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M2 macrophage + Pancreatic cancer

Aino Salmiheimo, Harri Mustonen, Sanna Vainionpää, Zhanlong Shen, Esko Kemppainen, Pauli Puolakkainen, Hanna Seppänen
OBJECTIVES: Tumour-associated macrophages participate in tumour development and progression. The aim of this study was to assess the interactions of pancreatic cancer cells and pro-inflammatory M1 and anti-inflammatory M2 macrophages, specifically their effect on pancreatic cancer cell migration and the changes in STAT-signalling. METHODS: Monocytes were isolated from healthy subjects and differentiated into macrophages with M-CSF. The macrophages were polarized towards M1 by IL-12 and towards M2 by IL-10...
April 24, 2017: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
Naveena B Janakiram, Altaf Mohammed, Taylor Bryant, Rebekah Ritchie, Nicole Stratton, Lydgia Jackson, Stan Lightfoot, Doris M Benbrook, Adam Asch, Mark L Lang, Chinthalapally V Rao
Role of unique T cell population, Natural Killer T (NKT) cells which have similar functions like NK cells in PC is not yet evaluated. In order to address the regulatory roles of NKT cells on tumor progression through tumor-associated macrophages (TAM) and their production of microsomal prostaglandin E synthase-1 (mPGES-1) and 5-lipoxygenase (5-LOX) in (Kras)-driven pancreatic tumor (KPT) progression, we crossed CD1d(-/-) mice deficient in both iNKT and vNKT cells with the Kras(G12D) mice. Loss of NKT cells significantly increased pancreatic intraepithelial neoplasia lesions [PanINs] and also increased 5-LOX and mPGES-1 expressions in M2 type macrophages and cancer stem like cells in pancreatic tumors...
April 18, 2017: Immunology
Erik Knudsen, Paris Vail, Uthra Balaji, Hoai Ngo, Ihab W Botros, Vladimir Makarov, Nadeem Riaz, Vinod P Balachandran, Steven D Leach, Debrah M Thompson, Timothy A Chan, Agnieszka K Witkiewicz
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunological features of PDAC to delineate impact on prognosis and to more effectively employ immunotherapy. EXPERIMENTAL DESIGN: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunological subtypes of PDAC that were confirmed in the Cancer Genome Atlas data set...
March 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Elvira Khialeeva, Joan W Chou, Denise E Allen, Alec M Chiu, Steven J Bensinger, Ellen M Carpenter
Reelin is a regulator of cell migration in the nervous system, and has other functions in the development of a number of non-neuronal tissues. In addition, alterations in reelin expression levels have been reported in breast, pancreatic, liver, gastric, and other cancers. Reelin is normally expressed in mammary gland stromal cells, but whether stromal reelin contributes to breast cancer progression is unknown. Herein, we used a syngeneic mouse mammary tumor transplantation model to examine the impact of host-derived reelin on breast cancer progression...
March 2017: Journal of Mammary Gland Biology and Neoplasia
Jane Cullis, Despina Siolas, Antonina Avanzi, Sugata Barui, Anirban Maitra, Dafna Bar-Sagi
Pancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of pancreatic ductal adenocarcinoma tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-paclitaxel (trade name Abraxane) is a nanoparticle albumin-bound formulation of paclitaxel that, in combination with gemcitabine, is currently the first-line treatment for pancreatic cancer. Here, we show that macrophages internalized nab-paclitaxel via macropinocytosis...
March 2017: Cancer Immunology Research
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...
February 2017: Cancer Medicine
Y D Seo, V G Pillarisetty
Despite recent advancements in multimodal therapy, pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. In the era of burgeoning immune therapies against previously difficult-to-treat malignancies, there has been growing interest in activating the immune system against PDA; however, unlike in other cancers such as melanoma and lymphoma, immunotherapy has not yielded many clinically significant results. To harness these mechanisms for therapeutic use, an in-depth understanding of T-cell programming in the immune microenvironment of PDA must be achieved...
March 2017: Cancer Gene Therapy
E Eriksson, R Moreno, I Milenova, L Liljenfeldt, L C Dieterich, L Christiansson, H Karlsson, G Ullenhag, S M Mangsbo, A Dimberg, R Alemany, A Loskog
CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer...
