High levels of reactive oxygen (ROS) and nitrogen (RNS) species can lead to the destruction of extracellular matrix facilitating tumor progression. ROS can activate matrix metalloproteinases (MMP), damage DNA and RNA. Therefore, the levels of MMP, ROS and RNS can serve as additional prognostic markers and for the estimation of the effectiveness of tumor therapy. Concerning gastric cancer, the prognostic role of MMP, its connection with the cancer staging remains controversial and correlations between the activity of MMP with the ROS and RNS levels are insufficiently confirmed. Superoxide generation rates, nitric oxide (NO) levels, concentrations of active forms of matrix metalloproteinases MMP-2 and MMP-9 in tumor and adjacent tissues of patients with stomach cancer at different disease stages were measured by electron spin resonance (ESR) including spin-trapping and polyacrylamide gel zymography. It is shown that the activity of MMP-2 and MMP-9 in tumor tissue correlate with the superoxide radicals generation rate and NO levels (r = 0.48÷0.67, p < 0.05). The activity of MMP-2 and MMP-9 in tumor tissues and superoxide radical generation rates correlate positively with the stage of regional dissemination (r = 0.45 and 0.37, correspondingly, p < 0.05), but MMP-2 and MMP-9 activity inversely depends on distant metastatic degree of stomach cancer (r = 0.58; p < 0.05). Additionally, the feasibility of ESR to locally determine oxidative stress is demonstrated.
Reactive oxygen species (ROS) Matrix metalloproteinases Stomach cancer Gastric cancer Electron spin resonance (ESR) Electron paramagnetic resonance (EPR) Metastasis
This is a preview of subscription content, log in to check access.
The work is performed in the framework of the cooperation agreement between R.E. Kavetsky Institute and Kazan Federal University according to the Russian Government Program of Competitive Growth of Kazan Federal University.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.
Compliance with ethical standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917CrossRefPubMedGoogle Scholar
Chissov VI, Starinsky VV, Petrova (2013) Malignant neoplasms in Russia in 2011 (incidence and mortality). Hertzen Research Institute of Oncology, Moscow [in Russian]Google Scholar
Fedorenko Z, Goulak LO, Gorokh YL, Ryshov AY, Soumkina OV, Koutsenko LB (2015) Cancer in Ukraine 2013–2014: incidence, mortality, activities of oncological service. Bulletin of national cancer registry of Ukraine vol 16. National Institute of Cancer, KyivGoogle Scholar
Sabesan A, Benett JJ (2015) Diagnosis, staging, and workup of gastric cancer. In: Strong VE (ed) Gastric cancer. Springer, Switzerland, pp 127–142CrossRefGoogle Scholar
Elliott RL, Head JF (2012) Cancer: tumor iron metabolism, mitochondrial dysfunction and tumor immunosuppression; “a tight partnership—was Warburg correct?”. J Cancer Ther 3:278–311CrossRefGoogle Scholar
Burlaka AP, Ganusevich II, Gafurov MR, Lukin SN, Sidorik EP (2013) Electron paramagnetic resonance study of tumor affected bone marrow. Cancer Microenviron 6:273–276CrossRefPubMedPubMedCentralGoogle Scholar
Burlaka AP, Sidorik EP, Ganusevich II, Osinsky SP (2006) Effects of radical oxygen species and NO: formation of intra-cellular hypoxia and activation of matrix metalloproteinases in tumor tissues. Exp Oncol 28:49–53PubMedGoogle Scholar
Burlaka AP, Sidorik EP, Ganusevich II, Leschenko YM, Osinsky SP (2006) High formation of superoxide anion and nitric oxide, and matrix metalloproteinases activity in vascular wall of rectal carcinoma vessels. Exp Oncol 28:323–325PubMedGoogle Scholar
Burlaka AP, Sidorik EP (2006) Radical forms of oxygen and nitrogen oxide in the tumors process. Naukova dumka, Kyiv [in Ukrainian]Google Scholar
Gauron C, Rampon C, Bouzaffour M, Ipendey E, Teilon J, Volovitch M, Vriz S (2013) Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed. Sci Rep 2084:123–133Google Scholar
Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Kalyanamaran B et al (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. PNAS 107:8788–8793CrossRefPubMedPubMedCentralGoogle Scholar
Shimokawa H (2013) Reactive oxygen species promote vascular smooth muscle cell proliferation. Circ Res 113:1040–1042CrossRefPubMedGoogle Scholar
Maeda H (2013) The link between infection and cancer: tumor vasculature, free radicals, and drug delivery to tumors via the EPR effect. Cancer Sci 104:779–789CrossRefPubMedGoogle Scholar
Kubben FJ, Sier CF, van Duijn W, Griffioen G, Hanemaaijer R, van de Velde CJ et al (2006) Matrix metalloproteinase–2 is a consistent prognostic factor in gastric cancer. Br J Cancer 94:1035–1040CrossRefPubMedPubMedCentralGoogle Scholar
Peña S (2010) Matrix metalloproteases as molecular markers in gastric cancer. Med Clin 134:123–126CrossRefGoogle Scholar
Wu CY, Wu MS, Chiang EP et al (2007) Plasma matrix metalloproteinase-9 level is better than serum matrix metalloproteinase-9 level to predict gastric cancer evolution. Clin Cancer Res 13:2054–2060CrossRefPubMedGoogle Scholar
Chu D, Zhang Z, Li Y et al (2011) Matrix metalloproteinase-9 is associated with disease-free survival and overall survival in patients with gastric cancer. Int J Cancer 129:887–895CrossRefPubMedGoogle Scholar
Gialeli C, Theocharis AD, Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS 278:16–27CrossRefGoogle Scholar
Shen W, Xi H, Wei B, Chen L (2014) The prognostic role of matrix metalloproteinase 2 in gastric cancer: a systematic review with meta-analysis. J Cancer Res Clin 140:1003–1009CrossRefGoogle Scholar
Sawada T, Yashiro M, Sentani K, Oue N, Yasui W, Miyazaki K et al (2015) New molecular staging with G-factor supplements TNM classification in gastric cancer: a multicen-ter collaborative research by the Japan Society for Gastroenterological Carcinogenesis G-Project committee. Gastric Cancer 18:119–128CrossRefPubMedPubMedCentralGoogle Scholar
American Joint Committee on Cancer (2010) AJCC cancer staging manual, 7th edn. Springer, New YorkCrossRefGoogle Scholar
Burlaka AP, Ganusevich II, Lukin SN, Gafurov MR, Sidorik EP (2014) Superoxide-and NO-dependent mechanisms of the reprogramming of bone marrow cells by tumor cells. Appl Magn Reson 11:1261–1273CrossRefGoogle Scholar
Burlaka A, Selyuk M, Gafurov M, Lukin S, Potaskalova V, Sidorik E (2014) Changes in mitochondrial functioning with electromagnetic radiation of ultra high frequency as revealed by electron paramagnetic resonance methods. Int J Rad Biol 90:357–362CrossRefPubMedGoogle Scholar