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Angiogenesis, Metastasis, and the Cellular Microenvironment

Nucleoside Diphosphate Kinase A/nm23-H1 Promotes Metastasis of NB69-Derived Human Neuroblastoma¹

¹ Department of Medicine, ² Rebecca and John Moores Cancer Center, and ³ Animal Care Program, University of California at San Diego, La Jolla, California

Requests for reprints: Christina L. Chang, University of California at San Diego, 4028 Basic Science Building, 9500 Gilman Drive, La Jolla, CA 92093-0688. Phone: 858-822-0307; Fax: 858-822-0301. E-mail: clchang{at}ucsd.edu

Nucleoside diphosphate kinase A (NDPK-A), encoded by the nm23-H1 gene, acts as a metastasis suppressor in certain human tumors such as breast carcinoma. However, evidence also points to NDPK-A functioning as a metastasis promoter in other human tumors including neuroblastoma. In fact, amplification and overexpression of nm23-H1 as well as S120G mutation of NDPK-A (NDPK-A^S120G) have been detected in 14% to 30% of patients with advanced stages of neuroblastoma. To test whether NDPK-A promotes neuroblastoma metastasis, we established stable transfectants and an orthotopic xenograft animal model from the human neuroblastoma NB69 cell line. We demonstrate that overexpressed NDPK-A or NDPK-A^S120G increased both incidence and colonization of neuroblastoma metastasis in animal lungs without significantly affecting primary tumor development. In vitro, these metastasis-associated NDPK-A aberrations abrogated retinoic acid-induced neuronal differentiation while increasing cloning efficiency, cell survival, and colony formation of NB69 derivatives. Furthermore, NDPK-A^S120G reduced cell adhesion and increased cell migration. Compared with its wild-type, NDPK-A^S120G appears more effective in promoting neuroblastoma metastasis. Our results provide the first evidence that NDPK-A behaves as a metastasis promoter at least in human neuroblastoma derived from NB69 cells. The findings not only suggest a prognostic value of NDPK-A in neuroblastoma patients but also caution NDPK-A-targeted treatment for patients with different tumor types.

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