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pancreatic cancer microenvironment

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https://www.readbyqxmd.com/read/28705232/hypoxia-inducible-factor-2%C3%AE-promotes-tumor-progression-and-has-crosstalk-with-wnt-%C3%AE-catenin-signaling-in-pancreatic-cancer
#1
Qi Zhang, Yu Lou, Jingying Zhang, Qihan Fu, Tao Wei, Xu Sun, Qi Chen, Jiaqi Yang, Xueli Bai, Tingbo Liang
BACKGROUND: Pancreatic cancer is a devastating disease that is characterized by persistent hypoxia. The roles of hypoxia-inducible factor-2α (hif-2α) are different to those of hif-1α, although both are critical for tumor cells to adapt to the hypoxic microenvironment. However, unlike the well-studied hif-1α, the role of hif-2α in tumors, including pancreatic cancer, is poorly understood. METHODS: Herein, we used a mutated hif-2α (A530T) to figure out the problem that wild-type hif-2α is quickly degraded which limits the study of its function...
July 14, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28705007/pancreas-adenocarcinoma-novel-therapeutics
#2
Benjamin A Krantz, Kenneth H Yu, Eileen M O'Reilly
Pancreatic ductal adenocarcinoma (PDAC) is the third highest cause of cancer-related deaths in the US, and is projected to be second only to non-small cell lung cancer (NSCLC) by the 2020s. Current therapies have a modest impact on survival and median overall survival (mOS) across all stages of disease remains under a year. Over the last decade, however, great strides have been made in the understanding of PDAC pathobiology including the role of the tumor microenvironment (TME), DNA damage repair and mechanism of immunosuppression...
June 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28705002/preclinical-models-of-pancreatic-ductal-adenocarcinoma
#3
Benjamin D Krempley, Kenneth H Yu
Unlike many other cancers, pancreatic ductal adenocarcinoma (PDAC) has seen only incremental improvement in mortality despite significant advances in our understanding of the underlying biology. A primary obstacle to progress has been our inability to properly model PDAC in a preclinical setting. PDAC is difficult to study because of its genetic heterogeneity, intricate stromal microenvironment, and complex interplay with our immune system. Finding a model that properly accounts for all these criteria remains difficult...
June 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28696100/thermosensitive-liposomal-codelivery-of-hsa-paclitaxel-and-hsa-ellagic-acid-complexes-for-enhanced-drug-perfusion-and-efficacy-against-pancreatic-cancer
#4
Yan Wei, Yuxi Wang, Dengning Xia, Shiyan Guo, Feng Wang, Xinxin Zhang, Yong Gan
Fibrotic stroma and tumor-promoting pancreatic stellate cells (PSCs), critical characters in the pancreatic ductal adenocarcinoma (PDA) microenvironment, promote a tumor-facilitating environment that simultaneously prevents drug penetration into tumor foci and stimulates tumor growth. Nab-PTX, a human serum albumin (HSA) nanoparticle of paclitaxel (PTX), indicates enhanced matrix penetration in PDA probably due to its small size in vivo and high affinity of HSA with secreted protein acidic and rich in cysteine (SPARC), overexpressed in the PDA stroma...
