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Pheochromocytomas and C-cell thyroid neoplasms in transgenic c-mos mice: a model for the human multiple endocrine
N Schulz1, F Propst, M P Rosenberg
1ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21701.
Abstract:
Transgenic mice carrying and expressing a mos protooncogene, linked to the Moloney murine sarcoma virus long terminal repeat, develop severe neurological defects and lens abnormalities. Here we report that after long latent periods, mice in three of four of these mos transgenic lines develop a high frequency of multicentric pheochromocytomas and/or medullary thyroid neoplasms. The pattern of tumor formation is remarkably similar to the human autosomal dominantly inherited neoplastic syndrome, multiple endocrine neoplasia type 2 (MEN 2), and tumors from these transgenic animals display the same neuroendocrine marker staining pattern as seen in MEN 2. The similarity between the tumor pathologies and presentation patterns of MEN 2 patients and mos transgenic mice suggests that they may arise through related pathways. The type of tumor presentation varies in a line-dependent manner indicating that there is interaction between the transgene and the genetic background. Moreover, when the non-tumor-bearing mos transgenic line is crossed to a different mouse background, the F1 offspring display the MEN 2 phenotype. These studies indicate that penetrance of the autosomal dominant mos transgenic phenotype is dependent on both integration site and background.
Insights
Transgenic mice expressing the mos protooncogene develop tumors resembling human multiple endocrine neoplasia type 2 (MEN 2). Tumor development and type depend on the mos transgene
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- The mos protooncogene plays a role in cell cycle regulation and has been implicated in various cancers.
- Multiple Endocrine Neoplasia type 2 (MEN 2) is a human autosomal dominant disorder characterized by tumors of endocrine glands.
Purpose of the Study:
- To investigate the long-term effects of mos protooncogene expression in transgenic mice.
- To determine if mos protooncogene expression in mice can model human MEN 2.
Main Methods:
- Generation of transgenic mice carrying the mos protooncogene linked to the Moloney murine sarcoma virus long terminal repeat.
- Observation of tumor development and characterization of tumor types and neuroendocrine marker expression.
- Genetic crossing of mos transgenic lines with different mouse backgrounds.
Main Results:
- Three of four mos transgenic mouse lines developed multicentric pheochromocytomas and/or medullary thyroid neoplasms after long latent periods.
- Tumor pathology and presentation patterns in mos transgenic mice closely mimicked human MEN 2.
- Tumorigenesis varied by transgenic line, indicating genetic background interaction.
- Crossing a non-tumorigenic mos line to a different background induced the MEN 2 phenotype in offspring.
Conclusions:
- The mos protooncogene can induce tumors resembling MEN 2 in mice.
- Tumor penetrance and phenotype are influenced by transgene integration site and genetic background.
- Mos transgenic mice serve as a valuable model for studying MEN 2 pathogenesis.