Few genes are associated with the capability of pancreatic ductal adenocarcinoma cells to grow in the liver of nude rats

Eyol,Ergül; Murtaga,Ahmed; Zhivkova-Galunska,Maria; Georges,Rania; Zepp,Michael; Djandji,Dominik; Kleeff,Jörg; Berger,Martin  R.; Adwan,Hassan

doi:10.3892/or.2012.2049

Few genes are associated with the capability of pancreatic ductal adenocarcinoma cells to grow in the liver of nude rats

Authors:
- Ergül Eyol
- Ahmed Murtaga
- Maria Zhivkova-Galunska
- Rania Georges
- Michael Zepp
- Dominik Djandji
- Jörg Kleeff
- Martin R. Berger
- Hassan Adwan
View Affiliations

Affiliations: Toxicology and Chemotherapy Unit, German Cancer Research Center, G401, Heidelberg, Germany, German Cancer Research Center, Molecular Immunology, Heidelberg, Germany, Department of General Surgery, Technical University of Munich, Munich, German
Published online on: September 20, 2012 https://doi.org/10.3892/or.2012.2049
Pages: 2177-2187

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Owing to aggressiveness and chemoresistance, pancreatic ductal adenocarcinoma (PDAC) is characterised by a poor prognosis. To address this disease-specific dilemma we aimed to establish animal models, which can be used for identifying new specific tumor markers, as well as serving as tools for potential therapeutic approaches. From a panel of sixteen pancreatic cancer cell lines, two human (Suit2-007 and Suit2-013) and a rat (ASML) cell line were selected for their properties to grow in the liver of male RNU rats and mimic liver metastasis of PDAC. For better monitoring of metastatic tumor growth in vivo, all three pancreatic cancer cell lines were stably transfected with eGFP and luciferase marker genes. In addition, the mRNA expression profile of 13 human PDAC cell lines was analyzed by BeadChip array analysis. Only 33 genes and 5 signaling pathways were identified as significantly associated with the ability of the cell lines to grow initially and/or consistently in rat liver. Only a minority of these genes (osteopontin, matrix metalloproteinase-1 and insulin-like growth factor 1) has been intensively studied and shown to be closely related to cancer progression. The function of the remaining 30 genes ranges from moderate to poorly investigated, and their function in cancer progression is still unclear. The ensuing three pancreatic cancer liver metastasis models vary in their aggressiveness and macroscopic growth. They will be used for preclinical evaluation of new therapeutic approaches aiming at the genes identified.

