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pancreatic cancer microenvironment

Famke Aeffner, Nathan T Martin, Mirza Peljto, Joshua C Black, Justin K Major, Maryam Jangani, Michael O Ports, Joseph S Krueger, G David Young
Tissue image analysis (tIA) is emerging as a powerful tool for quantifying biomarker expression and distribution in complex diseases and tissues. Pancreatic ductal adenocarcinoma (PDAC) develops in a highly complex and heterogeneous tissue environment and, generally, has a very poor prognosis. Early detection of PDAC is confounded by limited knowledge of the pre-neoplastic disease stages and limited methods to quantitatively assess disease heterogeneity. We sought to develop a tIA approach to assess the most common PDAC precursor lesions, pancreatic intraepithelial neoplasia (PanIN), in tissues from Kras(LSL-G12D/+); Trp53(LSL-R172H/+); Pdx-Cre (KPC) mice, a validated model of PDAC development...
October 24, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
Hung-Yi Liu, Tanja Greene, Tsai-Yu Lin, Camron S Dawes, Murray Korc, Chien-Chi Lin
: The complex network of biochemical and biophysical cues in the pancreatic desmoplasia not only presents challenges to the fundamental understanding of tumor progression, but also hinders the development of therapeutic strategies against pancreatic cancer. Residing in the desmoplasia, pancreatic stellate cells (PSCs) are the major stromal cells affecting the growth and metastasis of pancreatic cancer cells by means of paracrine effects and extracellular matrix protein deposition. PSCs remain in a quiescent/dormant state until they are 'activated' by various environmental cues...
October 18, 2016: Acta Biomaterialia
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
Timothy Chao, Emma E Furth, Robert H Vonderheide
Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas...
October 13, 2016: Cancer Immunology Research
Divya Ramchandani, Dusten Unruh, Clayton S Lewis, Vladimir Y Bogdanov, Georg F Weber
Molecules of the coagulation pathway predispose patients to cancer-associated thrombosis and also trigger intracellular signaling pathways that promote cancer progression. The primary transcript of tissue factor, the main physiologic trigger of blood clotting, can undergo alternative splicing yielding a secreted variant, termed asTF (alternatively spliced tissue factor). asTF is not required for normal hemostasis, but its expression levels positively correlate with advanced tumor stages in several cancers, including pancreatic adenocarcinoma...
October 10, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
Landon J Edgar, Ravi N Vellanki, Trevor D McKee, David Hedley, Bradly G Wouters, Mark Nitz
Changes in the oxygenation state of microenvironments within solid tumors are associated with the development of aggressive cancer phenotypes. Factors that influence cellular hypoxia have been characterized; however, methods for measuring the dynamics of oxygenation at a cellular level in vivo have been elusive. We report a series of tellurium-containing isotopologous probes for cellular hypoxia compatible with mass cytometry (MC)-technology that allows for highly parametric interrogation of single cells based on atomic mass spectrometry...
October 10, 2016: Angewandte Chemie
Shutaro Hori, Kazuaki Shimada, Yoshinori Ino, Seiji Oguro, Minoru Esaki, Satoshi Nara, Yoji Kishi, Tomoo Kosuge, Yukinori Hattori, Aoi Sukeda, Yuko Kitagawa, Yae Kanai, Nobuyoshi Hiraoka
As macroscopic appearance represents tumor microenvironment, it may also reflect the biological and clinicopathological characteristics of a cancer. The aim of the study was to evaluate the clinicopathological significance of the gross appearance of pancreatic ductal adenocarcinoma (PDA). We investigated fresh macroscopic features in 352 cases of PDA and their clinicopathological significance. Three unique gross features were found: a honeycomb-like appearance (diffusely distributed microcysts and interstitial fibrotic thickening), macroscopic necrosis, and a tube/branching structure (apparent small cylindrical or linear structure)...
