Eur J Pediatr Surg 2020; 30(04): 337-342
DOI: 10.1055/s-0039-1687869
Original Article
Georg Thieme Verlag KG Stuttgart · New York

The Roles of Neuropilin 2/VEGF-C Axis in a Series of Recurrent Lymphangioma

Xueqiang Yan*
1   Department of Pediatric Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Nannan Zheng*
1   Department of Pediatric Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Xiaoli Xiong
1   Department of Pediatric Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Xufei Duan
1   Department of Pediatric Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Jun Yang
1   Department of Pediatric Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Hongqiang Bian
1   Department of Pediatric Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Zhenchuang Zhu
1   Department of Pediatric Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Xiaofeng Xiong
1   Department of Pediatric Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
,
Xuyong Chen
2   The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio, United States
› Author Affiliations
Further Information

Publication History

17 December 2018

09 March 2019

Publication Date:
23 April 2019 (online)

Abstract

Introduction Vascular endothelial growth factor (VEGF) and its receptor act as a major contributor to lymphangioma, but their role on nonrecurrent and recurrent lymphangiomas remain unclear. We aim to investigate those factors in the generation of recurrent lymphangioma.

Materials and Methods Patients diagnosed with lymphangioma from January 2005 to December 2012 in our hospital were collected and divided into nonrecurrent and recurrent lymphangiomas. The clinical characteristics including age, sex, symptoms, location, and size of lymphangioma were collected. Surgical resection samples were collected for histology, protein and mRNA detection of VEGF-C, VEGF receptor-3 (VEGFR-3), and neuropilin 2 (Nrp2). Follow-ups including lymphangioma recurrent and the local symptoms such as ulcer were reviewed.

Results A total of 80 patients aged from 5 months to 12 years were enrolled in this study, 51 patients had no recurrence and other 29 patients suffered from recurrent lymphangioma. There was no significant difference in demographic data and clinical characters between the two groups (p > 0.05). Immunohistochemistry staining showed that VEGFR-3 remained unchanged between nonrecurrent and recurrent lymphangiomas (p > 0.05), and VEGF-C and Nrp2 were significantly increased in recurrent lymphangioma compared with nonrecurrent lymphangioma (p < 0.05). The same expression trend was proved as detected by protein and mRNA levels.

Conclusion The VEGF-C/Nrp2 axis was significantly increased in the recurrent lymphangioma, indicating that VEGF-C/Nrp2 targeted therapy may serve as a potential therapeutic strategy for recurrent lymphangioma.

* Xueqiang Yan and Nannan Zheng contributed equally to this article.


 
  • References

  • 1 Masood SN, Masood MF. Case report of fetal axillo-thoraco-abdominal cystic hygroma. Arch Gynecol Obstet 2010; 281 (01) 111-115
  • 2 Mirza B, Ijaz L, Iqbal S, Mustafa G, Saleem M, Sheikh A. Cystic hygroma of unusual sites: report of two cases. Afr J Paediatr Surg 2011; 8 (01) 85-88
  • 3 Mirza B, Ijaz L, Saleem M, Sharif M, Sheikh A. Cystic hygroma: an overview. J Cutan Aesthet Surg 2010; 3 (03) 139-144
  • 4 Ozeki M, Kanda K, Kawamoto N. , et al. Propranolol as an alternative treatment option for pediatric lymphatic malformation. Tohoku J Exp Med 2013; 229 (01) 61-66
  • 5 Paladino NC, Scerrino G, Chianetta D, Di Paola V, Gulotta G, Bonventre S. Recurrent cystic lymphangioma of the neck. Case report. Ann Ital Chir 2014; 85 (01) 69-74
  • 6 Itakura E, Yamamoto H, Oda Y, Furue M, Tsuneyoshi M. VEGF-C and VEGFR-3 in a series of lymphangiomas: is superficial lymphangioma a true lymphangioma?. Virchows Arch 2009; 454 (03) 317-325
  • 7 Huang HY, Ho CC, Huang PH, Hsu SM. Co-expression of VEGF-C and its receptors, VEGFR-2 and VEGFR-3, in endothelial cells of lymphangioma. Implication in autocrine or paracrine regulation of lymphangioma. Lab Invest 2001; 81 (12) 1729-1734
  • 8 Parker MW, Linkugel AD, Goel HL, Wu T, Mercurio AM, Vander Kooi CW. Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form. Structure 2015; 23 (04) 677-687
  • 9 Liao S, von der Weid PY. Lymphatic system: an active pathway for immune protection. Semin Cell Dev Biol 2015; 38: 83-89
  • 10 Ji RC, Eshita Y, Xing L, Miura M. Multiple expressions of lymphatic markers and morphological evolution of newly formed lymphatics in lymphangioma and lymph node lymphangiogenesis. Microvasc Res 2010; 80 (02) 195-201
  • 11 Pytowski B, Goldman J, Persaud K. , et al. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst 2005; 97 (01) 14-21
  • 12 Sidle DM, Maddalozzo J, Meier JD, Cornwell M, Stellmach V, Crawford SE. Altered pigment epithelium-derived factor and vascular endothelial growth factor levels in lymphangioma pathogenesis and clinical recurrence. Arch Otolaryngol Head Neck Surg 2005; 131 (11) 990-995
  • 13 Dumont DJ, Jussila L, Taipale J. , et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 1998; 282 (5390): 946-949
  • 14 Yuan L, Moyon D, Pardanaud L. , et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 2002; 129 (20) 4797-4806
  • 15 Stanton MJ, Dutta S, Zhang H. , et al. Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance. Cancer Res 2013; 73 (01) 160-171
  • 16 Tu DG, Chang WW, Jan MS, Tu CW, Lu YC, Tai CK. Promotion of metastasis of thyroid cancer cells via NRP-2-mediated induction. Oncol Lett 2016; 12 (05) 4224-4230
  • 17 Wang J, Huang Y, Zhang J. , et al. NRP-2 in tumor lymphangiogenesis and lymphatic metastasis. Cancer Lett 2018; 418: 176-184
  • 18 Xu Y, Yuan L, Mak J. , et al. Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol 2010; 188 (01) 115-130