Abstract
Lymphangioleiomyomatosis (LAM) is a rare systemic neoplastic disease that exclusively happens in women. Studies focusing on LAM and tuberous sclerosis complex (TSC) have made great progress in understanding the pathogenesis and searching for treatment. The inactive mutation of TSC1 or TSC2 is found in patients with LAM to activate the crucial mammalian target of rapamycin (mTOR) signaling pathway and result in enhanced cell proliferation and migration. However, it does not explain every step of tumorigenesis in LAM. Because cessation of rapamycin would break the stabilization of lung function or improved quality of life and lead to disease recurrent, continued studies on the pathogenesis of LAM are necessary to identify novel targets and new treatment. Researchers have found several aberrant regulations that affect the mTOR pathway such as its upstream or downstream molecules and compensatory pathways in LAM. Some therapeutic targets have been under study in clinical trials. New methods like genome-wide association studies have located a novel gene related to LAM. Herein, we review the current knowledge regarding pathogenesis and treatment of LAM and summarize novel targets of therapeutic potential recently.
Highlights
Lymphangioleiomyomatosis (LAM) is a rare low-grade neoplasm that predominantly affects young and middle-aged women [1, 2]
(8) epithelial–mesenchymal transition (EMT): extracellular regulated protein kinases (ERK) pathway and the constitutive mTOR complex 1 (mTORC1) pathway converge on the Fra1–ZEB-1/2 transcriptional network to promote migration and invasion; nuclear factor κB (NFκB) activated by Akt induces SNAIL1 stabilization which plays an integral role throughout EMT. [9] NR2F2: activated RAS upregulates COUP-TFII and increases lactate production; overproduction of lactate disrupts the interaction of TSC2 and rapidly accelerated fibrosarcoma (Ras) homolog enriched in brain (Rheb) to increase mTORC1 activity
Numerous signaling pathways are involved in EMT induction, including phosphoinositide 3-kinases (PI3K)/Akt pathway in which nuclear factor κB (NFκB) activated by Akt induces SNAIL1 stabilization that plays an integral role throughout EMT, and ZEB proteins which were mentioned earlier to engage the integration of mTORC1 and ERK pathway [78] (Figure 1)
Summary
Reviewed by: Jane Yu, University of Cincinnati, United States Rudolf Maria Huber, Ludwig Maximilian University of Munich, Germany. Specialty section: This article was submitted to Pulmonary Medicine, a section of the journal
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