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Inhibition of osteopontin reduces liver metastasis of human pancreatic cancer xenografts injected into the spleen in a mouse model

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Abstract

Purpose

Pancreatic cancer is associated with the poorest prognosis of any digestive cancer due to the high incidence of liver metastasis. This study evaluated the possibility that osteopontin (OPN) RNA interference (RNAi) and anti-OPN antibody (Ab) could have antimetastatic effects.

Methods

The differential gene expression was measured in a parental cell line, HPC-3, and an established highly liver metastatic cell line, HPC-3H4. This study investigated the effect of OPN RNAi and anti-OPN Ab on the metastatic ability of HPC-3H4 to the liver. An OPN RNAi-expressing vector was introduced into HPC-3H4 cells (HPC-3H4/miOPN), in which OPN production was reduced to the level of the parental HPC-3 cells. Finally, the ability of anti-OPN Ab to suppress liver metastasis was investigated.

Results

Osteopontin was upregulated 11.1-fold in HPC-3H4 in comparison to HPC-3. The metastatic rate of HPC-3H4/miOPN was significantly reduced to 25% in comparison to the 100% metastatic rate of HPC-3H4 and control HPC-3H4/miNeg cells (P < 0.01). The metastatic rate of the group given anti-OPN Ab was 50%.

Conclusion

OPN RNAi and anti-OPN Ab had remarkable inhibitory effects against liver metastasis by the pancreatic cancer cell line.

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References

  1. Yokoyama Y, Nimura Y, Nagino M. Advances in the treatment of pancreatic cancer: Limitations of surgery and evaluation of new therapeutic strategies. Surg Today 2009;39:466–475.

    Article  PubMed  Google Scholar 

  2. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer. JAMA 2007;297:267–277.

    Article  CAS  PubMed  Google Scholar 

  3. O’Brien ER, Garvin MR, Stewart DK, Hinohara T, Simpson JB, Schwartz SM, et al. Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Artesioscler Thromb 1994;14:1648–1656.

    Google Scholar 

  4. Weber GF, Ashkar S, Glimcher MJ, Cantor H. Receptor-ligand interaction between CD44 and osteopontin(Eta-1). Science 1996;271:509–512.

    Article  CAS  PubMed  Google Scholar 

  5. Bayless KJ, Davis GE. Identification of dual α4β1 integrin binding sites within a 38 amino acid domain in the N-terminal thrombin fragment of human osteopontin. J Biol Chem 2 2001;276:13483–13489.

    Article  CAS  Google Scholar 

  6. Oates AJ, Barraclough R, Rudland PS. The identification of osteopontin as a metastasis-related gene product in a rodent mammary tumour model. Oncogene 1996;13:97–104.

    CAS  PubMed  Google Scholar 

  7. Hotte SJ, Winquist EW, Stitt L, Wilson SM, Chambers AF. Plasma osteopontin: associations with survival and metastasis to bone in men with hormone-refractory prostate carcinoma. Cancer 2002;95:506–512.

    Article  CAS  PubMed  Google Scholar 

  8. Nishimori H, Yasoshima T, Denno R, Shishido T, Hata F, Honma T, et al. A new peritoneal dissemination model established from human pancreatic cancer cell line. Pancreas 2001;22:348–356.

    Article  CAS  PubMed  Google Scholar 

  9. Shishido T, Yasoshima T, Hirata K, Denno R, Mukaiya M, Ura H, et al. Establishment and characterization of human pancreatic carcinoma lines with a high metastatic potential in the liver of nude mice. Surg Today 1999;29:519–525.

    Article  CAS  PubMed  Google Scholar 

  10. Nishimori H, Yasoshima T, Hata F, Denno R, Yanai Y, Nomura H, et al. A novel nude mouse model of liver metastasis and peritoneal dissemination from the same human pancreatic cancer line. Pancreas 2002;24:242–250.

    Article  PubMed  Google Scholar 

  11. Nomura H, Nishimori H, Yasoshima T, Hata F, Sogahata K, Tanaka H, et al. A new experimental mouse model of peritoneal dissemination of human gastric cancer cells: analysis of the mechanism of peritoneal dissemination using cDNA macroarrays. Jpn J Cancer Res 2001;92:748–754.

    CAS  PubMed  Google Scholar 

  12. Nomura H, Nishimori H, Yasoshima T, Hata F, Tanaka H, Nakajima F, et al. A new liver metastatic and peritoneal dissemination model established from the same human pancreatic cancer cell line: analysis using cDNA macroarray. Clin Exp Metastasis 2002;19:391–399.

    Article  CAS  PubMed  Google Scholar 

  13. Yamaguchi K, Ura H, Yasoshima T, Shishido T, Denno R, Hirata K. Establishment and characterization of a human gastric carcinoma cell line that is highly metastatic to lymph nodes. J Exp Clin Cancer Res 2000;19:113–120.

    CAS  PubMed  Google Scholar 

  14. Ohno K, Hata F, Nishimori H, Yasoshima T, Yanai Y, Sogahata K, et al. Metastatic-associated biological properties and differential gene expression profiles in established highly liver and peritoneal metastatic cell lines of human pancreatic cancer. J Exp Clin Cancer Res 2003;22:623–631.

    CAS  PubMed  Google Scholar 

  15. Yamamoto N, Sakai F, Kon S, Morimoto J, Kimura C, Yamazaki H, et al. Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis. J Clin Invest 2003;112:181–188.

