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Silvio Holzner, Daniel Senfter, Serena Stadler, Anna Staribacher, Chi Huu Nguyen, Anna Gaggl, Silvana Geleff, Nicole Huttary, Sigurd Krieger, Walter Jäger, Helmut Dolznig, Robert M Mader, Georg Krupitza
Since cancer cells, when grown as spheroids, display drug sensitivity and radiation resistance patterns such as seen in vivo we recently established a three‑dimensional (3D) in vitro model recapitulating colorectal cancer (CRC)-triggered lymphatic endothelial cell (LEC)‑barrier breaching to study mechanisms of intra‑/extravasation. CRC metastasizes not only through lymphatics but also through blood vessels and here we extend the 3D model to the interaction of blood endothelial cells (BECs) with naïve and 5‑fluorouracil (5‑FU)‑resistant CRC CCL227 cells...
September 20, 2016: Oncology Reports
Rajendra Narayan Mitra, Chance A Nichols, Junjing Guo, Rasha Makkia, Mark J Cooper, Muna I Naash, Zongchao Han
We recently reported that the Ins2(Akita) mouse is a good model for late-onset diabetic retinopathy. Here, we investigated the effect of miR200-b, a potential anti-angiogenic factor, on VEGF receptor 2 (VEGFR-2) expression and to determine the underlying angiogenic response in mouse endothelial cells, and in retinas from aged Ins2(Akita) mice. MiR200-b and its native flanking sequences were amplified and cloned into a pCAG-eGFP vector directed by the ubiquitous CAG promoter (namely pCAG-miR200-b-IRES-eGFP)...
August 28, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Pui-Wah Choi, Junzheng Yang, Shu-Kay Ng, Colleen Feltmate, Michael G Muto, Kathleen Hasselblatt, Kyle Lafferty-Whyte, Lellean JeBailey, Laura MacConaill, William R Welch, Wing-Ping Fong, Ross S Berkowitz, Shu-Wing Ng
Increased inclusion cyst formation in the ovary is associated with ovarian cancer development. We employed in vitro three-dimensional (3D) organotypic models formed by normal human ovarian surface epithelial (OSE) cells and ovarian cancer cells to study the morphologies of normal and cancerous ovarian cortical inclusion cysts and the molecular changes during their transitions into stromal microenvironment. When compared with normal cysts that expressed tenascin, the cancerous cysts expressed high levels of laminin V and demonstrated polarized structures in Matrigel; and the cancer cells migrated collectively when the cyst structures were positioned in a stromal-like collagen I matrix...
January 26, 2016: Oncotarget
Shweta Bhatt, Manoj K Gupta, Mogher Khamaisi, Rachael Martinez, Marina A Gritsenko, Bridget K Wagner, Patrick Guye, Volker Busskamp, Jun Shirakawa, Gongxiong Wu, Chong Wee Liew, Therese R Clauss, Ivan Valdez, Abdelfattah El Ouaamari, Ercument Dirice, Tomozumi Takatani, Hillary A Keenan, Richard D Smith, George Church, Ron Weiss, Amy J Wagers, Wei-Jun Qian, George L King, Rohit N Kulkarni
The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild complications (Medalist -C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist -C...
August 4, 2015: Cell Metabolism
Shiv K Singh, Nai-Ming Chen, Elisabeth Hessmann, Jens Siveke, Marlen Lahmann, Garima Singh, Nadine Voelker, Sophia Vogt, Irene Esposito, Ansgar Schmidt, Cornelia Brendel, Thorsten Stiewe, Jochen Gaedcke, Marco Mernberger, Howard C Crawford, William R Bamlet, Jin-San Zhang, Xiao-Kun Li, Thomas C Smyrk, Daniel D Billadeau, Matthias Hebrok, Albrecht Neesse, Alexander Koenig, Volker Ellenrieder
In adaptation to oncogenic signals, pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transition (EMT), a process combining tumor cell dedifferentiation with acquisition of stemness features. However, the mechanisms linking oncogene-induced signaling pathways with EMT and stemness remain largely elusive. Here, we uncover the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity. In particular, we show that NFATc1 drives EMT reprogramming and maintains pancreatic cancer cells in a stem cell-like state through Sox2-dependent transcription of EMT and stemness factors...
February 12, 2015: EMBO Journal
Xiaofeng Xue, Ye Zhang, Qiaoming Zhi, Min Tu, Yue Xu, Jie Sun, Jishu Wei, Zipeng Lu, Yi Miao, Wentao Gao
BACKGROUND: Hepatocellular carcinoma (HCC) typically relies on tumor transformation and angiogenesis for its malignant behavior, including growth and metastasis. Previously, we reported that Vasohibin2 (VASH2) is preferentially expressed in hepatocellular carcinoma (HCC) tumor tissues and promotes angiogenesis. Here, we further investigated the role of VASH2 in HCC tumor progression. RESULTS: Bioinformatics analyses and luciferase reporter gene assays confirmed the post-transcriptional regulation of VASH2 by miR-200a/b/c...
