Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press140110.17650/1726-9784-2023-22-3-10-18REVIEWSОБЗОРЫ ЛИТЕРАТУРЫFeatures of regulation of hepcidin and ferroportin in cancer patients (literary review)Особенности регуляции гепсидина и ферропортина у онкологических больных (литературный обзор)https://orcid.org/0000-0002-4630-4988BlindarV. N.БлиндарьВ. Н.
Russian Federation

24 Kashirskoe Shosse, Moscow115522

115522 Москва, Каширское шоссе, 24

bld51@list.ruhttps://orcid.org/0000-0002-5854-9755ZubrikhinaG. N.ЗубрихинаГ. Н.
Russian Federation

24 Kashirskoe Shosse, Moscow115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-5769-3114DavydovaT. V.ДавыдоваТ. В.
Russian Federation

24 Kashirskoe Shosse, Moscow115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-8889-5384DobrovolskayaM. M.ДобровольскаяМ. М.
Russian Federation

24 Kashirskoe Shosse, Moscow115522

115522 Москва, Каширское шоссе, 24

N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России1810202322310181710202317102023https://bioterapevt.abvpress.ru/jour/article/view/1401

Background. The pathways of iron acquisition, outflow, storage and regulation are disrupted in cancer, which suggests that the reprogramming of iron metabolism is one of the central aspects of the survival of tumor cells.

Aim. Is to review and generalize modern literature data on the regulation of hepcidin, ferroportin and prospects for the correction of iron metabolism in cancer patients.

Materials and Methods. The paper presents the results of international and domestic studies of the peculiarities of iron metabolism and the prospects for its correction in cancer patients. The search for relevant sources was carried out in the web of Science, PubMed, Medline, eLibrary.ru systems for 1988–2023. Of the analyzed studies 61, the most relevant, were used to write a systematic review.

Results. Over the past decade, a new understanding has emerged of the role of proteins, in particular hepcidin and ferroportin, which regulate cellular iron in cancer growth, angiogenesis and metastasis. New treatment methods with hepcidin-modifying strategies and stabilizers of hypoxia-induced factors are emerging, but their therapeutic efficacy for correcting iron metabolism in cancer patients needs to be evaluated and clinical trials.

Conclusion. Analysis of the literature data has shown the high relevance of studies of the regulation of hepcidin and ferroportin in cancer patients and the need for further study of this problem.

Введение. Пути приобретения, оттока, хранения и регуляция железа нарушены при раке, что позволяет предположить то, что перепрограммирование метаболизма железа – один из центральных аспектов выживания опухолевых клеток.

Цель исследования – обзор и обобщение современных литературных данных об особенностях регуляции гепсидина, ферропортина и перспективах коррекции метаболизма железа у онкологических больных.

Материалы и методы. В работе представлены результаты международных и отечественных исследований особенностей метаболизма железа и перспективы коррекции его показателей у онкологических больных. Поиск соответствующих источников произведен в системах web of Science, PubMed, Medline, eLibrary.ru за период 1988–2023 гг. Из проанализированных исследований 61, наиболее актуальное, было использовано для написания систематического обзора.

Результаты. За последнее десятилетие появилось новое понимание роли белков, в частности гепсидина и ферропортина, которые регулируют клеточное железо, в росте рака, его ангиогенезе и метастазировании. Появляются новые методы лечения с модифицирующими гепсидин стратегиями и стабилизаторами факторов, индуцируемых гипоксией, но их терапевтическая эффективность для коррекции метаболизма железа у онкологических больных нуждается в оценке и клинических испытаниях.

