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A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis

Oncogene volume 22, pages 1771–1782 (2003)Cite this article

Abstract

In the present study, a model system for studying the role of nitric oxide (NO) in tumor growth and metastasis was reported. Incubation of Panc02 murine pancreatic adenocarcinoma cells in vitro with cytokines and interferon led to heterogeneous expression of NO synthase II (NOS II) protein. Clonal sublines expressing different levels of NOS II were then established using a limited dilution technique. After orthotopical implantation into the pancreas of syngeneic C57BL/6 mice, clones with a low level of NOS II expression produced tumors in pancreas, metastasized to the liver, and formed ascites, whereas those having a high level of NOS II expression did not. Liver-metastasis variants having low to high metastatic ability were also established using in vivo/in vitro passage. Compared with parental Panc02 cells exhibiting a high level of NOS II expression, these variants had a decreased level of NOS II expression. Furthermore, the heterogeneous Panc02 cells were injected intravenously into a large number of syngeneic mice. Variants that metastasized to the liver, lung, skin, peritoneum, ovary, and lymph nodes were established. All of the metastatic variants exhibited a lower level of NOS II expression than the parental Panc02 cell line did. However, the phenotypes of NOS II induction and metastatic ability were unstable. Multiple in vitro/in vivo selection led to stable low NOS II expression and high metastatic potential. Finally, to further confirm the role of NOS II expression derived from tumor cells in metastasis, poorly metastatic Panc02-H0 and highly metastatic Panc02-H7 cells were injected into the pancreas of syngeneic NOS II−/− mice, and groups of mice received i.p. injections of either phosphate-buffered saline or L-N6-(1-iminoethyl) lysine. Inhibition of NOS II activity in vivo significantly promoted distant liver metastasis. Collectively, these data show that NOS II expression is highly heterogeneous and dynamically regulated, which can directly influence tumor growth and metastasis.

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Acknowledgements

This work was supported in part by Grant 1R01-CA093829 from the National Cancer Institute, National Institutes of Health and the Research Project Grant #RPG-00-054-01-CMS from the American Cancer Society (to KX). We thank Judy King for expert help in the preparation of this manuscript and Don Norwood for editorial comments.

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Authors and Affiliations

  1. Department of Gastrointestinal Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, Texas, USA

    Bailiang Wang, Daoyan Wei, Vanessa E Crum, Erica L Richardson, Henry H Xiong, Yu Luo, James L Abbruzzese & Keping Xie

  2. Department of Neurosurgery, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, Texas, USA

    Suyun Huang

  3. Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, Texas, USA

    Suyun Huang & Keping Xie

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  1. Bailiang Wang
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Correspondence to Keping Xie.

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Wang, B., Wei, D., Crum, V. et al. A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis. Oncogene 22, 1771–1782 (2003). https://doi.org/10.1038/sj.onc.1206386

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