View Figures

View References

1	Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin. 54:8–29. 2004. View Article : Google Scholar
2	Ghaneh P, Kawesha A, Howes N, Jones L and Neoptolemos JP: Adjuvant therapy for pancreatic cancer. World J Surg. 23:937–945. 1999. View Article : Google Scholar
3	Alanen KA and Joensuu H: Long-term survival after pancreatic adenocarcinoma - often a misdiagnosis? Br J Cancer. 68:1004–1005. 1993. View Article : Google Scholar : PubMed/NCBI
4	Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar
5	Friess H, Ding J, Kleeff J, et al: Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer. Cell Mol Life Sci. 60:1180–1199. 2003.PubMed/NCBI
6	Kayed H, Kleeff J, Keleg S, et al: Indian hedgehog signaling pathway: expression and regulation in pancreatic cancer. Int J Cancer. 110:668–676. 2004. View Article : Google Scholar : PubMed/NCBI
7	Bardeesy N and DePinho RA: Pancreatic cancer biology and genetics. Nat Rev Cancer. 2:897–909. 2002. View Article : Google Scholar
8	Hansel DE, Kern SE and Hruban RH: Molecular pathogenesis of pancreatic cancer. Annu Rev Genomics Hum Genet. 4:237–256. 2003. View Article : Google Scholar : PubMed/NCBI
9	Matzku S, Komitowski D, Mildenberger M and Zoller M: Characterization of BSp73, a spontaneous rat tumor and its in vivo selected variants showing different metastasizing capacities. Invasion Metastasis. 3:109–123. 1983.PubMed/NCBI
10	Katz MH, Takimoto S, Spivack D, Moossa AR, Hoffman RM and Bouvet M: A novel red fluorescent protein orthotopic pancreatic cancer model for the preclinical evaluation of chemotherapeutics. J Surg Res. 113:151–160. 2003. View Article : Google Scholar : PubMed/NCBI
11	Sun FX, Tohgo A, Bouvet M, Yagi S, Nassirpour R, Moossa AR and Hoffman RM: Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model. Cancer Res. 63:80–85. 2003.PubMed/NCBI
12	Marincola FM, Drucker BJ, Siao DY, Hough KL and Holder WD Jr: The nude mouse as a model for the study of human pancreatic cancer. J Surg Res. 47:520–529. 1989. View Article : Google Scholar : PubMed/NCBI
13	Jimenez RE, Hartwig W, Antoniu BA, Compton CC, Warshaw AL and Fernandez-Del CC: Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control. Ann Surg. 231:644–654. 2000. View Article : Google Scholar : PubMed/NCBI
14	Tzanakakis GN, Margioris AN, Tsatsakis AM and Vezeridis MP: The metastatic potential of human pancreatic cell lines in the liver of nude mice correlates well with cathepsin B activity. Int J Gastrointest Cancer. 34:27–38. 2003. View Article : Google Scholar : PubMed/NCBI
15	Vernejoul F, Faure P, Benali N, et al: Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models. Cancer Res. 62:6124–6131. 2002.PubMed/NCBI
16	Samnick S, Romeike BF, Kubuschok B, et al: p-[123I]iodo-L-phenylalanine for detection of pancreatic cancer: basic investigations of the uptake characteristics in primary human pancreatic tumour cells and evaluation in in vivo models of human pancreatic adenocarcinoma. Eur J Nucl Med Mol Imaging. 31:532–541. 2004.
17	Raz A, Zoller M and Ben Z: Cell configuration and adhesive properties of metastasizing and non-metastasizing BSp73 rat adenocarcinoma cells. Exp Cell Res. 162:127–141. 1986. View Article : Google Scholar : PubMed/NCBI
18	Tuveson DA, Zhu L, Gopinathan A, et al: Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma. Cancer Res. 66:242–247. 2006. View Article : Google Scholar
19	Kokkinakis DM, Ahmed MM, Chendil D, Moschel RC and Pegg AE: Sensitization of pancreatic tumor xenografts to carmustine and temozolomide by inactivation of their O6-Methylguanine-DNA methyltransferase with O6-benzylguanine or O6-benzyl-2′-deoxyguanosine. Clin Cancer Res. 9:3801–3807. 2003.
20	Ito D, Fujimoto K, Mori T, et al: In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Int J Cancer. 118:2337–2343. 2006. View Article : Google Scholar : PubMed/NCBI
21	Sausville EA and Burger AM: Contributions of human tumor xenografts to anticancer drug development. Cancer Res. 66:3351–3354. 2006. View Article : Google Scholar : PubMed/NCBI
22	Eberwine J, Yeh H, Miyashiro K, et al: Analysis of gene expression in single live neurons. Proc Natl Acad Sci USA. 89:3010–3014. 1992. View Article : Google Scholar : PubMed/NCBI
23	Smyth GK: Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 3:Article 32004.
24	Smyth GK: Limma: linear models for microarray data. Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Gentleman R, Carey V, Dudoit S, Irizarry R and Huber W: Springer; New York: pp. 397–420. 2005, View Article : Google Scholar
25	Goeman JJ, van de Geer SA, de KF and van Houwelingen HC: A global test for groups of genes: testing association with a clinical outcome. Bioinformatics. 20:93–99. 2004. View Article : Google Scholar : PubMed/NCBI
