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 malformations were recently shown to be
caused by somatic activating mutations in the gene PIK3CA that encodes a catalytic subunit of the PI3-kinase – the
same mutations being 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 protein that 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.
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
“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