Abstract
Lymphangioleiomyomatosis (LAM) is a destructive lung disease that can arise sporadically or in adults suffering from the tumor syndrome tuberous sclerosis complex (TSC). Microscopic tumors (‘LAM nodules’) in the lung interstitium arise from lymphatic invasion and metastasis. These consist of smooth muscle-like cells (LAM cells) that exhibit markers of neural crest differentiation and loss of the tumor suppressor protein ‘tuberous sclerosis complex-2’ (TSC2). Consistent with a neural phenotype, expression of the neuropeptide urotensin-II and its receptor was detected in LAM nodules. We hypothesized that loss of TSC2 sensitizes cells to the oncogenic effects of urotensin-II. TSC2-deficient Eker rat uterine leiomyoma ELT3 cells were stably transfected with empty vector or plasmid for the expression of TSC2. Urotensin-II increased cell viability and proliferation in TSC2-deficient cells, but not in TSC2-reconstituted cells. When exposed to urotensin-II, TSC2-deficient cells exhibited greater migration, anchorage-independent cell growth, and matrix invasion. The effects of urotensin-II on TSC2-deficient cells were blocked by the urotensin receptor antagonist SB657510, and accompanied by activation of Erk mitogen-activated protein kinase and focal adhesion kinase. Urotensin-II-induced proliferation and migration were reproduced in TSC2-deficient human angiomyolipoma cells, but not in those stably expressing TSC2. In a mouse xenograft model, SB657510 blocked the growth of established ELT3 tumors, reduced the number of circulating tumor cells, and attenuated the production of VEGF-D, a clinical biomarker of LAM. Urotensin receptor antagonists may be selective therapeutic agents for the treatment of LAM or other neural crest-derived neoplasms featuring loss of TSC2 or increased expression of the urotensin receptor.
Highlights
Tuberous sclerosis complex (TSC) is a neurocutaneous tumor syndrome that occurs in approximately 1 in 6,000 live North American births [1, 2]
To determine whether loss of tuberous sclerosis complex-2’ (TSC2) sensitizes cells to the oncogenic effects of UII, we used TSC2-deficient Eker rat uterine carcinoma (ELT3) cells stably transfected with empty vector (V3) or a plasmid for expression of TSC2 (T3) as previously described [24]
UII increased the viability of V3 cells, but not T3 cells, in concentration-dependent fashion, and the effect was similar to that of epidermal growth factor (EGF; Figure 1A), a known mitogen in TSC2deficient cells [25]
Summary
Tuberous sclerosis complex (TSC) is a neurocutaneous tumor syndrome that occurs in approximately 1 in 6,000 live North American births [1, 2]. Clinical manifestations include tumors that consist of normally appearing tissue in unusual arrangements (i.e., hamartomas). Tumors such as renal angiomyolipomas (AML) or lymphangioleiomyomatosis of the lung (LAM) cause significant morbidity and mortality. The abnormal cells (‘LAM cells’) in renal AMLs or pulmonary LAM nodules exhibit markers of neoplastic transformation, as well as smooth muscle and neural crest differentiation. LAM cells can invade the lymphatic circulation, metastasize, and survive in colonized tissue [3]. The molecular mechanisms that mediate the oncogenic phenotype are therapeutic targets in TSC and LAM [4]
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