February 2017: Gene Therapy
Bingyan Liu, Yiping Jia, Jun Ma, Shaoqiu Wu, Haosheng Jiang, Yan Cao, Xianjun Sun, Xiang Yin, Shuo Yan, Mingyi Shang, Aiwu Mao
Pancreatic cancer is an aggressive malignancy with a high metastatic potential that results in a high mortality rate worldwide. Although macrophages have the potential to kill tumor cells and elicit immune responses against tumors, there is evidence that tumor-associated macrophages (TAMs) promote tumor progression and suppress T-cell responses. CC-chemokine ligand 20 (CCL20) and its unique receptor CC-chemokine receptor 6 (CCR6) are exploited by cancer cells for migration and metastasis and play important roles in the development and progression of cancer...
December 2016: Acta Biochimica et Biophysica Sinica
Mingzhu Yin, Xia Li, Shu Tan, Huanjiao Jenny Zhou, Weidong Ji, Stefania Bellone, Xiaocao Xu, Haifeng Zhang, Alessandro D Santin, Ge Lou, Wang Min
Tumor-associated macrophages (TAMs) can influence ovarian cancer growth, migration, and metastasis, but the detailed mechanisms underlying ovarian cancer metastasis remain unclear. Here, we have shown a strong correlation between TAM-associated spheroids and the clinical pathology of ovarian cancer. Further, we have determined that TAMs promote spheroid formation and tumor growth at early stages of transcoelomic metastasis in an established mouse model for epithelial ovarian cancer. M2 macrophage-like TAMs were localized in the center of spheroids and secreted EGF, which upregulated αMβ2 integrin on TAMs and ICAM-1 on tumor cells to promote association between tumor cells and TAM...
November 1, 2016: Journal of Clinical Investigation
Hridayesh Prakash, Vinod Nadella, Sandhya Singh, Hubertus Schmitz-Winnenthal
Pancreatic cancer is the fourth major cause of cancer related deaths in the world and 5 year survival is below 5%. Among various tumor directed therapies, stimulation of Toll-like receptors (TLR) has shown promising effects in various tumor models. However, pancreatic cancer cells frequently express these receptors themselves and their stimulation (TLR 2 and/or 4 particularly) within tumor microenvironment is known to potentially enhance tumor cell proliferation and cancer progression. Consistent stimulation of tumor associated macrophages (TAMs), in particular with tumor derived TLR ligand within the tumor microenvironment promotes cancer related inflammation, which is sterile, non-immunogenic and carcinogenic in nature...
2016: Scientific Reports
Leonie Mühlberg, Benjamin Kühnemuth, Eithne Costello, Victoria Shaw, Bence Sipos, Magdalena Huber, Heidi Griesmann, Sebastian Krug, Marvin Schober, Thomas M Gress, Patrick Michl
Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer...
June 2016: Oncoimmunology
Murray Korc
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer in which NF-κB pathways promote biological aggressiveness. In this issue of the JCI, Lesina et al. investigated the role of RelA, the p65 partner of p50 that together form the most common NF-κB complex, in the early stages of pancreatic malignant transformation and in established PDAC. By deleting Rela in the context of an oncogenic Kras-driven autochthonous model of PDAC, the authors demonstrated that RelA is a mediator of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP) that attenuates acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia (PanIN) formation, and PanIN progression to PDAC...
August 1, 2016: Journal of Clinical Investigation
Emelie Karnevi, Ann H Rosendahl, Katarzyna Said Hilmersson, Moin A Saleem, Roland Andersson
Pancreatic cancer is associated with a highly abundant stroma and low-grade inflammation. In the local tumour microenvironment, elevated glucose levels, the presence of tumour-associated stellate cells and macrophages are hypothesised to promote the tumour progression and invasion. The present study investigated the influence by the microenvironment on pancreatic cancer cell invasion in vitro. After co-culture with tumour-associated pancreatic stellate cells (TPSCs), pancreatic cancer cells displayed up to 8-fold reduction in levels of epithelial-mesenchymal transition (EMT) markers E-cadherin and ZO-1, while β-catenin and vimentin levels were increased...
August 15, 2016: Experimental Cell Research
Mei-Ju Su, Hibah Aldawsari, Mansoor Amiji
Exosomes are nano-sized endosome-derived small intraluminal vesicles, which are important facilitators of intercellular communication by transporting contents, such as protein, mRNA, and microRNAs, between neighboring cells, such as in the tumor microenvironment. The purpose of this study was to understand the mechanisms of exosomes-mediated cellular communication between human pancreatic cancer (Panc-1) cells and macrophages (J771.A1) using a Transwell co-culture system. Following characterization of exosome-mediated cellular communication and pro-tumoral baseline M2 macrophage polarization, the Panc-1 cells were transfected with microRNA-155 (miR-155) and microRNA-125b-2 (miR-125b2) expressing plasmid DNA using hyaluronic acid-poly(ethylene imine)/hyaluronic acid-poly(ethylene glycol) (HA-PEI/HA-PEG) self-assembling nanoparticle-based non-viral vectors...
