. 2021 Oct; 13(19):.
doi: 10.3390/cancers13194932.

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

Group Young Researchers In Inflammatory Carcinogenesis 1 Anna Maxi Wandmacher 2 Anne-Sophie Mehdorn 3 Susanne Sebens 1 
  • PMID: 34638420
  •     308 References
  •     3 citations


Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients.

Keywords: CAFs; PDAC; endothelial cells; immune cells; macrophages; microbiome; myofibroblasts; personalized medicine; tumor stroma.

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Gastroenterology, 2011 Jun 28; 141(4). PMID: 21704588
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Dangerous liaisons: pancreatic stellate cells and pancreatic cancer cells.
Minoti V Apte, Jeremy S Wilson.
J Gastroenterol Hepatol, 2012 Feb 15; 27 Suppl 2. PMID: 22320920
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Andrew C Dudley.
Cold Spring Harb Perspect Med, 2012 Mar 07; 2(3). PMID: 22393533    Free PMC article.
Highly Cited. Review.
Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming.
Sen Yang, Qiaofei Liu, Quan Liao.
Front Cell Dev Biol, 2021 Jan 29; 8. PMID: 33505964    Free PMC article.
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Int J Cancer, 2008 Nov 28; 124(4). PMID: 19035451    Free PMC article.
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Meredith L Stone, Gregory L Beatty.
Pharmacol Ther, 2019 Jun 04; 201. PMID: 31158393    Free PMC article.
Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing.
Cristina Belgiovine, Elisabeth Digifico, +2 authors, Fernando Torres Andón.
J Clin Med, 2020 Oct 15; 9(10). PMID: 33050070    Free PMC article.
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J Immunother Cancer, 2019 Nov 16; 7(1). PMID: 31730010    Free PMC article.
Purity Independent Subtyping of Tumors (PurIST), A Clinically Robust, Single-sample Classifier for Tumor Subtyping in Pancreatic Cancer.
Naim U Rashid, Xianlu L Peng, +16 authors, Jen Jen Yeh.
Clin Cancer Res, 2019 Nov 23; 26(1). PMID: 31754050    Free PMC article.
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Peter Bailey, David K Chang, +100 authors, Sean M Grimmond.
Nature, 2016 Feb 26; 531(7592). PMID: 26909576
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A circulating TH2 cytokines profile predicts survival in patients with resectable pancreatic adenocarcinoma.
Geny Piro, Francesca Simionato, +12 authors, Davide Melisi.
Oncoimmunology, 2017 Sep 22; 6(9). PMID: 28932629    Free PMC article.
Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages.
Hideyuki Takahashi, Koichi Sakakura, +4 authors, Kazuaki Chikamatsu.
Oncotarget, 2017 Jan 05; 8(5). PMID: 28052009    Free PMC article.
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BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial.
Bruno Bockorny, Valerya Semenisty, +23 authors, Manuel Hidalgo.
Nat Med, 2020 May 27; 26(6). PMID: 32451495
Distributions of retinoids, retinoid-binding proteins and related parameters in different types of liver cells isolated from young and old rats.
H F Hendriks, W S Blaner, +5 authors, D L Knook.
Eur J Biochem, 1988 Jan 15; 171(1-2). PMID: 2828051
Intratumoral α-SMA enhances the prognostic potency of CD34 associated with maintenance of microvessel integrity in hepatocellular carcinoma and pancreatic cancer.
Wen-Quan Wang, Liang Liu, +10 authors, Xian-Jun Yu.
PLoS One, 2013 Aug 14; 8(8). PMID: 23940715    Free PMC article.
Deciphering the Crosstalk Between Myeloid-Derived Suppressor Cells and Regulatory T Cells in Pancreatic Ductal Adenocarcinoma.
Carole Siret, Aurélie Collignon, +9 authors, Anna Martirosyan.
Front Immunol, 2020 Feb 11; 10. PMID: 32038621    Free PMC article.
