Metastatic Progression of Pancreatic Cancer: Changes in Antioxidant Enzymes and Cell Growth

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Abstract
Pancreatic cancer has a dismal prognosis due to the fact that patients present late when metastatic disease is already present. Previous studies have demonstrated that pancreatic cancer cells have decreased levels of MnSOD, which correlates well with increased rates of tumor cell proliferation. Recently, we have found that nude mice injected with MIA PaCa-2 human pancreatic cancer cells in the flank occasionally develop ascites and intra-abdominal metastatic deposits. Mice that developed ascites were sacrificed and the ascites cultured. Necropsy demonstrated metastatic tumors in the retroperitoneum, which were excised, digested, and cultured. Western blots, enzyme activity and enzyme activity gels were performed for manganese superoxide dismutase (MnSOD), copper/zinc (CuZnSOD), catalase, and glutathione peroxidase (GPx) in the ascites cell line, metastatic tumor cell line, MIA PaCa-2 primary pancreatic cancer cell line, and the Capan-1, a metastatic pancreatic cancer cell line. Cell growth, plating efficiency, growth in soft agar and growth in nude mice were determined in the ascites, metastatic tumor, and MIA PaCa-2 cell lines. MnSOD, CuZnSOD, and GPx protein and activity were increased in the ascites, metastatic tumor, and Capan-1 cell lines compared to MIA PaCa-2. The ascites and metastatic tumor cell lines had decreased cell growth, plating efficiency, and growth in soft agar, but the ascites cell line had increased cell growth in 4 and 1% O2 concentrations in vitro and more rapid growth in vivo. Metastatic disease is associated with changes in the content and activity of antioxidant enzymes with an associated change in growth characteristics depending on the O2 concentrations.