July 24, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28694739/chemotherapy-and-tumor-microenvironment-of-pancreatic-cancer
#5
REVIEW
Qiaofei Liu, Quan Liao, Yupei Zhao
Pancreatic cancer is an extremely dismal malignance. Chemotherapy has been widely applied to treat this intractable tumor. It has exclusive tumor microenvironment (TME), characterized by dense desmoplasia and profound infiltrations of immunosuppressive cells. Interactions between stromal cells and cancer cells play vital roles to affect the biological behaviors of pancreatic cancer. Targeting the stromal components of pancreatic cancer has shown promising results. In addition to the direct toxic effects of chemotherapeutic drugs on cancer cells, they can also remodel the TME, eventually affecting their efficacy...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28692661/the-extracellular-matrix-and-focal-adhesion-kinase-signaling-regulate-cancer-stem-cell-function-in-pancreatic-ductal-adenocarcinoma
#6
Asma Begum, Theodore Ewachiw, Clinton Jung, Ally Huang, K Jessica Norberg, Luigi Marchionni, Ross McMillan, Vesselin Penchev, N V Rajeshkumar, Anirban Maitra, Laura Wood, Chenguang Wang, Christopher Wolfgang, Ana DeJesus-Acosta, Daniel Laheru, Irina M Shapiro, Mahesh Padval, Jonathan A Pachter, David T Weaver, Zeshaan A Rasheed, William Matsui
Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28688208/human-profilin-1-is-a-negative-regulator-of-ctl-mediated-cell-killing-and-migration
#7
Rouven Schoppmeyer, Renping Zhao, He Cheng, Mohamed Hamed, Chen Liu, Xiao Zhou, Eva C Schwarz, Yan Zhou, Arne Knörck, Gertrud Schwär, Shunrong Ji, Liang Liu, Jiang Long, Volkhard Helms, Markus Hoth, Xianjun Yu, Bin Qu
The actin-binding protein profilin1 (PFN1) plays a central role in actin dynamics, which is essential for cytotoxic T lymphocyte (CTL) functions. The functional role of PFN1 in CTLs, however still remains elusive. Here, we identify PFN1 as the only member of the profilin family expressed in primary human CD8(+) T cells. Using in vitro assays, we find that PFN1 is a negative regulator of CTL-mediated elimination of target cells. Furthermore, PFN1 is involved in activation-induced lytic granule (LG) release, CTL migration and modulation of actin structures at the immunological synapse (IS)...
July 8, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28673320/the-clinical-importance-of-tumour-infiltrating-macrophages-and-dendritic-cells-in-periampullary-adenocarcinoma-differs-by-morphological-subtype
#8
Sebastian Lundgren, Emelie Karnevi, Jacob Elebro, Björn Nodin, Mikael C I Karlsson, Jakob Eberhard, Karin Leandersson, Karin Jirström
BACKGROUND: Dendritic cells (DC) and tumour-associated macrophages (TAM) are essential in linking the innate and adaptive immune response against tumour cells and tumour progression. These cells are also potential target for immunotherapy as well as providing a handle to investigate immune status in the tumour microenvironment. The aim of the present study was to examine their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological subtype...
July 3, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28668832/imaging-the-role-of-multinucleate-pancreatic-cancer-cells-and-cancer-associated-fibroblasts-in-peritoneal-metastasis-in-mouse-models
#9
Kosuke Hasegawa, Atsushi Suetsugu, Miki Nakamura, Takuro Matsumoto, Hitomi Aoki, Takahiro Kunisada, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Robert M Hoffman
BACKGROUND/AIM: The interaction between pancreatic-cancer cells and stromal cells in the tumor microenvironment (TME) is of particular importance in cancer progression and metastasis. The present report demonstrates the role of cancer-associated fibroblasts (CAFs) and multinucleate pancreatic-cancer cells in peritoneal metastasis. MATERIALS AND METHODS: An orthotopic mouse model of pancreatic cancer was established with the human pancreatic cancer cell line BxPC3, which stably expresses green fluorescent protein (GFP)...
July 2017: Anticancer Research
https://www.readbyqxmd.com/read/28662901/sonic-hedgehog-pathway-inhibition-normalizes-desmoplastic-tumor-microenvironment-to-improve-chemo-and-nanotherapy
#10
Fotios Mpekris, Panagiotis Papageorgis, Christiana Polydorou, Chrysovalantis Voutouri, Maria Kalli, Athanassios P Pirentis, Triantafyllos Stylianopoulos
Targeting the rich extracellular matrix of desmoplastic tumors has been successfully shown to normalize collagen and hyaluronan levels and re-engineer intratumoral mechanical forces, improving tumor perfusion and chemotherapy. As far as targeting the abundant cancer-associated fibroblasts (CAFs) in desmoplastic tumors is concerned, while both pharmacologic inhibition of the sonic-hedgehog pathway and genetic depletion of fibroblasts have been employed in pancreatic cancers, the results between the two methods have been contradictory...
