Lymphangioleiomyomatosis (LAM) is a severe multisystemic and predominantly female disease that primarily affects the lung. Because of its cellular characteristics, it is classified by the WHO as a tumor (PEComa), a slow, non-aggressive, abnormal, and sometimes nodular soft-tissue growth, alongside airways, blood, and lymphatic vessels in the lung. Current treatments, such as rapamycin, target the accelerated mTOR pathway (a signaling network that regulates cell growth and metabolism) found in LAM; however, it does not completely stop disease progression and may not work for every patient.

Recent research has frequently discussed the involvement of lymphatic vessels as facilitators of LAM cell dissemination in the body due to their close proximity to LAM-diseased cells. These cells may work together to promote lung damage and help LAM spread to other organs. Researchers recently studied how LAM cells and LAM-altered cells, such as fibroblasts (a type of cell found in connective tissue throughout the body that play a crucial role in maintaining the structural integrity of tissues, wound healing, and immune response)  and LECs (lymphatic endothelial cells play a key role in the immune response, transporting lymph fluid and regulating immune cells), contribute to disease progression. Researchers tested whether sorafenib, a multikinase inhibitor (MKI) targeting multiple receptors on these cells, could be a more effective treatment than rapamycin. (MKIs are a class of drugs that target multiple kinases at the same time; a kinase is a type of enzyme that speeds up chemical reactions in the body.) The researchers also mimicked a LAM lung nodule in a dish using a 3D cell-spheroid model (a tiny, ball-shaped cluster of cells that mimic real tissues more closely than traditional lab methods) to better understand how fibroblasts and LECs behave in LAM.

They found that LAM-associated fibroblasts (LAMFs) invade lung tissues more aggressively than normal fibroblasts and that LECs play a role in this process by interacting with LAMFs. This suggests that targeting multiple cell types, rather than just LAM cells, could improve treatment outcomes. The study compared sorafenib with rapamycin in these models. Sorafenib significantly reduced fibroblast and LEC invasion, performing better than rapamycin in key areas. It also reduced levels of VEGF-A and bFGF, two angiogenic molecules (growth factors that stimulate the formation of new blood vessels) linked to tumor growth and disease progression.

These findings suggest that MKIs, like sorafenib, could be promising new treatments for LAM in a subset of patients with nodular LAM, lymphatic involvement, end-stage disease, and particularly for patients who do not respond well to rapamycin. The study underscores the need to target multiple cell types in LAM rather than just LAM cells. It provides new insights into disease progression and suggests that sorafenib or similar drugs could benefit a subset of patients. Further research, including clinical trials, is needed to confirm these findings.

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