Заключение. Анализ литературных данных показал высокую актуальность исследований особенностей регуляции гепсидина и ферропортина у онкологических больных и необходимость дальнейшего изучения этой проблемы.

iron metabolismcancer patientshepcidinferroportinметаболизм железаонкологические больныегепсидинферропортинMutlu T., Ozoran E., Trabulus D.C. et al. Expression of genes related to iron homeostasis in breast cancer. Mol Biol Rep 2023;50:5157–63. DOI: 10.1007/s11033-023-08433-1Pourali L., Taghizadeh A., Akhoundi M.R. et al. Frequency of Chemotherapy Induced Anemia in Breast Cancer Patients. Int J Cancer Manag 2017;10(1):e4672. DOI: 10.17795/ijcp-4672Aapro M., Beguin Y., Bokemeyer C. et al. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Ann Oncol 2018; 29(Suppl 4):iv96– iv110. DOI: 10.1093/annonc/mdx758Jung M., Mertens C., Tomat E., Brüne B. Iron as a central player and promising target in cancer progression. Int J Mol Sci 2019;20(2):273. DOI: 10.3390/ijms20020273Madeddu C., Neri M., Sanna E. et al. Experimental drugs for chemotherapyand cancer-related anemia. J Pharm and Exper 2021;13:593–611. DOI: 0.2147/JEP.S262349Blindar V.N., Khagazheeva M.N., Davydova T.V. et al. Diagnosis and treatment of anemic syndrome in patients with breast cancer on the background neoadjuvant chemotherapy. Rossiyskiy bioterapevticheskiy zhurnal = Russian Journal of Biotherapy 2021;20(2):42–52. (In Russ.). DOI: 10.17650/1726-9784-2021-20-2-42-52Блиндарь В.Н., Хагажеева М.Н., Давыдова Т.В. и др. Диагностика и лечение анемического синдрома у больных раком молочной железы на фоне неоадъювантной химиотерапии. Российский биотерапевтический журнал 2021;20(2):42–52. DOI: 10.17650/1726-9784-2021-20-2-42-52Blindar V.N., Dobrovolskaya M.M., Khagazheeva M.N. et al. The role of interleukin-6 and hepcidin-25 in the pathogenesis of anemic syndrome associated with malignant neoplasms in cancer patients with breast cancer before neoadjuvant chemotherapy. Klinicheskaya Laboratornaya Diagnostika = Russian Clinical Laboratory Diagnostics 2021; 66(3):147–53. (In Russ.). DOI: 10.51620/0869-2084-2021-66-3-147-153Блиндарь В.Н., Добровольская М.М., Хагажеева М.Н. и др. Роль интерлейкина-6 и гепсидина-25 в патогенезе анемического синдрома, ассоциированного со злокачественными новообразованиями у онкологических больных раком молочной железы до неоадъювантной химиотерапии. Клиническая лабораторная диагностика 2021;66(3):147–53. DOI:10.51620/0869-2084-2021-66-3-147-153Nemeth E., Ganz T. Hepcidin-ferroportin interaction controls systemic iron homeostasis. Int J Mol Sci 2021;22(12):6493. DOI: 10.3390/ijms22126493Charostad J., Azaran A., Nakhaei M. et al. Upregulation of interleukin-6 in HPV-positive breast cancer patients. Iran J Immunol 2021;18(4):315–30. DOI: 10.22034/IJI.2021.89107.1930Julián-Serrano S., Yuan F., Wheeler W. et al. Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies. Am J Clinic Nutr 2021;114(4):1408–17. DOI: org/10.1093/ajcn/nqab217Ciniselli C.M., De Bortoli М., Taverna E. et al. Plasma hepcidin in early-stage breast cancer patients: no relationship with interleukin-6, erythropoietin and erythroferrone. Exp Rev Prot 2015;12(6):695–701. DOI: 10.1586/14789450.2015.1099436Tesfay L., Clausen K.A., Kim J.W. et al. Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res 2015;75(11):2254–63. DOI: 10.1158/0008-5472.CAN-14-2465Lu Ye, Cheng X., Li R. et al. The expression and clinical significance of ferroportin and hepcidin in breast cancer patients. The Journal of the Kuwait Medical Association 2016;48(4): 323–7.Blindar V.N., Zubrikhina G.N., Davydova T.V. et al. The development of the strategic approaches to modern diagnosis of anemic syndrome in patients with breast cancer. Klinicheskaya Laboratornaya Diagnostica = Russian Clinical Laboratory Diagnostics 2019;64(4):210–5. (In Russ.). DOI: 10.18821/0869-2084-2019-64-4-210-215Блиндарь В.Н., Зубрихина Г.Н., Давыдова Т.В. и др. Разработка стратегических подходов к современной диагностике анемического синдрома у больных раком молочной железы. Клиническая лабораторная диагностика. 2019;64(4):210–5. DOI: 10.18821/0869-2084-2019-64-4-210-215Shao X.N., Cao F., Tao M. the clinical value of hepcidin in breast cancer and its bone metastasis. Ann Clin Lab Sci 2017;47(2):120–8.Andrews N.C. Anemia of inflammation: the cytokinehepcidin link. J Clin Invest 2004;113(9):1251–3.De Bortoli M., Taverna E., Varinelli L. et al. Plasma hepcidin in early-stage breast cancer patients: no relationship with interleukin-6, erythropoietin and erythroferrone. Expert Rev Proteom 2015;12(6):695–701. DOI: 10.1586/14789450.2015.1099436Blindar V.N., Zubrikhina G.N., Davydova T.V. et al. Features of iron metabolism in breast cancer patients before adjuvant chemotherapy. Rossiyskiy bioterapevticheskiy zhurnal = Russian Journal of Biotherapy 2022;21 (1):33–41. (In Russ.). DOI: 10.17650/1726-9784-2022-21-1-33-41Блиндарь В.Н., Зубрихина Г.Н., Давыдова Т.В. и др. Особенности метаболизма железа у больных раком молочной железы до адъювантной химиотерапии. Российский биотерапевтический журнал 2022;21(1):33–41. DOI: 10.17650/1726-9784-2022-21-1-33-41Marques O., Porto G., Rêma A. et al. Local iron homeostasis in the breast ductal carcinoma microenvironment. BMC Cancer 2016;16:187. DOI: 10.1186/s12885-016-2228-yDobrovolskaya M.M. Zubrikhina G.N., Blindar V.N., Sytov A.V. Oxidative stress and endogenous intoxication in cancer patients. Klinicheskaya Laboratornaya Diagnostica = Russian Clinical Laboratory Diagnostics 2021;66(7):401–6. (In Russ.). DOI: 10.51620/0869-2084-2021-66-7-401-406Добровольская М.М., Зубрихина Г.Н., Блиндарь В.Н., Сытов А.В. Окислительный стресс и эндогенная интоксикация у онкологических больных. Клиническая лабораторная диагностика 2021;66(7):401–6. DOI: 10.51620/0869-2084-2021-66-7-401-406Demir H., Beipinar J., Urvay S. et al. Prognostic role of preoperative serum ferritin level in stage 2 colon cancer. Eur Rev Med and Pharmac Sci 2021;25(21):6473–9. DOI: 10.26355/eurrev_202111_27091Zhang S.P., Chen Y., Guo W.L. et al. Disordered hepcidinferroportin signaling promotes breast cancer growth. Cell Sign 2014;26(11):2539–50. DOI: 10.1016/j.cellsig.2014.07.029Wang J., Liu W., Lee J.K. Hepcidin downregulation correlates with disease aggressiveness and immune infiltration in liver cancer. Front Oncol 2021;11:714756.Manz D.H., Blanchette N.L., Paul B.T. et al. Iron and cancer: recent insights. Ann NY Acad Sci 2016;1368(1):149–61. DOI: /10.1111/nyas.13008Sornjai W., Nguyen V., Long F. et al. Iron and hepcidin mediate human colorectal cancer cell growth. Chem Biol Interact 