Hepatic Stellate Cell Regulation of Liver Regeneration and Repair.
Laura J Kitto, Neil C Henderson.
Hepatol Commun, 2021 Mar 09; 5(3). PMID: 33681672    Free PMC article.
Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts.
Sonakshi Bhattacharjee, Florian Hamberger, +21 authors, Robert F Schwabe.
J Clin Invest, 2021 Apr 28; 131(11). PMID: 33905375    Free PMC article.
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Heiner Schäfer, Claudia Geismann, +8 authors, Susanne Sebens.
Carcinogenesis, 2011 Nov 19; 33(1). PMID: 22095073
Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression.
Yu Zhu, John M Herndon, +12 authors, David G DeNardo.
Immunity, 2017 Aug 17; 47(2). PMID: 28813661    Free PMC article.
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Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.
Changqing Xie, Austin G Duffy, +16 authors, Tim F Greten.
Clin Cancer Res, 2020 Jan 31; 26(10). PMID: 31996388    Free PMC article.
Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers.
Erik S Knudsen, Paris Vail, +9 authors, Agnieszka K Witkiewicz.
Clin Cancer Res, 2017 Mar 30; 23(15). PMID: 28348045    Free PMC article.
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Gemcitabine mono-therapy versus gemcitabine plus targeted therapy in advanced pancreatic cancer: a meta-analysis of randomized phase III trials.
Alessandro Ottaiano, Monica Capozzi, +4 authors, Salvatore Tafuto.
Acta Oncol, 2017 Mar 04; 56(3). PMID: 28256961
Understanding metastasis in pancreatic cancer: a call for new clinical approaches.
David A Tuveson, John P Neoptolemos.
Cell, 2012 Jan 24; 148(1-2). PMID: 22265397
A novel murine model to deplete hepatic stellate cells uncovers their role in amplifying liver damage in mice.
Juan E Puche, Youngmin A Lee, +7 authors, Scott L Friedman.
Hepatology, 2012 Sep 11; 57(1). PMID: 22961591    Free PMC article.
TAMing pancreatic cancer: combat with a double edged sword.
Manendra Babu Lankadasari, Pramiti Mukhopadhyay, Sabira Mohammed, Kuzhuvelil B Harikumar.
Mol Cancer, 2019 Mar 31; 18(1). PMID: 30925924    Free PMC article.
Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer.
Takahiro Tsujikawa, Todd Crocenzi, +18 authors, Dung T Le.
Clin Cancer Res, 2020 Apr 11; 26(14). PMID: 32273276    Free PMC article.
Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression.
Megan M Kaneda, Paola Cappello, +13 authors, Judith A Varner.
Cancer Discov, 2016 May 15; 6(8). PMID: 27179037    Free PMC article.
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Human mesenchymal stem cell and epithelial hepatic carcinoma cell lines in admixture: concurrent stimulation of cancer-associated fibroblasts and epithelial-to-mesenchymal transition markers.
Syamal D Bhattacharya, Zhiyong Mi, +2 authors, Paul C Kuo.
Surgery, 2012 Sep 04; 152(3). PMID: 22938903    Free PMC article.
Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis.
Tuyen Thuy Bich Ho, Alessandro Nasti, +13 authors, Yoshio Sakai.
J Immunother Cancer, 2020 Nov 15; 8(2). PMID: 33188035    Free PMC article.
Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells.
Hannah Jonescheit, Hans-Heinrich Oberg, +5 authors, Daniela Wesch.
Cells, 2020 May 10; 9(5). PMID: 32384638    Free PMC article.
Cancer stem cells--the current status of an old concept: literature review and clinical approaches.
Lukasz Fulawka, Piotr Donizy, Agnieszka Halon.
Biol Res, 2015 Feb 28; 47. PMID: 25723910    Free PMC article.
Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy.
Jinyang Li, Katelyn T Byrne, +26 authors, Ben Z Stanger.
Immunity, 2018 Jul 01; 49(1). PMID: 29958801    Free PMC article.