26	Goeman JJ, Oosting J, Cleton-Jansen AM, Anninga JK and van Houwelingen HC: Testing association of a pathway with survival using gene expression data. Bioinformatics. 21:1950–1957. 2005. View Article : Google Scholar : PubMed/NCBI
27	R Development Core Team. A language and environment for statistical computing. R Foundation for Statistical Computing; Vienna: 2011
28	Iwamura T, Katsuki T and Ide K: Establishment and characterization of a human pancreatic cancer cell line (SUIT-2) producing carcinoembryonic antigen and carbohydrate antigen 19-9. Jpn J Cancer Res. 78:54–62. 1987.PubMed/NCBI
29	Taniguchi S, Iwamura T and Katsuki T: Correlation between spontaneous metastatic potential and type I collagenolytic activity in a human pancreatic cancer cell line (SUIT-2) and sublines. Clin Exp Metastasis. 10:259–266. 1992. View Article : Google Scholar : PubMed/NCBI
30	Friess H, Buchler M, Kruger M and Beger HG: Treatment of duct carcinoma of the pancreas with the LH-RH analogue buserelin. Pancreas. 7:516–521. 1992. View Article : Google Scholar : PubMed/NCBI
31	Fedarko NS, Jain A, Karadag A, Van Eman MR and Fisher LW: Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res. 7:4060–4066. 2001.PubMed/NCBI
32	Kolb A, Kleeff J, Guweidhi A, et al: Osteopontin influences the invasiveness of pancreatic cancer cells and is increased in neoplastic and inflammatory conditions. Cancer Biol Ther. 4:740–746. 2005. View Article : Google Scholar : PubMed/NCBI
33	Wong JC, Chan SK, Schaeffer DF, et al: Absence of MMP2 expression correlates with poor clinical outcomes in rectal cancer, and is distinct from MMP1-related outcomes in colon cancer. Clin Cancer Res. 17:4167–4176. 2011. View Article : Google Scholar : PubMed/NCBI
34	Hart K, Landvik NE, Lind H, Skaug V, Haugen A and Zienolddiny S: A combination of functional polymorphisms in the CASP8, MMP1, IL10 and SEPS1 genes affects risk of non-small cell lung cancer. Lung Cancer. 71:123–129. 2011. View Article : Google Scholar : PubMed/NCBI
35	Hoyo C, Murphy SK, Schildkraut JM, et al: IGF2R genetic variants, circulating IGF2 concentrations and colon cancer risk in African Americans and Whites. Dis Markers. 32:133–141. 2012. View Article : Google Scholar : PubMed/NCBI
36	Yee LD, Sabourin CL, Liu L, Li HM, Smith PJ, Seewaldt V and Kniss DA: Peroxisome proliferator-activated receptor gamma activation in human breast cancer. Int J Oncol. 15:967–973. 1999.PubMed/NCBI
37	Guan YF, Zhang YH, Breyer RM, Davis L and Breyer MD: Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death. Neoplasia. 1:330–339. 1999. View Article : Google Scholar
38	Gupta RA, Brockman JA, Sarraf P, Willson TM and DuBois RN: Target genes of peroxisome proliferator-activated receptor gamma in colorectal cancer cells. J Biol Chem. 276:29681–29687. 2001. View Article : Google Scholar : PubMed/NCBI
39	Huxley R, Ansary-Moghaddam A, Berrington de GA, Barzi F and Woodward M: Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 92:2076–2083. 2005. View Article : Google Scholar : PubMed/NCBI
40	Uhlmann ME, Georges RB, Boleij A, Eyol E, Kubarenko A, Adwan H and Berger MR: Influence of osteopontin expression on the metastatic growth of CC531 rat colorectal carcinoma cells in rat liver. Cancer Gene Ther. 18:795–805. 2011. View Article : Google Scholar : PubMed/NCBI
41	Georges RB, Adwan H, Hamdi H, Hielscher T, Linnemann U and Berger MR: The insulin-like growth factor binding proteins 3 and 7 are associated with colorectal cancer and liver metastasis. Cancer Biol Ther. 12:69–79. 2011. View Article : Google Scholar : PubMed/NCBI
42	Georges R, Bergmann F, Hamdi H, et al: Sequential biphasic changes in claudin1 and claudin4 expression are correlated to colorectal cancer progression and liver metastasis. J Cell Mol Med. 16:260–272. 2012. View Article : Google Scholar : PubMed/NCBI
43	Wittmer A, Khazaie K and Berger MR: Quantitative detection of lac-Z-transfected CC531 colon carcinoma cells in an orthotopic rat liver metastasis model. Clin Exp Metastasis. 17:369–376. 1999. View Article : Google Scholar : PubMed/NCBI
44	Ewing J: The Problems of melanoma. Br Med J. 2:852–856. 1930. View Article : Google Scholar
45	Ewing J: Neoplastic diseases. Saunders-Verlag; Philadelphia: pp. 125–129. 1928
46	Paget S: The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8:98–101. 1989.PubMed/NCBI
47	Chishima T, Miyagi Y, Wang X, Yamaoka H, Shimada H, Moossa AR and Hoffman RM: Cancer invasion and micrometastasis visualized in live tissue by green fluorescent protein expression. Cancer Res. 57:2042–2047. 1997.PubMed/NCBI