Colorectal Cancer and Mitochondrial Dysfunctions of the Adjunct Adipose Tissues: A Case Study.

A P Burlaka,M R Gafurov,I I Ganusevich,A A Burlaka,A V Vovk,S N Lukin

doi:10.1155/2018/2169036

Abstract

Excess body weight has been causally linked to an increased risk of different cancer types, including colorectal cancer (CRC) but the mechanisms underlying this association are practically unknown. We investigate redox state-superoxide (SO) generation rate, activity of complex I in electron transport chain (ETC) of mitochondria and of dinitrosyl iron complexes by electron paramagnetic resonance; activity of matrix metalloproteinase (gelatinase) MMP-2 and MMP-9 by gel zymography of adipose tissues (AT) from 46 patients (64.0 ± 1.6 y.o.) with CRC (II–III stages, pT2–3N0–2M0) in the AT adjacent to tumor (ATAT) and at a distance of 3 cm from the tumor (ATD) to follow the connection of the AT redox state with some of the tumor microenvironment indicators. We have incubated the AT species with the tumor necrosis factor α (TNF-α) to follow its influence on the measured values. As a control, normal AT (NAT) obtained during the liposuction is used. Tumor-induced changes in mitochondrial ETC of ATAT, particularly for Complex I, lead to the enhanced SO generation and consequent oxidative modifications of DNA in ATAT (up to 6.1 times higher than that in NAT and 3.7 times higher than that in ATD, p < 0.05). Gelatinase activity in ATAT is significantly higher than in ATD. A considerable effect of TNF-α on ATAT and ATD (but not on NAT, i.e., only on the tissues where the reprogramming of metabolism has already occurred under the influence of tumor) manifested in increase of cellular hypoxia, gelatinase activity, and SO generation rate is observed. The results can be used for better understanding the mechanism(s) of metabolic symbiosis of tumor and AT as well as serving as a basis for new therapeutic approaches.

Highlights

Obesity is recognized as the second highest risk factor for cancer after tobacco smoking [1,2,3,4,5,6,7]
In normal AT (NAT) and AT adjacent to tumor (ATAT) the following signals could be registered [30]: (1) with g ≈ 1.94 from the iron-sulfur (FeS) cluster N2 of NADH: ubiquinone oxidoreductase, called respiratory complex I of electron transport chain (ETC); (2) from “the “free” radical centers practically completely localized in mitochondria, semiquinones of flavoproteins found in the inner membrane of mitochondria and coenzyme Q semiquinones at g ≈ 2 .00; (3) signal at g ≈ 2.03 due to the formation of NO and N types FeS-protein complexes; (4) signal with g ≈ 2.25 related to the activity of the cytochrome P-450
We found that the reduction of activity of Complex I of ETC of mitochondria in ATAT depends on the degree of differentiation of the tumor (Figure 4)

Summary

Introduction

Obesity is recognized as the second highest risk factor for cancer after tobacco smoking [1,2,3,4,5,6,7]. Epidemiological studies show that overweight can account up to 20 % of all cancer-related deaths [3, 4]. “Understanding the link between being overweight or obese and a wide variety of cancers, as well as the biological mechanisms involved, remains an evolving and currently very active area of research” [8]. “The complex physiological changes that occur with obesity include alterations in the adipose tissue (AT) production of bioactive factors, growth factors, hormones, and reactive oxygen species (ROS) that can impact” the cancer development [10]

Objectives

Methods

Results

Discussion

Conclusion