Tumor-associated redox state in metastatic colorectal cancer
DOI:
https://doi.org/10.32471/exp-oncology.2312-8852.vol-41-no-2.13128Keywords:
“free iron”, EPR, lactoferrin, matrix metalloproteinase-2, matrix metalloproteinase-9, metastatic colorectal cancer, NO, spin traps, superoxide radicalsAbstract
Summary. The high incidence of recurrence and metastasizing in colorectal cancer (CRC) poses the challenge for the improvement in long-term treatment outcome. Aim: To determine the major indicators of redox-formative molecules in the tissue of metastatic CRC (mCRC), stages Т2–4N0–2M0G2–3, namely the rate of superoxide radical (SR) generation, nitric oxide (NO) content, the activity of matrix metalloproteinases (MMP), lactoferrin (LF) content, and “free” iron and their association with some clinical and pathological characteristics of the patients. Materials and Methods: mCRC samples from 51 patients were analyzed (stage II, 31 patients; stage III, 20 patients). The LF and “free” iron were assessed by electron paramagnetic resonance (EPR) at the temperature of 77 °K. The rate of SR and NO generation was determined with spin traps (ТЕМРО-Н, diethyl dithiocarbamate). The activity of MMP-2 and -9 was measured by gelatin zymography using SDS-polyacrylamide gel electrophoresis. Ki-67 expression was analyzed by immunofluorescence technique. Results: In tumors with metastases into the regional lymph nodes (N1–2 category), SR generation rate was 2.2-fold higher than in the tumors categorized as N0. In G3 mCRC, SR generation rate was 1.7-fold higher than in G2-tumors (р < 0.05). The rate of SR generation correlated inversely with differentiation grade of the tumor (r = –0.61; р < 0.05). MMP-2 and -9 activities in mCRC tissue correlated with SR generation rate and NO level (r = 0.44 ÷ 0.53, p < 0.05). The direct correlation between LF content and the stage of the disease (r = 0.42) and “free” iron content (r = 0.61) was demonstrated while the correlation between LF content and tumor differentiation grade was inverse (r = –0.57; р < 0.05). Conclusions: The altered tumor-associated redox state in mCRC tissue contributes to the increased cell proliferation and formation of aggressive phenotype of the tumor. The assays for the content of redox-formative components in mCRC may be used as additional prognostic markers of the course of the disease in CRC patients.
References
Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015; 21: 1350–6.
Fedorenko ZP, Mykhailovych YuY, Gulak LO, et al. Cancer in Ukraine 2016–2017. Morbidity, mortality, indi-cators of the oncology service activity. Bull Nat Cancer Registry of Ukraine 2018; 19: 24–5.
Van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25: iii1–9.
Cao H, Xu E, Liu H, et al. Epithelial-mesenchymal transition in colorectal cancer metastasis: A system review. Pathol Res Pract 2015; 211: 557–69.
Weinberg F, Hamanaka R, Wheaton WW, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. PNAS 2010; 107: 8788–93.
Cheng H, Wang L, Mollica M, et al. Nitric oxide in cancer metastasis. Cancer Lett 2014; 353: 1–7.
Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer 2013; 13: 342–55.
Burlaka AP, Vovk AV, Ganusevich II, et al. Superoxide-and NO-dependent mechanisms of formation of metastatic microenvironment distant sites of metastasis in patients with colorectal cancer. Oncologiya 2017; 19: 64–70 (in Ukrainian).
DeClerk 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.
Muñoz M, García-Erce JA, Remacha ÁF. Disorders of iron metabolism. Part II: iron deficiency and iron overload. J Clin Pathol 2011; 64: 287–96.
Bystrom LM, Guzman ML, Rivella S. Iron and reactive oxygen species: friends or foes of cancer cells? Antioxid Redox Signal 2014; 20: 1917–24.
Pusatcioglu CK, Nemeth E, Fantuzzi G, et al. Systemic and tumor level iron regulation in men with colorectal cancer: a case control study. Nutr Metab (Lond) 2014; 11: 21.
Xue Х, Shah YM. Intestinal iron homeostasis and colon tumorigenesis. Nutrients 2013; 5: 2333–51.
Fingleton B. Matrix metalloproteinases: roles in cancer and metastasis. Front Biosci 2006; 11: 479–91.
Ganusevich II. Role of matrix metalloproteinases (MMP) in malignant neoplasms. Characteristics of MMP, regulation of their activity, prognostic value. Oncologiya 2010; 12: 10–6 (in Russian).
Hadler-Olsen E, Winberg JO, Uhlin-Hansen L. Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol 2013; 34: 2041–51.
Meteoglu I, Erdogdu IH, Tuncyurek P, et al. 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. Gastroenterol Res Pract 2015: ID 945392.
Reczek CR, Chandel NS. The two faces of reactive oxygen species in cancer. Ann Rev Cancer Biol 2017; 1: 79–98.
Peiris-Pagès M, Martinez-Outschoorn UE, Sotgia F, et al. Metastasis and oxidative stress: are antioxidants a metabolic driver of progression? Cell Metab 2015; 22: 956–8.
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