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Lymphatic malformations: mechanistic insights and evolving therapeutic frontiers
Milena Petkova, Ingvar Ferby, Taija Mäkinen
Milena Petkova, Ingvar Ferby, Taija Mäkinen
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Lymphatic malformations: mechanistic insights and evolving therapeutic frontiers

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Abstract

The lymphatic vascular system is gaining recognition for its multifaceted role and broad pathological significance. Once perceived as a mere conduit for interstitial fluid and immune cell transport, recent research has unveiled its active involvement in critical physiological processes and common diseases, including inflammation, autoimmune diseases, and atherosclerosis. Consequently, abnormal development or functionality of lymphatic vessels can result in serious health complications. Here, we discuss lymphatic malformations (LMs), which are localized lesions that manifest as fluid-filled cysts or extensive infiltrative lymphatic vessel overgrowth, often associated with debilitating, even life-threatening, consequences. Genetic causes of LMs have been uncovered, and several promising drug-based therapies are currently under investigation and will be discussed.

Authors

Milena Petkova, Ingvar Ferby, Taija Mäkinen

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Figure 3

Proinflammatory paracrine signaling as a potential target for the treatment of Pik3caH1047R-driven microcystic LM.

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Proinflammatory paracrine signaling as a potential target for the treatm...
In a mouse model of LM, expression of oncogenic Pik3caH1047R (black stars) in LECs (green vessels) leads to lymphatic vessel overgrowth (blue vessels). This overgrowth is associated with a proinflammatory phenotype of LECs, promoting the recruitment of macrophages that, in turn, produce prolymphangiogenic VEGF-C and drive progressive vessel growth. In addition to PI3K pathway inhibitors, the use of antiinflammatory therapy, such as COX2 inhibitor celecoxib, and VEGF-C blockade has proven effective in limiting Pik3ca-driven lymphatic overgrowth in mice (51).

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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