Recent Progress in Lymphangioma

Abstract

Lymphangioma is a common type of congenital vascular disease in children with a broad spectrum of clinical manifestations. The current classification of lymphangioma by International Society for the Study of Vascular Anomalies is largely based on the clinical manifestations and complications and is not sufficient for selection of therapeutic strategies and prognosis prediction. The clinical management and outcome of lymphangioma largely depend on the clinical classification and the location of the disease, ranging from spontaneous regression with no treatment to severe sequelae even with comprehensive treatment. Recently, rapid progression has been made toward elucidating the molecular pathology of lymphangioma and the development of treatments. Several signaling pathways have been revealed to be involved in the progression and development of lymphangioma, and specific inhibitors targeting these pathways have been investigated for clinical applications and clinical trials. Some drugs already currently in clinical use for other diseases were found to be effective for lymphangioma, although the mechanisms underlying the anti-tumor effects remain unclear. Molecular classification based on molecular pathology and investigation of the molecular mechanisms of current clinical drugs is the next step toward developing more effective individualized treatment of children with lymphangioma with reduced side effects.

Keywords: classification; lymphangioma; molecular biology; precision medicine; signaling pathway.

Figure 1

The international society of the study of vascular anomalies classification of lymphatic malformations.

Figure 2

The structure of class I PI3Ks. PtdIns-(4,5)-P2 serves as the substrate of PI3Ks, which are heterodimeric molecules composed of both a catalytic subunit (p110α, β, γ, and δ) and a regulatory subunit (p85α, p55α, p50α, p85β, and p55γ. PIK3CA, encoding the PI3K catalytic subunit p110α, which can affect the activity of PI3K and the level of phosphorylation of AKT, may lead to excessive proliferation of lymphatic endothelial cells. All p85 isoforms have two Src homology 2 (SH2) domains and are encoded by PIK3R1 (which encodes p85α, p55α and p50α), PIK3R2 (which encodes p85β) and PIK3R3 (which encodes p55γ). The PIK3R3 mutation exists in patients with LM, but the mechanism of the PIK3R3 mutation to the LM phenotype needs further investigations.

Figure 3

Involvement of the dysregulated PI3K/AKT/mTOR signaling pathway in LM. In the PI3K/AKT/mTOR signaling pathway, the somatic mutations on PIK3CA are specifically discovered in LM-LECs. Also, some LM can present as part of PROS, the inhibitors against PI3K, i.e., LY294002, BYL719 and Wortmannin, may provide a new therapeutic target for the treatment of LM. The mutations on PIK3CA can increase AKT-Thr₃₀₈ phosphorylation, triggering high cellular proliferative and sprouting potential of LM-LECs, which could be inhibited by the specific small molecular inhibitors, such as ARQ092, MK-2206. MK-2206 may be worthy of further treatment of LM. Sirolimus can potently and specifically inhibit the activity mTOR. PIK3CA mutation can repress ANG2 by conducting phosphorylation-dependent inactivation of FOXO1, which is the essential transcription factors for ANG2 expression. The decreased expression of ANG2 makes lymphatic vessels more stable and muscular. Furthermore, the inhibitors against PI3K, AKT, mTOR, provide a new therapeutic target for the treatment of LM.

Figure 4

Involvement of dysregulated VEGF-C and receptor pathways in LM. SOX18 and COUP-TFII transcription factors in embryonic vein together activate the expression of PROX1 in venous endothelial cell subsets. Sirolimus can rapidly reduce the expression of Prox1, VEGFR-3 mRNA and protein, which may be related to the inhibition of Prox1 transcriptional activity. The mechanism of propranolol in the treatment of LM may be closely related to the members of the VEGF family, such as VEGF-C. Both VEGF-C and neuropilin2 (Nrp2) are upregulated in recurrent lymphangiomas. These findings imply that targeting VEGF-C/Nrp2 may be a potential therapeutic strategy for recurrent lymphangioma. FOXC2 haploinsufficiency may be associated with macrocystic LM. BMP modulators have certain therapeutic potential, such as dorsomorphin, may support the participation of BMP pathways in the study of LM therapy. However, it needs further clinical trials to prove potential clinical benefits in the treatment of LM.

Figure 5

Involvement of Wnt signaling pathways in LM. PROX1 forms complexes with β-catenin and the TCF/LEF transcription factor TCF7L1 to enhance Wnt / β-catenin signaling and promote the expression of FOXC2 in LECs, thus accelerating the development of lymphatic vessels. The nuclear localization of β-catenin in the endothelium of LM has been found. Wnt modulators have certain therapeutic potential, such as LDN-193189 and calyculin A, these drugs may support the participation of Wnt pathways in the study of LM therapy. Furthermore, the modulators against Wnt signaling pathways may supply a new therapeutic target for the treatment of LM.

Figure 6

The RAS/RAF/MEK/ERK signaling pathway in LM and potential therapeutics. EphB4 and NRAS mutations activate the RAS/MEK/ERK signaling pathway. NRAS gene mutation in lymphatic endothelial cells of GLA and KLA has been discovered, MAPK inhibitors (U0126) require clinical trials to explore their potential in the treatment of LM. The somatic cell activation mutation of NRAS in lymphatic endothelium can increase phosphorylation of AKT and ERK in lymphatic endothelial cells of GLA. Recently, a new drug, trametinib, blocking the enhanced phosphorylation of ERK and reducing the viability of the endothelial cells, maybe a promising choice for the treatment of GLA. CCLA, is connected with the mutation in EPHB4 following the autosomal dominant inheritance. The inhibitors against RAS, MAPK, and EPHB4 may provide a new therapeutic target for the treatment of LM.