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patient derived xenograft metastasis

Zhongyan Hua, Xiao Gu, Yudi Dong, Fei Tan, Zhihui Liu, Carol J Thiele, Zhijie Li
Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to be associated with poor prognosis in neuroblastoma (NB) patients. Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. In this study, we investigated the role of BDNF/TrkB on metastasis in NB. A tetracycline-regulated TrkB-expressing NB cell line (TB3) was used. Scratch wound healing assay, Boyden chamber migration, and invasion assays were performed to study the migration and invasion of TB3 cells...
October 17, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Tao Zhang, Suoyuan Li, Jingjie Li, Fei Yin, Yingqi Hua, Zhouying Wang, Binhui Lin, Hongsheng Wang, Dongqing Zou, Zifei Zhou, Jing Xu, Chengqing Yi, Zhengdong Cai
Signal transducer and activator of transcription 3 (STAT3) has important roles in cancer aggressiveness and has been confirmed as an attractive target for cancer therapy. In this study, we used a dual-luciferase assay to identify that pectolinarigenin inhibited STAT3 activity. Further studies showed pectolinarigenin inhibited constitutive and interleukin-6-induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus and blocked STAT3 DNA-binding activity in osteosarcoma cells. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNA methyltransferase 1/HDAC1 histone deacetylase 1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma...
October 13, 2016: Cell Death & Disease
Chunxiang Ye, Xiuyun Tian, Guanjun Yue, Liang Yan, Xiaoya Guan, Shan Wang, Chunyi Hao
CD26/DPPIV is a glycosylated transmembrane type II protein and has a multitude of biological functions, while its impact on the malignant phenotypes of cancer cells has not been fully understood. This study aimed to investigate the effect of CD26 on growth and metastasis of pancreatic cancer cells in vitro and in vivo. We found in this study that CD26 expression was higher in cell lines that derived from the metastatic sites than those from the primary tumor sites. In specimens of pancreatic cancer patients, CD26 expression was higher in cancerous tissues than in paired normal tissues...
October 7, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Hongjuan Zhao, Rosalie Nolley, Andy M W Chan, Erinn B Rankin, Donna M Peehl
MET plays an important role in the development and progression of papillary renal cell carcinoma (pRCC). Evaluation of efficacy of MET inhibitors against pRCC has been hampered by limited preclinical models depicting MET abnormalities. We established a new patient-derived xenograft (PDX) model of pRCC carrying an activating mutation of MET and tested the ability of cabozantinib, an inhibitor of receptor tyrosine kinases including MET, to inhibit tumor growth and metastasis. Precision-cut, thin tissue slices from a pRCC specimen obtained by nephrectomy were implanted under the renal capsule of RAG2(-/-)γC(-/-) mice to establish first generation TSG-RCC-030...
August 11, 2016: Cancer Biology & Therapy
Rachel Eyre, Denis G Alférez, Kath Spence, Mohamed Kamal, Frances L Shaw, Bruno M Simões, Angélica Santiago-Gómez, Aida Sarmiento-Castro, Maria Bramley, Mohammed Absar, Zahida Saad, Sumohan Chatterjee, Cliona Kirwan, Ashu Gandhi, Anne C Armstrong, Andrew M Wardley, Ciara S O'Brien, Gillian Farnie, Sacha J Howell, Robert B Clarke
Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice...
September 28, 2016: Journal of Mammary Gland Biology and Neoplasia
S Lefort, A Thuleau, Y Kieffer, P Sirven, I Bieche, E Marangoni, A Vincent-Salomon, F Mechta-Grigoriou
The CXCR4 receptor and its ligand CXCL12 (also named stromal cell-derived factor 1, SDF1) have a critical role in chemotaxis and homing, key steps in cancer metastasis. Although myofibroblasts expressing CXCL12 are associated with the presence of axillary metastases in HER2 breast cancers (BC), the therapeutic interest of targeting CXCR4/CXCL12 axis in the different BC subtypes remains unclear. Here, we investigate this question by testing antitumor activity of CXCR4 inhibitors in patient-derived xenografts (PDX), which faithfully reproduce human tumor properties...
September 26, 2016: Oncogene
Yuansheng Duan, Shu Zhang, Longlong Wang, Xuan Zhou, Qinghua He, Su Liu, Kai Yue, Xudong Wang
Aberrant overexpression of C-X-C chemokine receptor type 4 (CXCR4) is a critical event during tumor metastasis. It has been previously reported that the expression of CXCR4 is linked with epithelial-mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC) tissues derived from patients. The present study addresses the role of CXCR4 in EMT in tongue squamous cell carcinoma (TSCCA) cells in vitro and in xenograft models. Small interfering (si) RNA sequences targeting the CXCR4 gene were transfected into TSCCA cells...
