THE REDOX STATUS OF ADIPOSE TISSUE: EFFECTS ON THE MICROENVIRONMENT AND PROGRESSION OF GASTRIC CANCER
Keywords:
gastric cancer, dysfunctional adipose tissue, obesity, superoxide radicals, matrix metalloproteinases, mitochondrial dysfunction.Abstract
Summary. Obesity is an important factor in the development and course of some types of cancer, particularly
tumors of the gastrointestinal tract. Adipose tissue (AT)
negatively affects the function of other tissues and organs
and, thus, obesity aggravates the course of cancer. However, the mechanisms responsible for these interactions,
are not quite clear yet today. Aim: to investigate the redox
state of the adjacent to the tumor of AT (ATAT), its relationship with some factors of the microenvironment and
metastasis of gastric cancer (GC). Objects and methods:
we investigated 11 samples of normal AT (NAT) practically from healthy individuals (after liposuction); samples of the tumor, ATAT and AT at a distance of 3 cm
from the tumor 45 patients with GC II–IV stages. The
presence of obesity in patients with GC was determined
by calculating and interpreting body mass index (BMI).
Also electron paramagnetic resonance, gel zymography, immunohistochemical, biochemical, and statistical
methods were used. Results: mitochondrial dysfunction
of adipocytes causes changes in redox status og ATAT
with GC, and, as a consequence, the respective activation of the redox-dependent factors. The speed of generating superoxide radicals (SR) in the mitochondria of
adipocytes of ATAT is significantly higher (in almost
4 times) than in NAT. The level of oxidative-induced
DNA mutations and gelatinase activity correlate with
the levels of generation CP mitochondria of adipocytes.
Defects in the mechanism of oxidative phosphorylation
activate several redox-sensitive factors in the tumor (hypoxia-inducible factor-1-alpha (HIF-1α), tumor-associated macrophage, tumor-associated adipocytes). Dysfunctional AT is a modifier of microenvironment of GC
that contributes to its progression. The redox state disbalance of dysfunctional AT is associated with obesity
and the degree of its severity correlates with BMI of the
patients. High levels of SR generation and gelatinase activity in ATAT are important factors in the progression
of tumors associated with distant metastasis and may
have prognostic value in the treatment of GC. Conclusion: understanding redox mechanisms of the symbiosis
of the tumor cells and adipocytes can help to find new
targets and prognostic markers for cancer patients who
are overweight, that will provide new approaches to the
individualization of anticancer therapy.
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 2015; 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.
Nieman KM, Romero IL, van Houten B, et al. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta 2013; 1831 (10): 1533–41.
Schwartz B, Yehuda-Shnaidman E. Putative role of adipose tissue in growth and metabolism of colon cancer cells. Front Oncol 2014; 26 (4): 164.
Kwan HY, Chao X, Su T, et al. Dietary lipids and adipocytes: potential therapeutic targets in cancers. J Nutr Biochem
; 26 (4): 303–11.
Unger R, Clark GO, Scherer PE, Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys
Acta 2010; 1801: 209–14.
Guh DP, Zhang W, Bansback N, et al. The incidence of comorbidities related to obesity and overweight: A systematic review and meta-analysis. Biomed Central Public Health 2009; 9: 1–20.
Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic diseases. Nat Rev Immunol 2011; 11:
–97.
Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796–808.
Maury E, Ehala-Aleksejev K, Guiot Y, et al. Adipokines oversecreted by omental adipose tissue in human obesity. Am J Physiol Endocrinol Metab 2007; 293: E656–E665.
Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494–505.
Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96: 939–49.
da Costa RM, Fais RS, Dechandt CR, et al. Increased mitochondrial ROS generation mediates the loss of the anti-contractile effects of perivascular adipose tissue in high-fat diet obese mice. Br J Pharmacol 2016; 8. doi: 10.1111/bph.13687.
Pérez S, Taléns-Visconti R, Rius-Pérez S, et al. Redox signaling in the gastrointestinal tract. Free Radic Biol Med 2017; 104: 75–103.
BMI Classification. Global Database on Body Mass Index. World Health Organization, 2006; 27: 2012.
Burlaka AP, Ganusevich II, Golotiuk VV, et al. Superoxideand NO-dependent mechanisms of antitumor and antimetastatic effect of L-arginine hydrochloride and coenzyme Q10. Exp Oncol 2016; 38 (1): 31–5.
Cидорик ЄП, Бурлака АП, Коваленко НГ. Вміст молекулярних маркерів модифікації гуаніну — 8-охоdGu і 8-охоG, індукованих радикальними формами кисню, прихімічному канцерогенезі вмолочних залозах і пухлинному процесі шлунково-кишкового тракту. Доповіді Нац акад наук України 2005; (12): 177–81.
De Clerk YA, Perez N, Shimada H, et al. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 1992; 52: 701–8.
Cieplak P, Stronqin AY. Matrix metalloproteinases — From the cleavage data to the prediction tools and beyond. Biochim Biophys Acta 2017; 17: pii: S0167–4889(17)30064–2.
Осинський СП, Бубновська ЛМ, Oсинський ДС та ін. Клінічне та прогностичне значененя гіпоксія-асоційованих факторів пухлинного мікрооточення раку шлунка. Онкологія 2015; 17 (3): 162–8.
Ганусевич ІІ, Гуменюк ЛД, Мамонтова ЛА та ін. Пухлиноасоційовані макрофаги та вміст активних форм желатиназ у тканині раку шлунка: зв’язок з виживаністю хворих. Онкологія 2013; 15 (3): 14–9.
Ганусевич ІІ, Гуменюк ЛД, Ковельська АВ, МамонтоваЛА. Пухлинно-асоційовані адипоцити та індекс маси тіла: зв’язок з перебігом раку шлунка. Матеріали XIII З’їзду онкологів та радіобіологів України 26–28 травня 2016 р., Київ, с. 192.
