Redox state markers of tumors in patients with colorectal cancer

Authors

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

DOI:

https://doi.org/10.11603/mcch.2410-681X.2016.v0.i4.7254

Keywords:

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

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.

References

Burlaka A. P. Radykalni formy kysniu ta oksydu azotu pry pukhlynnomu protsesi / A. P. Burlaka, Ie. P. Sydoryk. K. : Naukova dumka, 2006. – 227 s.

Porushennia u systemi tseruloplazmin-transferyn u khvorykh na rak priamoi kyshky / A. P. Burlaka, I. I. Hanusevych, V. V. Holotiuk [ta in.] // Onkolohiia. – 2014. – 16, № 3. – S. 206–210.

Mitokhondrialnyi redoks-kontrol matryksnykh metaloproteinaz ta metastazuvannia u khvorykh na rak molochnoi zalozy / A. P. Burlaka, I. I. Hanusevych, Ie. V. Luk’ianchuk [ta in.] // Onkolohiia. – 2010. – 12. – № 4. – S. 377–382.

Gibbons J. A. Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer / J. A. Gibbons, J. R. Kanwar, R. K. Kanwar // BMC. Cancer. – 2015. – 15. – Р. 1–16.

Muñoz M. Disorders of iron metabolism. Part II: iron deficiency and iron overload / M. Muñoz, J. A. García-Erce, Á. F. Remacha // J. Clin. Pathol. – 2011. – 64. – Р. 287–296.

Nuclear Factor Kappa B, Matrix Metalloproteinase-1, p53, and Ki-67 Expressions in the Primary Tumors and the Lymph Node Metastases of Colorectal Cancer Cases / I. Meteoglu, I. H. Erdogdu, P. Tuncyurek [et al.] // Gastroenterology Research and Practice. – 2015. – Р. 945392.

Torti S. V. Iron and cancer: more ore to be mined / S. V. Torti, F. M. Torti // Nat. Rev. Cancer. – 2013. – 13. – Р. 342–355.

Bovine lactoferrin counteracts Toll-like receptor mediated activation signals in antigen presenting cells / P. Puddu, D. Latorre, M. Carollo [et al.] // PLoS ONE. – 2011. – 6. – P. 22504.

Cancer prevention by bovine lactoferrin: from animal studies to human trial / H. Тsuda, T. Kozu, G. Iinuma [et al.] // Biometals. – 2010. – 23. – P. 399–409.

Prognostic significance of Ki-67 expression in rectal carcinoid tumors / S. M. Hong, Y. S. Kim, J. S. Moon [et al.] // Korean J. Gastroenterol. – 2013. – 61. – P. 82–87.

Statin‐induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: intermediacy of nitric oxide and antioxidant defence mechanisms / A. K. Kanugula, P. N. Gollavilli, S. B. Vasamsetti [et al.] // FEBS J. – 2014. – 281. – P. 3719–3238.

Iron and reactive oxygen species: friends or foes of cancer cells? / L. M. Bystrom, M. L. Guzman, S. Rivella // Antioxid Redox Signal. – 2014. – 20 (12). – P. 1917–1924.

Systemic and tumor level iron regulation in men with colorectal cancer: a case control study / C. K. Pusatcioglu, E. Nemeth, G. Fantuzzi [et al.] // Nutr. Metab. (Lond). – 2014. – 11. – P. 21.

Xue Х. Intestinal Iron Homeostasis and Colon Tumorigenesis / Х. Xue, Y. M. Shah // Nutrients. – 2013. – 5 (7). – P. 2333–2351.

Holotiuk V. V. Marker mitotychnoi aktyvnosti pukhlynnykh klityn Ki-67 v otsintsi efektyvnosti neoad’iuvantnoi khimiopromenevoi terapii u khvorykh na rak priamoi kyshky / V. V. Holotiuk // Visnyk morfolohii. – 2015. – 2 (21). – S. 465–468.

Published

2017-02-17

How to Cite

Burlaka, A. P., Holotiuk, V. V., Vovk, A. V., & Lukin, S. M. (2017). Redox state markers of tumors in patients with colorectal cancer. Medical and Clinical Chemistry, (4), 39–44. https://doi.org/10.11603/mcch.2410-681X.2016.v0.i4.7254

Issue

Section

ORIGINAL INVESTIGATIONS