September 2016: Oncology Letters
Laura Mercatali, Federico La Manna, Arwin Groenewoud, Roberto Casadei, Federica Recine, Giacomo Miserocchi, Federica Pieri, Chiara Liverani, Alberto Bongiovanni, Chiara Spadazzi, Alessandro de Vita, Gabri van der Pluijm, Andrea Giorgini, Roberto Biagini, Dino Amadori, Toni Ibrahim, Ewa Snaar-Jagalska
Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX) rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF) embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231)...
2016: International Journal of Molecular Sciences
Chi-Kuan Chen, Wen-Hsuan Yu, Tsu-Yao Cheng, Min-Wei Chen, Chia-Yi Su, Yi-Chieh Yang, Tsang-Chih Kuo, Ming-Tsan Lin, Ya-Chi Huang, Michael Hsiao, Kuo-Tai Hua, Mien-Chie Hung, Min-Liang Kuo
Hepatocellular carcinoma (HCC) relies on angiogenesis for growth and metastasis. Leukocyte cell-derived chemotaxin 2 (LECT2) is a cytokine and preferentially expressed in the liver. Previous studies have found that LECT2 targets to both immune and tumor cells to suppress HCC development and vascular invasion. Although LECT2 did not affect HCC cells growth in vitro, it still suppressed HCC xenografts growth in immune-deficient mice, suggesting other cells such as stroma cells may also be targeted by LECT2. Here, we sought to determine the role of LECT2 in tumor angiogenesis in HCC patients...
2016: Scientific Reports
David J Agorku, Stefan Tomiuk, Kerstin Klingner, Stefan Wild, Silvia Rüberg, Lisa Zatrieb, Andreas Bosio, Julia Schueler, Olaf Hardt
The use of in vitro cell line models for cancer research has been a useful tool. However, it has been shown that these models fail to reliably mimic patient tumors in different assays(1). Human tumor xenografts represent the gold standard with respect to tumor biology, drug discovery, and metastasis research (2-4). Tumor xenografts can be derived from different types of material like tumor cell lines, tumor tissue from primary patient tumors(4) or serially transplanted tumors. When propagated in vivo, xenografted tissue is infiltrated and vascularized by cells of mouse origin...
2016: Journal of Visualized Experiments: JoVE
Einar K Rofstad, Ruixia Huang, Kanthi Galappathi, Lise Mari K Andersen, Catherine S Wegner, Anette Hauge, Jon-Vidar Gaustad, Trude G Simonsen
Studies of cell line-derived human tumor xenografts have suggested that the lymphatics seen in immunohistochemical preparations from non-peripheral regions of tumors are nonfunctional. In this investigation, lymphangiogenesis, hemangiogenesis, and lymph node metastasis were studied in patient-derived xenograft (PDX) models of carcinoma of the uterine cervix. Lymph vessel density (LVD) and blood vessel density (BVD) were measured in immunohistochemical preparations. The expression of angiogenesis-related genes was investigated by quantitative PCR...
July 29, 2016: Oncotarget
Michael Ngo, Arum Han, Anita Lakatos, Debashis Sahoo, Stephanie J Hachey, Kipp Weiskopf, Andrew H Beck, Irving L Weissman, Alexander D Boiko
The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts...
August 9, 2016: Cell Reports
Li Du, Yi-Jia Li, Marwan Fakih, Rebecca L Wiatrek, Marjun Duldulao, Zhenbin Chen, Peiguo Chu, Julio Garcia-Aguilar, Yuan Chen
Cancer stem cells (CSCs) have key roles in treatment resistance, tumour metastasis and relapse. Using colorectal cancer (CC) cell lines, patient-derived xenograft (PDX) tissues and patient tissues, here we report that CC CSCs, which resist chemoradiation, have higher SUMO activating enzyme (E1) and global SUMOylation levels than non-CSCs. Knockdown of SUMO E1 or SUMO conjugating enzyme (E2) inhibits CC CSC maintenance and self-renewal, while overexpression of SUMO E1 or E2 increases CC cell stemness. We found that SUMOylation regulates CSCs through Oct-1, a transcription factor for aldehyde dehydrogenases (ALDHs)...
2016: Nature Communications
Nakho Chang, Hye Won Lee, Joung Eun Lim, Da Eun Jeong, Hye Jin Song, Sudong Kim, Do-Hyun Nam, Hyun Hwan Sung, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Han-Yong Choi, Hwang Gyun Jeon
Muscle-invasive bladder cancer (MIBC) consists of a heterogeneous group of tumors with a high rate of metastasis and mortality. To facilitate the in-depth investigation and validation of tailored strategies for MIBC treatment, we have developed an integrated approach using advanced high-throughput drug screening and a clinically relevant patient-derived preclinical platform. We isolated patient-derived tumor cells (PDCs) from a rare MIBC case (BD-138T) that harbors concomitant epidermal growth factor receptor (EGFR) amplification and phosphatase and tensin homolog (PTEN) deletion...
