Development of a LAM model by using human TSC2-/- cells derived from a renal angiomyolipoma. A pharmacological evaluation

Lymphangioleiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by the diffuse proliferation and invasion of abnormal smooth muscle cells (LAM cells) in involved organs, cystic degeneration of lung parenchyma, infiltration of the axial lymphatics, and renal tumors (e.g. angiomyolipomas [AML]). LAM affects between 30-40% of women with tuberous sclerosis complex (TSC), a tumor suppressor gene syndrome characterized by the development of benign tumors e.g., renal AML. TSC is caused by mutations in the TSC1 or TSC2 genes, encoding hamartin and tuberin, respectively, which regulate mammalian target of rapamycin (mTOR).

We have recently reported the novel finding that the in vitro growth of smooth muscle-like cells derived from the renal AML form a TSC2 patient (TSC2-/- ASM cells) depends on the availability of epidermal growth factor (EGF) and functionality of EGR receptor (EGFR). At present, there are no animal models of disease involving the lung. Developing a model to study metastasis of TSC tumor cells may help to explain how they migrate from tissue to tissue and why the LAM cells metastasize to the lung only in women. Our preliminary data using a mouse model injected with TSC2-/- ASM cells, by i.p. and endonasal administration, demonstrated cystic lung degeneration and lymphatic infiltration of the lung similar to that seen in LAM. Moreover, TSC2-/- ASM cells were found in lymph nodes.