June 27, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28656348/pap-reg3a-favors-perineural-invasion-in-pancreatic-adenocarcinoma-and-serves-as-a-prognostic-marker
#11
Jérémy Nigri, Meritxell Gironella, Christian Bressy, Elena Vila-Navarro, Julie Roques, Sophie Lac, Caroline Bontemps, Coraline Kozaczyk, Jérôme Cros, Daniel Pietrasz, Raphaël Maréchal, Jean-Luc Van Laethem, Juan Iovanna, Jean-Baptiste Bachet, Emma Folch-Puy, Richard Tomasini
Pancreatic ductal adenocarcinoma (PDA) is a fatal and insidious malignant disease for which clinicians' tools are restricted by the current limits in knowledge of how tumor and stromal cells act during the disease. Among PDA hallmarks, neural remodeling (NR) and perineural invasion (PNI) drastically influence quality of life and patient survival. Indeed, NR and PNI are associated with neuropathic pain and metastasis, respectively, both of which impact clinicians' decisions and therapeutic options. The aim of this study was to determine the impact and clinical relevance of the peritumoral microenvironment, through pancreatitis-associated protein (PAP/REG3A) expression, on PNI in pancreatic cancer...
June 27, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28652266/long-non-coding-rna-jhdm1d-as1-promotes-tumor-growth-by-regulating-angiogenesis-in-response-to-nutrient-starvation
#12
Ayano Kondo, Aya Nonaka, Teppei Shimamura, Shogo Yamamoto, Tetsuo Yoshida, Tatsuhiko Kodama, Hiroyuki Aburatani, Tsuyoshi Osawa
Long non-coding RNAs play a pivotal role in tumor progression, but their role in cancer cells in the nutrient-starved tumor microenvironment remains unknown. Here, we show that a nutrient starvation-responsive long non-coding RNA, JHDM1D antisense 1 (JHDM1D-AS1), promotes tumorigenesis by regulating angiogenesis in response to nutrient starvation. Expression of JHDM1D-AS1 was increased in cancer cells. In addition, expression of JHDM1D-AS1 was increased in clinical tumor samples compared to that in normal tissue...
June 26, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28652247/posttranscriptional-upregulation-of-idh1-by-hur-establishes-a-powerful-survival-phenotype-in-pancreatic-cancer-cells
#13
Mahsa Zarei, Shruti Lal, Seth J Parker, Avinoam Nevler, Ali Vaziri-Gohar, Katerina Dukleska, Nicole C Mambelli-Lisboa, Cynthia Moffat, Fernando F Blanco, Saswati N Chand, Masaya Jimbo, Joseph A Cozzitorto, Wei Jiang, Charles J Yeo, Eric Londin, Erin L Seifert, Christian M Metallo, Jonathan R Brody, Jordan M Winter
Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDA). Glucose or glutamine withdrawal resulted in a 5-10-fold protective effect with chemotherapy treatment. PDA xenografts were less sensitive to gemcitabine in hypoglycemic mice compared to hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n=107) with elevated serum glucose levels (HgbA1C>6...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28638792/immunotherapy-in-pancreatic-cancer-unleash-its-potential-through-novel-combinations
#14
REVIEW
Songchuan Guo, Merly Contratto, George Miller, Lawrence Leichman, Jennifer Wu
Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States, with poor response to current standard of care, short progression-free and overall survival. Immunotherapies that target cytotoxic T lymphocyte antigen-4, programmed cell death protein-1, and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma, renal cell carcinoma, and non-small cell lung cancer due to high numbers of somatic mutations, combined with cytotoxic T-cell responses...
June 10, 2017: World Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28631007/how-schwann-cells-facilitate-cancer-progression-in-nerves
#15
REVIEW
Sylvie Deborde, Richard J Wong
Recent studies have demonstrated a critical role for nerves in enabling tumor progression. The association of nerves with cancer cells is well established for a variety of malignant tumors, including pancreatic, prostate and the head and neck cancers. This association is often correlated with poor prognosis. A strong partnership between cancer cells and nerve cells leads to both cancer progression and expansion of the nerve network. This relationship is supported by molecular pathways related to nerve growth and repair...
