Lymphangioleiomyomatosis (LAM) is a multisystem disorder characterized by cystic lung disease and abdominal tumors (e.g., lymphangioleiomyomas, angiomyolipomas). The disease, which often presents in middle-aged women, is characterized by the proliferation of abnormal smooth muscle cells, LAM cells, which contain mutations in one of two tuberous sclerosis complex genes (TSC), TSC1 or TSC2. LAM occurs more frequently in women with TSC, an autosomal dominant disorder. A clinical protocol has enabled the Branch to assemble a large cohort of patients with LAM and to document the natural history of the disease, the histopathological findings, the radiographic appearance, characteristic pulmonary function abnormalities, and the association with tuberous sclerosis complex. LAM cells proliferate in the lungs and in the lymphatics of the thorax and retroperitoneum resulting respectively, in pulmonary cysts and lymphangioleiomyomas. Accumulation of LAM cells in the lymphatics may cause mural thickening, obstruction, dilatation, and development of cystic collections of chylous fluid, termed """"""""lymphangioleiomyomas"""""""", which may have CT characteristics similar to those of malignant neoplasms. By CT, however, lymphangioleiomyomas have been shown to increase in size during the day, whereas with malignancy, negligible growth is expected in a single day. To define the sonographic features of abdominal and pelvic lymphangioleiomyomas in lymphangioleiomyomatosis (LAM) and to evaluate the utility of sonography in visualizing diurnal change in the size of the masses, 44 patients with LAM and abdominal and pelvic lymphangioleiomyomas found on screening CT underwent sonography. Of these, 22 patients were studied twice on the same day, in the morning and the late afternoon. Among 44 patients, 49 masses were scanned. Anatomic distribution of the masses was as follows: retroperitoneal (29/44 patients, 66%), pelvic (10/44, 23%), and both retroperitoneal and pelvic (5/44, 11%). Of the 49 masses, 12 (24%) were cystic, 16 (33%) were solid, and 21 (43%) were complex. In 22 patients who underwent sonography in the morning and afternoon, the masses increased in size during the day in all 21 patients in whom the masses were visualized in both studies. In three of 21 patients, the echotexture of the masses changed between the morning and afternoon studies, in two, from solid to complex, and in the other, from hyperechoic to isoechoic (relative to the liver). Sonographic characteristics of lymphangioleiomyomas were similar to those of neoplasms such as lymphoma and ovarian cancer (a similarity that sometimes prompts biopsy). Repeated sonography, morning and afternoon, may be useful to document diurnal variation in size and echotexture to confirm the diagnosis of lymphangioleiomyoma and avoid biopsy. LAM lesions result from the proliferation of benign-appearing LAM cells, which are characterized by loss of heterozygosity (LOH) of one of the TSC genes. LAM cells are believed to migrate among the involved organs, lungs, kidney, and lymphatics. Because of the apparently metastatic behavior of LAM, we tried to isolate LAM cells from body fluids. A cell fraction separated by density gradient centrifugation from blood had TSC2 LOH in 33 of 60 (55%) LAM patients. Cells with TSC2 LOH were also found in urine from 11 of 14 (79%) patients with AML and in chylous fluid from 1 of 3 (33%) patients. Identification of LAM cells with TSC2 LOH in body fluids was not correlated with severity of lung disease or extrapulmonary involvement and was found in one patient after double lung transplantation. These studies are compatible with a multisite origin for LAM cells. They establish the existence of disseminated, potentially metastatic LAM cells through a relatively simple, noninvasive procedure that should be valuable for molecular and genetic studies of somatic mutations in LAM and perhaps other metastatic diseases. Patients with TSC are predisposed to developing tumors in the brain, eyes, heart, kidneys, lung, and skin. Although typically benign, these tumors cause significant morbidity, including seizures, mental retardation, and disfigurement. In the skin, angiofibromas and periungual fibromas exhibit angiogenesis, fibrosis and abundant mononuclear phagocytes. The tendency to form multiple tumors is a consequence of inactivating mutations in a tumor suppressor gene, either TSC1 or TSC2 and loss of function of these gene products, respectively, hamartin and tuberin, leading to abnormalities in signaling through the mammalian target of rapamycin, mTOR. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor-derived cells for altered gene and protein expression. Fibroblast-like cells from angiofibromas and periungual fibromas produced levels of MCP-1 mRNA and protein higher than those of TSC fibroblasts from the same patient?s normal-appearing skin. Conditioned medium from angiofibroma cells stimulated chemotaxis of a human monocytic cell line, an effect blocked by neutralizing MCP-1 antibody. Observations that relate overexpression of MCP-1 to loss of tuberin function include: 1) Eker rat embryonic fibroblasts null for Tsc2 (EEF Tsc2-/-) produced 28-times as much MCP-1 protein as EEF Tsc2+/+ cells; 2) transient expression of wild-type but not mutant human TSC2 by EEF Tsc2-/- cells significantly inhibited MCP-1 production; and 3) FTI-277 or rapamycin, which inhibit, at different points, the signaling pathway that is hyperactivated after loss of TSC2, decreased MCP-1 production by EEF Tsc2-/- cells. MCP-1, by stimulating angiogenesis and fibrogenesis and recruiting monocytic cells, may play important roles in TSC tumorigenesis and offer a new therapeutic target. In TSC and LAM, mutations in TSC1 and TSC2 results in enhanced activity of mTOR, a serine/threonine kinase, which regulates cell growth and proliferation in part via the activation of p70 S6 kinase (S6K). Rapamycin is an antineoplastic agent that, in complex with FKBP12, is a specific inhibitor of mTOR through interaction with its FKBP12-rapamycin binding domain, thereby causing G1 cell cycle arrest. Rapamycin is currently in use in a Phase I trial in LAM/TSC with the primary focus on the size of renal angiomyolipomas. Of concern, however, is that cancer cells often develop resistance to rapamycin, and alternative inhibitors of mTOR are needed. 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) blocks mTOR kinase activity, but it also inhibits phosphatidylinositol 3-kinase (PI3K), an enzyme that regulates cellular functions in addition to proliferation. We hypothesized that a close structural analog, 2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one (LY303511) might inhibit mTOR-dependent cell proliferation without unwanted effects on PI3K. In human lung epithelial adenocarcinoma (A549) cells, LY303511, like rapamycin, inhibited mTOR-dependent phosphorylation of S6K, but not PI3K-dependent phosphorylation of Akt. LY303511 blocked proliferation in A549 as well as in primary pulmonary artery smooth muscle cells, without causing apoptosis. In contrast to rapamycin, LY303511 reduced G2/M progression as well as G2/M-specific cyclins in A549 cells. Consistent with an additional mTOR-independent kinase target, LY303511 inhibited catalytic activity of casein kinase 2, a known regulator of G1 and G2/M progression. In addition to its antiproliferative effect on cells in vitro, LY303511 inhibited the growth of human prostate adenocarcinoma tumor implants in athymic mice. Given its inhibition of cell proliferation via mTOR-dependent and independent mechanisms, LY303511 has therapeutic potential with antineoplastic actions that are independent of PI3K inhibition.
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