A variable percentage of cells within the<unk>  lesion contain mutational inactivation of the Tuberous Sclerosis Complex (TSC1 or TSC2) tumor suppressor genes. TSC1 mutations cause a less severe clinical phenotype than TSC2 mutations. The discovery of TSC1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) led to successful use of rapamycin analog sirolimus in clinical trials and FDA approval of sirolimus for treatment of<unk> . TSC1 and TSC2 form a tumor suppressor complex that regulates mammalian target of rapamycin (mTOR) signaling complex by directly controlling the activity of the small GTPase Rheb via the GTPase activating protein (GAP) domain of TSC2. Rheb binds to Raptor and controls the activity of mTOR complex 1 (mTORC1) that directly phosphorylates p70 S6 kinase (S6K1) and 4E-BP1. mTOR forms two physically and functionally distinct multiprotein complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2. MTORC1 consists of five proteins including Raptor that positively regulate mTOR activity. MTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC2 and modulates the assembly of the actin cytoskeleton through Rho GTPases, and Rac1 is required for mTOR activation. In TSC2-null and human<unk>  cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival. Loss of TSC1/TSC2 in<unk>  induces uncontrolled<unk>  cell growth and increases<unk>  cell viability. Upregulation of STAT1 and STAT3 and autophagy are known mediators of<unk>  cell viability and survival.<unk>  cells behave, in many ways, like metastatic tumor cells.<unk>  cells appear to arise from an extrapulmonary source and migrate to the lung. Increased<unk>  cell migration and invasiveness is rescued by TSC2 re-expression. The cellular and molecular mechanisms of neoplastic transformation and lung parenchymal destruction by<unk>  cells remain unknown. Lung remodeling may be mediated by an imbalance between matrix degrading metalloproteinases (MMPs) and their endogenous inhibitors TIMPs. The invasive cell phenotype in<unk>  is associated with TIMP-3 downregulation and TSC2-dependent upregulation of MMPs. Clinical and histopathological evidence demonstrate the lymphatic involvement in<unk> . The prevailing hypothesis is that<unk>  lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts. VEGF-D serum levels are increased in<unk>  compared to other cystic lung diseases, including pulmonary Langerhans cell histiocytosis, emphysema, Sjögren's syndrome, or Birt–Hogg–Dubé syndrome. VEGF-D levels correlate with the severity of<unk> , evaluated as a measure of CT grade (the abundance of chylous effusions and lymphatic involvement). VEGF-D is a secreted homodimeric glycoprotein and a member of the VEGF family of growth factors, is known for its role in cancer lymphangiogenesis and metastasis. Proteolytic processing of VEGF-D affects cognate binding to VEGFR3. Histopathologically,<unk>  lesions are surrounded by cells that stain for VEGFR3, the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin. VEGF-D binds to the receptor protein tyrosine kinases VEGFR-2 and VEGFR-349 in humans, and to VEGFR3 in mice. Surprisingly, knock-out of VEGF-D in mice has little effect on lymphatic system development. Nevertheless, during tumorigenesis VEGF-D promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells. However, little is known about a role of abnormal lymphatics and VEGF-D in<unk>  pathogenesis.
Lymphangioleiomyomatosis
Intravenous leiomyomatosis
Lymphangiomatosis
Angiodysplasia
Adenomyomatosis
Papillomatosis
Bagassosis
Fibromuscular dysplasia