Lymphangioleiomyomatosis: A Disease Involving the Lymphatic System

Abstract

LAM appears to be a disease involving a dysfunction of the lymphatic system and a fascinating model of tumor dissemination that is exclusively lymphangitic. LAM-associated lymphangiogenesis that mediates the shedding of LCCs seems to play a central role in the dissemination of LAM cells and progression in LAM and it may also be a potential therapeutic target as well as the dysregulated mTOR signaling pathway.

Biological Basis of Therapeutic Lymphangiogenesis

“…LAM is a rare cystic pulmonary disease that affects primarily women of child-bearing age (for reviews on LAM, see elsewhere 188,189 ). LAM is characterized by the infiltration of abnormal smooth muscle-like cells (LAM cells) through the pulmonary interstitium, perivascular spaces, and the lymphatics, leading to obstruction of small airways and subsequent respiratory failure or to disruption of the lymphatics, resulting in chylous pleural effusion.…”

“…LAM cells are often closely associated with the lymphatic endothelium, may be present in lymph nodes, and express abundant VEGF-D, readily detectable in patient serum. 189 Thus, the progression of LAM may be dependent on the ability of LAM cells to invade the lymphatic system, which suggests that inhibitors of lymphangiogenesis should be evaluated in treatment of LAM.…”

NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline

“…Transformed smooth musclelike cells arise from an unknown source, metastasize via blood and lymph (21), infiltrate the lung (1), and proliferate, forming nodules The surface expression of NKG2DL on transformed or stressed cells results in engagement of NKG2D on NK or CD8 cytotoxic T cells followed by target cell lysis. Immune surveillance by NKG2D-NKG-D2L interactions plays a critical role in suppressing tumor initiation in mice and humans (22).…”

Lymphangioleiomyomatosis — a wolf in sheep’s clothing

“…Kumasaka et al have proposed that LAM cells, through their expression of VEGF-C and VEGF-D, drive a lymphangiogenic program that demarcates the LAM cells into endothelium-rimmed islands (27,28). After budding into the lumen, LAM cell clusters leapfrog up the lymphatic tree through serial cycles of implantation and shedding, and are transported by lymphatic flow to the venous circulation and the pulmonary microvasculature (125). The VEGFR-3-expressing endothelial cells that envelope the LAM cell clusters may serve to shield mutation-bearing LAM cells from immune surveillance against novel or ectopic surface antigens they express, such as the glycolipid GD-3 (126).…”