview of the AA cascade and focuses on the roles of its inhibitors and their implication in cancer treatment. In particular, emphasis is placed on the inhibition of cell proliferation and neo-angiogenesis through inhibition of the enzymes COX-2, 5-LOX and CYP450. Downstream effects of inhibition of AA metabolites are analysed and the molecular mechanisms of action of a selected number of inhibitors of catalytic pathways reviewed. Lastly, the benefits of dietary omega-3 fatty acids and their mechanisms of action leading to reduced cancer risk and impeded cancer cell growth are mentioned. Finally, a proposal is put forward, suggesting a novel and integrated approach in viewing the molecular mechanisms and complex interactions responsible for the involvement of AA metabolites in carcinogenesis and the protective effects of omega-3 fatty acids in inflammation and tumour prevention. PMID:19239926

  4. The detection of EpCAM+ and EpCAM– circulating tumor cells

    NARCIS (Netherlands)

    Wit, de Sanne; Dalum, van Guus; Lenferink, Aufried; Tibbe, Arjan G.J.; Hilterman, T. Jeroen N.; Groen, Harry J.M.; Rijn, van Cees J.M.; Terstappen, Leon W.M.M.

    2015-01-01

    EpCAM expressing circulating tumor cells, detected by CellSearch, are predictive of short survival in several cancers and may serve as a liquid biopsy to guide therapy. Here we investigate the presence of EpCAM+ CTC detected by CellSearch and EpCAM– CTC discarded by CellSearch, after EpCAM based enr

  5. The detection of EpCAM(+) and EpCAM(-) circulating tumor cells

    NARCIS (Netherlands)

    de Wit, Sanne; van Dalum, Guus; Lenferink, Aufried T. M.; Tibbe, Arjan G. J.; Hiltermann, T. Jeroen N.; Groen, Harry J. M.; van Rijn, Cees J. M.; Terstappen, Leon W. M. M.

    2015-01-01

    EpCAM expressing circulating tumor cells, detected by CellSearch, are predictive of short survival in several cancers and may serve as a liquid biopsy to guide therapy. Here we investigate the presence of EpCAM(+) CTC detected by CellSearch and EpCAM(-) CTC discarded by CellSearch, after EpCAM based

  6. The tumour distribution of bromodeoxyuridine labelled S-phase cells is found to be strongly dose dependant

    International Nuclear Information System (INIS)

    Bromodeoxyurdine (BrdU) is used extensively to measure the fraction of S-phase cells in tumours. Unlike endogenous markers of proliferation, such as PCNA and Ki-67, BrdU is exogenously administered and reaches the tumour via vasculature where it must then distribute throughout the tissue in order to label S-phase cells. Interest in using BrdU labelling of histological sections to evaluate the distribution of the effect of different treatment modalities on tumours led us to study the ability of BrdU to distribute within tissue. The study used SiHa (human cervix squamous cell carcinoma) xenografts, a tumour that exhibits cords of cells extending up to 150 μm away from blood vessels. A quantitative microscopy-based technique was employed to determine the distribution of S-phase labelled cells relative to the vasculature over a dose range of 25-2000 mg/kg BrdU. Detection of BrdU incorporation in DNA was carried out immunohistochemically and vasculature was identified using perfusion of carbocyanine, a fluorescent perivascular stain. Analysis of BrdU labelling distribution in the tissue found that a dose of 1000 mg/kg was required to label cells furthest from vasculature. Dosing at lower levels resulted in only the cells close to blood vessels being labelled. This result is surprising since 100 mg/kg BrdU is commonly used in flow cytometry studies. Results were compared with penetration seen in vitro using multilayered cell culture, a three-dimensional tissue culture model of solid tumours. Using multilayered cell culture, an exposure of 100 μM BrdU for 1 hour was required for labelling of S-phase cells 150 μm into the tissue, while cells adjacent to the edge of the tissue could be adequately labelled with just 5 μM BrdU for 1 hour. The AUC for a 100 mg/kg BrdU dose in mice was found to be ∼30 μM x h

  7. Parallel evolution of tumour subclones mimics diversity between tumours.

    Science.gov (United States)

    Martinez, Pierre; Birkbak, Nicolai Juul; Gerlinger, Marco; McGranahan, Nicholas; Burrell, Rebecca A; Rowan, Andrew J; Joshi, Tejal; Fisher, Rosalie; Larkin, James; Szallasi, Zoltan; Swanton, Charles

