Tumor Neutrophil Elastase Is Closely Associated With the Direct Extension of Non-small Cell Lung Cancer Into the Aorta

Yamashita, Jun‐ichi; Ogawa, Michio; Abe, Michio; Hayashi, Naoki; Kurusu, Yuji; Kawahara, Katsunobu; Shirakusa, Takayuki

doi:10.1378/chest.111.4.885

Cited by 46 publications

(28 citation statements)

References 9 publications

(1 reference statement)

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“…The distribution of patients with predicted intermediate and high activity was almost equal (43% vs. 47%, respectively). This data suggest that intermediate and high NE activity could play a role in LC, which is in concordance with results of Yamashita and co-workers who showed that elevated levels of NE facilitate the invasion of cancer cell [26].…”

Section: Discussionsupporting

confidence: 92%

Alpha-1-antitrypsin Phenotypes and Neutrophil Elastase Gene Promoter Polymorphisms in Lung Cancer

Topić

Ljujić

Nikolić

et al. 2010

Pathol. Oncol. Res.

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Imbalance between neutrophil elastase and alpha-1-antitrypsin (AAT) leads to emphysema in smokers as well as in patients with inherited alpha-1-antitrypsin deficiency. AAT as a proven inhibitor of apoptosis may play role in lung cancer (LC) progression. The aim was to analyse AAT protein variants and polymorphism in promoter region of the neutrophil elastase gene (ELA2) in patients with primary lung cancer. AAT phenotypisation by isoelectric focusing method and ELA2 gene promoter characterization by DNA sequencing were performed in 66 patients with primary lung cancer. Results showed that the frequency of M1 allele and PiM1 homozygotes in LC patients was significantly higher when compared to the healthy subjects (f = 0.6360 and 0.7424 respectively). The most frequent ELA2 promoter region genotypes in LC patients were -903TT and -741GG. There were significantly more patients with intermediate and high ELA2 genotype activity, compared to those with low activity (91% vs. 9%, respectively). In conclusion, we found that PiM1 homozygosity could be associated with the lung cancer, probably due to increased synthesis of this antiapoptotic protein. Non-MM variants of AAT and ELA2 genotypes with predicted intermediate or high activity could also represent a risk factor for aggressive form of lung cancer associated with extrathoracic metastases.

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Section: Discussionsupporting

confidence: 92%

Alpha-1-antitrypsin Phenotypes and Neutrophil Elastase Gene Promoter Polymorphisms in Lung Cancer

Topić

Ljujić

Nikolić

et al. 2010

Pathol. Oncol. Res.

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“…Surgical stress induces organ dysfunction through an uncontrolled inflammatory response, due to the overproduction of proinflammatory mediators (12,13) by macrophages and lymphocytes. In clinical practice, we often experience cases of rapid recurrence or regrowth of tumors after major cancer surgery, or perioperative surgical complications with inflammatory responses that involve the release of NE by neutrophils and also by cancer cells, as reported by Yamashita et al (15)(16)(17) Given these perioperative and oncological circumstances, we have focused on the NE that is released from neutrophils and tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Sivelestat, a specific neutrophil elastase inhibitor, suppresses the growth of gastric carcinoma cells by preventing the release of transforming growth factor‐α

