期刊
CIRCULATION RESEARCH
卷 129, 期 1, 页码 136-154出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.121.318142
关键词
capillaries; lymphangiogenesis; mutation; neoplasms; sirolimus
资金
- Knut and Alice Wallenberg Foundation [2018.0218]
- Swedish Research Council [2020-02692]
- Swedish Cancer Society [19 0220 Pj, 19 0219 Us]
- Goran Gustafsson Foundation
- European Union [814316, 874708]
- Fonds de la Recherche Scientifique-FNRS grant [T.0247.19]
- Fund Generet [2018J1810250-211305]
- Region wallonne dans le cadre du financement de l'axe strategique FRFS-WELBIO [WELBIO-CR-2019C-06]
- Lymphatic Malformation Institute
- Wihuri Foundation
- Novo Nordisk Foundation [NNF16OC0023554]
- Sigrid Juselius Foundation
- Hospital District of Helsinki and Uusimaa Research Grant
- Cancer Foundation Finland
- Academy of Finland [335721, 307366, 312516]
- Academy of Finland (AKA) [335721, 312516, 312516] Funding Source: Academy of Finland (AKA)
- Marie Curie Actions (MSCA) [814316] Funding Source: Marie Curie Actions (MSCA)
- Swedish Research Council [2020-02692] Funding Source: Swedish Research Council
Lymphatic vessels play a crucial role in maintaining tissue fluid homeostasis and immune surveillance. Developmental or functional defects in lymphatic vessels can lead to lymphedema. Recent advancements have identified genetic causes and molecular pathways underlying lymphatic malformations and complex lymphatic anomalies, paving the way for targeted therapies.
Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell-autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.
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