Top

Published in:

01-10-2013 | Original Article

Aspirin prolongs survival and reduces the number of Foxp3⁺ regulatory T cells in a genetically engineered mouse model of pancreatic cancer

Authors: Lars Plassmeier, Richard Knoop, Jens Waldmann, Rebecca Kesselring, Malte Buchholz, Stefan Fichtner-Feigl, Detlef K. Bartsch, Volker Fendrich

Published in: Langenbeck's Archives of Surgery | Issue 7/2013

Abstract

Background and aims

Gemcitabine became the reference regimen for advanced pancreatic cancer after a randomized trial showed significant improvement in the median overall survival. Since then, the combination of gemcitabine with a variety of cytotoxic and targeted agents has generally shown no significant survival advantage as compared with gemcitabine alone. Only the addition of erlotinib to gemcitabine resulted in a significant but very small improvement in overall survival, coming along with a very uncomfortable rash in the patients. Therefore, new adjuvant agents with very low toxic levels are needed. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemotherapeutic potential of aspirin as an adjuvant agent to gemcitabine.

Methods

Drug treatment was initiated at the age of 3 months. LsL-Kras ^G12D; Pdx1-Cre or LsL-Kras ^G12D; LsL-Trp53 ^R172H; Pdx1-Cre transgenic mice were randomly assigned to receive either mock treatment, gemcitabine, or a combination of gemcitabine and aspirin. All mice were treated until death. The effect of aspirin was evaluated by histopathological analyses and immunostaining.

Results

Gemcitabine prolonged overall median survival of LsL-Kras ^G12D; LsL-Trp53 ^R172H; Pdx1-Cre mice by 31 days as compared to mock-treated animals (median survival, 190 vs. 159 days; p = 0.396). Addition of aspirin to gemcitabine even extended the survival for ten more days, leading to a prolonged survival by 41 days, reaching virtually statistical significance versus the control group (median survival, 200 vs. 159 days; p = 0.05). Furthermore, we found that administration of aspirin in combination with gemcitabine reduced the number of Foxp3⁺ regulatory T cells significantly.

Conclusion

In conclusion, we identified aspirin as an effective adjuvant agent to gemcitabine in the treatment of PDAC. While fundamental differences in biology suggest the need for caution in equating mouse tumors with their human counterparts, mouse models nevertheless represent an important source of insight regarding human neoplasia. Further studies are necessary to confirm the hypothesis that aspirin might be an effective well-tolerated chemotherapeutic adjuvant agent for pancreatic cancer.

ACS. Cancer Facts & Figures 2007. 2007

Jemal A, Siegel R, Ward E et al (2006) Cancer statistics, 2006. CA: Cancer J Clin 56:106–130CrossRef

Feldmann G, Maitra A (2008) Molecular genetics of pancreatic ductal adenocarcinomas and recent implications for translational efforts. J Mol Diagn 10:111–122PubMedCrossRef

Burris HA III, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMed

Di Marco M, Di Cicilia R, Macchini M et al (2010) Metastatic pancreatic cancer: is gemcitabine still the best standard treatment? Oncol Rep 23:1183–1192PubMedCrossRef

Conroy T, Desseigne F, Ychou M et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–1825PubMedCrossRef

Colucci G, Giuliani F, Gebbia V et al (2002) Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 94:902–911PubMedCrossRef

Cunningham D, Chau I, Stocken DD et al (2009) Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27:5513–5518PubMedCrossRef

Louvet C, Labianca R, Hammel P et al (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516PubMedCrossRef

10.

Oettle H, Richards D, Ramanathan RK et al (2005) A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unrespectable or metastatic pancreatic cancer. Ann Oncol 16:1639–1645PubMedCrossRef

11.

Rocha Lima CM, Green MR, Rotche R et al (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:3776–3783PubMedCrossRef

12.

Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966PubMedCrossRef

13.

Maitra A, Ashfaq R, Gunn CR, Rahman A, Yeo CJ, Sohn TA, Cameron JL, Hruban RH, Wilentz RE (2002) Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol 118:194–201PubMedCrossRef

14.

