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A unique allogenic model of metastatic pheochromocytoma: PC12 rat pheochromocytoma xenografts to nude mice and establishment of metastases-derived PC12 variants

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Abstract

Local invasion and metastatic spread to distant sites are major causes of death in patients with malignant pheochromocytoma. Since appropriate in vivo models do not exist, little is known about the underlying mech-anisms of tumor growth and invasion. We, therefore, developed an animal model of malignant pheochromo-cytoma and established organotropic metastatic variants of PC12 rat pheochromocytoma cells. PC12 cells were established as xenografts to BALB/c NCR-NU mice. Subsequent to development of tumors or metas-tases, primary cultures from local tumors, metastases to lymph nodes, lungs and liver were established. These were subcultured in vitro and reinjected for up to five successive in vivo/in vitro cycles. Xenografted PC12 cells grew tumors with a doubling time of 6.78 ± 0.58 days during log phase of tumor growth, killing hosts within 5-12 weeks depending on the experimental conditions. Tumors reproducibly metastasized to lymph nodes and the lung. Spontaneous metastases to the liver were not observed, but were achieved by intrasplenic injection of parent PC12 cells. In vitro, the metastatic cell lines displayed striking differences in morphology, overall growth patterns and nutritional requirements as well as binding to purified extracellular matrix pro-teins compared to the parent cell line. In vivo, the metastatic variants showed marked enhancement of metastatic ability. This is the first report of PC12 rat pheochromocytoma cells to exhibit the malignant phe-notype in vivo. We also established variant PC12 cell lines that preferentially metastasized to specific sites and that had acquired different in vitro behavior and ability to metastasize. This unique model system should be useful for further studies relating to the invasion and metastases of pheochromocytoma and may prove valuable for investigations of novel antineoplastic therapies in vitro and in vivo. © Rapid Science Ltd.

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Authors and Affiliations

  1. Departments of Surgery, Philipps-University of Marburg, Marburg, Germany

    Andreas Zielke & Matthias Rothmund

  2. Division of Gastroenterology, Henry Ford Hospital, Detroit, MI, USA

    Robert S. Bresalier & Quan-Yang Duh

  3. Mount Zion Medical Center of the University of California at San Francisco, San Francisco, USA

    Allan E. Siperstein & Orlo H. Clark

Authors
  1. Andreas Zielke
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  2. Robert S. Bresalier
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  3. Allan E. Siperstein
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  4. Orlo H. Clark
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  5. Matthias Rothmund
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  6. Quan-Yang Duh
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Zielke, A., Bresalier, R.S., Siperstein, A.E. et al. A unique allogenic model of metastatic pheochromocytoma: PC12 rat pheochromocytoma xenografts to nude mice and establishment of metastases-derived PC12 variants. Clin Exp Metastasis 16, 341–352 (1998). https://doi.org/10.1023/A:1006565530421

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