Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma
Naofumi Yoshida, Seiji Yamamoto, Takeru Hamashima, Noriko Okuno, Naruho Okita, Shinjiro Horikawa, Masao Hayashi, Dang Thanh Chung, Quang Linh Nguyen, Koichi Nishiyama, Teruhiko Makino, Yoko Ishii, Kei Tomihara, Tadamichi Shimizu, Masabumi Shibuya, Makoto Noguchi, Masakiyo Sasahara
Abstract
knockout (β-KO) fibroblasts had reduced expression of VEGF-D and SVEP1 and overproduced Amphiregulin. Dysregulation of these three factors was involved in the cyst-like and uneven distribution of lymphatic vessels observed in the β-KO mice. Similarly, in human cystic lymphangioma, which is one of the intractable diseases and mostly occurs in childhood, fibroblasts surrounding cystic lymphatics highly expressed Amphiregulin. Moreover, fibroblast-derived Amphiregulin could induce the expression of Amphiregulin in lymphatic endothelial cells. The dual source of Amphiregulin activated EGFR expressed on the lymphatic endothelial cells. This exacerbation cascade induced proliferation of lymphatic endothelial cells to form cystic lymphangioma. Ultimately, excessive Amphiregulin produced by fibroblasts surrounding lymphatics and by lymphatic endothelial cells per se results in pathogenesis of cystic lymphangioma and will be a fascinating therapeutic target of cystic lymphangioma.