Highly Cited.
Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs.
Betul Gok Yavuz, Gurcan Gunaydin, +4 authors, Dicle Guc.
Sci Rep, 2019 Mar 01; 9(1). PMID: 30816272    Free PMC article.
γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation.
Donnele Daley, Constantinos Pantelis Zambirinis, +17 authors, George Miller.
Cell, 2016 Aug 30; 166(6). PMID: 27569912    Free PMC article.
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Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia.
L Rønnov-Jessen, O W Petersen.
Lab Invest, 1993 Jun 01; 68(6). PMID: 8515656
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PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation.
Muhammad Zaeem Noman, Giacomo Desantis, +5 authors, Salem Chouaib.
J Exp Med, 2014 Apr 30; 211(5). PMID: 24778419    Free PMC article.
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Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies.
Roheena Z Panni, John M Herndon, +13 authors, David G DeNardo.
Sci Transl Med, 2019 Jul 05; 11(499). PMID: 31270275    Free PMC article.
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Promotion of tumor cell migration by extracellular matrix proteins in human pancreatic cancer.
Eduard Ryschich, Akmal Khamidjanov, +3 authors, Jan Schmidt.
Pancreas, 2009 Nov 07; 38(7). PMID: 19893454
Stromal fibroblasts in cancer: a novel tumor-promoting cell type.
Akira Orimo, Robert A Weinberg.
Cell Cycle, 2006 Aug 02; 5(15). PMID: 16880743
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Pancreatic cancer stroma: an update on therapeutic targeting strategies.
Abdel N Hosein, Rolf A Brekken, Anirban Maitra.
Nat Rev Gastroenterol Hepatol, 2020 May 13; 17(8). PMID: 32393771    Free PMC article.
Human γδ T lymphocytes are licensed for professional antigen presentation by interaction with opsonized target cells.
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J Immunol, 2012 Jan 18; 188(4). PMID: 22250090
Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia.
Mitsuro Kanda, Hanno Matthaei, +8 authors, Michael Goggins.
Gastroenterology, 2012 Jan 10; 142(4). PMID: 22226782    Free PMC article.
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Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure.
María Elena Fernández-Sánchez, Sandrine Barbier, +19 authors, Emmanuel Farge.
Nature, 2015 May 15; 523(7558). PMID: 25970250
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Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels.
Maya W Haaker, Arie B Vaandrager, J Bernd Helms.
Biochim Biophys Acta Mol Cell Biol Lipids, 2020 Feb 28; 1865(6). PMID: 32105672
Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.
Richard A Moffitt, Raoud Marayati, +15 authors, Jen Jen Yeh.
Nat Genet, 2015 Sep 08; 47(10). PMID: 26343385    Free PMC article.
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Cancer Statistics, 2021.
Rebecca L Siegel, Kimberly D Miller, Hannah E Fuchs, Ahmedin Jemal.
CA Cancer J Clin, 2021 Jan 13; 71(1). PMID: 33433946
Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer.
Marcus Ruscetti, John P Morris, +17 authors, Scott W Lowe.
Cell, 2020 Apr 03; 181(2). PMID: 32234521    Free PMC article.
Atorvastatin (Lipitor) attenuates the effects of aspirin on pancreatic cancerogenesis and the chemotherapeutic efficacy of gemcitabine on pancreatic cancer by promoting M2 polarized tumor associated macrophages.
Qiaofei Liu, Yuan Li, +6 authors, Yupei Zhao.
J Exp Clin Cancer Res, 2016 Feb 18; 35. PMID: 26879926    Free PMC article.
CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.
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Pancreas, 2004 Jan 07; 28(1). PMID: 14707745
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Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage.
Kyu Jin Choi, Jae-Kyung Nam, +2 authors, Yoon-Jin Lee.
Exp Mol Med, 2020 May 30; 52(5). PMID: 32467609    Free PMC article.
Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1- and slug-dependent: role in malignant transformation of pancreatic cancer.
