Abstract
Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease, characterized by the proliferation of abnormal smooth muscle-like cells (LAM cells) in the lungs and along axial lymphatics, usually of females. Additionally, LAM-associated lymphangiogenesis is present in LAM lesions. LAM occurs as either a pulmonary manifestation of tuberous sclerosis complex (TSC-LAM) or a sporadic disease (sporadic LAM) often accompanying renal angiomyolipoma (AML). Previously, LAM was considered hamartomatous in nature but is now recognized as a neoplastic disease with either TSC1 or TSC2 mutations, both of which are tumor suppressor genes. TSC-LAM can occur due to a loss-of-function type mutation of either of these TSC genes, whereas sporadic LAM is solely a TSC2 disease. A recent discovery was that not all LAM cells within LAM lesions harbor the TSC mutation; instead, only a small fraction of LAM cells bear the pathogenic mutation. Furthermore, the involvement of an alternative genetic basis other than that from the TSC genes has been suggested. Studies of surface markers on LAM cells in the blood and body fluids demonstrated that LAM cells are phenotypically heterogeneous dependent on where LAM cells exist. Loss-of-heterozygosity (LOH) analysis of LAM cells in the blood and body fluids determined that LAM cells are genetically heterogeneous; that is, about 20 % of LAM patients showed different extents of LOH regions in LAM cells isolated from multiple sites.
LAM-associated lymphangiogenesis is regulated by not only lymphatic endothelial cell growth factor, VEGF-D produced by LAM cells, but also the non-collagenous-1 domain (NC1 domain) of type IV collagen α5, named lamstatin. Lymphangiogenesis and estrogen seem to have cooperative roles in the progression of this disease. Estrogen operates in several intracellular signaling pathways that are relevant to the pathogenesis of LAM. In this milieu, estrogen enhances matrix metalloproteinase-2 production by LAM cells and promotes the survival of circulating LAM cells. LAM cells can enter the lymphatic stream either through activated mTORC1-mediated cellular and biochemical events or via lymphangiogenesis-mediated fragmentation of LAM lesions to shed LAM cell clusters.
Given that LAM cells are neoplastic, we must establish where such cells originate and identify their normal counterparts. The female genital tract including the uterus is an attractive candidate, since the majority of LAM patients examined had LAM lesions in the uterus and nearby lymph nodes. Another yet unsolved but important question is why LAM is limited to females; so far, we have no clues to the answer in terms of genetic background, biochemical composition, or cellular mechanisms.
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Seyama, K. (2017). Lymphangioleiomyomatosis. In: Azuma, A., Schechter, M. (eds) Treatment of Cystic Fibrosis and Other Rare Lung Diseases. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0348-0977-1_5
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