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pancreatic cancer PSCs

Sounik Saha, Xunhao Xiong, Prabir K Chakraborty, Khader Shameer, Rochelle R Arvizo, Rachel A Kudgus, Shailendra Kumar Dhar Dwivedi, Md Nazir Hossen, Elizabeth M Gillies, J David Robertson, Joel T Dudley, Raul A Urrutia, Russell G Postier, Resham Bhattacharya, Priyabrata Mukherjee
Altered tumor microenvironment (TME) arising from a bidirectional crosstalk between the pancreatic cancer cells (PCCs) and the pancreatic stellate cells (PSCs) is implicated in the dismal prognosis in pancreatic ductal adenocarcinoma (PDAC), yet effective strategies to disrupt the crosstalk is lacking. Here, we demonstrate that gold nanoparticles (AuNPs) inhibit proliferation and migration of both PCCs and PSCs by disrupting the bidirectional communication via alteration of the cell secretome. Analyzing the key proteins identified from a functional network of AuNP-altered secretome in PCCs and PSCs, we demonstrate that AuNPs impair secretions of major hub node proteins in both cell types and transform activated PSCs toward a lipid-rich quiescent phenotype...
October 19, 2016: ACS Nano
Yang Liu, Fan Li, Feng Gao, Lingxi Xing, Peng Qin, Xingxin Liang, Jiajie Zhang, Xiaohui Qiao, Lizhou Lin, Qian Zhao, Lianfang Du
Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths. The nucleoside analog gemcitabine has been the cornerstone of adjuvant chemotherapy in PDAC for decades. However, gemcitabine resistance develops within weeks of chemotherapy initiation, which might be intrinsic to cancer cells and influenced by tumor microenvironment. Recently, pancreatic stellate cells (PSCs) have greatly increased our attention on tumor microenvironment-mediated drug resistance. Periostin is exclusively overexpressed in PSCs and the stroma of PDAC creating a tumor-supportive microenvironment in the pancreas...
September 30, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Benedikt Fels, Nikolaj Nielsen, Albrecht Schwab
The tumor environment contributes importantly to tumor cell behavior and cancer progression. Aside from biochemical constituents, physical factors of the environment also influence the tumor. Growing evidence suggests that mechanics [e.g., tumor (stroma) elasticity, tissue pressure] are critical players of cancer progression. Underlying mechanobiological mechanisms involve among others the regulation of focal adhesion molecules, cytoskeletal modifications, and mechanosensitive (MS) ion channels of cancer- and tumor-associated cells...
October 2016: European Biophysics Journal: EBJ
Matthew J Ware, Vazrik Keshishian, Justin J Law, Jason C Ho, Carlos A Favela, Paul Rees, Billie Smith, Sayeeduddin Mohammad, Rosa F Hwang, Kimal Rajapakshe, Cristian Coarfa, Shixia Huang, Dean P Edwards, Stuart J Corr, Biana Godin, Steven A Curley
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic/stromal reaction, which contributes to the poor clinical outcome of this disease. Therefore, greater understanding of the stroma development and tumor-stroma interactions is highly required. Pancreatic stellate cells (PSC) are myofibroblast-like cells located in exocrine areas of the pancreas, which as a result of inflammation produced by PDAC migrate and accumulate in the tumor mass, secreting extracellular matrix components and producing the dense PDAC stroma...
November 2016: Biomaterials
Courey Averett, Arun Bhardwaj, Sumit Arora, Sanjeev K Srivastava, Mohammad Aslam Khan, Aamir Ahmad, Seema Singh, James E Carter, Moh'd Khushman, Ajay P Singh
The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases...
September 8, 2016: Carcinogenesis
Rachel A Hesler, Jennifer J Huang, Mark D Starr, Victoria M Treboschi, Alyssa G Bernanke, Andrew B Nixon, Shannon J McCall, Rebekah R White, Gerard C Blobe
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. While low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3...
