title: Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo.
abstract: Squamous cell carcinoma (SCC) is the main histological type of oral cancer. Its growth rate and incidence of metastasis to regional lymph nodes is influenced by various factors, including hypoxic conditions. We have previously reported that transcutaneous CO2 induces mitochondrial apoptosis and decreases lung metastasis by reoxygenating sarcoma cells. However, previous studies have not determined the sequential mechanism by which transcutaneous CO2 suppresses growth of epithelial tumors, including SCCs. Moreover, there is no report that transcutaneous CO2 suppresses lymphogenous metastasis using human cell lines xenografts. In this study, we examined the effects of transcutaneous CO2 on cancer apoptosis and lymphogenous metastasis using human SCC xenografts. Our results showed that transcutaneous CO2 affects expressions of PGC-1α and TFAM and protein levels of cleavage products of caspase-3, caspase-9 and PARP, which relatives mitochondrial apoptosis. They also showed that transcutaneous CO2 significantly inhibits SCC tumor growth and affects expressions of HIF-1α, VEGF, MMP-2 and MMP-9, which play essential roles in tumor angiogenesis, invasion and metastasis. In conclusion, transcutaneous CO2 suppressed tumor growth, increased mitochondrial apoptosis and decreased the number of lymph node metastasis in human SCC by decreasing intra-tumoral hypoxia and suppressing metastatic potential with no observable effect in vivo. Our findings indicate that transcutaneous CO2 could be a novel therapeutic tool for treating human SCC.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takeda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: NeoChemir, Kobe, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueha
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sakakibara
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Minoda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Teruya
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Minamikawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shibuya
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Akisue
authors.affiliation: Division of Rehabilitation Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yoshitada
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Komori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002245:Carbon Dioxide / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D002245:Carbon Dioxide