    2013-08-01

    Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome. PMID:23716380

  8. miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours

    Science.gov (United States)

    Biagioni, Francesca; Bossel Ben-Moshe, Noa; Fontemaggi, Giulia; Canu, Valeria; Mori, Federica; Antoniani, Barbara; Di Benedetto, Anna; Santoro, Raffaela; Germoni, Sabrina; De Angelis, Fernanda; Cambria, Anna; Avraham, Roi; Grasso, Giuseppe; Strano, Sabrina; Muti, Paola; Mottolese, Marcella; Yarden, Yosef; Domany, Eytan; Blandino, Giovanni

    2012-01-01

    Deregulated proliferation is a hallmark of cancer cells. Here, we show that microRNA-10b* is a master regulator of breast cancer cell proliferation and is downregulated in tumoural samples versus matched peritumoural counterparts. Two canonical CpG islands (5 kb) upstream from the precursor sequence are hypermethylated in the analysed breast cancer tissues. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumours inhibits cell proliferation and impairs tumour growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease-free survival, relapse-free survival and metastasis-free survival when compared to patients with low expression. This also suggests that restoration of microRNA-10b* expression might have therapeutic promise. PMID:23125021

  9. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells.

    Directory of Open Access Journals (Sweden)

    Nicolas Goudin

    Full Text Available Natural regulatory T (Treg cells interfere with multiple functions, which are crucial for the development of strong anti-tumour responses. In a model of 4T1 mammary carcinoma, depletion of CD25+Tregs results in tumour regression in Balb/c mice, but the mechanisms underlying this process are not fully understood. Here, we show that partial Treg depletion leads to the generation of a particular effector CD8 T cell subset expressing CD11c and low level of PD-1 in tumour draining lymph nodes. These cells have the capacity to migrate into the tumour, to kill DCs, and to locally regulate the anti-tumour response. These events are concordant with a substantial increase in CD11b+ resident dendritic cells (DCs subsets in draining lymph nodes followed by CD8+ DCs. These results indicate that Treg depletion leads to tumour regression by unmasking an increase of DC subsets as a part of a program that optimizes the microenvironment by orchestrating the activation, amplification, and migration of high numbers of fully differentiated CD8+CD11c+PD1lo effector T cells to the tumour sites. They also indicate that a critical pattern of DC subsets correlates with the evolution of the anti-tumour response and provide a template for Treg depletion and DC-based therapy.

  10. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells.

    Science.gov (United States)

    Goudin, Nicolas; Chappert, Pascal; Mégret, Jérome; Gross, David-Alexandre; Rocha, Benedita; Azogui, Orly

    2016-01-01

    Natural regulatory T (Treg) cells interfere with multiple functions, which are crucial for the development of strong anti-tumour responses. In a model of 4T1 mammary carcinoma, depletion of CD25+Tregs results in tumour regression in Balb/c mice, but the mechanisms underlying this process are not fully understood. Here, we show that partial Treg depletion leads to the generation of a particular effector CD8 T cell subset expressing CD11c and low level of PD-1 in tumour draining lymph nodes. These cells have the capacity to migrate into the tumour, to kill DCs, and to locally regulate the anti-tumour response. These events are concordant with a substantial increase in CD11b+ resident dendritic cells (DCs) subsets in draining lymph nodes followed by CD8+ DCs. These results indicate that Treg depletion leads to tumour regression by unmasking an increase of DC subsets as a part of a program that optimizes the microenvironment by orchestrating the activation, amplification, and migration of high numbers of fully differentiated CD8+CD11c+PD1lo effector T cells to the tumour sites. They also indicate that a critical pattern of DC subsets correlates with the evolution of the anti-tumour response and provide a template for Treg depletion and DC-based therapy. PMID:27341421

  11. Immunology of naturally transmissible tumours.

    Science.gov (United States)

    Siddle, Hannah V; Kaufman, Jim

    2015-01-01

    Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution. PMID:25187312

  12. Inverse relationship between tumour proliferation markers and connexin expression in a malignant cardiac tumour originating from mesenchymal stem cell engineered tissue in a rat in-vivo model.

