Most tumor cells show different metabolic pathways than normal cells. Even under the conditions of sufficient oxygen, they produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, which is known as aerobic glycolysis or the Warburg effect. Lung cancer is a malignant tumor with one of the highest incidence and mortality rates in the world at present. However, the exact mechanisms underlying lung cancer development remain unclear. The three key enzymes of glycolysis are hexokinase, phosphofructokinase, and pyruvate kinase. Lactate dehydrogenase catalyzes the transfer of pyruvate to lactate. All four enzymes have been reported to be overexpressed in tumors, including lung cancer, and can be regulated by many oncoproteins to promote tumor proliferation, migration, and metastasis with dependence or independence of glycolysis. The discovery of aerobic glycolysis in the 1920s has provided new means and potential therapeutic targets for lung cancer.

BackgroundTumor cells produce various cytokines and chemokines that attract leukocytes. Leukocytes can amplify parenchymal innate immune responses, and have been shown to contribute to tumor promotion. Neutrophils are among the first cells to arrive at sites of inflammation, and the increased number of tumor-associated neutrophils is linked to poorer outcome in patients with lung cancer.ResultsWe have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model of lung cancer (CC-LR). This was associated with severe lung neutrophilic influx due to the increased level of neutrophil chemoattractant, KC. To further study the role of neutrophils in lung tumorigenesis, we depleted neutrophils in CC-LR mice using an anti-neutrophil antibody. This resulted in a significant reduction in lung tumor number. We further selectively inhibited the main receptor for neutrophil chemo-attractant KC, CXCR2. Similarly, this resulted in suppression of neutrophil recruitment into the lung of CC-LR mice followed by significant tumor reduction. Neutrophil elastase (NE) is a potent elastolytic enzyme produced by neutrophils at the site of inflammation. We crossed the CC-LR mice with NE knock-out mice, and found that lack of NE significantly inhibits lung cancer development. These were associated with significant reduction in tumor cell proliferation and angiogenesis.ConclusionWe conclude that lung cancer promotion by inflammation is partly mediated by activation of the IL-8/CXCR2 pathway and subsequent recruitment of neutrophils and release of neutrophil elastase. This provides a baseline for future clinical trials using the IL-8/CXCR2 pathway or NE inhibitors in patients with lung cancer.

Lung cancer is the leading cause of cancer related death, 90% of lung cancer patients die of metastasis. Many microRNAs (miRNAs) are deregulated in cancer. They are involved in tumorigenesis and function as oncogenes or tumor suppressor genes. Recent studies show that miRNAs may be responsible for tumor metastasis. Several functional studies show that miR-26a plays an important role in carcinogenesis; however, none of these studies is related to tumor metastasis. In the present study, we investigated the effect of miR-26a on metastasis potential of lung cancer cells. Our data showed that miR-26a expression level was higher in lymph node metastasis tumor tissues than in primary tumor tissues. Ectopic expression of miR-26a dramatically enhanced lung cancer cell migration and invasion abilities. Metastasis-related genes matrix metallopeptidase 2 (MMP-2), vascular endothelial growth factor (VEGF), Twist and β-catenin were upregulated. Phosphatase and tensin homolog (PTEN) was a direct target of miR-26a. Further mechanistic study revealed that miR-26a increased AKT phosphorylation and nuclear factor kappa B (NFκB) transcriptional activation. Our study demonstrated that miR-26a enhanced lung cancer cell metastasis potential via modulation of metastasis-related gene expression, and activation of AKT pathway by PTEN suppression, suggesting that miR-26a might be a potential therapeutic candidate in patients with metastatic lung cancer.