et al. 2006

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Neutrophil elastase is a neutral serine proteinase produced by polymorphonuclear leukocytes and monocytes/macrophages, especially under surgical stress. In the present study, we investigated whether NE promotes cell growth by activation of EGFR to elucidate whether surgical stress induces tumor proliferation and progression. Furthermore, we examined the antitumor effect of a specific NE inhibitor, sivelestat. Cell growth assays were carried out in vitro and in vivo using TMK-1 gastric cancer cells. TMK-1 cell growth was stimulated to 118% of that of the control cells after 48 h stimulation with 1 µ µ µ µg/mL NE according to an MTT assay. Sivelestat inhibited cell growth to 23.4 and 58.0% of control values at concentrations of 100 and 1000 µ µ µ µg/mL, respectively. NE rapidly phosphorylated EGFR in only 5 min and triggered the ERK1/2-mitogenic signaling pathway in TMK-1. It was further demonstrated that NE-induced EGFR phosphorylation was transactivated through TGF-α α α α, using ELISA. (1) NE degrades a broad spectrum of extracellular matrix and cell surface proteins, such as elastin, interstitial collagens, proteoglycans, fibronectin, laminin, and type IV collagens.(2-5) Under normal physiological conditions, the proteolytic activity of elastase released by recruited neutrophils is strictly regulated by antiproteases, such as alpha-1-protease inhibitor and secretary leukoprotease inhibitor. However, under conditions of physiological disturbance, such as the presence of neoplasms, surgical stress, or inflammation, the balance between elastase and antiprotease is disrupted, and the predominant elastolytic activity causes the destruction of THE extracellular matrix. NE also cleaves pro-TGF-α on the surface of human airway epithelial cells through its proteolytic activity and releases mature, soluble TGF-α on human airway epithelial cells.(6) Release of TGF-α activates the EGFR signaling cascade, (6) resulting in mucinous secretion in the peripheral airways that might cause severe respiratory complications after major surgical stress or severe inflammatory response.Recently, a specific synthetic NE inhibitor, sivelestat, has been developed and used clinically in Japan for the treatment of various inflammatory diseases. The anti-inflammatory effects of sivelestat are effective for the alleviation of surgical stress, and can reduce morbidity and organ dysfunction, including acute respiratory distress syndrome. As mentioned above, sivelestat inhibits the NE-induced release of TGF-α from the cell membrane.As we have previously demonstrated, gastric and esophageal carcinoma cells have been found to have multi-autocrine loops for the development of growth and metastatic potential (7)(8)(9)(10)(11) in laboratory studies. In the clinical setting, relapses or rapid recurrences are often observed after extensive resection of gastric and esophageal tumors, suggesting that strong inflammatory responses are present, including the release of NE, which might cause the rapid spread of cancer cells. These facts prompted us to exam...

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“…A previous study suggests that individuals with elastolytic damage in lung tissue may have a higher risk for lung cancer than those with normal lung tissue [1]. NE was associated with aggressiveness of the tumor, suggesting its involvement in the invasion of the tumor and association with poor prognosis in non-small cell lung cancer [7].…”

Section: Introductionmentioning

confidence: 97%

Polymorphisms in the promoter region of neutrophil elastase gene and lung cancer risk

et al. 2005

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SummaryThe neutrophil elastase (NE) gene encodes a powerful serine protease that is involved in the process of normal tissue turnover, natural host defense or tissue damage in acute and chronic inflammatory disorders. Furthermore, NE was suggested as one of the determinant factors of individual susceptibility to lung cancer resulting from imbalance between α1-antitrypsin (AT) and NE. To determine whether NE plays a role in risk for lung cancer, we screened polymorphisms in the promoter region of the NE gene and assessed the role of the NE polymorphisms in the risk for lung cancer. We confirmed three previously identified polymorphisms which are located at −903, −741, and extra 52 bp STS relative to the transcription initiation site. In addition, two new polymorphisms at −832 (G/T) and −789 (C/T) were identified. Their rare allelic frequencies of new polymorphism are 0.02 and 0.01, respectively, among Caucasians. The prevalence of the NE −903 (T/T) and (T/G) genotypes were 0.88 and 0.12 in controls as compared to 0.96 and 0.04 in lung cancer patients using genomic DNA isolated from 113 Caucasian lung cancer cases and 131 controls. A significant increase in lung cancer risk was observed for expected high NE activity genotypes (OR = 3.2, 95% CI = 1.02-10.3) as compared to low NE activity genotypes. These results were consistent with previous in vitro functional analysis, which reported an approximately two-fold increase enzyme expression with the −903T/−741G allele as compared to the −903G/ −741A variant. These results confirm that the NE promoter region polymorphisms may influence in risk for lung cancer.

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Tumor Neutrophil Elastase Is Closely Associated With the Direct Extension of Non-small Cell Lung Cancer Into the Aorta

Cited by 46 publications

References 9 publications

Alpha-1-antitrypsin Phenotypes and Neutrophil Elastase Gene Promoter Polymorphisms in Lung Cancer

Alpha-1-antitrypsin Phenotypes and Neutrophil Elastase Gene Promoter Polymorphisms in Lung Cancer

Sivelestat, a specific neutrophil elastase inhibitor, suppresses the growth of gastric carcinoma cells by preventing the release of transforming growth factor‐α

Polymorphisms in the promoter region of neutrophil elastase gene and lung cancer risk

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