REDOX-DEPENDENT MECHANISMS OF INFLAMMATION IN ADIPOSE TISSUE OF PATIENTS WITH RECTAL CANCER
Keywords:
superoxide radicals, mitochondria, nitric oxide, adipose tissue, rectum cancer.Abstract
Summary. The study of tumor involvement in metabolism changes adjacent to the tumor fatty tissue (ATFT)
are important for understanding the complex relationships between the tumor and fatty tissue (FT) that contribute to the progression of the disease. The source of the
damaging effects on FT can be mitochondrial superoxide
radicals (SR) and NO˙ of tumors, which may contribute to the progression of the latter due to the activation
it redox-dependent pathways. Given the fact that FT
is an important energy source for tumor cells, understanding the mechanism of metabolic symbiosis in tumor
cells from FT can be the basis to create new therapeutic approaches. Objective: to carry out the redox-dependent mechanisms in normal fatty tissue (NFT) obtained
from patients without oncological disease, ATFT at a
distance of 3 cm from the ATFT, the activity of metalloproteinases (MMP-2, -9) in this tissues and the effect of TNF-α in it. Object and Methods: the study was
conducted on 46 samples of ATFT patients with rectal
cancer (RC) II–III stages (pT2–3pN0–2pM0) and 26
samples FT. As control was used the FT of 11 healthy
men, taken after performing liposuction in a specialized medical center, in observance of sterility. Among
the examined patients the number of women and men
was 21 and 25, respectively, and the average age was of
64.0 ± 1.6 years. The used methods were electron paramagnetic resonance at the temperature of liquid nitrogen and the technology Spin Traps, sonograph in polyacrylamide gels, biochemical, and statistical methods.
Results: influencing electron transport chain (ETC) of
mitochondria ATFT, particularly for Complex 1, the
tumor causes an increase in the speed of generating the
SR and, accordingly, oxidative modifications of DNA
in ATFT. The level of generation of SR, and the oxidation-induced DNA mutations in the mitochondria of
the latter, were respectively at 6.1 and 5.8 times higher
in comparison with NFT (p < 0.05, p < 0.05) and 3.7
and 3.5 times higher than those in distant FT (p < 0.05,
p < 0.05). Gelatinase activity of MMP-2, -9 ATFT was
significantly higher than in distant FT. There was a significant effect of in vitro TNF-α on mitochondria ATFT
and distant FT (but not NFT), which is manifested by
increase in cellular hypoxia, speed of generating the SR,
gelatinase activity. Conclusions: under the influence of
factors of a malignant tumor the protumor phenotype is
formed of ATFT, which is characterized by high levels
of SR, oxidative modifications of DNA and activity of
MMP. Incubation of NFT, distant FT and ATFT with
proinflamation cytokine TNF-α causes changes in the
redox state of the mitochondria and activation of several
inflammatory factors (SR, NO˙, MMP) in the tissues,
where there was already reprogramming of metabolism
under the influence of the tumor — in ATFT and, to a
lesser extent, distant FT
References
Schwartz В, Yehuda-Shnaidman E. Putative role of adipose
tissue in growth and metabolism of colon cancer cells. Front Oncol 2014; 4: 164.
Marseglia L, Manti S, D’Angelo G, et al. Oxidative stress
in obesity: a critical component in human diseases. Int J Mol Sci
; 16 (1): 378–400.
Liu GS, Chan EC, Higuchi M, et al. Redox mechanisms in
regulation of adipocyte differentiation: beyond a general stress response. Cells 2012; 1 (4): 976–93.
Ramos-Nino ME. The role of chronic inflammation in obesity-associated cancers. ISRN Oncol 2013; 2013: 697521.
Burlaka АP, Sidorik EP, Ganusevich ІІ, et al. Effects of radical oxygen species and NO: formation of intracellular hypoxia and
activation of matrix metalloproteinases in tumor tissues. Exp Oncol 2006; 28 (1): 49–53.
Sullivan LB, Chandel NS. Mitochondrial reactive oxygen
species and cancer. Cancer Metab 2014; 2: 17.