October 5, 2016: Virchows Archiv: An International Journal of Pathology
Julie Leca, Sébastien Martinez, Sophie Lac, Jérémy Nigri, Véronique Secq, Marion Rubis, Christian Bressy, Arnauld Sergé, Marie-Noelle Lavaut, Nelson Dusetti, Céline Loncle, Julie Roques, Daniel Pietrasz, Corinne Bousquet, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean Baptiste Bachet, Christine Brun, Juan L Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini
The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk...
October 4, 2016: Journal of Clinical Investigation
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
Jaemin Lee, Jinhoi Song, Eun-Soo Kwon, Seongyea Jo, Min Kyung Kang, Yeon Jeong Kim, Yeonsil Hwang, Hosung Bae, Tae Heung Kang, Suhwan Chang, Hee Jun Cho, Song Cheol Kim, Seokho Kim, Sang Seok Koh
CTHRC1 (collagen triple-helix repeat-containing 1), a protein secreted during the tissue-repair process, is highly expressed in several malignant tumors, including pancreatic cancer. We recently showed that CTHRC1 has an important role in the progression and metastasis of pancreatic cancer. Although CTHRC1 secretion affects tumor cells, how it promotes tumorigenesis in the context of the microenvironment is largely unknown. Here we identified a novel role of CTHRC1 as a potent endothelial activator that promotes angiogenesis by recruiting bone marrow-derived cells to the tumor microenvironment during tumorigenesis...
September 30, 2016: Experimental & Molecular Medicine
Jonathan A Moreno, Antonio Sanchez, Robert M Hoffman, Saima Nur, Maria P Lambros
Pancreatic cancer remains one of the cancers for which survival has not improved substantially in the last few decades. Only 7% of diagnosed patients will survive longer than five years. In order to understand and mimic the microenvironment of pancreatic tumors, we utilized a murine orthotopic model of pancreatic cancer that allows non-invasive imaging of tumor progression in real time. Pancreatic cancer cells expressing green fluorescent protein (PANC-1 GFP) were suspended in basement membrane matrix, high concentration, (e...
2016: Journal of Visualized Experiments: JoVE
Hani M Babiker, Irbaz B Riaz, Syed R Shah, Daniel D Von Hoff, Mitesh J Borad
Pancreatic cancer is an aggressive malignancy with poor survival and high mortality rate with 250 000 deaths per year worldwide. The unique pancreatic cancer microenvironment serves as a major obstacle in the effective treatment of this malignancy. The microenvironment consists not only of pancreatic ductal adenocarcinoma cells but also comprises cells of pancreatic cancer stellate, vascular, and immune origin combined with a dense extracellular matrix containing collagen. The aforementioned pathology leads to an increased intratumor pressure combined with an erratic vascular proliferation within the tumor causing hypoxia and decreased drug delivery...
September 28, 2016: Anti-cancer Drugs
Jason R Pitarresi, Xin Liu, Sudarshana M Sharma, Maria C Cuitiño, Raleigh D Kladney, Thomas A Mace, Sydney Donohue, Sunayana G Nayak, Chunjing Qu, James Lee, Sarah A Woelke, Stefan Trela, Kyle LaPak, Lianbo Yu, Joseph McElroy, Thomas J Rosol, Reena Shakya, Thomas Ludwig, Gregory B Lesinski, Soledad A Fernandez, Stephen F Konieczny, Gustavo Leone, Jinghai Wu, Michael C Ostrowski
Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls...
September 2016: Neoplasia: An International Journal for Oncology Research
Misako Sato-Matsubara, Norifumi Kawada
Nielsen SR, Quaranta V, Linford A, et al.(1) (Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol. 2016;18:549-60) recently described a new mechanism for the tumor-stromal interaction in the metastatic progression of pancreatic ductal adenocarcinoma (PDAC) in the liver via granulin that is secreted by metastasis-associated macrophages (MAMs).(1) MAM-derived granulin transactivates hepatic stellate cells (hStCs), which leads to the production of periostin and extracellular matrix (ECM) at the metastatic site...
