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pancreatic cancer microenvironment

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https://www.readbyqxmd.com/read/28105371/unfolding-anti-tumor-immunity-er-stress-responses-sculpt-tolerogenic-myeloid-cells-in-cancer
#1
REVIEW
Juan R Cubillos-Ruiz, Eslam Mohamed, Paulo C Rodriguez
Established tumors build a stressful and hostile microenvironment that blocks the development of protective innate and adaptive immune responses. Different subsets of immunoregulatory myeloid populations, including dendritic cells, myeloid-derived suppressor cells (MDSCs) and macrophages, accumulate in the stressed tumor milieu and represent a major impediment to the success of various forms of cancer immunotherapy. Specific conditions and factors within tumor masses, including hypoxia, nutrient starvation, low pH, and increased levels of free radicals, provoke a state of "endoplasmic reticulum (ER) stress" in both malignant cells and infiltrating myeloid cells...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28099006/constituents-of-the-rhizomes-of-boesenbergia-pandurata-and-their-antiausterity-activities-against-the-panc-1-human-pancreatic-cancer-line
#2
Nhan Trung Nguyen, Mai Thanh Thi Nguyen, Hai Xuan Nguyen, Phu Hoang Dang, Dya Fita Dibwe, Hiroyasu Esumi, Suresh Awale
Human pancreatic cancer cell lines have a remarkable tolerance to nutrition starvation, which enables them to survive under a tumor microenvironment. The search for agents that preferentially inhibit the survival of cancer cells under low nutrient conditions represents a novel antiausterity strategy in anticancer drug discovery. In this investigation, a methanol extract of the rhizomes of Boesenbergia pandurata showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 6...
January 18, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28097809/cancer-associated-fibroblasts-promote-m2-polarization-of-macrophages-in-pancreatic-ductal-adenocarcinoma
#3
Aibin Zhang, Yigang Qian, Zhou Ye, Haiyong Chen, Haiyang Xie, Lin Zhou, Yan Shen, Shusen Zheng
Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia with infiltration of distinct cellular components. Cancer-associated fibroblasts (CAFs) has been shown to be among the most prominent cells and played a significant role in shaping the tumor microenvironment by interacting with other type of cells. Here, we aimed to investigate the effect of CAFs in modulating phenotype of tumor-associated macrophages (TAM). Under treatment of CAFs conditioned medium (CM) or direct co-culture with CAFs, monocytes exhibited enhanced expression of CD206 and CD163 compared with control group (P < 0...
January 18, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28096419/stromal-cues-regulate-the-pancreatic-cancer-epigenome-and-metabolome
#4
Mara H Sherman, Ruth T Yu, Tiffany W Tseng, Cristovao M Sousa, Sihao Liu, Morgan L Truitt, Nanhai He, Ning Ding, Christopher Liddle, Annette R Atkins, Mathias Leblanc, Eric A Collisson, John M Asara, Alec C Kimmelman, Michael Downes, Ronald M Evans
A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28092668/upregulation-of-ret-induces-perineurial-invasion-of-pancreatic-adenocarcinoma
#5
M Amit, S Na'ara, L Leider-Trejo, Y Binenbaum, N Kulish, E Fridman, A Shabtai-Orbach, R J Wong, Z Gil
Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28090321/gm-csf-signalling-blockade-and-chemotherapeutic-agents-act-in-concert-to-inhibit-the-function-of-myeloid-derived-suppressor-cells-in-vitro
#6
Tessa Gargett, Susan N Christo, Timothy R Hercus, Nazim Abbas, Nimit Singhal, Angel F Lopez, Michael P Brown
Immune evasion is a recently defined hallmark of cancer, and immunotherapeutic approaches that stimulate an immune response to tumours are gaining recognition. However tumours may evade the immune response and resist immune-targeted treatment by promoting an immune-suppressive environment and stimulating the differentiation or recruitment of immunosuppressive cells. Myeloid-derived suppressor cells (MDSC) have been identified in a range of cancers and are often associated with tumour progression and poor patient outcomes...
December 2016: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/28077438/fibroblast-drug-scavenging-increases-intratumoural-gemcitabine-accumulation-in-murine-pancreas-cancer
#7
E Hessmann, M S Patzak, L Klein, N Chen, V Kari, I Ramu, T E Bapiro, K K Frese, A Gopinathan, F M Richards, D I Jodrell, C Verbeke, X Li, R Heuchel, J M Löhr, S A Johnsen, T M Gress, V Ellenrieder, A Neesse
OBJECTIVE: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery. DESIGN: Gemcitabine metabolites were analysed in LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry...
