Carcinogenesis as Side Effects of Iron and Oxygen Utilization: From the Unveiled Truth toward Ultimate Bioengineering

Abstract

Evolution from the first life on earth to humans took ~3.8 billion years. During the time there have been countless struggles among the species. Mycobacterium tuberculosis was the last major uncontrollable species against the human public health worldwide. After the victory with antibiotics, cancer has become the leading cause of death since 1981 in Japan. Considering that life inevitably depends on ceaseless electron transfers through iron and oxygen, we believe that carcinogenesis is intrinsically unavoidable side effects of using iron and oxygen. Many animal models unequivocally revealed that excess iron is a risk for carcinogenesis. This is supported by a variety of human epidemiological data on cancer risk and prognosis. Cancer is basically a disease of the genome with persistently activated oncogenes and inactivated tumor suppressor genes through which iron addiction with ferroptosis-resistance is maintained. Engineering has made a great advance in the past 50 years. In particular, nanotechnology is distinct in that the size of the engineered molecules is similar to that of our biomolecules. While some nano-molecules are found carcinogenic, there are principles to avoid such carcinogenicity with a smart possibility to use nano-molecules to specifically kill cancer cells. Non-thermal plasma is another modality to fight against cancer.

Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin

“…Further studies are warranted to confirm the current results. Nanomaterials, including asbestos, can be a carcinogen but some of them also can be drugs [ 44 ]. FedEVs may be used as a biomarker in the extracellular fluid in the near future.…”

Embryonal erythropoiesis and aging exploit ferroptosis

“…Ferroptosis inhibitors are reportedly protective in preclinical models of neurodegenerative diseases, including Parkinson's, Huntington's and Alzheimer's disease [ [7] , [8] , [9] , [10] ]. Carcinogenesis is now recognized as a process to obtain ferroptosis-resistance by acquisition of somatic mutations [ 4 , 11 , 12 ]. Of note, many drug-resistant and aggressive cancer cells may depend on the suppression of ferroptosis for growth and survival [ 13 ], which may represent a therapeutic vulnerability for such cancers [ 12 , 14 , 15 ].…”

“…Carcinogenesis is now recognized as a process to obtain ferroptosis-resistance by acquisition of somatic mutations [ 4 , 11 , 12 ]. Of note, many drug-resistant and aggressive cancer cells may depend on the suppression of ferroptosis for growth and survival [ 13 ], which may represent a therapeutic vulnerability for such cancers [ 12 , 14 , 15 ]. Ferroptosis is also associated with intestinal ischemia-reperfusion injury, where ACSL4 activation plays a critical role in this lethal process [ 16 ].…”

Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles

“…Accordingly, iron would be present in excess during aging by the decrease in metabolic rate, causing ferroptosis time-dependently in a fraction of cells in various organs of rats [35]. Excess iron has also been associated with carcinogenesis, according to the human epidemiological study of the general population or specific diseases, including genetic hemochromatosis and ovarian endometriosis [36][37][38] as well as various animal studies [4,8,39]. The responsible mechanisms are: 1) increased intracellular iron catalyzes Fenton reaction to gen-erate hydroxyl radicals, leading to mutagenic oxidative DNA lesions [40][41][42]; 2) iron is necessary for cellular proliferation as cofactors of many enzymes [4,8,10,33,43,44].…”

“…The first life on earth was born under the ancient sea of abundant Fe(II) 3.8 Gya [1,2], and it is generally accepted that no independent life on earth can live without iron [3]. Iron is a major redox-active transition metal, which is used for various electron transfer reactions in the form of Fe(II), Fe-S cluster or heme [4]. During evolution, the life obtained the sulfhydryl systems [5], including glutathione, to counteract iron toxicity when present in excess, which might have been just insoluble FeS at first [6,7].…”