RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/- mice.
Alterations in pathways mediated by retinoblastoma susceptibility gene (RB) product are among the most common in human cancer. Mice with a single copy of the Rb gene are shown to develop a syndrome of multiple neuroendocrine neoplasia. The earliest Rb-deficient atypical cells were identified in the intermediate and anterior lobes of the pituitary, the thyroid and parathyroid glands, and the adrenal medulla within the first 3 months of postnatal development. These cells form gross tumors with various degrees of malignancy by postnatal day 350. By age of 380 days, 84% of Rb+/- mice exhibited lung metastases from C-cell thyroid carcinomas. Expression of a human RB transgene in the Rb+/- mice suppressed carcinogenesis in all tissues studied. Of particular clinical relevance, the frequency of lung metastases also was reduced to 12% in Rb+/- mice by repeated i.v. administration of lipid-entrapped, polycation-condensed RB complementary DNA. Thus, in spite of long latency periods during which secondary alterations can accumulate, the initial loss of Rb function remains essential for tumor progression in multiple types of neuroendocrine cells. Restoration of RB function in humans may prove an effective general approach to the treatment of RB-deficient disseminated tumors.
Nikitin
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AY
Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center, San Antonio, TX 78245-3207, USA.
Juárez-Pérez
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MI
Li
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Huang
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Lee
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WH
D000818:Animals; D002678:Chimera; D016161:Genes, Retinoblastoma; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008822:Mice, Transgenic; D009377:Multiple Endocrine Neoplasia / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics
D016160:Retinoblastoma Protein