    CAS  PubMed  Google Scholar 

  16. Thalmann GN, Sikes RA, Devoll RE, Kiefer JA, Markwalder R, Klima I, et al. Osteopontin: possible role in prostate cancer progression. Clin Cancer Res 1999;5:2271–2277.

    CAS  PubMed  Google Scholar 

  17. Wu Y, Denhardt DT, Rittling SR. Osteopontin is required for full expression of the transformed phenotype by the ras oncogene. Br J Cancer 2000;83:156–163.

    Article  CAS  PubMed  Google Scholar 

  18. Ophascharoensuk V, Giachelli CM, Gordon K, Hughes J, Pichler R, Brown P, et al. Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int 1999;56:571–580.

    Article  CAS  PubMed  Google Scholar 

  19. Rudland PS, Platt-Higgins A, El-Tanani M, De Silva Rudland S, Barraclough R, Winstanley JH, et al. Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer. Cancer Res 2002;62:3417–3427.

    CAS  PubMed  Google Scholar 

  20. Agrawal D, Chen T, Irby R, Quackenbush J, Chambers AF, Szabo M, et al. Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling. J Natl Cancer Inst 2002;94:513–521.

    CAS  PubMed  Google Scholar 

  21. Kim YW, Park YK, Lee J, Ko SW, Yang MH. Expression of osteopontin and osteonectin in breast cancer. J Korean Med Sci 1998;13:652–657.

    CAS  PubMed  Google Scholar 

  22. Shijubo N, Uede T, Kon S, Maeda M, Segawa T, Imada A, et al. Vascular Endothelial Growth Factor and Osteopontin in Stage I Lung Adenocarcinoma. Am J Respir Crit Care Med 1999;160:1269–1273.

    CAS  PubMed  Google Scholar 

  23. Kim JH, Skates SJ, Uede T, Wong KK, Schorge JO, Feltmate CM, et al. Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 2002;287:1671–1679.

    Article  CAS  PubMed  Google Scholar 

  24. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003;9:416–423.

    Article  CAS  PubMed  Google Scholar 

  25. Mi Z, Guo H, Russell MB, Liu Y, Sullenger BA, Kuo PC. RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells. Mol Ther 2008;17:153–161.

    Article  PubMed  CAS  Google Scholar 

  26. Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, et al. Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology 2008;48:1834–1842.

    Article  CAS  PubMed  Google Scholar 

  27. Zhao J, Dong L, Lu B, Wu G, Xu D, Chen J, et al. Downregulation of osteopontin suppresses growth and metastasis of hepatocellular carcinoma via induction of apoptosis. Gastroenterology 2008;135:956–968.

    Article  CAS  PubMed  Google Scholar 

  28. Koopmann J, Fedarko NS, Jain A, Maitra A, Iacobuzio-Donahue C, Rahman A, et al. Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2004;13:487–491.

    CAS  PubMed  Google Scholar 

  29. Kolb A, Kleeff J, Guweidhi A, Esposito I, Giese NA, Adwan H, et al. Osteopontin influences the invasiveness of pancreatic cancer cells and is increased in neoplastic and inflammatory conditions. Cancer Biol Ther 2005;4:740–746.

    Article  CAS  PubMed  Google Scholar 

  30. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  31. Tuck AB, Hota C, Chambers AF. Osteopontin (OPN)-induced increase in human mammary epithelial cell invasiveness is urokinase (uPA)-dependent. Breast Cancer Res Threat 2001;70:197–204.

    Article  CAS  Google Scholar 

  32. Behrend EI, Craig AM, Wilson SM, Denhardt DT, Chambers AF. Reduced malignancy of ras-transformed NIH 3T3 cells expressing antisense osteopontin RNA. Cancer Res 1994;54:832–837.

    CAS  PubMed  Google Scholar 

  33. Miyauchi A, Alvarez J, Greenfield EM, Teti A, Grano M, Colucci S, et al. Recognition of Osteopontin and related peptide by anαβ3 integrin stimulates immediate cell signals in osteoclasts. J Biol Chem 1 1991;266:20369–203674.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Sapporo Medical University School of Medicine, S1W17, Chuo-ku, Sapporo, 060-8556, Japan

    Keisuke Ohno, Hidefumi Nishimori, Rika Fukui, Koichi Okuya, Yasutoshi Kimura & Koichi Hirata

  2. Department of Pathology, Sapporo Medical University School of Medicine, S1W17, Chuo-ku, Sapporo, 060-8556, Japan

    Kenjiro Kamiguchi & Noriyuki Sato

  3. Department of Nursing, Sapporo Medical University School of Health Sciences, Sapporo, Japan

    Ryuichi Denno

  4. Laboratory of Sapporo Cancer and Integrative Medicine, Shinsapporo Keiaikai Hospital, Sapporo, Japan

    Takahiro Yasoshima

  5. Doto Hospital, Sapporo, Japan

    Fumitake Hata

  6. Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Shigeyuki Kon & Toshimitsu Uede

Authors
  1. Keisuke Ohno
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  2. Hidefumi Nishimori
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  3. Takahiro Yasoshima
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Ohno, K., Nishimori, H., Yasoshima, T. et al. Inhibition of osteopontin reduces liver metastasis of human pancreatic cancer xenografts injected into the spleen in a mouse model. Surg Today 40, 347–356 (2010). https://doi.org/10.1007/s00595-009-4082-x

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  • DOI: https://doi.org/10.1007/s00595-009-4082-x

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