title: Periostin directly and indirectly promotes tumor lymphangiogenesis of head and neck cancer.
abstract: BACKGROUND
  Metastasis to regional lymph nodes via lymphatic vessels plays a key role in cancer progression. Tumor lymphangiogenesis is known to promote lymphatic metastasis, and vascular endothelial growth factor C (VEGF-C) is a critical activator of tumor lymphangiogenesis during the process of metastasis. We previously identified periostin as an invasion- and angiogenesis-promoting factor in head and neck squamous cell carcinoma (HNSCC). In this study, we discovered a novel role for periostin in tumor lymphangiogenesis.
  
  
  RESULTS
  Periostin overexpression upregulated VEGF-C mRNA expression in HNSCC cells. By using conditioned media from periostin-overexpressing HNSCC cells, we examined tube formation of lymphatic endothelial cells. Conditioned media from periostin-overexpressing cells promoted tube formation. To know the correlation between periostin and VEGF-C, we compared Periostin expression with VEGF-C expression in 54 HNSCC cases by immunohistochemistry. Periostin expression was correlated well with VEGF-C expression in HNSCC cases. Moreover, correlation between periostin and VEGF-C secretion was observed in serum from HNSCC patients. Interestingly, periostin itself promoted tube formation of lymphatic endothelial cells independently of VEGF-C. Periostin-promoted lymphangiogenesis was mediated by Src and Akt activity. Indeed possible correlation between periostin and lymphatic status in periostin-overexpressing xenograft tumors and HNSCC cases was observed.
  
  
  CONCLUSIONS
  Our findings suggest that periostin itself as well as periostin-induced upregulation of VEGF-C may promote lymphangiogenesis. We suggest that periostin may be a marker for prediction of malignant behaviors in HNSCC and a potential target for future therapeutic intervention to obstruct tumoral lymphatic invasion and lymphangiogenesis in HNSCC patients.
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. yasusei@tokushima-u.ac.jp
authors.forename: Yasusei
authors.initials: Y
authors.lastname: Kudo
authors.forename: Shinji
authors.initials: S
authors.lastname: Iizuka
authors.forename: Maki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Phuong Thao
authors.initials: PT
authors.lastname: Nguyen
authors.forename: Samadarani B S M
authors.initials: SB
authors.lastname: Siriwardena
authors.forename: Takaaki
authors.initials: T
authors.lastname: Tsunematsu
authors.forename: Mariko
authors.initials: M
authors.lastname: Ohbayashi
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ando
authors.forename: Daijiro
authors.initials: D
authors.lastname: Hatakeyama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shibata
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
authors.forename: Ikuko
authors.initials: I
authors.lastname: Ogawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Takata
mesh_terms: D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics; D008954:Models, Biological; D009389:Neovascularization, Pathologic
chemical_list: D015815:Cell Adhesion Molecules; C512835:POSTN protein, human