    Directory of Open Access Journals (Sweden)

    StefanDhein

    2013-04-01

    Conclusions and hypothesis: These observations strongly suggest the hypothesis, that invasive tumour growth is accompanied by reduction in connexins. This implicates that gap junction communication between tumour and normal tissue is reduced or absent, which could mean that growth and differentiation signals can not be exchanged.

  13. Arterial Blood, Rather Than Venous Blood, is a Better Source for Circulating Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Mizue Terai

    2015-11-01

    Interpretation: Our data indicate that arterial blood specimens might be a better source of circulating uveal melanoma cells. Although less conveniently processed, perhaps arterial blood should be evaluated as sample source for measurement of CTCs.

  14. Pathophysiology of tumour-induced microangiopathic haemolytic anaemia.

    Science.gov (United States)

    Chalasani, Pavani; Segar, Jennifer M; Marron, Marilyn; Stopeck, Alison

    2016-01-01

    Cancer-associated microangiopathic haemolytic anaemia (CA-MAHA) is a syndrome characterised by Coombs-negative haemolytic anaemia and thrombocytopenia. It is primarily seen in advanced solid tumours and is distinct from thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome. Diagnosis is often delayed and patients have a high mortality. We present the case of CA-MAHA in a patient with metastatic breast cancer treated successfully with early initiation of chemotherapy. In addition, we report longitudinal laboratory evaluation of circulating tumour cells and microparticles and suggest a hypothesis for the mechanism behind CA-MAHA. PMID:26744538

  15. Cell-mediated immunity in operable bronchial carcinoma: the effect of injecting irradiated autologous tumour cells and BCG

    International Nuclear Information System (INIS)

    In 52 patients undergoing tests of cell-mediated immunity before surgical resection of bronchial carcinoma a positive tuberculin test result was found in 71% compared with 68% of age - and sex-matched controls. Sensitization to DNCB occurred in 52% of 37 patients but in 78% controls. There was depression of lymphocyte transformation by PPD in 19 patients compared with controls (p=0.001), but there was no difference in lymphocyte transformation by PHA pr pokeweed mitogen between 34 patients and controls. In a pilot study patients were randomly allocated to autograft (eight) or non-autograft (seven) groups. The autograft group were given an intradermal injection of a suspension of irradiated autologous tumour-cells mixed with intradermal BCG on the day of operation. Tests of cell-mediated immunity were repeated two weeks after operation. Five patients in each group received a course of radiotherapy to the mediastinum three weeks after operation. There was a rise in a cutaneous tuberculin reactivity (p=0.08) and total leucocyte count (p=0.09) in the autograft group postoperatively with a fall in total lymphocyte and T lymphocyte counts in the non-autograft group (p<0.05). These differences, however, were not followed by any difference in the frequency of tumour recurrence or the survival rate two years after operation. The results show that the immunological surveillance mechanism is impaired even in patients with early bronchial carcinoma and that it is possible to overcome postoperative immunological depression with specific immunotherapy combined with BCG. This treatment did not produce any clinical advantage in this small number of patients and the skin lesions caused the patients considerable discomfort. (author)

  16. Failure of anti-D immunoglobulin to remove fetal red cells from maternal circulation.

    Science.gov (United States)

    Revill, J A; Emblin, K F; Hutchinson, R M

    1979-01-01

    A Rhesus negative female was found post delivery to have circulating cells of fetal origin. The neonate was typed as D-positive. In spite of more than conventionally adequate doses of anti-D immunoglobulin given to the mother, the fetal cell count in the maternal circulation remained unchanged. Further investigation showed the fetus to be a Du variant and to exhibit a diminished reaction with the batch of anti-D immunoglobulin used. PMID:111422

  17. Circulating human basophils lack the features of professional antigen presenting cells

    OpenAIRE

    Sharma, Meenu; Hegde, Pushpa; Aimanianda, Vishukumar; Beau, Remi; Sénéchal, Helene; Poncet, Pascal; Latgé, Jean-Paul; Kaveri, Srini V; Bayry, Jagadeesh

    2013-01-01

    Recent reports in mice demonstrate that basophils function as antigen presenting cells (APC). They express MHC class II and co-stimulatory molecules CD80 and CD86, capture and present soluble antigens or IgE-antigen complexes and polarize Th2 responses. Therefore, we explored whether human circulating basophils possess the features of professional APC. We found that unlike dendritic cells (DC) and monocytes, steady-state circulating human basophils did not express HLA-DR and co-stimulatory mo...