2016: Scientific Reports
Qiaofei Liu, Zheyu Niu, Yuan Li, Mengyi Wang, Boju Pan, Zhaohui Lu, Quan Liao, Yupei Zhao
Interactions between pancreatic cancer cells and inflammatory cells play crucial roles in the biological behavior of pancreatic cancer. Abundant infiltration of immunoglobulin G4 (IgG4)-positive plasma cells in the pancreas is the most significant feature of autoimmune pancreatitis; however, the clinical significance of IgG4-positive plasma cell infiltration in pancreatic cancer has not previously been reported. Herein, we analyzed intratumoral and peritumoral infiltrations of IgG4-positive plasma cells in 95 pancreatic cancer cases after curative resection...
August 2016: Cancer Immunology, Immunotherapy: CII
Lena Seifert, Gregor Werba, Shaun Tiwari, Nancy Ngoc Giao Ly, Susanna Nguy, Sara Alothman, Dalia Alqunaibit, Antonina Avanzi, Donnele Daley, Rocky Barilla, Daniel Tippens, Alejandro Torres-Hernandez, Mautin Hundeyin, Vishnu R Mani, Cristina Hajdu, Ilenia Pellicciotta, Philmo Oh, Kevin Du, George Miller
BACKGROUND & AIMS: The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci...
June 2016: Gastroenterology
Qiaofei Liu, Yuan Li, Zheyu Niu, Yi Zong, Mengyi Wang, Lutian Yao, Zhaohui Lu, Quan Liao, Yupei Zhao
BACKGROUND: Interactions of inflammatory cells with pancreatic cancer cells play crucial roles in pancreatic cancer, however the dynamic changes of inflammatory cell populations in pancreatic cancerogensis and after chemotherapy have not been well eclucidated. The combinational use of aspirin and atrovastatin (Lipitor) have been widely prescribled for cardio-cerebral vascular diseases mainly by regulation of inflammations, and they have been also reported to have plausible anti-tumor effects, however their potential roles in pancreatic cancerogenesis and chemotherapeutic effects have been seldom investigated...
February 16, 2016: Journal of Experimental & Clinical Cancer Research: CR
Lutian Yao, Mengyi Wang, Zheyu Niu, Qiaofei Liu, Xiang Gao, Li Zhou, Quan Liao, Yupei Zhao
Pancreatic cancer is characterized as inflammatory malignancy with a dismal prognosis. There is abundant intratumoral infiltration of macrophages, and most of these tumor associated macrophages (TAM) are induced to be M2 phenotype. The M2 polarized TAM has been demonstrated to promote progression and induce chemo-resistance of pancreatic cancer. Interleukin (IL)-27 is a novel member of IL-12 cytokine family and its roles in regulation of phenotypes and functions of TAM remain largely unknown. In this study, we demonstrated IL-27 significantly inhibited the M2 macrophages polarization and dampened the proliferation, migration and metastasis of pancreatic cancer cells and as well enhanced the efficacy of gemcitabine...
January 2017: Cytokine
Mouad Edderkaoui, Shiping Xu, Chintan Chheda, Susan Morvaridi, Robert W Hu, Paul J Grippo, Emman Mascariñas, Daniel R Principe, Beatrice Knudsen, Jing Xue, Aida Habtezion, Dale Uyeminami, Kent E Pinkerton, Stephen J Pandol
Smoking is a major risk factor for developing pancreatic adenocarcinoma (PDAC); however, little is known about the mechanisms involved. Here we employed a genetic animal model of early stages of PDAC that overexpresses oncogenic Kras in the pancreas to investigate the mechanisms of smoking-induced promotion of the disease in vivo. We confirmed the regulation of the interactions between the tumor microenvironment cells using in vitro cellular systems. Aerial exposure to cigarette smoke stimulated development of pancreatic intraepithelial neaoplasia (PanIN) lesions associated with a tumor microenvironment-containing features of human PDAC including fibrosis, activated stellate cells, M2-macrophages and markers of epithelial-mesenchymal transition (EMT)...
February 16, 2016: Oncotarget
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