Tumor hypoxia enhances non-small cell lung cancer metastasis by selectively promoting macrophage M2 polarization through the activation of ERK signaling

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.

Sulforaphane inhibits hypoxia-induced HIF-1α and VEGF expression and migration of human colon cancer cells

“…Accumulating evidence in solid tumors has shown that HIF-1α overexpression, either as a result of intratumoral hypoxia or genetic alterations, activates gene transcription, and the protein products contribute to basement membrane migration and invasion (25,37,38). In this study, treatment with sulforaphane inhibited hypoxia-induced migration by HCT116 cells (Fig.…”

Sevoflurane suppresses hypoxia-induced growth and metastasis of lung cancer cells via inhibiting hypoxia-inducible factor-1α

“…Numerous studies documented that the hypoxia microenvironment was able to enhance tumor progression [9,15]. A growing body of evidence demonstrated that there is a high correlation between hypoxia and lung cancer metastasis and poor prognosis [16,17]. Unfortunately, the OLV anesthesia technique, widely used during lung cancer surgery, aggravates hypoxia, which promotes the invasiveness of lung cancer [11].…”

Cycling hypoxia: A key feature of the tumor microenvironment

“…Isolated macrophages from cycling hypoxia-exposed tumors increased cancer cell proliferation and migration in vitro [91]. In another in vivo model where mice were exposed to 8 % O 2 4 hours per day during 5 weeks, Zhang et al observed an aggressive tumor behavior with enhanced metastases that was correlated with more M2-like macrophages within the tumors [92]. Of note, Kalliomaki et al have reported that cycling hypoxia exposure induced an accumulation of tumor-associated macrophages detected by an immunostaining for F4/80, a macrophage marker, in vivo in mammary tumors of MMTV-PyMT transgenic mice.…”