  18. Metastasis-Initiating Cells in Renal Cancer

    OpenAIRE

    Khan, Mohammed I.; Czarnecka, Anna M; Duchnowska, Renata; Kukwa, Wojciech; Szczylik, Cezary

    2013-01-01

    Metastasis is a complex process that propagates cells from the primary or initial site of the cancer occurrence to distant parts of the body. Cancer cells break from the cancer site and circulate through the bloodstream or lymph vessels, allowing them to reach nearly all parts of the body. These circulating tumour cells (CTCs) contain specialized metastasis-initiating cells (MICs) that reside in the biological heterogeneous primary tumour. Researchers have hypothesized that metastasis of rena...

  19. Effect of chronic morphine administration on circulating dendritic cells in SIV-infected rhesus macaques.

    Science.gov (United States)

    Cornwell, William D; Wagner, Wendeline; Lewis, Mark G; Fan, Xiaoxuan; Rappaport, Jay; Rogers, Thomas J

    2016-06-15

    We studied the effect of chronic morphine administration on the circulating dendritic cell population dynamics associated with SIV infection using rhesus macaques. Animals were either first infected with SIV and then given chronic morphine, or visa versa. SIV infection increased the numbers of myeloid DCs (mDCs), but morphine treatment attenuated this mDC expansion. In contrast, morphine increased the numbers of plasmacytoid DCs (pDCs) in SIV-infected animals. Finally, chronic morphine administration (no SIV) transiently increased the numbers of circulating pDCs. These results show that chronic morphine induces a significant alteration in the available circulating levels of critical antigen-presenting cells. PMID:27235346

  20. Circulating rotavirus-specific T cells have a poor functional profile

    International Nuclear Information System (INIS)

    Frequencies of circulating T cells producing IFN-γ, TNF-α, and IL-2, and percentages of T cells proliferating after stimulation with rotavirus (RV), tetanus toxoid, and influenza were evaluated in PBMC derived from healthy adults and children. In addition, the potential anergic state of RV-specific T cells was analyzed by stimulation of PBMC with RV antigen in the presence of three anergy inhibitors (rIL-2, rIL-12, or DGKα-i). The quality and magnitude of RV-T cell responses were significantly lower than those of tetanus toxoid and influenza antigens. RV-CD4 T cell response was enriched in monofunctional IFN-γ+ cells, while influenza-CD4 and tetanus toxoid-CD4 T cell responses were enriched in multifunctional T cells. Moreover, rIL-2 – unlike rIL-12 or DGKα-i – increased the frequencies of RV-CD4 TNF-α+, CD4 IFN-γ+, and CD8 IFN-γ+ cells. Thus, circulating RV-T cells seem to have a relatively poor functional profile that may be partially reversed in vitro by the addition of rIL-2. - Highlights: • The quality and magnitude of circulating RV-T cell responses are relatively poor. • Circulating RV-CD4 T cells are enriched in monofunctional IFN-γ+ cells. • Treatment with rIL-2 increased the frequencies of cytokine secreting RV-T cells

  1. Influence of X-rays on early response gene expression in rat astrocytes and brain tumour cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Vrdoljak, E.; Borchardt, P.E.; Bill, C.A.; Stephens, L.C.; Tofilon, P.J. [Anderson (M.D.) Cancer Center, Houston, TX (United States)

    1994-12-01

    The effects of ionizing radiation on c-fos, c-jun and jun-B mRNA levels were determined in cultures of rat perinatal type 1 astrocytes and two rat brain tumour cell lines, 175A and 9L. In astrocyte cultures X-ray doses as low as 1 Gy induced the expression of c-fos and jun-B but had essentially no effect on c-jun. The maximum increase in expression was found 1 h after irradiation, which then rapidly returned to control levels. These findings suggest that astrocytes may play a role in mediating the radiation response of the central nervous system via X-ray-induced changes in gene expression. In contrast, doses of up to 20 Gy had no effect on c-fos, c-jun and jun-B mRNA levels in the two brain tumour cell lines. In addition, whereas 12-0-tetradecanoylphorbol-13-acetate induced the expression of these genes in astrocytes, it had little or no effect on fos or jun expression in 9L or 175A cells. These results suggest that the signal transduction pathways mediating radiation-induced genes expression may be different in normal astrocytes and brain tumour cells. (author).

