New effective way to inhibit lymphatic malformations


Lymphatic malformation is a debilitating and often incurable disease. Taija Mäkinen’s research group has in an international collaboration studied cellular mechanisms leading to abnormal vessel growth and identified a combination therapy that may allow effective treatment of these malformations.

Lymphatic malformations are often congenital vascular anomalies that are characterised by abnormal vessel growth. These malformations may appear as large fluid-filled cysts (macrocystic type), which can often be treated or surgically removed. However, they can also grow invasively in the tissues (microcystic type). Despite causing pain and organ dysfunction, there is currently no curative therapy for microcystic lymphatic malformation.

Lymphatic malformations were recently shown to be caused by activating mutations in the gene PIK3CA. The same mutations are common in cancer and certain overgrowth syndromes. In the present study the researchers have studied the effects of PIK3CA mutation in the vasculature and seen that it causes both types of lymphatic malformations.

“We have used animal models to study the mechanism for how PIK3CA influences the formation of lymphatic malformations. PIK3CA encodes a subunit of the signaling protein PI3-kinase, which affects many cellular functions, including the formation of lymphatic vessels. In our experiments we found that depending on when during development the mutation is induced, it can result in the formation of either macrocystic or microcystic lymphatic malformations,” says Taija Mäkinen who has led the study.

The researchers also found that although the mutant cells had hyperactive PI3-kinase signalling, additional stimulation by vascular endothelial growth factor C (VEGF-C) was required for the malformations to grow.

The substance Rapamycin, which affects the signalling downstream of PIK3CA, has been used to treat vascular malformations in humans. Rapamycin can stop the growth of vascular malformations and improve the patients’ quality of life, but regression of the lesion is rarely achieved and it is unclear if patients need life-long treatment.

“We therefore used our mouse model to test the treatment with a substance that blocks VEGF-C signalling and found that it was more effective than Rapamycin in inhibiting the growth of lymphatic malformations. When we combined both treatments we even saw a regression of the lymphatic vessels. This suggests that this combination could be a new, effective therapy for PIK3CA-driven microcystic lymphatic malformations,” says Taija Mäkinen.

The study was performed in collaboration with researchers in Belgium, Finland, Spain and Germany, and has been published in the journal Nature Communications.

More information:
Article in Nature Communications
Taija Mäkinen’s research

Confocal microscope image of a microcystic lymphatic malformation
Confocal microscope image of a microcystic lymphatic malformation growing in the
ear skin of an adult mouse. Lymphatic vessels are observed in green.