LAM/TSC cells cause pulmonary nodule development by endonasal administration in nude mice

Tuberous Sclerosis Complex (TSC) is characterized by the multiorgan development of benign tumors and is related to lymphangioleiomyomatosis (LAM), a rare disease caused by abnormal growth of smooth muscle (ASM) cells within lung parenchyma and axial lymphatics. From an angiomyolipoma of a TSC2 patient and from chylous of a TSC-associated LAM patient, TSC2-/- ASM and LAM/TSC cells, respectively, have been isolated. Proliferation depends on epidermal growth factor (EGF) and antibodies to EGF receptor (anti-EGFR) caused cell death. We developed animal models by endonasal administration of TSC2-/- ASM or LAM/TSC cells in immunodeficient female athymic nude mice. Both cells were infiltrated into pulmonary alveolar walls where they caused enlarged alveolar spaces. Only LAM/TSC cell administration was associated to nodules development in lung parenchyma in 30 weeks. Pulmonary nodules arose in 46% of LAM/TSC cell administrated mice. This percentage significantly decreased after anti-EGFR (25%) or rapamycin (33%) treatments. Pulmonary nodules were localized near lymphatic and blood vessels or bronchioli and showed positivity to phospho-S6, and estrogen and progesterone receptors. Within the nodules we identified human LAM/TSC cells. In conclusion, LAM/TSC cells, but not TSC2-/- ASM cells, caused pulmonary nodule formation. Rapamycin and more significantly anti-EGFR antibody reduced the number of pulmonary metastases.