  2. Influence of X-rays on early response gene expression in rat astrocytes and brain tumour cell lines

    International Nuclear Information System (INIS)

    The effects of ionizing radiation on c-fos, c-jun and jun-B mRNA levels were determined in cultures of rat perinatal type 1 astrocytes and two rat brain tumour cell lines, 175A and 9L. In astrocyte cultures X-ray doses as low as 1 Gy induced the expression of c-fos and jun-B but had essentially no effect on c-jun. The maximum increase in expression was found 1 h after irradiation, which then rapidly returned to control levels. These findings suggest that astrocytes may play a role in mediating the radiation response of the central nervous system via X-ray-induced changes in gene expression. In contrast, doses of up to 20 Gy had no effect on c-fos, c-jun and jun-B mRNA levels in the two brain tumour cell lines. In addition, whereas 12-0-tetradecanoylphorbol-13-acetate induced the expression of these genes in astrocytes, it had little or no effect on fos or jun expression in 9L or 175A cells. These results suggest that the signal transduction pathways mediating radiation-induced genes expression may be different in normal astrocytes and brain tumour cells. (author)

  3. Mir-34a mimics are potential therapeutic agents for p53-mutated and chemo-resistant brain tumour cells.

    Directory of Open Access Journals (Sweden)

    Yuen Ngan Fan

    Full Text Available Chemotherapeutic drug resistance and relapse remains a major challenge for paediatric (medulloblastoma and adult (glioblastoma brain tumour treatment. Medulloblastoma tumours and cell lines with mutations in the p53 signalling pathway have been shown to be specifically insensitive to DNA damaging agents. The aim of this study was to investigate the potential of triggering cell death in p53 mutated medulloblastoma cells by a direct activation of pro-death signalling downstream of p53 activation. Since non-coding microRNAs (miRNAs have the ability to fine tune the expression of a variety of target genes, orchestrating multiple downstream effects, we hypothesised that triggering the expression of a p53 target miRNA could induce cell death in chemo-resistant cells. Treatment with etoposide, increased miR-34a levels in a p53-dependent fashion and the level of miR-34a transcription was correlated with the cell sensitivity to etoposide. miR-34a activity was validated by measuring the expression levels of one of its well described target: the NADH dependent sirtuin1 (SIRT1. Whilst drugs directly targeting SIRT1, were potent to trigger cell death at high concentrations only, introduction of synthetic miR-34a mimics was able to induce cell death in p53 mutated medulloblastoma and glioblastoma cell lines. Our results show that the need of a functional p53 signaling pathway can be bypassed by direct activation of miR-34a in brain tumour cells.

  4. YOLK SAC TUMOUR IN A PREMENARCHAL GIRL : A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Sourav

    2015-03-01

    Full Text Available Yolk sac tumour, otherwise known as endodermal sinus tumour, is a rare and highly malignant germ cell tumour accounting for approximately 10% of malignant germ cell tumours. The tumour usually presents as a rapidly growing mass in young women. Here we present a case of a young premenarchal girl with a huge ovarian tumour which proved to be a yolk sac tumour and was successfully managed.

  5. The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma.

    Science.gov (United States)

    Hunter, J E; Butterworth, J A; Zhao, B; Sellier, H; Campbell, K J; Thomas, H D; Bacon, C M; Cockell, S J; Gewurz, B E; Perkins, N D

    2016-06-30

    The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel-/- mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg-driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the Eμ-Myc lymphoma cells but, counterintuitively, c-rel-/- Eμ-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c-Rel led to earlier onset of disease, microarray gene expression analysis was performed on B cells from 4-week-old, wild-type and c-rel-/- Eμ-Myc mice. Extensive changes in gene expression were not seen at this age, but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Quantitative PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant Eμ-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover, Bach2 expression was also downregulated in c-rel-/- TCL1-Tg mice and RelA Thr505Ala mutant Eμ-Myc mice. Analysis of wild-type Eμ-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel-/- mice. Confirming the relevance of these findings to human disease, analysis of chromatin immunoprecipitation sequencing data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-κB/IκB kinase pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. These data reveal a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context-dependent complexity of NF-κB signalling in

  6. Antiproliferative activity and apoptotic effects of Filipendula ulmaria pollen against C26 mice colon tumour cells

    Directory of Open Access Journals (Sweden)

