A Novel Immunocompetent Mouse Model of Pancreatic Cancer with Robust Stroma: a Valuable Tool for Preclinical Evaluation of New Therapies

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• 作者：Kaustav Majumder ; Nivedita Arora ; Shrey Modi…
• 关键词：Pancreatic cancer ; Immunocompetent mouse model ; Stroma ; Syngeneic
• 刊名：Journal of Gastrointestinal Surgery
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：20
• 期：1
• 页码：53-65
• 全文大小：2,842 KB
• 参考文献：1.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29.PubMed CrossRef
  2.Izeradjene K, Hingorani SR. Targets, trials, and travails in pancreas cancer. J Natl Compr Canc Netw 2007; 5: 1042-1053.PubMed
  3.Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med 2014; 371: 1039-1049.PubMed CrossRef
  4.Olive KP, Jacobetz MA, Davidson CJ et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457-1461.PubMed PubMedCentral CrossRef
  5.Hotz HG, Reber HA, Hotz B et al. An orthotopic nude mouse model for evaluating pathophysiology and therapy of pancreatic cancer. Pancreas 2003; 26: e89-98.PubMed CrossRef
  6.Schwarz RE, McCarty TM, Peralta EA et al. An orthotopic in vivo model of human pancreatic cancer. Surgery 1999; 126: 562-567.PubMed CrossRef
  7.Saluja AK, Dudeja V. Relevance of animal models of pancreatic cancer and pancreatitis to human disease. Gastroenterology 2013; 144: 1194-1198.PubMed CrossRef
  8.Hingorani SR, Wang L, Multani AS et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005; 7: 469-483.PubMed CrossRef
  9.Chugh R, Sangwan V, Patil SP et al. A preclinical evaluation of Minnelide as a therapeutic agent against pancreatic cancer. Sci Transl Med 2012; 4: 156ra139.
  10.Sangwan V, Banerjee S, Jensen KM et al. Primary and Liver Metastasis-Derived Cell Lines From KrasG12D; Trp53R172H; Pdx-1 Cre Animals Undergo Apoptosis in Response to Triptolide. Pancreas 2015; 44: 583-589.PubMed CrossRef
  11.Vonderheide RH, Bayne LJ. Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr Opin Immunol 2013; 25: 200-205.PubMed PubMedCentral CrossRef
  12.Kabashima-Niibe A, Higuchi H, Takaishi H et al. Mesenchymal stem cells regulate epithelial-mesenchymal transition and tumor progression of pancreatic cancer cells. Cancer Sci 2013; 104: 157-164.PubMed CrossRef
  13.Porembka MR, Mitchem JB, Belt BA et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 2012; 61: 1373-1385.PubMed PubMedCentral CrossRef
  14.Pylayeva-Gupta Y, Lee KE, Hajdu CH et al. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012; 21: 836-847.PubMed PubMedCentral CrossRef
  15.Bayne LJ, Beatty GL, Jhala N et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012; 21: 822-835.PubMed PubMedCentral CrossRef
  16.Sideras K, Braat H, Kwekkeboom J et al. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies. Cancer Treat Rev 2014; 40: 513-522.PubMed CrossRef
  17.Hwang RF, Moore T, Arumugam T et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 2008; 68: 918-926.PubMed PubMedCentral CrossRef
  18.Ikenaga N, Ohuchida K, Mizumoto K et al. CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology 2010; 139: 1041-1051, 1051 e1041-1048.
  19.Siolas D, Hannon GJ. Patient-derived tumor xenografts: transforming clinical samples into mouse models. Cancer Res 2013; 73: 5315-5319.PubMed PubMedCentral CrossRef
  20.Hezel AF, Kimmelman AC, Stanger BZ et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006; 20: 1218-1249.PubMed CrossRef
  21.Aguirre AJ, Bardeesy N, Sinha M et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003; 17: 3112-3126.PubMed PubMedCentral CrossRef
  22.Tinder TL, Subramani DB, Basu GD et al. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma. J Immunol 2008; 181: 3116-3125.PubMed PubMedCentral CrossRef
  23.Westphalen CB, Olive KP. Genetically engineered mouse models of pancreatic cancer. Cancer J 2012; 18: 502-510.PubMed PubMedCentral CrossRef
  24.Clark CE, Hingorani SR, Mick R et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007; 67: 9518-9527.PubMed CrossRef
  25.Feig C, Gopinathan A, Neesse A et al. The pancreas cancer microenvironment. Clin Cancer Res 2012; 18: 4266-4276.PubMed PubMedCentral CrossRef
  26.Provenzano PP, Cuevas C, Chang AE et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012; 21: 418-429.PubMed PubMedCentral CrossRef
  27.Westerheide SD, Kawahara TL, Orton K, Morimoto RI. Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J Biol Chem 2006; 281: 9616-9622.PubMed CrossRef
  28.Dudeja V, Mujumdar N, Phillips P et al. Heat shock protein 70 inhibits apoptosis in cancer cells through simultaneous and independent mechanisms. Gastroenterology 2009; 136: 1772-1782.PubMed PubMedCentral CrossRef
  29.Phillips PA, Dudeja V, McCarroll JA et al. Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res 2007; 67: 9407-9416.PubMed CrossRef
  30.Dudeja V, Chugh RK, Sangwan V et al. Prosurvival role of heat shock factor 1 in the pathogenesis of pancreatobiliary tumors. Am J Physiol Gastrointest Liver Physiol 2011; 300: G948-955.PubMed PubMedCentral CrossRef
  31.Antonoff MB, Chugh R, Borja-Cacho D et al. Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo. Surgery 2009; 146: 282-290.PubMed CrossRef
  32.Banerjee S, Thayanithy V, Sangwan V et al. Minnelide reduces tumor burden in preclinical models of osteosarcoma. Cancer Lett 2013; 335: 412-420.PubMed PubMedCentral CrossRef
  33.Caicedo-Granados E, Lin R, Fujisawa C et al. Wild-type p53 reactivation by small-molecule Minnelide in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma. Oral Oncol 2014; 50: 1149-1156.PubMed PubMedCentral CrossRef
  34.Li H, Pan GF, Jiang ZZ et al. Triptolide inhibits human breast cancer MCF-7 cell growth via downregulation of the ERalpha-mediated signaling pathway. Acta Pharmacol Sin 2015.
  35.Oliveira AR, Beyer G, Chugh R et al. Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F. Lab Invest 2015.
  36.Rivard C, Geller M, Schnettler E et al. Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug. Gynecol Oncol 2014; 135: 318-324.PubMed PubMedCentral CrossRef
  37.Wang BY, Cao J, Chen JW, Liu QY. Triptolide induces apoptosis of gastric cancer cells via inhibiting the overexpression of MDM2. Med Oncol 2014; 31: 270.PubMed CrossRef
  
