@article{10.1371/journal.pone.0044488, doi = {10.1371/journal.pone.0044488}, author = {Kudo, Yasusei AND Iizuka, Shinji AND Yoshida, Maki AND Nguyen, Phuong Thao AND Siriwardena, Samadarani B. S. M. AND Tsunematsu, Takaaki AND Ohbayashi, Mariko AND Ando, Toshinori AND Hatakeyama, Daijiro AND Shibata, Toshiyuki AND Koizumi, Keiichi AND Maeda, Masahiro AND Ishimaru, Naozumi AND Ogawa, Ikuko AND Takata, Takashi}, journal = {PLOS ONE}, publisher = {Public Library of Science}, title = {Periostin Directly and Indirectly Promotes Tumor Lymphangiogenesis of Head and Neck Cancer}, year = {2012}, month = {08}, volume = {7}, url = {https://doi.org/10.1371/journal.pone.0044488}, pages = {1-14}, 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. Methods and Findings 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.}, number = {8}, }