September 19, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Cathy Quemener, Jessica Baud, Kevin Boye, Alexandre Dubrac, Clotilde Billottet, Fabienne Soulet, Florence Darlot, Laurent Dumartin, Marie Sire, Renaud Grepin, Thomas Daubon, Fabienne Rayne, Harald Wodrich, Anne Couvelard, Raphael Pineau, Martin Schilling, Vincent Castronovo, Shih-Che Sue, Kim Clarke, Abderrahim Lomri, Abdel-Majid Khatib, Martin Hagedorn, Hervé Prats, Andreas Bikfalvi
The CXCL4 paralog CXCL4L1 is a little studied chemokine that has been suggested to exert an anti-angiogenic function. However, CXCL4L1 is also expressed in patient tumors, tumor cell lines and murine xenografts, prompting a more detailed analysis of its role in cancer pathogenesis. We used genetic and antibody-based approaches to attenuate CXCL4L1 in models of pancreatic adenocarcinoma (PDAC). Mechanisms of expression were assessed in cell co-culture experiments, murine and avian xenotransplants, including through an evaluation of CpG methylation and mutation of critical CpG residues...
September 9, 2016: Cancer Research
Xin Liu, Jason R Pitarresi, Maria C Cuitiño, Raleigh D Kladney, Sarah A Woelke, Gina M Sizemore, Sunayana G Nayak, Onur Egriboz, Patrick G Schweickert, Lianbo Yu, Stefan Trela, Daniel J Schilling, Shannon K Halloran, Maokun Li, Shourik Dutta, Soledad A Fernandez, Thomas J Rosol, Gregory B Lesinski, Reena Shakya, Thomas Ludwig, Stephen F Konieczny, Gustavo Leone, Jinghai Wu, Michael C Ostrowski
The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM...
September 1, 2016: Genes & Development
Nicole M Aiello, David L Bajor, Robert J Norgard, Amine Sahmoud, Neha Bhagwat, Minh N Pham, Toby C Cornish, Christine A Iacobuzio-Donahue, Robert H Vonderheide, Ben Z Stanger
Most cancer-associated deaths result from metastasis. However, it remains unknown whether the size, microenvironment or other features of a metastatic lesion dictate its behaviour or determine the efficacy of chemotherapy in the adjuvant (micrometastatic) setting. Here we delineate the natural history of metastasis in an autochthonous model of pancreatic ductal adenocarcinoma (PDAC), using lineage tracing to examine the evolution of disseminated cancer cells and their associated microenvironment. With increasing size, lesions shift from mesenchymal to epithelial histology, become hypovascular and accumulate a desmoplastic stroma, ultimately recapitulating the primary tumours from which they arose...
2016: Nature Communications
Erik S Knudsen, Uthra Balaji, Elizaveta Freinkman, Peter McCue, Agnieszka K Witkiewicz
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The aggressiveness and therapeutic recalcitrance of this malignancy has been attributed to multiple factors including the influence of an active desmoplastic stroma. How the stromal microenvironment of PDAC contributes to the fatal nature of this disease is not well defined. In the analysis of clinical specimens, we observed diverse expression of the hypoxic marker carbonic anhydrase IX and the lactate transporter MCT4 in the stromal compartment...
September 7, 2016: Oncotarget
Gauri R Varadhachary, Robert A Wolff
At present, front-line therapy for metastatic pancreatic ductal adenocarcinoma is combination chemotherapy, most commonly FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) or gemcitabine and nanoparticle albumin-bound paclitaxel. Despite a better understanding of the genomic landscape and the importance of the tumor microenvironment, we have not made a seismic shift in the overall survival for this disease. Given our growing understanding of the biology of pancreatic ductal adenocarcinoma, the question remains whether novel, noncytotoxic agents will augment or even replace conventional chemotherapy...
September 2016: Journal of Oncology Practice
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
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