January 10, 2017: Gut
https://www.readbyqxmd.com/read/28073003/employing-metabolism-to-improve-the-diagnosis-and-treatment-of-pancreatic-cancer
#8
REVIEW
Christopher J Halbrook, Costas A Lyssiotis
Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28069592/mir-142-modulates-human-pancreatic-cancer-proliferation-and-invasion-by-targeting-hypoxia-inducible-factor-1-hif-1%C3%AE-in-the-tumor-microenvironments
#9
Yebin Lu, Niandong Ji, Wei Wei, Weijia Sun, Xuejun Gong, Xitao Wang
MicroRNAs regulate most protein-coding genes, including genes important in cancer and other diseases. In our study, we demonstrated that the expression of miR-142 could be significantly suppressed in pancreatic cancer specimens and cell lines, comparing to their adjacent tissues and normal pancreatic cells. Growth and invasion of PANC-1 and SW1990 cells were attenuated by overexpression of miR-142 in vitro With the help of bioinformatics analysis, hypoxia-inducible factor 1 (HIF-1α) was identified to be a direct target of miR-142, and luciferase reporter experiment confirmed this discovery...
January 9, 2017: Biology Open
https://www.readbyqxmd.com/read/28053127/potent-emt-and-csc-phenotypes-are-induced-by-oncostatin-m-in-pancreatic-cancer
#10
Jacob M Smigiel, Neetha Parameswaran, Mark W Jackson
: Pancreatic ductal adenocarcinoma (PDAC) is referred to as a silent killer due to the lack of clear symptoms, a lack of early detection methods, and a high frequency of metastasis at diagnosis. In addition, pancreatic cancer is remarkably resistant to chemotherapy, and clinical treatment options remain limited. The tumor microenvironment (TME) and associated factors are important determinants of metastatic capacity and drug resistance. Here, oncostatin M (OSM), an IL-6 cytokine family member, was identified as an important driver of mesenchymal and cancer stem cell (CSC) phenotypes...
January 4, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28034553/microenvironment-in-determining-chemo-resistance-in-pancreatic-cancer-neighborhood-matters
#11
REVIEW
Patricia Dauer, Alice Nomura, Ashok Saluja, Sulagna Banerjee
Every year, nearly 300,000 people are diagnosed with pancreatic cancer worldwide, and an equivalent number succumb to this disease. One of the major challenges of pancreatic cancer that contributes to its poor survival rates is the development of resistance to the standard chemotherapy. Heterogeneity of the tumor, the dense fibroblastic stroma, and the aggressive biology of the tumor all contribute to the chemoresistant phenotype. In addition, the acellular components of the tumor microenvironment like hypoxia, stress pathways in the stromal cells, and the cytokines that are secreted by the immune cells, have a definitive role in orchestrating the chemoresistant property of the tumor...
December 23, 2016: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
https://www.readbyqxmd.com/read/28024339/using-gold-nanoparticles-to-disrupt-the-tumor-microenvironment-an-emerging-therapeutic-strategy
#12
Jilian R Melamed, Rachel S Riley, Danielle M Valcourt, Emily S Day
Gold nanoparticles have received much attention recently as carriers for anticancer drugs and therapeutic oligonucleotides, but little research has investigated their potential to act as stand-alone therapeutics. Previous studies interrogating their short- and long-term systemic toxicity have found that although gold nanoparticles accumulate within and clear slowly from the liver and spleen, they do not appear to exert toxic effects in these organs. Interestingly, gold nanoparticles innately exhibit the ability to modulate the tumor microenvironment specifically by interfering with crosstalk between tumor cells and stromal cells...
December 27, 2016: ACS Nano
https://www.readbyqxmd.com/read/28024135/-pancreatic-cancer-microenvironment
#13
REVIEW
Krzysztof Dąbkowski, Barbara Bogacka, Maciej Tarnowski, Teresa Starzyńska
Pancreatic cancer remains one of the deadliest solid tumors in humans and an unsolved problem of today's medicine. Experimental studies reveal that the heterogeneous and complex pancreatic cancer microenvironment is responsible, not only for cancer growth, spread, development of metastases, but also for cancer recurrence and chemotherapy resistance. Chemotherapy affecting the cancer stroma is still under clinical and experimental research and remains hope for cure of pancreatic cancer. We present the cancer microenvironment characteristics and summary of experimental studies with use of agents affecting pancreatic cancer stroma...
December 22, 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
https://www.readbyqxmd.com/read/28008233/folic-acid-conjugated-amphiphilic-alternating-copolymer-as-a-new-active-tumor-targeting-drug-delivery-platform
#14
Xia Li, Myron R Szewczuk, Cecile Malardier-Jugroot
Targeted drug delivery using polymeric nanostructures is an emerging cancer research area, engineered for safer, more efficient, and effective use of chemotherapeutic drugs. A pH-responsive, active targeting delivery system was designed using folic acid functionalized amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA). The polymeric template is pH responsive, forming amphiphilic nanostructures at pH 7, allowing the encapsulation of hydrophobic drugs on its interior...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27999205/muty-homolog-myh-inhibition-reduces-pancreatic-cancer-cell-growth-and-increases-chemosensitivity
#15
George Sharbeen, Janet Youkhana, Amanda Mawson, Joshua McCarroll, Andrea Nunez, Andrew Biankin, Amber Johns, David Goldstein, Phoebe Phillips
Patients with pancreatic ductal adenocarcinoma (PC) have a poor prognosis due to metastases and chemoresistance. PC is characterized by extensive fibrosis, which creates a hypoxic microenvironment, and leads to increased chemoresistance and intracellular oxidative stress. Thus, proteins that protect against oxidative stress are potential therapeutic targets for PC. A key protein that maintains genomic integrity against oxidative damage is MutY-Homolog (MYH). No prior studies have investigated the function of MYH in PC cells...