2014: Cell Communication and Signaling: CCS
Mingyang Lu, Mohit Kumar Jolly, Jose' Onuchic, Eshel Ben-Jacob
Understanding epithelial-mesenchymal transitions (EMT) during cancer metastasis remains a major challenge in modern biology. Recent observations of cell behavior together with progress in mapping the underlying regulatory genetic networks led to new understandings of carcinoma metastasis. It is now established that the genetic network that regulates the EMT also enables an epithelial-mesenchymal hybrid phenotype. These hybrid cells possess mixed carcinoma epithelial and mesenchymal characteristics that enable specialized capabilities such as collective cell migration...
September 1, 2014: Cancer Research
Karen H Hales, Sheree C Speckman, Nawneet K Kurrey, Dale B Hales
BACKGROUND: The laying hen model of spontaneous epithelial ovarian cancer (EOC) is unique in that it is the only model that enables observations of early events in disease progression and is therefore also uniquely suited for chemoprevention trials. Previous studies on the effect of dietary flaxseed in laying hens have revealed the potential for both amelioration and prevention of ovarian cancer. The objective of this study was to assess the effect of flaxseed on genes and pathways that are dysregulated in tumors...
2014: BMC Genomics
Ningxia Sun, Qing Zhang, Chen Xu, Qian Zhao, Yan Ma, Xinmei Lu, Liang Wang, Wen Li
The molecular mechanism underlying ovarian cancer invasiveness and metastasis remains unclear. Since significant downregulation in microRNA 200 (miRNA200) family (miR200a, miR200b, and miR200c) has been reported in the invasive ovarian cancer cells, here, we used two human ovarian cancer cell lines, OVCAR3 and SKOV3, to study the molecular basis of miR200, matrix metalloproteinase 3 (MMP3) activation, and cancer invasiveness. We found that overexpression of either miR200 family member in OVCAR3 or SKOV3 cells significantly inhibited production and secretion of MMP3 and cancer invasiveness...
November 2014: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Kazuya Sugiyama, Hiroaki Kajiyama, Kiyosumi Shibata, Hong Yuan, Fumitaka Kikkawa, Takeshi Senga
The TGFβ-mediated alteration of the tumor microenvironment plays a crucial role in tumor progression. Mesothelial cells are the primary components of the tumor microenvironment for ovarian cancer cells; however, the exact role of TGFβ-stimulated mesothelial cells in ovarian cancer progression remains uncertain. In this report, we examined the effects of TGFβ-treated mesothelial cells on ovarian cancer progression. We show that TGFβ-stimulated human primary mesothelial cells (HPMC) are able to promote cancer cell attachment and proliferation and the activation of the promoter activities of MMP-2 and MMP-9, which are metalloproteinases necessary for tumor invasion...
August 2014: Molecular Cancer Therapeutics
Evgeny Izumchenko, Xiaofei Chang, Christina Michailidi, Luciane Kagohara, Rajani Ravi, Keren Paz, Mariana Brait, Mohammad O Hoque, Shizhang Ling, Atul Bedi, David Sidransky
Although specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR tyrosine kinase inhibitors (TKI), these genetic alterations are present in only a minority of patients. Patients with tumors expressing wild-type EGFR lack reliable predictive markers of their clinical response to EGFR TKIs. Although epithelial-mesenchymal transition (EMT) has been inversely correlated with the response of cancers to EGFR-targeted therapy, the precise molecular mechanisms underlying this association have not been defined and no specific EMT-associated biomarker of clinical benefit has been identified...
July 15, 2014: Cancer Research
Lin Wang, Miao-Jun Zhu, Ai-Min Ren, Hong-Fei Wu, Wu-Mei Han, Ruo-Ying Tan, Rui-Qin Tu
Epithelial ovarian cancer (EOC) is the most common gynecologic malignancy. To identify the micro-ribonucleic acids (miRNAs) expression profile in EOC tissues that may serve as a novel diagnostic biomarker for EOC detection, the expression of 1722 miRNAs from 15 normal ovarian tissue samples and 48 ovarian cancer samples was profiled by using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. A ten-microRNA signature (hsa-miR-1271-5p, hsa-miR-574-3p, hsa-miR-182-5p, hsa-miR-183-5p, hsa-miR-96-5p, hsa-miR-15b-5p, hsa-miR-182-3p, hsa-miR-141-5p, hsa-miR-130b-5p, and hsa-miR-135b-3p) was identified to be able to distinguish human ovarian cancer tissues from normal tissues with 97% sensitivity and 92% specificity...
2014: PloS One
Yongqing Liu, Ester Sánchez-Tilló, Xiaoqin Lu, Li Huang, Brian Clem, Sucheta Telang, Alfred B Jenson, Miriam Cuatrecasas, Jason Chesney, Antonio Postigo, Douglas C Dean
Ras mutations are frequent in cancer cells where they drive proliferation and resistance to apoptosis. However in primary cells, mutant Ras instead can cause oncogene-induced senescence, a tumor suppressor function linked to repression of the polycomb factor Bmi1, which normally regulates cell cycle inhibitory cyclin-dependent kinase inhibitors (cdki). It is unclear how Ras causes repression of Bmi1 in primary cells to suppress tumor formation while inducing the gene in cancer cells to drive tumor progression...