    Mărgăoan Rodica

    2016-06-01

    Full Text Available Honeybee collected pollen exhibits high nutritional and pharmaceutical benefits for the human diet and medicine. Pollen’s antioxidant, anti-ageing, anti-inflammatory, anti-atherosclerosis, and cardioprotective activity, depending on the floral origin, are well known. Recent studies proposed that pollen may also be an excellent cancer-fighting candidate, as pollen harbours high amounts of phenolic substances. In our study, Filipendula ulmaria pollen (bee collected was methanol-water extracted and used to verify its in vitro pharmacological activities on C26 mice cancer tumour cells. Three different concentrations of the extract were tested in antitumour assays. Monitoring was done after 6, 12, 24, and 48 hours. Promising results were obtained for antiproliferative and apoptotic activity of the pollen extracts, with high efficiency for the highest concentration (1 mg/mL. For both activities, time and concentration-dependent effects were observed. Pollen extracts or bee collected pollen has a high potential as an antitumour agent for use in human medicine, because they are both rich in bioactive compounds.

  7. Antitumour effects of combined radio- and parvovirotherapy in N-Ras-positive tumour cells

    International Nuclear Information System (INIS)

    Many innovative approaches have attempted to challenge the dominant position of surgery, chemotherapy and radiotherapy as the major therapeutic modalities to treat cancer. However, only recently some new agents have appeared that achieve effects comparable to the ones of these established treatments. A novel class of such therapeutics consists of oncolytic viruses with several main representatives, namely adeno-, herpes, reo- and parvovirus. The latter class of anticancer agents has proven to be quite effective in many preclinical models and is now considered for a phase I clinical trial in patients with glioma and pancreatic cancer. An important question to be answered is whether virotherapy can be combined with standard treatments to achieve an enhanced antitumor effect still at a low level of toxicity. Here we present data concerning the application of irradiation together with H-1PV parvovirus infection comparing their toxic effects on normal and Ras -transformed fibroblasts. This proved to be a potent combination achieving high level of synergistic toxicity on transformed cells at doses, which did not affect the viability of normal human fibroblasts. This strategy holds promise to become a part of the clinical treatment of radioresistant tumours. (authors)

  8. Aberrant DNA methylation at genes associated with a stem cell-like phenotype in cholangiocarcinoma tumours

    Science.gov (United States)

    Dai, Wei; Siddiq, Afshan; Walley, Andrew J; Limpaiboon, Temduang; Brown, Robert

    2013-01-01

    Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterised. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium’s HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly epigenetically regulated in this tumour type. Using a linear model for microarray data we identified 1610 differentially methylated autosomal CpG sites with 809 CpG sites (representing 603 genes) being hypermethylated and 801 CpG sites (representing 712 genes) being hypomethylated in cholangiocarcinoma versus adjacent normal tissues (false discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12 and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. PMID:24089088

  9. Prospective assessment of MRI for imaging retroperitoneal metastases from testicular germ cell tumours

    Energy Technology Data Exchange (ETDEWEB)

    Sohaib, S.A. [Department of Radiology, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey (United Kingdom)], E-mail: aslam.sohaib@rmh.nhs.uk; Koh, D.M. [Department of Radiology, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey (United Kingdom); Barbachano, Y. [Department of Computing and Statistics, Royal Marsden Hospital, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey (United Kingdom); Parikh, J.; Husband, J.E.S. [Department of Radiology, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey (United Kingdom); Dearnaley, D.P.; Horwich, A.; Huddart, R. [Department of Academic Urology Unit, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey (United Kingdom)

    2009-04-15

    Aim: To determine the sensitivity of magnetic resonance imaging (MRI) in the detection of retroperitoneal lymph nodes in patients with testicular germ cell tumours (TGCT). Methods and materials: A prospective study of 52 patients (mean age 34 years, range 18-54 years) was performed. Imaging of the retroperitoneum was performed using multidetector computed tomography (CT) and 1.5 T MRI systems. The CT and MRI images were read independently by three observers. The number, size, and site of enlarged nodes ({>=}10 mm maximum short axis diameter) were recorded. Retroperitoneal nodal detection on MRI was compared to CT. Results: Twenty-two (42%) of the 52 patients had no retroperitoneal disease; in remaining 30 patients 51 enlarged nodes were identified. On a per patient basis readers 1, 2, and 3 identified nodal disease in 28 of 29, 29 of 30, and 24 of 30 patients, respectively, using MRI compared to CT. Thus for experienced radiologists (readers 1 and 2) MRI is comparable to CT for nodal detection (i.e., this study excludes MRI being inferior to CT with 80% power and 5% type 1 error). Conclusion: MRI offers an alternative method for staging the retroperitoneum in young patients being followed for TGCT and has the major advantage of avoiding exposure to ionizing radiation.

