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RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/- mice
A Y Nikitin1, M I Juárez-Pérez, S Li
1Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center, San Antonio, TX 78245-3207, USA.
Abstract:
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.
Insights
Loss of the retinoblastoma susceptibility gene (RB) function drives neuroendocrine tumors in mice. Restoring RB function, even late, can suppress tumor growth and metastasis, offering a potential cancer treatment strategy.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Alterations in retinoblastoma susceptibility gene (RB) pathways are frequent in human cancers.
- Loss of RB gene function is implicated in tumor development.
Purpose of the Study:
- To investigate the role of RB gene loss in neuroendocrine neoplasia.
- To evaluate the therapeutic potential of restoring RB function in established tumors.
Main Methods:
- Utilized a mouse model with a single functional copy of the Rb gene (Rb+/-).
- Monitored tumor development and metastasis in Rb+/- mice.
- Assessed the effect of introducing a human RB transgene and RB complementary DNA (cDNA) therapy.
Main Results:
- Rb+/- mice developed multiple neuroendocrine tumors, including pituitary, thyroid, and adrenal neoplasms.
- Tumors showed varying degrees of malignancy, with high rates of lung metastasis from thyroid carcinomas.
- Expression of an RB transgene and RB cDNA therapy significantly suppressed tumor progression and reduced lung metastases.
Conclusions:
- The initial loss of RB function is critical for the progression of neuroendocrine tumors.
- Restoring RB function can be an effective strategy for treating RB-deficient disseminated cancers.
- RB gene therapy holds promise for treating human cancers with RB pathway alterations.