2020;319:109021. DOI: 10.1016/j.cbi.2020.109021Torti S.V., Torti F.M. Iron and Cancer: Vision 2020. Cancer Res 2020;80(24):5435–48. DOI: 10.1158/0008-5472.CAN-20-2017Al Tameemi W., Dale T.P., Al-Jumaily R.M.Kh. et al. Hypoxiamodified cancer cell metabolism. Front Cell and Devel Biol 2019;7:4. DOI: 10.3389/fcell.2019.00004Nefedova N.A., Kharlova O.A., Danilova N.V. et al. Markers of angiogenesis in tumor growth. Arxiv patologii = Archive of Pathology 2016;78(2):55–63. (In Russ.). DOI: org/10.17116/patol201678255-62Нефедова Н.А., Харлова О.А., Данилова Н.В. и др. Маркеры ангиогенеза при опухолевом росте. Архив патологии 2016;78(2):55–63. DOI: 10.17116/patol201678255-62Vasiliev A.G. Neoangiogenesis and tumor growth. Rossijskie biomedicinskie issledovaniya = Russian Biomedical Research 2017;2(4):4–10. (In Russ.).Васильев А.Г. Неоангиогенез и опухолевый рост. Российские биомедицинские исследования. 2017;2(4):4–10.Liu Z., Wu Z., Fan Y., Fang Y. An overview of biological research on hypoxia-inducible factors (HIFs). Endokrynol Pol 2020;71(5):432–40. DOI: 10.5603/EP.a2020.0064Huang G., Yan J., Xu C. et al. The crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Cell Death Dis 2021;12(2):215. DOI: 10.1038/s41419-021-03505-1Astashkin E.I. Effect of hypoxia on the life of tumor cells and its correlation by chemical agents and drags. Farmateka 2016;9: 20–7. (In Russ.).Асташкин Е.И. Влияние гипоксии на жизнедеятельность опухолевых клеток и его коррекция химическими агентами и лекарствами. Фарматека 2016;9:20–7.Forciniti S., Greco L., Grizzi F. et al. Iron metabolism in cancer progression. Int J Mol Sci 2020;21(6):2257. DOI: 10.3390 /ijms21062257Pasricha S.R., McHugh C., Draksmith H. Hepcidin regulation by erythropoiesis: the current history. Annu Rev Nutr 2016;36: 417–34. DOI: 10.1146/annurev-nutr-071715-050731Vela D., Vela-Gaxha Z. Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications. Exp Mol Med 2018;50(2):e436. DOI: 10.1038/emm.2017.273Durigovaa A., Lamy P.J., Thezenas S. et al. Anemia and iron biomarkers in patients with early breast cancer. Diagnostic value of hepcidin and soluble transferrin receptor quantification. Clin Chem Lab Med 2013;519):1833–41. DOI: 10.1515/cclm-2013-0031Serrano S.J., Yuan F.C., Wheeler W. et al. Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: A pathway analysis of genome-wide association studies. Am J Clin Nutr 2021;114(4):1408–17. DOI: org/10.1093/ajcn/nqab2171Xiao X., Alfaro-Magallanes V.M., Babitt J.L. Bone morphogenic proteins in iron homeostasis. Bone 2020;138:115495. DOI: 10.1016/j.bone.2020.115495Park C.H., Valore E.V., Waring A.J. et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276(11):7806–10. DOI: 10.1074/jbc.M008922200Sasu B.J., Cooke K.S., Arvedson T.L. et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood 2010;115: 3616–24. DOI: 10.1182/blood-2009-09-245977Steinbicke U., Sachidanandan C., Vonner A.J. et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood 2011;117:4915–23. DOI: 10.1182/blood-2010-10-313064Guo S., Casu C., Gardenghi S. et al. Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice. J Clin Invest 2013;123:1531–41. DOI: 10.1172/JCI66969Ramos E., Ruchala P., Goodnough J.B. et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood 2012;120:3829–36. DOI: 10.1182/blood-2012-07-440743Wozney J.M., Rosen V., Celeste A.J. et al. Novel regulators of bone formation: molecular clones and activities. Science 1988; 242(4885):1528–34. DOI: 10.1126/science.3201241Rider C.C. Heparin/heparan sulphate binding in the TGF-beta cytokine superfamily. Biochem Soc Trans 2006;34(Pt 3):458–60. DOI: 10.1042/BST0340458Poli M., Girelli D., Campostrini N. et al. Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo. Blood 2011;117(3):997–1004. DOI: 10.1182/blood-2010-06-289082Ritchie J.P., Ramani V.C., Ren Y. et al. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin Cancer Res 2011;17(6):1382–93. DOI: 10.1158/1078-0432.CCR-10-2476Borsig L. Heparin as an indicator of cancer progression. Mol Biol Transl Sci 2010;93:335–49. DOI 10.1016/С1877-1173(10)93014–7Kautz L., Jung G., Nemeth E., Ganz T. Erythroferrone contributes to recovery from anemia of inflammation. Blood 2014;124(16):2569–74. DOI: 10.1182/blood-2014-06-584607Castro-Mollo M., Gera S., Ruiz-Martinez M. et al. The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry. Elife 2021;10:e68217. DOI: 10.7554/eLife.68217Witcher D.R., Leung D., Hill K.A., De Rosa D.C. LY2928057, an antibody targeting ferroportin, is a potent inhibitor of hepcidin activity and increases iron mobilization in normal cynomolgus monkeys. Blood 2013;122(21):3433. DOI: 10.1182/blood.V122.21.3433.3433Ross S., Biswas K., Rottman J. et al. Identification of antibody and small molecule antagonists of ferroportinhepcidin interaction. Biol Front Pharm 2017;8:838. DOI: 10.3389/fphar.2017.00838Mross K., Richly H., Fischer R. et al. First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and antagonizing VEGF-A, in patients with advanced solid tumors. PLoS One 2013;8(12):e83232. DOI: 10.1371/journal.pone.0083232Vyoral D., Petrak J. Therapeutic potential of hepcidin – the master regulator of iron metabolism. Pharmacological research 2017;115:242–54. DOI: 10.1016/j.phrs.2016.11.010Ren F., Li J., WangY. et al. The effects of angelica sinensis polysaccharide on tumor growth and iron metabolism by regulating hepcidin intumor-bearing mice. Cell Physiol Biochem 2018;47(3):1084–94. DOI: 10.1159/000490185Shevra C.R., Singh Sh., Singh N. et al. Interleukin-6 and interleukin-4 levels in multiple myeloma and correlation of interleukin-6 with β2 microglobulin and serum creatinine. Clin Cancer Investig J 2015;4:211–5. DOI: 10.4103/2278-0513.148963Song S.N., Iwahashi M., Tomosugi N. et al. Comparative evaluation of the effects of treatment with tocilizumab and TNFalpha inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients. Arthritis Res Ther 2013;15(5):141. DOI: 10.1186/ar4323Jiang L., Kon N., Li T. et al. Ferroptosis as a p53-mediated activity during tumor suppression. Nature 2015;520(7545):57–62. DOI: 10.1038/nature14344Gnanapradeepan K., Basu S., Barnoud T. et al. Tumor suppressor p53 in the control of metabolism and ferroptosis. Front Endocrinol 2018;9:124. DOI: 10.3389/fendo.2018.00124Hassania B., Vandenabil P., Vanden Berge T. Targeting ferroptosis to eliminate cancer. Cancer cell 2019;35(6):830–49. DOI: 10.1016/j.ccell.2019.04.002Rodriguez R., Schreiber S.L., Conrad M. Persistent cancer cells: iron dependence and vulnerability to ferroptosis. Mol Cell 2022;82(4):728–40. DOI: 10.1016/j.molcel.2021.12.001