Abstract
Pancreatic cancer has a dismal prognosis for patients due to late diagnosis and ineffective treatment options. There is a desperate need for more accurate disease models to enable improved therapies and diagnostic tests to reach the clinic. Pancreatic tumours have a high content of desmoplastic stroma, which forms a stiff, hypoxic tumour mass and contributes significantly to tumour development and metastatic spread. Therefore, 2D cell culture is not sufficient for understanding the complex biology of this disease. 3D in vitro models offer a more representative method of culturing cells for research in the laboratory. There are many different 3D models that can be used in research, organoids formed from patient or murine tumours are grown embedded in collagen or matrigel matrices, giving the potential for screening treatment options and personalised therapy in the future. Also, organotypic models using pancreatic cancer cell lines and stromal cells can be easily manipulated to study different aspects of pancreatic cancer and new therapeutic options in the laboratory. There are new emerging pancreatic cancer 3D models being developed, including microchip technology or synthetic scaffolds instead collagen and matrigel. All of these 3D culturing methods give an advantage over traditional 2D cell culture and could lead to improved understanding of this disease, translating to a better prognosis for patients in the clinic.
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References
Apte MV, Wilson JS, Lugea A, Pandol SJ (2013) A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144:1210–1219
Baker LA, Tiriac H, Clevers H, Tuveson DA (2016) Modeling pancreatic cancer with organoids. Trends in cancer 2:176–190
Bardeesy N, Depinho RA (2002) Pancreatic cancer biology and genetics. Nat Rev Cancer 2:897–909
Beer M, Kuppalu N, Stefanini M, Becker H, Schulz I, Manoli S, Schuette J, Schmees C, Casazza A, Stelzle M, Arcangeli A (2017) A novel microfluidic 3D platform for culturing pancreatic ductal adenocarcinoma cells: comparison with in vitro cultures and in vivo xenografts. Sci Rep 7:1325
Boj SF, Hwang C-I, Baker LA, Chio IIC, Engle DD, Corbo V, Jager M, Ponz-Sarvise M, Tiriac H, Spector MS, Gracanin A, Oni T, Yu KH., van Boxtel R, Huch M, Rivera KD, Wilson JP, Feigin ME, Öhlund D, Handly-Santana A, Ardito-Abraham CM, Ludwig M, Elyada E, Alagesan B, Biffi G, Yordanov GN, Delcuze B, Creighton B, Wright K, Park Y, Morsink FHM, Molenaar IQ, Rinkes IHB, Cuppen E, Hao Y, Jin Y, Nijman IJ, Iacobuzio-Donahue C, Leach SD, Pappin DJ, Hammell M, Klimstra DS, Basturk O, Hruban RH, Offerhaus GJ, Vries RGJ, Clevers H, Tuveson DA (2015) Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338
Carapuça E F, Gemenetzidis E, Feig C, Bapiro TE, Williams MD, Wilson AS, Delvecchio FR, Arumugam P, Grose RP, Lemoine NR, Richards FM, Kocher HM (2016) Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma. The J Pathol
Chiellini F, Puppi D, Piras AM, Morelli A, Bartoli C, Migone C (2016) Modelling of pancreatic ductal adenocarcinoma in vitro with three-dimensional microstructured hydrogels. RSC Adv 6:54226–54235
Coleman SJ, Watt J, Arumugam P, Solaini L, Carapuca E, Ghallab M, Grose RP, Kocher HM (2014) Pancreatic cancer organotypics: High throughput, preclinical models for pharmacological agent evaluation. World J Gastroenterol 20:8471–8481
Deer EL, Gonzalez-Hernandez J, Coursen JD, Shea JE, Ngatia J, Scaife CL, Firpo MA, Mulvihill SJ (2010) Phenotype and Genotype of Pancreatic Cancer Cell Lines. Pancreas 39:425–435
Distler M, Aust D, Weitz J, Pilarsky C, Grützmann R, Tzmann R (2014) Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. BioMed Res Int 2014, 11
Froeling FEM, Mirza TA, Feakins RM, Seedhar A, Elia G, Hart IR, Kocher HM (2009) Organotypic culture model of pancreatic cancer demonstrates that stromal cells modulate E-Cadherin, β-Catenin, and Ezrin expression in tumor cells. Am J Pathol 175:636–648
Greggio C, De Franceschi F, Figueiredo-Larsen M, Gobaa S, Ranga A, Semb H, Lutolf M, Grapin-Botton A (2013) Artificial three-dimensional niches deconstruct pancreas development in vitro. Development 140:4452–4462
Huang L, Holtzinger A, Jagan I, Begora M, Lohse I, Ngai N, Nostro C, Wang R, Muthuswamy LB, Crawford HC, Arrowsmith C, Kalloger SE, Renouf DJ, Connor AA, Cleary S, Schaeffer DF, Roehrl M, Tsao M-S, Gallinger S, Keller G, Muthuswamy SK (2015) Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids. Nat Med 21:1364–1371
Jiang X, Seo YD, Chang JH, Coveler A, Nigjeh EN, Pan S, Jalikis F, Yeung RS, Crispe IN, Pillarisetty VG (2017) Long-lived pancreatic ductal adenocarcinoma slice cultures enable precise study of the immune microenvironment. OncoImmunology 6:e1333210