June 19, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28628715/overcoming-the-resistance-of-pancreatic-cancer-to-immune-checkpoint-inhibitors
#16
REVIEW
Richard A Skelton, Ammar Javed, Lei Zheng, Jin He
Immunotherapy has become a new modality of cancer treatment, but has had a limited success in treating PDAC. A combination approach to immunotherapy, using both immune checkpoint inhibitors and immune activating agonists, is needed, as PDAC does not respond to single-agent checkpoint inhibitors. Studies have also supported using vaccine-based therapies to prime the tumor microenvironment of PDAC with effector T-cells. Other therapeutic strategies including epigenetic agents, stroma modulators, radiotherapy, and T-cell transfer therapies may also prime the tumor microenvironment to overcome resistance to immune checkpoint inhibitors...
July 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28626793/acidic-ph-targeted-chitosan-capped-mesoporous-silica-coated-gold-nanorods-facilitate-detection-of-pancreatic-tumors-via-multispectral-optoacoustic-tomography
#17
Matthew R Zeiderman, Desiree E Morgan, John D Christein, William E Grizzle, Kelly M McMasters, Lacey R McNally
We present a cancer nanomedicine based on acidic pH targeted gold nanorods designed for multispectral optoacoustic tomography (MSOT). We have designed gold nanorods coated with mesoporous silica and subsequently capped with chitosan (CMGs). We have conjugated pH-sensitive variant 7 pHLIP peptide to the CMGs (V7-CMG) to provide targeting specificity to the acidic tumor microenvironment. In vitro, treatment of S2VP10 and MiaPaca2 cells with V7-CMG containing gemcitabine resulted in significantly greater cytotoxicity with 97% and 96...
July 11, 2016: ACS Biomaterials Science & Engineering
https://www.readbyqxmd.com/read/28620142/magnetic-resonance-imaging-of-rrx-001-pharmacodynamics-in-preclinical-tumors
#18
Natarajan Raghunand, Jan Scicinski, Gerald P Guntle, Bhumasamudram Jagadish, Eugene A Mash, Elizabeth Bruckheimer, Bryan Oronsky, Ronald L Korn
RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing's Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd-LC7-SH to the Cys34 residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI and in vivo T1 maps acquired 50 min (T150 min) after injection of 0...
June 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28615524/interleukin-15-stimulates-natural-killer-cell-mediated-killing-of-both-human-pancreatic-cancer-and-stellate-cells
#19
Jonas R M Van Audenaerde, Jorrit De Waele, Elly Marcq, Jinthe Van Loenhout, Eva Lion, Johan M J Van den Bergh, Ralf Jesenofsky, Atsushi Masamune, Geert Roeyen, Patrick Pauwels, Filip Lardon, Marc Peeters, Evelien L J Smits
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC)...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611425/pancreatic-adenocarcinoma-response-to-chemotherapy-enhanced-with-non-invasive-radio-frequency-evaluated-via-an-integrated-experimental-computational-approach
#20
Matthew J Ware, Louis T Curtis, Min Wu, Jason C Ho, Stuart J Corr, Steven A Curley, Biana Godin, Hermann B Frieboes
Although chemotherapy combined with radiofrequency exposure has shown promise in cancer treatment by coupling drug cytotoxicity with thermal ablation or thermally-induced cytotoxicity, limited access of the drug to tumor loci in hypo-vascularized lesions has hampered clinical application. We recently showed that high-intensity short-wave capacitively coupled radiofrequency (RF) electric-fields may reach inaccessible targets in vivo. This non-invasive RF combined with gemcitabine (Gem) chemotherapy enhanced drug uptake and effect in pancreatic adenocarcinoma (PDAC), notorious for having poor response and limited therapeutic options, but without inducing thermal injury...
June 13, 2017: Scientific Reports
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