A mouse model for neuroendocrine tumorigenesis
To study the genetic and molecular basis for the development of neuroendocrine tumors, we generated a colony of Rb+/– p53+/– mice that develop a tumor spectrum characteristic of the human multiple endocrine neoplasia (MEN1 and MEN2) syndromes, including pituitary tumors, medullary thyroid cancer (MT...
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| Format: | Dissertation |
| Language: | English |
| Published: |
ProQuest Dissertations & Theses
01-01-2000
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| Online Access: | Get full text |
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| Summary: | To study the genetic and molecular basis for the development of neuroendocrine tumors, we generated a colony of Rb+/– p53+/– mice that develop a tumor spectrum characteristic of the human multiple endocrine neoplasia (MEN1 and MEN2) syndromes, including pituitary tumors, medullary thyroid cancer (MTC), and pancreatic islet cell cancer. In this study, we demonstrated that loss of RB function occurs in the pituitary and thyroid endocrine tumors observed in these mice. In addition, we demonstrated that acquired somatic mutations of the Ret gene were associated with the murine MTC that developed in 6/9 Rb+/– p53+/– mice. In contrast, we did not detect Ret or MEN1 gene mutations in the pituitary tumors that developed in these mice. To study whether the loss of RB has an effect on murine lung tumor histology, we backcrossed the Rb+/– p53+/– genotype into the A/J mouse strain, which is more susceptible to lung cancer. We found that A/J x 129 Rb+/– p53+/– mice developed a high frequency of lung tumors that exhibited loss of RB function instead of loss of p16 function, which contrasts with endogenous murine lung tumors that result from mutations in the p16 but not the Rb gene. Although these tumors developed faster than endogenous lung tumors observed in wildtype A/J mice, they were of non-neuroendocrine origin and histologically similar to what has been observed in p16–/– murine lung tumors. Our study demonstrates the ability of the gene knockout model to recapitulate somatic multi-step tumorigenesis in murine MTC and suggests that the development of selected murine neuroendocrine tumors requires the mutational dysregulation of at least two different pathways. In addition, our study suggests that inactivation of Rb versus p16 in mouse lung does not predetermine the development of murine neuroendocrine lung tumors. |
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| ISBN: | 0599746726 9780599746725 |