Claudia Geismann, Mascha Morscheck, +10 authors, Susanne Sebens Müerköster.
Cancer Res, 2009 May 14; 69(10). PMID: 19435915
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Elisabeth Hessmann, Soeren M Buchholz, +4 authors, Albrecht Neesse.
Physiol Rev, 2020 Apr 17; 100(4). PMID: 32297835
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John D Martin, Giorgio Seano, Rakesh K Jain.
Annu Rev Physiol, 2019 Feb 12; 81. PMID: 30742782    Free PMC article.
Highly Cited. Review.
Pancreatic Stellate Cells Promote Tumor Progression by Promoting an Immunosuppressive Microenvironment in Murine Models of Pancreatic Cancer.
Caixia Li, Lihua Cui, +6 authors, Shukun Zhang.
Pancreas, 2019 Dec 20; 49(1). PMID: 31856087
Pancreatic cancer stem cells: A state or an entity?
Patrick C Hermann, Bruno Sainz.
Semin Cancer Biol, 2018 Aug 22; 53. PMID: 30130664
Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature.
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Cancer Res, 2016 Oct 19; 76(24). PMID: 27754848
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Int J Cancer, 2014 Jan 25; 135(4). PMID: 24458546
Highly Cited.
A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma.
Devalingam Mahalingam, Sanjay Goel, +10 authors, Monica M Mita.
Cancers (Basel), 2018 May 26; 10(6). PMID: 29799479    Free PMC article.
The presence of tumour-associated lymphocytes confers a good prognosis in pancreatic ductal adenocarcinoma: an immunohistochemical study of tissue microarrays.
Nilanjana Tewari, Abed M Zaitoun, +3 authors, Dileep N Lobo.
BMC Cancer, 2013 Sep 26; 13. PMID: 24063854    Free PMC article.
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M V Apte, J S Wilson.
Pancreas, 2003 Oct 25; 27(4). PMID: 14576494
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Giulia Biffi, David A Tuveson.
Physiol Rev, 2020 May 30; 101(1). PMID: 32466724    Free PMC article.
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Oncogene, 2016 Dec 20; 36(21). PMID: 27991933    Free PMC article.
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J Natl Cancer Inst, 2007 Jul 27; 99(15). PMID: 17652277
Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer.
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Cancer Res, 2013 Aug 02; 73(18). PMID: 23903958
Highly Cited.
Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity.
Colin Hutton, Felix Heider, +24 authors, Claus Jørgensen.
Cancer Cell, 2021 Jul 24; 39(9). PMID: 34297917    Free PMC article.
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Nat Rev Clin Oncol, 2009 Sep 09; 6(10). PMID: 19736552
Highly Cited. Review.
M1 and M2 Macrophages: Oracles of Health and Disease.
Charles D Mills.
Crit Rev Immunol, 2013 Feb 23; 32(6). PMID: 23428224
Highly Cited. Review.
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J Surg Res, 2009 Sep 22; 167(2). PMID: 19765725
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Mesenchymal Stem Cells Promote Pancreatic Tumor Growth by Inducing Alternative Polarization of Macrophages.
Esha Mathew, Arthur L Brannon, +6 authors, Marina Pasca di Magliano.
Neoplasia, 2016 Mar 20; 18(3). PMID: 26992915    Free PMC article.
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Shuo Li, Hua-Xiang Xu, +10 authors, Liang Liu.
Angiogenesis, 2018 Sep 01; 22(1). PMID: 30168025
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Ralf Hass, Juliane von der Ohe, Hendrik Ungefroren.
Cancers (Basel), 2020 Dec 17; 12(12). PMID: 33322354    Free PMC article.
The pancreatic stellate cell: a star on the rise in pancreatic diseases.
M Bishr Omary, Aurelia Lugea, Anson W Lowe, Stephen J Pandol.
J Clin Invest, 2007 Jan 04; 117(1). PMID: 17200706    Free PMC article.
Highly Cited. Review.