Kadaba R, Birke H, Wang J, Hooper S, Andl CD, Di Maggio F, Soylu E, Ghallab M, Bor D, Froeling FEM, Bhattacharya S, Rustgi AK, Sahai E, Chelala C, Sasieni P, Kocher HM (2013) Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes. J Pathol 230:107–117
Koikawa K, Ohuchida K, Takesue S, Ando Y, Kibe S, Nakayama H, Endo S, Abe T, Okumura T, Horioka K, Sada M, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Ohuchida R, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M (2018) Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180. Cancer Lett 412:143–154
Li X, Nadauld L, Ootani A, Corney DC, Pai RK, Gevaert O, Cantrell MA, Rack PG, Neal JT, Chan CWM, Yeung T, Gong X, Yuan J, Wilhelmy J, Robine S, Attardi LD, Plevritis SK, Hung KE, Chen C-Z, Ji HP, Kuo CJ (2014) Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat Med 20:769–777
Loessner D, Holzapfel BM, Clements JA (2014) Engineered microenvironments provide new insights into ovarian and prostate cancer progression and drug responses. Adv Drug Deliv Rev 79–80:193–213
Loessner D, Meinert C, Kaemmerer E, Martine LC, Yue K, Levett PA, Klein TJ, Melchels FP, Khademhosseini A, Hutmacher DW (2016) Functionalization, preparation and use of cell-laden gelatin methacryloyl-based hydrogels as modular tissue culture platforms. Nat Protoc 11:727–746
Longati P, Jia X, Eimer J, Wagman A, Witt M-R, Rehnmark S, Verbeke C, Toftgård R, Löhr M, Heuchel RL (2013) 3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing. BMC Cancer 13:95
Moreira L, Bakir B, Chatterji P, Dantes Z, Reichert M, Rustgi AK (2018) Pancreas 3D organoids: current and future aspects as a research platform for personalized medicine in pancreatic cancer. Cell Mol Gastroenterol Hepatol 5:289–298
Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, Lolkema MP, Buchholz M, Olive KP, Gress TM, Tuveson DA (2011) Stromal biology and therapy in pancreatic cancer. Gut 60:861–868
Nielsen MFB, Mortensen MB, Detlefsen S (2016) Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 22:2678–2700
Olive KP, Tuveson DA (2006) The use of targeted mouse models for preclinical testing of novel cancer therapeutics. Clin Cancer Res 12:5277–5287
Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H, Toda S, Sugihara H, Fujimoto K, Weissman IL, Capecchi MR, Kuo CJ (2009) Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med 15:701–706
Pérez-Mancera PA, Guerra C, Barbacid M, Tuveson DA (2012) What we have learned about pancreatic cancer from mouse models. Gastroenterology 142:1079–1092
Puls TJ, Tan X, Whittington CF, Voytik-Harbin SL (2017) 3D collagen fibrillar microstructure guides pancreatic cancer cell phenotype and serves as a critical design parameter for phenotypic models of EMT. PLoS ONE 12:e0188870
Scavuzzo MA, Yang D, Borowiak M (2017) Organotypic pancreatoids with native mesenchyme develop Insulin producing endocrine cells. Sci Rep 7:10810
Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30
Sugiyama T, Benitez CM, Ghodasara A, Liu L, Mclean GW, Lee J, Blauwkamp TA, Nusse R, Wright CV, Gu G, Kim SK (2013) Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Proc Natl Acad Sci U S A 110:12691–12696
Tsai S, Mcolash L, Palen K, Johnson B, Duris C, Yang Q, Dwinell MB, Hunt B, Evans DB, Gershan J, James MA (2018) Development of primary human pancreatic cancer organoids, matched stromal and immune cells and 3D tumor microenvironment models. BMC Cancer 18:335–335
Vaira V, Fedele G, Pyne S, Fasoli E, Zadra G, Bailey D, Snyder E, Faversani A, Coggi G, Flavin R, Bosari S, Loda M (2010) Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors. Proc Natl Acad Sci U S A 107:8352–8356
Walsh AJ, Castellanos JA, Nagathihalli NS, Merchant NB, Skala MC (2016) Optical imaging of drug-induced metabolism changes in murine and human pancreatic cancer organoids reveals heterogeneous drug response. Pancreas 45:863–869
Whatcott CJ, Diep CH, Jiang P, Watanabe A, Lobello J, Sima C, Hostetter G, Shepard HM, Von Hoff DD, Han H (2015) Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res 21:3561–3568
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Coetzee, A., Grose, R., Kocher, H. (2019). Pancreatic Cancer Organotypic Models. In: Bagnoli, F., Rappuoli, R. (eds) Three Dimensional Human Organotypic Models for Biomedical Research. Current Topics in Microbiology and Immunology, vol 430. Springer, Cham. https://doi.org/10.1007/82_2019_155
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DOI: https://doi.org/10.1007/82_2019_155
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