Intermittent hypoxia promotes melanoma lung metastasis via oxidative stress and inflammation responses in a mouse model of obstructive sleep apnea

Abstract

BackgroundRecently, increased tumor incidence and cancer-related mortality have been reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), the hallmark feature of OSA, contributes to the metastasis of tumors. However, the molecular mechanisms by which tumor metastasis is accelerated by OSA-like IH remain to be elucidated.MethodsC57BL/6 J male mice were subjected to intravenous injection of B16F10 melanoma cells before receiving IH treatment. Then, the animals were randomly distributed into three groups (n = 8 each): normoxia (N) group, IH group, and antioxidant tempol group (IHT, exposed to IH after treatment with tempol). After the mice were sacrificed, the number and weight of lung metastatic colonies were assessed. The lung tissues with tumor metastasis were analyzed for markers of oxidative stress and inflammation and for HIF-1α using western blotting and real-time PCR (qRT-PCR). The level of reactive oxygen species (ROS) in B16F10 cell was also assessed after N, IH and IH with tempol treatments.ResultsCompared with normoxia, IH significantly increased the number and weight of mouse lung metastatic colonies. Treatment of B16F10 cells with IH significantly enhanced ROS generation. Lung tissues with tumor metastasis provided evidence of increased oxidative stress, as assessed by p22phox and SOD mRNA levels and the NRF2 protein level, as well as increased inflammation, as assessed by TNF-α and IL-6 mRNA levels and the NF-κB P65 protein level. HIF-1α protein levels were increased in response to IH treatment. Tempol, an important antioxidant, ameliorated IH-induced melanoma lung metastasis in mice and reduced oxidative stress and inflammation responses.ConclusionsThese results support the hypothesis that oxidative stress and inflammation responses play an important role in the pathogenesis of OSA-like IH-induced melanoma lung metastasis in mice. Antioxidant intervention provides a novel strategy for the prevention and treatment of cancer in OSA populations.

Models of intermittent hypoxia and obstructive sleep apnea: molecular pathways and their contribution to cancer

“…Most cancer-related OSA studies employ the airtight box model to generate intermittent hypoxia independent of the other physiological effects associated with OSA. Several studies have been published in the last 5 years, mostly with melanoma and lung cancer models (5,7,9,51,85). These confirm an important role for systemic intermittent hypoxia in tumor growth and metastasis.…”

“…Mouse models of intermittent hypoxia mimicking OSA show enhanced cancer growth, invasion, and metastasis (5,7,9,85). Intermittent hypoxia enhances both the early and late stages of metastasis, which was confirmed in a spontaneous and an induced metastasis model (subcutaneous or intravenous injection of melanoma cells, respectively) (7).…”

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

“…46,47,[84][85][86][87][88][89] These microenvironmental stress related changes in cancer cell metabolism are frequently associated with greater ROS production. 90 1.4 | Switch in redox control from de novo GSH synthesis to NADPH from the PPP in advanced cancer cells One major mechanism for enhancing ROS levels in cancer cells occurs via a feedback amplification loop involving ROS-mediated increase in cytosolic NADPH production. Thus, metabolic profiling 91,92 and other studies described below have shown for many cancer cell types that glycolysis is partly shunted via Glc6PDH into the oxidative PPP F I G U R E 2 The thioredoxin reductase (TrxR/Trx) system of thiol:oxidoreductases for redox regulation.…”

“…The tumor microenvironment during rapacious growth phases will concomitantly cause intermittent periods of hypoxia, acidosis, and nutrient deprivation resulting in hypoglycemia, all factors which consequently induce a major reprogramming of cancer cell metabolism . These microenvironmental stress related changes in cancer cell metabolism are frequently associated with greater ROS production …”

Sleep apnoea and immune regulation: The story is only beginning

“…The processes are also under the influence of multiple triggers and pathways, and the clinical implications of activation of PD‐L1/PD‐1 axis need to be put into perspective. One interesting point in the story of OSA and cancer is that, among various malignancies, melanoma has been most consistently observed to be associated with OSA, especially in younger patients, and IH was shown to promote melanoma lung metastasis via oxidative stress and inflammation . Melanoma is also a tumour that is highly amenable to immunotherapy targeting the PD‐L1/PD‐1 axis …”