  10. Migration of microchimeric fetal cells into maternal circulation before placenta formation

    OpenAIRE

    Sunami, Rei; Komuro, Mayuko; Tagaya, Hikaru; Hirata, Shuji

    2010-01-01

    Fetal cell microchimerism is defined as the persistence of pluripotent fetal cells in the maternal body long after delivery. The exact process by which fetal cells cross the placental barrier and enter maternal circulation is still being investigated. We reported that fetal cells persist only in the maternal bone marrow and may give rise to subpopulations with the ability to differentiate into the tissue-specific mature cells within injured maternal organs. Moreover, most of the fetal cells e...

  11. Interplay of Stem Cell Characteristics, EMT, and Microtentacles in Circulating Breast Tumor Cells

    Energy Technology Data Exchange (ETDEWEB)

    Charpentier, Monica [Program in Molecular Medicine, University of Maryland School of Medicine, 655 W. Baltimore St., Bressler Bldg., Rm 10-20, Baltimore, MD 21201 (United States); Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore St., Bressler Bldg., Rm 10-29, Baltimore, MD 21201 (United States); Martin, Stuart, E-mail: ssmartin@som.umaryland.edu [Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore St., Bressler Bldg., Rm 10-29, Baltimore, MD 21201 (United States); Department of Physiology, University of Maryland School of Medicine, 655 W. Baltimore St., Bressler Bldg., Rm 10-29, Baltimore, MD 21201 (United States)

    2013-11-14

    Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis.

  12. Interplay of Stem Cell Characteristics, EMT, and Microtentacles in Circulating Breast Tumor Cells

    Directory of Open Access Journals (Sweden)

    Stuart Martin

    2013-11-01

    Full Text Available Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs and the epithelial-to-mesenchymal transition (EMT cooperate to produce circulating tumor cells (CTCs that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs, which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis.

  13. Interplay of Stem Cell Characteristics, EMT, and Microtentacles in Circulating Breast Tumor Cells

    International Nuclear Information System (INIS)

    Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis

  14. Cornering metastases: therapeutic targeting of circulating tumor cells and stem cells.

    Directory of Open Access Journals (Sweden)

    Bishoy eFaltas

    2012-07-01

    Full Text Available The last decade has witnessed an evolution of our understanding of the biology of the metastatic cascade. Recent insights into the metastatic process show that it is complex, dynamic and multi-directional. This process starts at a very early stage in the natural history of solid tumor growth leading to early development of metastases that grow in parallel with the primary tumor. The role of stem cells in perpetuating cancer metastases is increasingly becoming more evident. At the same time, there is a growing recognition of the crucial role circulating tumor cells (CTCs play in the development of metastases. These insights have laid the biological foundations for therapeutic targeting of CTCs, a promising area of research that aims to reduce cancer morbidity and mortality by preventing the development of metastases at a very early stage. The hematogenous transport phase of the metastatic cascade provides critical access to CTCs for therapeutic targeting aiming to interrupt the metastatic process. Recent advances in the fields of nanotechnology and micro-fluidics have led to the development of several devices for in-vivo targeting of CTC during transit in the circulation. Selectin-coated tubes that target cell adhesion molecules, immuno-magnetic separators and in-vivo photoacoustic flow cytometers are currently being developed for this purpose. On the pharmacological front, several pharmacological and immunological agents targeting cancer stem cells are currently being developed. Such agents may ultimately prove to be effective against circulating tumor stem cells (CTSCs. Although still in its infancy, therapeutic targeting of CTCs and CTSCs offers an unprecedented opportunity to prevent the development of metastasis and potentially alter the natural history of cancer. By rendering cancer a local disease, these approaches could lead to major reductions in metastasis-related morbidity and mortality.