July 12, 2016: Oncotarget
Theresa A Reno, Sun-Wing Tong, Jun Wu, John M Fidler, Rebecca Nelson, Jae Y Kim, Dan J Raz
BACKGROUND: The natural compound triptolide has been shown to decrease cell proliferation and induce apoptosis and cellular senescence. We previously demonstrated that triptolide decreases tumor formation and metastasis of human non-small cell lung cancer cells (NSCLC). Due to the toxicity of triptolide, derivatives of the natural compound have been developed that show more favorable toxicity profiles and pharmacokinetics in animal models. The purpose of this study was to evaluate MRx102 as a novel therapeutic for lung cancer...
2016: BMC Cancer
David Vallerand, Gérald Massonnet, Fatima Kébir, David Gentien, Zofia Maciorowski, Pierre De la Grange, Brigitte Sigal-Zafrani, Marion Richardson, Sandrine Humbert, Aurélie Thuleau, Franck Assayag, Ludmilla de Plater, André Nicolas, Suzy Scholl, Elisabetta Marangoni, Stefan Weigand, Sergio Roman-Roman, Ariel Savina, Didier Decaudin
Drug discovery efforts have focused on the tumor microenvironment in recent years. However, few studies have characterized the stroma component in patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs). In this study, we characterized the stroma in various models of breast cancer tumors in mice. We performed transcriptomic and flow cytometry analyses on murine populations for a series of 25 PDXs and the two most commonly used GEMs (MMTV-PyMT and MMTV-erBb2). We sorted macrophages from five models...
2016: PloS One
Natalya Beglyarova, Eugenia Banina, Yan Zhou, Ramilia Mukhamadeeva, Grigorii Andrianov, Egor Bobrov, Elena Lysenko, Natalya Skobeleva, Linara Gabitova, Diana Restifo, Max Pressman, Ilya G Serebriiskii, John P Hoffman, Keren Paz, Diana Behrens, Vladimir Khazak, Sandra A Jablonski, Louis M Weiner, Erica A Golemis, Igor Astsaturov
PURPOSE: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients. EXPERIMENTAL DESIGN: We first developed a panel of new physiological models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX)...
July 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Marta Paez-Ribes, Shan Man, Ping Xu, Robert S Kerbel
Several approaches are being evaluated to improve the historically limited value of studying transplanted primary tumors derived by injection of cells from established cell lines for predicting subsequent cancer therapy outcomes in patients and clinical trials. These approaches include use of genetically engineered mouse models (GEMMs) of spontaneous tumors, or patient tumor tissue derived xenografts (PDXs). Almost all such therapy studies utilizing such models involve treatment of established primary tumors...
2016: PloS One
Wen Hsin Lee, Lee Yee Choong, Naing Naing Mon, SsuYi Lu, Qingsong Lin, Brendan Pang, Benedict Yan, Vedula Sri Ram Krishna, Himanshu Singh, Tuan Zea Tan, Jean Paul Thiery, Chwee Teck Lim, Patrick Boon Ooi Tan, Martin Johansson, Christian Harteneck, Yoon Pin Lim
Metastasis is a significant health issue. The standard mode of care is combination of chemotherapy and targeted therapeutics but the 5-year survival rate remains low. New/better drug targets that can improve outcomes of patients with metastatic disease are needed. Metastasis is a complex process, with each step conferred by a set of genetic aberrations. Mapping the molecular changes associated with metastasis improves our understanding of the etiology of this disease and contributes to the pipeline of targeted therapeutics...
2016: Scientific Reports
Jan P Nicolay, Karin Müller-Decker, Anne Schroeder, Markus Brechmann, Markus Möbs, Cyrill Géraud, Chalid Assaf, Sergij Goerdt, Peter H Krammer, Karsten Gülow
Despite intensive efforts in recent years, a curative therapy for cutaneous T-cell lymphoma (CTCL) has not yet been developed. Therefore, the establishment of new therapeutic approaches with higher efficacy rates and milder side effects is strongly desired. A characteristic feature of the malignant T-cell population in CTCL is resistance toward cell death resulting from constitutive NF-κB activation. Therefore, NF-κB-dependent cell death resistance represents an interesting therapeutic target in CTCL because an NF-κB-directed therapy would leave bystander T cells widely unaffected...
August 11, 2016: Blood
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