Talks：

Potential Mechanisms of Carcinogenesis in Obstructive Sleep Apnea (OSA)

Name：

陳永哲(Yung-Che Chen)

Position：

Pulmonologist, Attending Physician

Affiliation：

Division of Pulmonary and Critical Care Medicine, Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, Kaohsiung, Taiwan

Email：

yungchechen@yahoo.com.tw

Photo：

Research Interests：

Translational Research On Obstructive Sleep Apnea, Pulmonary TB, and Chronic Obstructive Pulmonary Disease

Selected Publications：

◆ Su MC, Chen YC, Huang KT, Wang CC, Lin MC, Lin HC. Association of metabolic factors with high-sensitivity C-reactive protein in patients with sleep-disordered breathing. Eur Arch Otorhinolaryngol. 2013 Feb; 270(2):749-54. ◆ Huang KT, Chin CH, Tseng CC, Chang HC, Chen YC, Wang CC, Lin MC, Lin HC, Su MC. The influence of obesity on different genders in patients with obstructive sleep apnea. Scientific World Journal. 2014;2014:487215. ◆ Chen YC, Su MC, Liou CW, Liu SF, Chen CJ, Lin HC, Hsiao CC, Wang TY, Wang CC, Chin CH, Huang KT, Lin AS, Lin MC. Co-upregulation of Toll-like receptors 2 and 6 on peripheral blood cells in patients with obstructive sleep apnea. Sleep Breath. 2015;19(3):873-82. ◆ Chen YC, Chen TW, Su MC, Chen CJ, Chen KD, Liou CW, Tang P, Wang TY, Chang JC, Wang CC, Lin HC, Chin CH, Huang KT, Lin MC, Hsiao CC. Whole Genome DNA Methylation Analysis of Obstructive Sleep Apnea: IL1R2, NPR2, AR, SP140 Methylation and Clinical Phenotype. Sleep. 2016 Apr 1;39(4):743-55. ◆ Chen YC, Chen KD, Su MC, Chin CH, Chen CJ, Liou CW, Chen TW, Chang YC, Huang KT, Wang CC, Wang TY, Chang JC, Lin YY, Zheng YX, Lin MC, Hsiao CC. Genome-wide gene expression array identifies novel genes related to disease severity and excessive daytime sleepiness in patients with obstructive sleep apnea. PLoS One. 2017 May 17;12(5):e0176575.

Abstract：

Tumor hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted (acute, cyclic), or when a tumor outgrows its vascular supply (chronic, stable). It is a negative prognostic factor due to its association with an aggressive tumor phenotype and therapeutic resistance. In parallel with cyclic hypoxia phenomenon in cancer, chronic intermittent hypoxia (IH) with re-oxygengation characterizes obstructive sleep apnea (OSA), which has recently been implicated in increased incidence and more adverse prognosis of cancer. The application of IH patterns in OSA-related cancer studies is delivered both to living mice in vivo and directly to the cells in vitro. Interrogating identical animals subjected to an environment that only differs in the oxygen content of the breathed air (IH versus normoxia) has provided solid evidence into the specific effects of IH on cancer—particularly in cancer progression (tumor growth and metastasis). Similarly, implementation of sleep fragmentation (SF) paradigms has begun to unravel the potential role of sleep disruption in cancer biology. In vivo and in vitro IH not only exert local effects in the tumor cells per se, but also elicit changes in the host immune and metabolic responses, and pro-inflammatory and angiogenic molecules are released from different tissues and organs contributing to the oncogenic processes. Oxidative Stress from overproduction of reactive oxygen species (ROS) in IH conditions is the first step involved in mutagenesis, carcinogenesis and aging. IH induces chemoresistance through the activation of ROS mediated anti-apoptosis pathway, and induces lung tumor malignancy through cyclooxygengase 2/PGE2 pathway. Hypoxia Inducible Factor (HIF)-1–dependent signaling increases tumor angiogenesis and vasculogenesis through augmenting VEGF transcription and SDF-1 secretion by cancer stem cell. IH response pathways result in cancer cells acquiring epithelial-mesenchymal transition (EMT) and stemness through HIF-1α and HIF-2α. IH impairs cytotoxic T lymphocyte development, and recruits immunosuppressive cells, including tumor-associated macrophage(TAMs) with shift to M2 polarization. Surprisingly, fragmented sleep per se accelerates tumor growth and progression through recruitment of tumor-associated macrophages and toll-like receptor 4 signaling, and induces altered CD8+ T-Cell lymphocyte function. A limitation of the studies investigating IH is the lack of consensus and homogeneity in the magnitude and frequency of IH exposures in both cancer and OSA-related studies. Second is lack of considering if there is any addictive effect of IH plus concomitant intermittent hypercapnia or IH plus SF? In the future, further research may focus on early identification of OSA patients at high risk for malignancy, effective prevention of tumor progression, and reduction of treatment resistance in patients with both OSA and cancer.