Periostin Directly and Indirectly Promotes Tumor Lymphangiogenesis of Head and Neck Cancer
Identifieur interne : 004044 ( Main/Merge ); précédent : 004043; suivant : 004045Periostin Directly and Indirectly Promotes Tumor Lymphangiogenesis of Head and Neck Cancer
Auteurs : Yasusei Kudo [Japon] ; Shinji Iizuka [Japon] ; Maki Yoshida [Japon] ; Phuong Thao Nguyen [Japon] ; Samadarani B. S. M. Siriwardena [Japon] ; Takaaki Tsunematsu [Japon] ; Mariko Ohbayashi [Japon] ; Toshinori Ando [Japon] ; Daijiro Hatakeyama [Japon] ; Toshiyuki Shibata [Japon] ; Keiichi Koizumi [Japon] ; Masahiro Maeda [Japon] ; Naozumi Ishimaru [Japon] ; Ikuko Ogawa [Japon] ; Takashi Takata [Japon]Source :
- PLoS ONE [ 1932-6203 ] ; 2012.
Abstract
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.
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.
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.
Url:
DOI: 10.1371/journal.pone.0044488
PubMed: 22952986
PubMed Central: 3431354
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Periostin Directly and Indirectly Promotes Tumor Lymphangiogenesis of Head and Neck Cancer</title><author><name sortKey="Kudo, Yasusei" sort="Kudo, Yasusei" uniqKey="Kudo Y" first="Yasusei" last="Kudo">Yasusei Kudo</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima</wicri:regionArea><wicri:noRegion>Tokushima</wicri:noRegion></affiliation></author><author><name sortKey="Iizuka, Shinji" sort="Iizuka, Shinji" uniqKey="Iizuka S" first="Shinji" last="Iizuka">Shinji Iizuka</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Yoshida, Maki" sort="Yoshida, Maki" uniqKey="Yoshida M" first="Maki" last="Yoshida">Maki Yoshida</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Nguyen, Phuong Thao" sort="Nguyen, Phuong Thao" uniqKey="Nguyen P" first="Phuong Thao" last="Nguyen">Phuong Thao Nguyen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Siriwardena, Samadarani B S M" sort="Siriwardena, Samadarani B S M" uniqKey="Siriwardena S" first="Samadarani B. S. M." last="Siriwardena">Samadarani B. S. M. Siriwardena</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Tsunematsu, Takaaki" sort="Tsunematsu, Takaaki" uniqKey="Tsunematsu T" first="Takaaki" last="Tsunematsu">Takaaki Tsunematsu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Ohbayashi, Mariko" sort="Ohbayashi, Mariko" uniqKey="Ohbayashi M" first="Mariko" last="Ohbayashi">Mariko Ohbayashi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Ando, Toshinori" sort="Ando, Toshinori" uniqKey="Ando T" first="Toshinori" last="Ando">Toshinori Ando</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Hatakeyama, Daijiro" sort="Hatakeyama, Daijiro" uniqKey="Hatakeyama D" first="Daijiro" last="Hatakeyama">Daijiro Hatakeyama</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu</wicri:regionArea><wicri:noRegion>Gifu</wicri:noRegion></affiliation></author><author><name sortKey="Shibata, Toshiyuki" sort="Shibata, Toshiyuki" uniqKey="Shibata T" first="Toshiyuki" last="Shibata">Toshiyuki Shibata</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu</wicri:regionArea><wicri:noRegion>Gifu</wicri:noRegion></affiliation></author><author><name sortKey="Koizumi, Keiichi" sort="Koizumi, Keiichi" uniqKey="Koizumi K" first="Keiichi" last="Koizumi">Keiichi Koizumi</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Department of Kampo Diagnostic, Institute of Natural Medicine, University of Toyama, Toyama, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Kampo Diagnostic, Institute of Natural Medicine, University of Toyama, Toyama</wicri:regionArea><wicri:noRegion>Toyama</wicri:noRegion></affiliation></author><author><name sortKey="Maeda, Masahiro" sort="Maeda, Masahiro" uniqKey="Maeda M" first="Masahiro" last="Maeda">Masahiro Maeda</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Department of Research and Development, Immuno-Biological Laboratories, Co., Ltd., Fujioka-shi, Gunma, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Research and Development, Immuno-Biological Laboratories, Co., Ltd., Fujioka-shi, Gunma</wicri:regionArea><wicri:noRegion>Gunma</wicri:noRegion></affiliation></author><author><name sortKey="Ishimaru, Naozumi" sort="Ishimaru, Naozumi" uniqKey="Ishimaru N" first="Naozumi" last="Ishimaru">Naozumi Ishimaru</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima</wicri:regionArea><wicri:noRegion>Tokushima</wicri:noRegion></affiliation></author><author><name sortKey="Ogawa, Ikuko" sort="Ogawa, Ikuko" uniqKey="Ogawa I" first="Ikuko" last="Ogawa">Ikuko Ogawa</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Takata, Takashi" sort="Takata, Takashi" uniqKey="Takata T" first="Takashi" last="Takata">Takashi Takata</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22952986</idno><idno type="pmc">3431354</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431354</idno><idno type="RBID">PMC:3431354</idno><idno