• 作者单位：Kaustav Majumder (1)
  Nivedita Arora (1)
  Shrey Modi (1)
  Rohit Chugh (1)
  Alice Nomura (1)
  Bhuwan Giri (1)
  Rajinder Dawra (1)
  Sundaram Ramakrishnan (1)
  Sulagna Banerjee (1)
  Ashok Saluja (1)
  Vikas Dudeja (1)
  
  1. Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
  
• 刊物主题：Surgery; Gastroenterology;
• 出版者：Springer US
• ISSN：1873-4626

文摘

A valid preclinical tumor model should recapitulate the tumor microenvironment. Immune and stromal components are absent in immunodeficient models of pancreatic cancer. While these components are present in genetically engineered models such as KrasG12D; Trp53R172H; Pdx-1Cre (KPC), immense variability in development of invasive disease makes them unsuitable for evaluation of novel therapies. We have generated a novel mouse model of pancreatic cancer by implanting tumor fragments from KPC mice into the pancreas of wild type mice. Three-millimeter tumor pieces from KPC mice were implanted into the pancreas of C57BL/6J mice. Four to eight weeks later, tumors were harvested, and stromal and immune components were evaluated. The efficacy of Minnelide, a novel compound which has been shown to be effective against pancreatic cancer in a number of preclinical murine models, was evaluated. In our model, consistent tumor growth and metastases were observed. Tumors demonstrated intense desmoplasia and leukocytic infiltration which was comparable to that in the genetically engineered KPC model and significantly more than that observed in KPC tumor-derived cell line implantation model. Minnelide treatment resulted in a significant decrease in the tumor weight and volume. This novel model demonstrates a consistent growth rate and tumor-associated mortality and recapitulates the tumor microenvironment. This convenient model is a valuable tool to evaluate novel therapies. Keywords Pancreatic cancer Immunocompetent mouse model Stroma Syngeneic