Бурлака АП, Сидорик ЄП. Радикальні форми кисню
та оксиду азоту при пухлинному процесі. К: Наукова думка,
227 с.
Shabalina IG, Vrbacký M, Pecinová A, et al. ROS production in brown adipose tissue mitochondria: the question of UCP1-
dependence. Biochim Biophys Acta 2014; 1837 (12): 2017–30.
Cawthorn WP, Sethi JK. TNF-alpha and adipocyte biology. FEBS Lett 2008; 582 (1):117–31.
Burlaka AP, Sidorik EP, Ganusevich II, et al. High formation of superoxide anion and nitric oxide, and matrix metalloproteinases activity in vascular wall of rectal carcinoma vessels. Exp
Oncol 2006; 28: 323–5.
Burlaka AP, Ganusevich II, Lukin SN, et al. Superoxideand NO-dependent mechanisms of the reprogramming of bone
marrow cells by tumor cells. Appl Magn Reson 2014; 45: 1261–73.
Tormos KV, Anso E, Hamanaka RB, et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab
; 14: 537–44.
Kassenbrock K, Plaks V, Werb Z. Matrix metalloproneinases
regulators of the tumor microenvironment. Cell 2010; 141: 52–67.
Noel A, Guttierez-Fernandez A, Sounni NE, et al. New and
paradoxical roles of matrix metalloproteinases in the tumor microenvironment. Front Pharmacol 2012; 3: 1–9.
Al-Zhoughbi W, Huang J, Paramasivan GS, et al. Tumor macroenvironment and metabolism. Semin Oncol 2014;
: 281–95.
Nieman Km, Romero Il, Van Houten B, et al. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim
Biophys Acta 2013; 1831: 1533–41.
Liou G-Y, Storz P. Reactive oxygen species in cancer. Free
Radic Res 2010; 44 (5): e10.3109.
Van Kempen LC, Visser KE, Coussens LM. Inflammation,
proteases and cancer. Eur J Cancer 2006; 42: 728–34.
Lewis CE, Pollard JW. Distinct role of macrophages
in different tumor microenvironments. Cancer Res 2006; 66:
–11.
Marconi C, Bianchini F, Mannini A, et al. Tumoral and
macrophage uPAR and MMP-9 contribute to the invasiveness
of B16 murine melanoma cells. Clin Exp Metastasis 2008; 25:
–31.
Kim KC, Lee CH. MAP kinase activation is required for the
MMP-9 induction by TNF-stimulation. Arch Pharm Res 2005;
(11): 1257–62.
Lee IT, Lin CC, Wu YC, et al. TNF-alpha induces matrix
metalloproteinase-9 expression in A549 cells: role of TNFR1/
TRAF2/PKCalpha-dependent signaling pathways. J Cell Physiol 2010; 224 (2): 454–64.
Tsai C-L, Chen W-C, Hsieh H-L, et al. TNF-α induces
matrix metalloproteinase-9-dependent soluble intercellular adhesion molecule-1 release via TRAF2-mediated MAPKs and
NF-κB activation in osteoblast-like MC3T3-E1 cells. J Biomed
Sci 2014; 21: 12.
Lee SJ, Park SS, Cho YH, et al. Activation of matrix metalloproteinase-9 by TNF-alpha in human urinary bladder cancer
HT1376 cells: the role of MAP kinase signaling pathways. Oncol
Rep 2008; 19 (4): 1007–13.
Steenport M, Khan KMF, Du B, et al. Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9:
evidence for the role of TNF-α and cyclooxygenase-2. J Immunol 2009; 183: 8119–27.
Kesanakurti D, Chetty C, Bhoopathi P, et al. Suppression of MMP-2 attenuates TNF-α induced NF-κB activation
and leads to JNK mediated cell death in glioma. PLoS One 2011;
(5): e19341.
De Groef L, Salinas-Navarro M, Van Imschoot G, et al.
Decreased TNF levels and improved retinal ganglion cell survival
in MMP-2 null mice suggest a role for MMP-2 as TNF sheddase.
Mediators Inflamm 2015; 2015: 108617.
