Animal models of lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC)

Abstract

Animal models of lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC) are highly desired to enable detailed investigation of the pathogenesis of these diseases. Multiple rats and mice have been generated in which a mutation similar to that occurring in TSC patients is present in an allele of Tsc1 or Tsc2. Unfortunately, these mice do not develop pathologic lesions that match those seen in LAM or TSC. However, these Tsc rodent models have been useful in confirming the two-hit model of tumor development in TSC, and in providing systems in which therapeutic trials (e.g., rapamycin) can be performed. In addition, conditional alleles of both Tsc1 and Tsc2 have provided the opportunity to target loss of these genes to specific tissues and organs, to probe the in vivo function of these genes, and attempt to generate better models. Efforts to generate an authentic LAM model are impeded by a lack of understanding of the cell of origin of this process. However, ongoing studies provide hope that such a model will be generated in the coming years.

FIG. 1.

Tsc mouse liver hemangiomas. H&E stained pictures of liver hemangiomas from the Tsc1^+/− (A, B: 14 months old) and Tsc2^+/− mice (C, D: 12 months old) are shown. Note dilated aberrant, disorganized vascular channels with prominent hyperplastic endothelium, containing red blood cells. In C, some vessel lumens approach 1 mm in diameter, very large for the mouse. Scale bars 50 μm.

FIG. 2.

Tsc mouse kidney cystadenomas. H&E stained pictures of kidney cystadenomas from the Tsc1^+/− (A, B; 14 months old) and Tsc2^+/− mice (C, D; 12 months old) are shown. Note the prominent hyperplastic epithelial cells making up these tumors, with cell fragments in the lumen of some cystic regions. In B, note lack of organization and nuclear and cytoplasmic pleomorphism, consistent with malignancy. In all images, note prominent vascularization. Scale bars 50 μm.