Redox state markers of tumors in patients with colorectal cancer

A. P. Burlaka, V. V. Holotiuk, A. V. Vovk, S. M. Lukin

Abstract


In terms of cancer disease the redox state of a body and focuses of tumor growth is largely determined by reprogramming mitochondria metabolism and features of functioning of metal-containing proteins, in particular, iron-containing proteins: lactoferrin (LF) and transferrin (TF). Oxidation-induced modifications of genes LF and TF lead to violation of their iron-binding and iron-transporting functions, which leads to accumulation of free iron (FI) in tissues and blood in high concentrations. The appearance of FI is registered in tumor tissue as a result of oxidation-induced destruction of heme and non-heme iron-containing proteins. LF regulates the bioavailability of iron at the realization of metabolic functions of a cell, in particular, proliferation, which marker is the expression of nuclear antigen Ki-67. The purpose of the work was to investigate levels of LF, TF, FI in tumors of patients with colorectal cancer (CRC) at stages II and III (T2-4N0-2M0G2-3) and determine their predictive value during the neoadjuvant antitumor therapy.

Surgical samples of tumor-affected and intact rectal mucosa (at a distance of 15 cm from the tumor) were studied. The samples were taken from 67 patients (36 men and 31 women, mean age 63±1.3 years) with a diagnosis of rectal adenocarcinoma, among wich 38 patients had the II stage and 29 - the third stage of the disease. The rates of LF, TF, FI in a tumor were determined by electron paramagnetic resonance (EPR) spectroscopy method at the temperature of liquid nitrogen (T=77 K). Superoxide-generating activity of tumor tissues was studied by EPR method using Spin Traps. Expression of the proliferation marker Ki-67 in surgical specimens of a tumor-affected and intact rectum of patients with CRC were investigated by immunohistochemical method. Statistical analysis was performed using the licensed application Origin 7.0. The difference between the results were considered significant at p <0.05.

It has been revealed that in medium and low differentiated rectal tumors the content of LF was 15 and 50 times higher, respectively, compared to the intact rectal mucosa (p<0.05). TF level in the intact rectal mucosa was within physiological norm. 'FI' level in low differentiated rectal adenocarcinomas was 9 times higher than in the conditionally healthy tissue and three times higher than the 'FI' level of G2-tumors (p<0.05). The rate of generation of superoxide radicals (SR) in adenocarcinomas with medium and low differentiation was 2 and 3.7 times higher, respectively, than the rate in the intact rectal mucosa (p<0.05). The level of expression of Ki-67 in intact mucosa was 33.2 ± 2.61 cu, while in the G2 and G3 tumors it was significantly higher, and it was 38.01 ± 2.94 cu and 52.65 ± 4.48 cu, respectively (P<0.001). The level of immunosignal of Ki-67 in the tumor parenchyma correlated with the tumor stage, degree of tumor differentiation, level of LF and FI

It has been revealed an increase in levels of LF, FI, proliferation marker Ki-67 and SR generation rate in rectal adenocarcinomas, depending on the degree of differentiation of tumors. The favorable clinical course of disease in patients with CRC is characterized by reduced levels of LF, FI and Ki-67 expression, but the tumor progression - by an increase in these levels.


Keywords


rectal cancer; lactoferrin; transferrin; superoxide radicals; “free iron”; Ki-67.

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DOI: http://dx.doi.org/10.11603/mcch.2410-681X.2016.v0.i4.7254

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