Sclabas GM, Uwagawa T, Schmidt C, Hess KR, Evans DB, Abbruzzese JL, Chiao PJ (2005) Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin. Cancer 12:2485–2490CrossRef

15.

Fendrich V, Chen NM, Neef M, Waldmann J, Bucholz M, Feldmann G, Slater EP, Maitra A, Bartsch DK (2010) The angiotensin-I-converting enzyme inhibitor enalapril and aspirin delay progression of pancreatic intraepithelial neoplasia and cancer formation in a genetically engineered mouse model of pancreatic cancer. Gut 59:630–637PubMedCrossRef

16.

Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–450PubMedCrossRef

17.

Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson D (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483PubMedCrossRef

18.

Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, Crowley D, Jacks T (2004) Mutant p53 gain of function in two mouse models of Li–Fraumeni syndrome. Cell 119:847–860PubMedCrossRef

19.

Fendrich V, Schneider R, Maitra A, Jacobsen ID, Opfermann T, Bartsch DK (2011) Detection of precursor lesions of pancreatic adenocarcinoma in PET-CT in a genetically engineered mouse model of pancreatic cancer. Neoplasia 13:180–186PubMed

20.

Dong QG, Sclabas GM, Fujioka S et al (2002) The function of multiple IkappaB: NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene 21:6510–6519PubMedCrossRef

21.

Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265:956–959PubMedCrossRef

22.

Betts G, Jones E, Junaid S, El-Shanawany T, Scurr M, Mizen P, Kumar M, Jones S, Rees B, Williams G, Gallimore A, Godkin A (2012) Suppression of tumour-specific CD4+ T cells by regulatory T cells is associated with progression of human colorectal cancer. Gut 61:1163–1171PubMedCrossRef

23.

Kobayashi N, Kubota K, Kato S, Watanabe S, Shimamura T, Kirikoshi H, Saito S, Ueda M, Endo I, Inayama Y, Maeda S, Nakajima A (2010) FOXP3+ regulatory T cells and tumoral indoleamine 2,3-dioxygenase expression predicts the carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas. Pancreatology 10:631–640PubMedCrossRef

24.

Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grüssel S, Sipos B, Grützmann R, Pilarsky C, Ungefroren H, Saeger HD, Klöppel G, Kabelitz D, Kalthoff H (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67:8344–8350PubMedCrossRef

25.

Van Dyke T, Jacks T (2002) Cancer modeling in the modern era: progress and challenges. Cell 108:135–144PubMedCrossRef

Title: Aspirin prolongs survival and reduces the number of Foxp3+ regulatory T cells in a genetically engineered mouse model of pancreatic cancer
Authors: Lars Plassmeier
Richard Knoop
Jens Waldmann
Rebecca Kesselring
Malte Buchholz
Stefan Fichtner-Feigl
Detlef K. Bartsch
Volker Fendrich
Publication date: 01-10-2013
Publisher: Springer Berlin Heidelberg
Published in: Langenbeck's Archives of Surgery / Issue 7/2013
Print ISSN: 1435-2443
Electronic ISSN: 1435-2451
DOI: https://doi.org/10.1007/s00423-013-1105-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Aspirin prolongs survival and reduces the number of Foxp3⁺ regulatory T cells in a genetically engineered mouse model of pancreatic cancer

Abstract

Background and aims

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background and aims

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 7/2013

Laparoscopic surgery of liver tumors

Prognostic impact of lymph node involvement and the extent of lymphadenectomy (LAD) in adenocarcinoma of the esophagogastric junction (AEG)

Transvaginal specimen removal after laparoscopic distal pancreatic resection

Elevated preoperative C-reactive protein levels are a risk factor for the development of postoperative infectious complications following elective colorectal surgery

Anastomotic leakage after low anterior resection for rectal cancer: comparison of stapled versus compression anastomosis

A proposal for an algorithm enhancing transparency and achieving harmonization for patient selection in rescue allocation for liver allografts in Germany