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(American Journal of Pathology. 2005;167:1093-1103.)
© 2005 American Society for Investigative Pathology

Isolation and Growth of Smooth Muscle-Like Cells Derived from Tuberous Sclerosis Complex-2 Human Renal Angiomyolipoma

Epidermal Growth Factor Is the Required Growth Factor

Elena Lesma^*, Vera Grande^*, Stephana Carelli^*, Diego Brancaccio, Maria Paola Canevini, Rosa Maria Alfano, Guido Coggi, Anna Maria Di Giulio^* and Alfredo Gorio^*

From the Laboratory of Pharmacology^* and Pathological Anatomy Section, and Department of Medicine, Surgery, and Dentistry, Faculty of Medicine, University of Milan, Milan; and San Paolo Hospital, Milan, Italy

Tuberous sclerosis complex (TSC) is a tumor suppressor gene disorder characterized by mutations in the TSC1 or TSC2 genes. These mutations lead to the development of benign tumors involving smooth muscle cells, causing life-threatening lymphangioleiomyomatosis. We isolated and characterized two types of cells bearing a mutation in TSC2 exon 18 from a renal angiomyolipoma of a TSC patient: one population of -actin-positive smooth muscle-like cells with loss of heterozygosity for the TSC2 gene (A⁺ cells) and another of nonloss of heterozygosity keratin 8/18-positive epithelial-like cells (R⁺ cells). Unlike control aortic vascular smooth muscle cells, A⁺ cells required epidermal growth factor (EGF) to grow and substituting EGF with insulin-like growth factor (IGF)-1 failed to increase the cell number; however, omission of EGF did not cause cell loss. The A⁺ cells constantly released IGF-1 into the culture medium and constitutively showed a high degree of S6K phosphorylation even when grown in serum-free medium. Exposure to antibodies against EGF and IGF-1 receptors caused a rapid loss of A⁺ cells: 50% by 5 days and 100% by 12 days. Signal transduction mediated by EGF and IGF-I receptors is therefore involved in A⁺ cell survival. These results may offer a novel therapeutic perspective for the treatment of TSC complications and lymphangioleiomyomatosis.

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