December 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27991933/cancer-foxp3-directly-activated-ccl5-to-recruit-foxp3-treg-cells-in-pancreatic-ductal-adenocarcinoma
#16
X Wang, M Lang, T Zhao, X Feng, C Zheng, C Huang, J Hao, J Dong, L Luo, X Li, C Lan, W Yu, M Yu, S Yang, H Ren
Forkheadbox protein 3 (FOXP3), initially identified as a key transcription factor for regulatory T cells (Treg cells), was also expressed in many tumors including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC progression remains elusive. In this study, we utilized 120 PDAC tissues after radical resection to detect cancer-FOXP3 and Treg cells by immunohistochemistry and evaluated clinical and pathological features of these patients. Cancer-FOXP3 was positively correlated with Treg cells accumulation in tumor tissues derived from PDAC patients...
December 19, 2016: Oncogene
https://www.readbyqxmd.com/read/27987431/acriflavine-inhibits-acquired-drug-resistance-by-blocking-the-epithelial-to-mesenchymal-transition-and-the-unfolded-protein-response
#17
Jeroen Dekervel, Ashenafi Bulle, Petra Windmolders, Diether Lambrechts, Eric Van Cutsem, Chris Verslype, Jos van Pelt
: Epithelial-to-mesenchymal transition (EMT) is linked to tumor invasion, drug resistance and aggressive disease and this is largely dependent on the cell's microenvironment. Acriflavine (ACF) is an old antibacterial drug recently also suggested as anticancer agent and HIF inhibitor. We wanted to study the effect of acriflavine on EMT in different human cancer models. Pancreatic cancer cells (Panc-1) were exposed to TGF-β1 or cobalt chloride (to mimick severe hypoxia) to induce EMT. For our third model we exposed HepG2 liver cancer cells to sorafenib which resulted in development of acquired drug resistance with strong features of EMT and aggressive behavior...
December 14, 2016: Translational Oncology
https://www.readbyqxmd.com/read/27941651/toll-like-receptor-2-4-and-9-signaling-promotes-autoregulative-tumor-cell-growth-and-vegf-pdgf-expression-in-human-pancreatic-cancer
#18
Tanja Grimmig, Romana Moench, Jennifer Kreckel, Stephanie Haack, Felix Rueckert, Roberta Rehder, Sudipta Tripathi, Carmen Ribas, Anil Chandraker, Christoph T Germer, Martin Gasser, Ana Maria Waaga-Gasser
Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers...
December 8, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27939096/focal-adhesion-kinase-a-promising-therapeutic-target-in-pancreatic-adenocarcinoma
#19
Emilie Decaup, Julia Rochotte, Stéphane Pyronnet, Corinne Bousquet, Christine Jean
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly cancer, characterized by a uniquely immunosuppressive and fibrotic microenvironment responsible for its high chemoresistance. Jiang et al. identify FAK (focal adhesion kinase) activity as an interesting therapeutic target, the inhibition of which drastically reduces PDAC microenvironment deleterious features. In combination with gemcitabine and immune-checkpoint therapy, FAK inhibitor promotes long-term tumor stasis with extended survival in PDAC mouse models...
December 6, 2016: Clinics and Research in Hepatology and Gastroenterology
https://www.readbyqxmd.com/read/27936345/targeting-integrin-linked-kinase-to-suppress-oncogenic-kras-signaling-in-pancreatic-cancer
#20
Po-Chen Chu, Samuel K Kulp, Tanios Bekaii-Saab, Ching-Shih Chen
Although oncogenic KRAS represents a therapeutically relevant target in pancreatic cancer, it is deemed "non-druggable" because of the intrinsic difficulty in designing direct inhibitors of KRAS. Our recent work demonstrated a KRAS-integrin-linked kinase (ILK) regulatory feedback loop that allows pancreatic cancer cells to regulate KRAS expression and to interact with the tumor microenvironment to promote aggressive phenotype. KRAS induces E2F1-mediated transcriptional activation of ILK expression, and ILK, in turn, controls KRAS expression via hnRNPA1, which binds and destabilizes the G-quadruplex in the KRAS promoter...
December 9, 2016: Small GTPases
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