type="doi">10.1371/journal.pone.0044488</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">004445</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004445</idno><idno type="wicri:Area/Pmc/Curation">004444</idno><idno type="wicri:explorRef" wicri:stream="Pmc" 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Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima</wicri:regionArea><wicri:noRegion>Tokushima</wicri:noRegion></affiliation></author><author><name sortKey="Iizuka, Shinji" sort="Iizuka, Shinji" uniqKey="Iizuka S" first="Shinji" last="Iizuka">Shinji Iizuka</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Yoshida, Maki" sort="Yoshida, Maki" uniqKey="Yoshida M" first="Maki" last="Yoshida">Maki Yoshida</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Nguyen, Phuong Thao" sort="Nguyen, Phuong Thao" uniqKey="Nguyen P" first="Phuong Thao" last="Nguyen">Phuong Thao Nguyen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Siriwardena, Samadarani B S M" sort="Siriwardena, Samadarani B S M" uniqKey="Siriwardena S" first="Samadarani B. S. M." last="Siriwardena">Samadarani B. S. M. Siriwardena</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Tsunematsu, Takaaki" sort="Tsunematsu, Takaaki" uniqKey="Tsunematsu T" first="Takaaki" last="Tsunematsu">Takaaki Tsunematsu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Ohbayashi, Mariko" sort="Ohbayashi, Mariko" uniqKey="Ohbayashi M" first="Mariko" last="Ohbayashi">Mariko Ohbayashi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Ando, Toshinori" sort="Ando, Toshinori" uniqKey="Ando T" first="Toshinori" last="Ando">Toshinori Ando</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Hatakeyama, Daijiro" sort="Hatakeyama, Daijiro" uniqKey="Hatakeyama D" first="Daijiro" last="Hatakeyama">Daijiro Hatakeyama</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu</wicri:regionArea><wicri:noRegion>Gifu</wicri:noRegion></affiliation></author><author><name sortKey="Shibata, Toshiyuki" sort="Shibata, Toshiyuki" uniqKey="Shibata T" first="Toshiyuki" last="Shibata">Toshiyuki Shibata</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu</wicri:regionArea><wicri:noRegion>Gifu</wicri:noRegion></affiliation></author><author><name sortKey="Koizumi, Keiichi" sort="Koizumi, Keiichi" uniqKey="Koizumi K" first="Keiichi" last="Koizumi">Keiichi Koizumi</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Department of Kampo Diagnostic, Institute of Natural Medicine, University of Toyama, Toyama, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Kampo Diagnostic, Institute of Natural Medicine, University of Toyama, Toyama</wicri:regionArea><wicri:noRegion>Toyama</wicri:noRegion></affiliation></author><author><name sortKey="Maeda, Masahiro" sort="Maeda, Masahiro" uniqKey="Maeda M" first="Masahiro" last="Maeda">Masahiro Maeda</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Department of Research and Development, Immuno-Biological Laboratories, Co., Ltd., Fujioka-shi, Gunma, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Research and Development, Immuno-Biological Laboratories, Co., Ltd., Fujioka-shi, Gunma</wicri:regionArea><wicri:noRegion>Gunma</wicri:noRegion></affiliation></author><author><name sortKey="Ishimaru, Naozumi" sort="Ishimaru, Naozumi" uniqKey="Ishimaru N" first="Naozumi" last="Ishimaru">Naozumi Ishimaru</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima</wicri:regionArea><wicri:noRegion>Tokushima</wicri:noRegion></affiliation></author><author><name sortKey="Ogawa, Ikuko" sort="Ogawa, Ikuko" uniqKey="Ogawa I" first="Ikuko" last="Ogawa">Ikuko Ogawa</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author><author><name sortKey="Takata, Takashi" sort="Takata, Takashi" uniqKey="Takata T" first="Takashi" last="Takata">Takashi Takata</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima</wicri:regionArea><wicri:noRegion>Hiroshima</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>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.</p></sec><sec><title>Methods and Findings</title><p>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.</p></sec><sec><title>Conclusions</title><p>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.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Mao, L" uniqKey="Mao L">L Mao</name></author><author><name sortKey="Hong, Wk" uniqKey="Hong W">WK Hong</name></author><author><name sortKey="Papadimitrakopoulou, Va" uniqKey="Papadimitrakopoulou V">VA Papadimitrakopoulou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Forastiere, A" uniqKey="Forastiere A">A Forastiere</name></author><author><name sortKey="Koch, W" uniqKey="Koch W">W Koch</name></author><author><name sortKey="Trotti, A" uniqKey="Trotti A">A Trotti</name></author><author><name sortKey="Sidransky, D" uniqKey="Sidransky D">D 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