September 7, 2016: Carcinogenesis
Nagaraj S Nagathihalli, Jason A Castellanos, Michael N VanSaun, Xizi Dai, Mahogany Ambrose, Qiaozhi Guo, Yanhua Xiong, Nipun B Merchant
Pancreatic ductal adenocarcinoma (PDAC) is a dynamic tumor supported by several stromal elements such as pancreatic stellate cells (PSC). Significant crosstalk exists between PSCs and tumor cells to stimulate oncogenic signaling and malignant progression of PDAC. However, how PSCs activate intercellular signaling in PDAC cells remains to be elucidated. We have previously shown that activated signal transducer and activator of transcription 3 (STAT3) signaling is a key component in the progression of pancreatic neoplasia...
September 1, 2016: Oncotarget
Antonios Chronopoulos, Benjamin Robinson, Muge Sarper, Ernesto Cortes, Vera Auernheimer, Dariusz Lachowski, Simon Attwood, Rebeca García, Saba Ghassemi, Ben Fabry, Armando Del Río Hernández
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models...
2016: Nature Communications
Wei-Wei Zhang, Shu-Hui Zhan, Chang-Xin Geng, Xin Sun, Mert Erkan, Jörg Kleeff, Xiang-Jun Xie
Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a transmembrane glycoprotein that is involved in tumor progression and metastasis. In the present study, the expression and functional role of ALCAM in pancreatic cancer cells and pancreatic stellate cells (PSCs) was investigated. Tissue specimens were obtained from patients with pancreatic ductal adenocarcinoma (n=56) or chronic pancreatitis (CP; n=10), who underwent pancreatic resection, and from normal pancreatic tissue samples (n=10). Immunohistochemistry was used to analyze the localization and expression of ALCAM in pancreatic tissues...
October 2016: Molecular Medicine Reports
Yang Liu, Fan Li, Feng Gao, Lingxi Xing, Peng Qin, Xingxin Liang, Jiajie Zhang, Xiaohui Qiao, Lizhou Lin, Qian Zhao, Lianfang Du
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic reaction. Pancreatic stellate cells (PSCs) are the principal effector cells responsible for stroma production. Aberrant up-regulation of periostin expression has been reported in activated PSCs. In this study, we investigated the role of periostin and the mechanisms underlying its aberrant upregulation in PDAC. We used lentiviral shRNA and human recombinant periostin protein to down and up regulate periostin expression in vitro...
August 23, 2016: Oncotarget
Andrea Giannuzzo, Mara Saccomano, Joanna Napp, Maria Ellegaard, Frauke Alves, Ivana Novak
The ATP-gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC...
December 1, 2016: International Journal of Cancer. Journal International du Cancer
Cristovão M Sousa, Douglas E Biancur, Xiaoxu Wang, Christopher J Halbrook, Mara H Sherman, Li Zhang, Daniel Kremer, Rosa F Hwang, Agnes K Witkiewicz, Haoqiang Ying, John M Asara, Ronald M Evans, Lewis C Cantley, Costas A Lyssiotis, Alec C Kimmelman
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)...
August 25, 2016: Nature
Monika A Jakubowska, Pawel E Ferdek, Oleg V Gerasimenko, Julia V Gerasimenko, Ole H Petersen
The mammalian diffuse stellate cell system comprises retinoid-storing cells capable of remarkable transformations from a quiescent to an activated myofibroblast-like phenotype. Activated pancreatic stellate cells (PSCs) attract attention owing to the pivotal role they play in development of tissue fibrosis in chronic pancreatitis and pancreatic cancer. However, little is known about the actual role of PSCs in the normal pancreas. These enigmatic cells have recently been shown to respond to physiological stimuli in a manner that is markedly different from their neighbouring pancreatic acinar cells (PACs)...
August 2016: Open Biology
Masaki Yoshida, Yoshihiro Miyasaka, Kenoki Ohuchida, Takashi Okumura, Biao Zheng, Nobuhiro Torata, Hayato Fujita, Toshinaga Nabae, Tatsuya Manabe, Masaya Shimamoto, Takao Ohtsuka, Kazuhiro Mizumoto, Masafumi Nakamura
Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several anti-fibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting anti-fibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model...