February 14, 2014: Journal of Biological Chemistry
Marco Pieraccioli, Francesca Imbastari, Alexey Antonov, Gerry Melino, Giuseppe Raschellà
Tumor progression to metastasis is a complex, sequential process that requires proliferation, resistance to apoptosis, motility and invasion to colonize at distant sites. The acquisition of these features implies a phenotypic plasticity by tumor cells that must adapt to different conditions by modulating several signaling pathways (1) during the journey to the final site of metastasis. Several transcription factors and microRNA play a role in tumor progression, but less is known about the control of their expression during this process...
July 15, 2013: Cell Cycle
Olga K Mirzoeva, Eric A Collisson, Peter M Schaefer, Byron Hann, Yun K Hom, Andrew H Ko, W Michael Korn
Mutations in the KRAS oncogene are dominant features in pancreatic ductal adenocarcinoma (PDA). Because KRAS itself is considered "undruggable," targeting pathways downstream of KRAS are being explored as a rational therapeutic strategy. We investigated the consequences of MAP-ERK kinase (MEK) inhibition in a large PDA cell line panel. Inhibition of MEK activated phosphoinositide 3-kinase in an EGF receptor (EGFR)-dependent fashion and combinations of MEK and EGFR inhibitors synergistically induced apoptosis...
October 2013: Molecular Cancer Therapeutics
Elizabeth A Guancial, Joaquim Bellmunt, Shuyuan Yeh, Jonathan E Rosenberg, David M Berman
PURPOSE: Micro ribonucleic acid (miR) expression is altered in urologic malignancies, including bladder cancer (BC). Individual miRs have been shown to modulate multiple signaling pathways that contribute to BC. We reviewed the primary literature on the role of miRs in BC; we provide a general introduction to the processing, regulation, and function of miRs as tumor suppressors and oncogenes and critically evaluate the literature on the implications of altered miR expression in BC. MATERIALS AND METHODS: We searched the English language literature for original and review articles in PubMed from 1993 to March 2013, using the terms "microRNA" and "bladder cancer," "transitional cell carcinoma," or "urothelial carcinoma...
January 2014: Urologic Oncology
Marco Pieraccioli, Francesca Imbastari, Alexey Antonov, Gerry Melino, Giuseppe Raschellà
Tumor progression to metastasis is a complex, sequential process that requires proliferation, resistance to apoptosis, motility and invasion to colonize at distant sites. The acquisition of these features implies a phenotypic plasticity by tumor cells that must adapt to different conditions by modulating several signaling pathways ( 1) during the journey to the final site of metastasis. Several transcription factors and microRNA play a role in tumor progression, but less is known about the control of their expression during this process...
June 24, 2013: Cell Cycle
Chun-Sheng Wang, Zhi-Ren Zhang, Shan-Hua Piao, Tie-Zhu An
MicroRNAs are ~22 nt long small noncoding RNA molecules that silence post-transcription gene expression. It has proven that microRNAs are widely expressed in eukaryotes and play an important role in the regulation of cell differentiation and development, growth metabolism, and many other cell activities. Induced pluripotent stem cells (iPS) are a type of pluripotent stem cells reprogrammed from somatic cells and exhibit the essential characteristics of embryonic stem cells. iPS technology has been widely applied in the biological and medical fields, and the key of it is reprogramming of somatic epigenetic state...
December 2012: Yi Chuan, Hereditas
Emma R Dorris, Paul Smyth, John J O'Leary, Orla Sheils
MicroRNAs (miRNAs) are small non-coding RNAs approximately 22 nucleotides in length that function as regulators of gene expression. Dysregulation of miRNAs has been associated with initiation and progression of oncogenesis in humans. Our group has previously described a unique miRNA expression signature, including the MIR200 family member MIR141, which can differentiate papillary thyroid cancer (PTC) cell lines from a control thyroid cell line. An investigation into the expression of MIR141 in a series of archival thyroid malignancies [n = 140; classic PTC (cPTC), follicular variant PTC, follicular thyroid carcinoma, Hashimoto thyroiditis (HT), or control thyrocytes] was performed...
2012: Frontiers in Endocrinology
Léon C van Kempen, Karin van den Hurk, Vladimir Lazar, Stefan Michiels, Véronique Winnepenninckx, Marguerite Stas, Alan Spatz, Joost J van den Oord
Loss of E-cadherin expression in melanoma correlates with increased tumor thickness and reduced disease-free survival. The molecular mechanisms underpinning its differential expression in melanoma tissue remain elusive. MicroRNAs (miRNAs) have been implicated in tumor progression and regulation of E-cadherin expression. Here, we demonstrate a significant correlation between tumor thickness and loss of expression of miR-200a, miR-200c, and miR-203 in a series of 23 frozen primary melanomas, where it was confirmed in two subsequent validation series (series 1: six nevi, 15 primary melanomas, and 16 metastases; series 2: 11 matched pairs of primary melanomas and metastases)...
October 2012: Virchows Archiv: An International Journal of Pathology
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