The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma.
Sona Ciernikova, Maria Novisedlakova, +2 authors, Michal Mego.
Biomedicines, 2020 Dec 09; 8(12). PMID: 33287196    Free PMC article.
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Clin Cancer Res, 2015 May 16; 21(19). PMID: 25977344
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Julie Garcia, Maria José Sandi, +4 authors, Roselyne Tournaire.
EMBO Rep, 2012 Mar 17; 13(5). PMID: 22421998    Free PMC article.
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Yasmin Issa, Daniel Nummer, +7 authors, Peter Altevogt.
J Mol Med (Berl), 2008 Oct 22; 87(1). PMID: 18931829
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Magdalena Huber, Corinna U Brehm, +7 authors, Matthias Lauth.
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Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells.
Max G Bachem, Marion Schünemann, +6 authors, Guido Adler.
Gastroenterology, 2005 Apr 13; 128(4). PMID: 15825074
Highly Cited.
A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas.
Olca Basturk, Seung-Mo Hong, +21 authors, Baltimore Consensus Meeting.
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Ole Helm, Ruben Mennrich, +11 authors, Susanne Sebens.
PLoS One, 2014 May 07; 9(5). PMID: 24797069    Free PMC article.
The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer.
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Tumour Biol, 2016 Jan 08; 37(7). PMID: 26738860
Highly Cited.
Angiogenesis in Pancreatic Cancer: Pre-Clinical and Clinical Studies.
Tiziana Annese, Roberto Tamma, Simona Ruggieri, Domenico Ribatti.
Cancers (Basel), 2019 Mar 21; 11(3). PMID: 30889903    Free PMC article.
Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner.
Thomas A Mace, Zeenath Ameen, +9 authors, Gregory B Lesinski.
Cancer Res, 2013 Mar 22; 73(10). PMID: 23514705    Free PMC article.
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Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis.
Neil P Dufton, Claire R Peghaire, +10 authors, Anna M Randi.
Nat Commun, 2017 Oct 14; 8(1). PMID: 29026072    Free PMC article.
The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.
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Science, 2018 Jan 06; 359(6371). PMID: 29302014    Free PMC article.
Highly Cited.
A small population of liver endothelial cells undergoes endothelial-to-mesenchymal transition in response to chronic liver injury.
Jordi Ribera, Montse Pauta, +8 authors, Manuel Morales-Ruiz.
Am J Physiol Gastrointest Liver Physiol, 2017 Aug 12; 313(5). PMID: 28798084
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Patrick Michl, Thomas M Gress.
Gut, 2012 Nov 01; 62(2). PMID: 23112132
Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.
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Highly Cited.
Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer.
Rogier Aäron Gaiser, Asif Halimi, +9 authors, Margaret Sällberg Chen.
Gut, 2019 Mar 16; 68(12). PMID: 30872392    Free PMC article.
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Cancer cells increase endothelial cell tube formation and survival by activating the PI3K/Akt signalling pathway.
Hao-Wei Cheng, Yi-Fang Chen, +6 authors, Jeremy J W Chen.
J Exp Clin Cancer Res, 2017 Feb 09; 36(1). PMID: 28173828    Free PMC article.
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Cell Mol Life Sci, 2019 Nov 07; 77(9). PMID: 31690961    Free PMC article.
Highly Cited. Review.
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Sci Rep, 2019 Mar 30; 9(1). PMID: 30923340    Free PMC article.
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Jens Lohr, Birgit Knoechel, Abul K Abbas.
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Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer.
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Am J Physiol Gastrointest Liver Physiol, 2008 Aug 02; 295(4). PMID: 18669622
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Louisa Bolm, Simon Cigolla, +5 authors, Ulrich Friedrich Wellner.
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Highly Cited. Review.
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Pancreatic Fibroblast Heterogeneity: From Development to Cancer.
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Highly Cited. Review.
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Highly Cited. Review.
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Pancreatology, 2018 May 21; 18(5). PMID: 29778400
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