Tuberous Sclerosis Complex (TSC) is a multi-organ disorder caused by mutations of the TSC1 or TSC2 genes. A key function of these genes is to inhibit mTORC1 (mechanistic target of rapamycin complex 1) kinase signaling. Cells
deficient for TSC1 or TSC2 have increased mTORC1 signaling and give rise to benign tumors though as a rule, true malignancies are rarely seen. In contrast,
other disorders with increased mTOR signaling typically have overt malignancies. A better understanding of genetic mechanisms
that govern the transformation to benign cells to malignant ones is critical to understand cancer pathogenesis. We generated
a zebrafish model of TSC and cancer progression by placing a heterozygous mutation of the tsc2 gene in a p53 mutant background. Unlike tsc2 heterozygous mutant zebrafish that never exhibited cancers, compound tsc2;p53 mutants had malignant tumors in multiple organs. Tumorigenesis was enhanced compared to p53 mutant zebrafish. p53 mutants also had increased mTORC1 signaling that was further enhanced in tsc2;p53 compound mutants. We found increased expression of Hif1-a, Hif2-a and Vegf-c in tsc2;p53 compound mutant zebrafish. Expression of these proteins likely underlies the increased angiogenesis seen in compound mutant
zebrafish compared to p53 mutants and may further drive cancer progression. Treatment of p53 and compound mutant zebrafish with the mTORC1 inhibitor rapamycin caused rapid shrinkage of tumor size and decreased caliber
of tumor associated blood vessels.
This is the first report using an animal model to show interactions of tsc2/mTORC1 and p53 during tumorigenesis. These results may explain why patients with TSC rarely have malignant tumors but also
suggest that cancer arising in patients without TSC may be influenced by the status of TSC1/TSC2 mutations and be potentially treatable with mTORC1 inhibitors.