Tumor hypoxia enhances Non-Small Cell Lung Cancer metastasis by selectively promoting macrophage M2 polarization through the activation of ERK signaling

// Jun Zhang 1,* , Ji Cao 1,* , Shenglin Ma 2,3 , Rong Dong 1 , Wen Meng 2 , Meidan Ying 1 , Qinjie Weng 1 , Zibo Chen 5 , Jian Ma 1 , Qingxia Fang 4 , Qiaojun He 1 and Bo Yang 1 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China 2 Hangzhou First People’s Hospital, Huansha Road, Hangzhou, China 3 The second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China 4 Zhejiang Provincial People’s hospital, Shangtang Road, Hangzhou, China 5 College of Materials Science and Engineering, Central South University of Forestry and Technology, Changsha, China * These authors contributed equally to this work Correspondence: Bo Yang, email: // Keywords : Hypoxia; Macrophage; Metastasis; Polarization; NSCLC Received : January 13, 2014 Accepted : March 20, 2014 Published : March 22, 2014 Abstract Hypoxia is a common phenomenon occurring in the majority of human tumors and has been proved to play an important role in tumor progression. However, it remains unclear that whether the action of hypoxia on macrophages is a main driving force of hypoxia-mediated aggressive tumor behaviors. In the present study, we observe that high density of M2 macrophages is associated with metastasis in adenocarcinoma Non-Small Cell Lung Cancer (NSCLC) patients. By applying the in vivo hypoxia model, the results suggest that intermittent hypoxia significantly promotes the metastasis of Lewis lung carcinoma (LLC), accompanied with more CD209 + macrophages infiltrated in primary tumor tissue. More intriguingly, by skewing macrophages polarization away from the M1- to a tumor-promoting M2-like phenotype, hypoxia and IL-6 cooperate to enhance the LLC metastasis both in vitro and in vivo . In addition, we also demonstrate that skewing of macrophage M2 polarization by hypoxia relies substantially on activation of ERK signaling. Collectively, these observations unveil a novel tumor hypoxia concept involving the macrophage phenotype shift and provide direct evidence for lung cancer intervention through modulating the phenotype of macrophages.