  15. SPINDLE CELL RHABDOMYOSARCOMA MASQUERADING AS PSEUDO-TUMOUR OF THE ORBIT

    Directory of Open Access Journals (Sweden)

    Anitha

    2016-03-01

    Full Text Available Paediatric solid neoplasms are a global burden causing highest incidence of mortality in children. Among the soft tissue tumours in children, Rhabdomyosarcoma is the most common. They possess variety of histologies that differ among various age groups. Here, we discuss a case of a 3-year-old child diagnosed with embryonal rhabdomyosarcoma, which initially mimicked an orbital pseudo-tumour. Histopathology and Immunohistochemistry confirmed the diagnosis. This case report has uncommon clinical and radiological presentation of rhabdomyosarcoma.

  16. In Silico Modelling of Treatment-Induced Tumour Cell Kill: Developments and Advances

    OpenAIRE

    Marcu, Loredana G.; Harriss-Phillips, Wendy M.

    2012-01-01

    Mathematical and stochastic computer (in silico) models of tumour growth and treatment response of the past and current eras are presented, outlining the aims of the models, model methodology, the key parameters used to describe the tumour system, and treatment modality applied, as well as reported outcomes from simulations. Fractionated radiotherapy, chemotherapy, and combined therapies are reviewed, providing a comprehensive overview of the modelling literature for current modellers and rad...

  17. Bleomycin induced flagellate erythema in a patient with thalamic mixed germ cell tumour: Report of a rare adverse effect

    OpenAIRE

    Ahitagni Biswas; Pramod Kumar Julka

    2016-01-01

    Bleomycin induced flagellate dermatitis is an uncommon and unique adverse effect. With the declining use of bleomycin, this complication is becoming increasingly infrequent in day-to-day clinical practice. We herein describe a case of a 13 year old male patient with left thalamic mixed germ cell tumour treated by multimodality approach, who developed flagellate erythema after two cycles of combination chemotherapy with bleomycin, etoposide and cisplatin (BEP). This brief report highlights the...

  18. Long-term follow-up is crucial after treatment for granulosa cell tumours of the ovary

    OpenAIRE

    Mangili, G; Ottolina, J; Gadducci, A.; Giorda, G.; van Breda, E.; Savarese, A.; Candiani, M; Frigerio, L; Scarfone, G; Pignata, S; Rossi, R.; Marinaccio, M; Lorusso, D

    2013-01-01

    Objective: The aim of this study is to evaluate the long-term outcome of granulosa cell tumour (GCT) of the ovary in a large series of patients treated in MITO centres (Multicentre Italian Trials in Ovarian Cancer) and to define prognostic parameters for relapse and survival. Methods: A retrospective multi-institutional review of patients with GCTs of the ovary treated or referred to MITO centres was conducted. Surgical outcome, intraoperative and pathological findings and follow-up data were...

  19. Mouse Model of Devil Facial Tumour Disease Establishes That an Effective Immune Response Can be Generated Against the Cancer Cells

    OpenAIRE

    Pinfold, Terry L.; Brown, Gabriella K.; Bettiol, Silvana S.; Woods, Gregory M.

    2014-01-01

    The largest carnivorous marsupial in Australia, the Tasmanian devil (Sarcophilus harrisii) is facing extinction in the wild due to a transmissible cancer known as Devil Facial Tumour Disease (DFTD). DFTD is a clonal cell line transmitted from host to host with 100% mortality and no known immunity. While it was first considered that low genetic diversity of the population of devils enabled the allograft transmission of DFTD recent evidence reveals that genetically diverse animals succumb to th...

  20. Delivery of size-controlled long-circulating polymersomes in solid tumours, visualized by quantum dots and optical imaging in vivo

    OpenAIRE

    Bakalova, Rumiana; Lazarova, Desislava; Nikolova, Biliana; Atanasova, Severina; Zlateva, Genoveva; Zhelev, Zhivko; Aoki, Ichio

    2014-01-01

    The present study was designed to investigate whether poly-ion complex hollow vesicles (polymersomes), based on chemically modified chitosan, are appropriate for passive tumour targeting in the context of their application as drug carriers. The experiments were performed on colon cancer-grafted mice. The mice were subjected to anaesthesia and injected intravenously with water-soluble nanoparticles: (1) QD705-labelled polymersomes (average size ∼120 nm; size distribution ∼10%) or (2) native QD...