August 3, 2016: Cancer Science
Vegard Tjomsland, Eva Pomianowska, Monica Aasrum, Dagny Sandnes, Caroline Sophie Verbeke, Ivar Prydz Gladhaug
Pancreatic ductal adenocarcinoma is characterized by a prominent fibroinflammatory stroma with both tumor-promoting and tumor-suppressive functions. The pancreatic stellate cell (PSC) is the major cellular stromal component and the main producer of extracellular matrix proteins, including collagens, which are degraded by metalloproteinases (MMPs). PSCs interact with cancer cells through various factors, including transforming growth factor (TGF)β and interleukin (IL)-1α. The role of TGFβ in the dual nature of tumor stroma, i...
July 2016: Neoplasia: An International Journal for Oncology Research
Na Li, Yang Li, Zengxun Li, Chongbiao Huang, Yanhui Yang, Mingxiao Lang, Junli Cao, Wenna Jiang, Yu Xu, Jie Dong, He Ren
Hypoxia inducible factor 1 (HIF-1) is a transcription factor composed of two subunits, namely, HIF-1α and HIF-1β, in which HIF-1β is constitutively expressed. HIF-1 upregulates several hypoxia-responsive proteins, including angiogenesis factors, glycolysis solution enzymes, and cell survival proteins. HIF-1 is also associated with the degree of inflammation in the tumor region, but the exact mechanism remains unclear. This study aims to identify the molecular mechanism of recruiting monocytes/macrophages by HIF-1α in pancreatic ductal adenocarcinoma (PDAC) and the effects of macrophages on pancreatic stellate cells (PSCs)...
2016: International Journal of Molecular Sciences
Sujit Suklabaidya, Biswajit Das, Syed Azmal Ali, Sumeet Jain, Sharada Swaminathan, Ashok K Mohanty, Susen K Panda, Pujarini Dash, Subhankar Chakraborty, Surinder K Batra, Shantibhusan Senapati
Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC...
May 31, 2016: Oncotarget
Osama Al-Assar, Martin-Immanuel Bittner, Serena Lunardi, Michael R Stratford, W Gillies McKenna, Thomas B Brunner
AIMS: We have previously shown in a phase I trial that nelfinavir (NFV) is safe with chemoradiation in PDAC with good signs for efficacy. Reverse translationally, we aimed to test the influence of PSCs on nelfinavir mediated radiosensitization to PDAC preclinically, because PDAC is very rich in desmoplasia and PSCs are known to mediate radioresistance. METHODS: In a direct co-culture model of several PDAC cell lines with PSC we performed clonogenic assays +/- nelfinavir...
May 2016: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Arun Bhardwaj, Sanjeev K Srivastava, Seema Singh, Nikhil Tyagi, Sumit Arora, James E Carter, Moh'd Khushman, Ajay P Singh
Extensive desmoplasia is a prominent pathological characteristic of pancreatic cancer (PC) that not only impacts tumor development, but therapeutic outcome as well. Recently, we demonstrated a novel role of MYB, an oncogenic transcription factor, in PC growth and metastasis. Here we studied its effect on pancreatic tumor histopathology and associated molecular and biological mechanisms. Tumor-xenografts derived from orthotopic-inoculation of MYB-overexpressing PC cells exhibited far-greater desmoplasia in histological analyses compared with those derived from MYB-silenced PC cells...
July 29, 2016: Journal of Biological Chemistry
Joao Incio, Hao Liu, Priya Suboj, Shan M Chin, Ivy X Chen, Matthias Pinter, Mei R Ng, Hadi T Nia, Jelena Grahovac, Shannon Kao, Suboj Babykutty, Yuhui Huang, Keehoon Jung, Nuh N Rahbari, Xiaoxing Han, Vikash P Chauhan, John D Martin, Julia Kahn, Peigen Huang, Vikram Desphande, James Michaelson, Theodoros P Michelakos, Cristina R Ferrone, Raquel Soares, Yves Boucher, Dai Fukumura, Rakesh K Jain
UNLABELLED: It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy...
August 2016: Cancer Discovery
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