Transcutaneous Carbon Dioxide Induces Mitochondrial Apoptosis and Suppresses Metastasis of Oral Squamous Cell Carcinoma In Vivo

Daisuke Takeda,Yasuyuki Shibuya,Takahide Komori,Yusuke Imai,Takeshi Ueha,Takumi Hasegawa,Teruya Kawamoto,Yoshitada Sakai,Toshihiro Akisue,Masahiro Kurosaka,Masaya Minoda,Tsutomu Minamikawa,Akiko Sakakibara

doi:10.1371/journal.pone.0100530

Daisuke Takeda, Yasuyuki Shibuya + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0100530

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Journal: PloS one	Publication Date: Jul 2, 2014
Citations: 58	License type: CC BY 4.0

Affiliation: Kobe University, NeoChemir (Japan)

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.

Highlights

Squamous cell carcinoma (SCC), the main histological type of oral cancer, comprises over 90% of all oral malignancies
Hypoxia inducible factors (HIFs)-1a is strongly induced under hypoxic conditions, and activates transcription of genes involved in metastasis, including matrix metalloproteinases (MMPs)
We have shown that, in human malignant fibrous histiocytoma (MFH) xenografts, transcutaneous CO2 decreases expression of HIF-1a and induces mitochondrial apoptosis, in turn increasing proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) and mitochondrial transcription factor A (TFAM) [9,14]

Summary

Introduction

Squamous cell carcinoma (SCC), the main histological type of oral cancer, comprises over 90% of all oral malignancies. Lymph node metastasis is a well-established negative prognostic indicator in the treatment of squamous cell carcinoma of the head and neck [2]. Overexpression of HIF-1a, an oxygen-dependent a subunit of HIF, has been associated with tumor cell growth, lymph node metastasis and survival in head and neck tumors [6,7,8]. HIF-1a mediates the adaptation of cancer cells to hypoxic environments by controlling expression of hundreds of genes, including vascular endothelial growth factor (VEGF). Increased expression of certain MMPs correlates with tumor growth, invasion, and poor prognosis in patients with malignancies. Decreasing activity of HIF-1a and/or MMPs by reducing tumor hypoxia could be an effective strategy in cancer treatment, there is currently no effective way of achieving reduction of hypoxia in tumors [5,9]

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