Is Oxidative Stress sufficient by itself as an indicator and compelling basis for a carcinogenic concern?

Oxidative Stress as a Precursor and Mechanism for Carcinogenicity
IARC and others (Smith et al) have identified 10 key characteristics which may be used/considered in the evaluation of carcinogenicity, one of which is oxidative stress.  How strong or compelling, if at all, would the data need to be for considering OS as a putative  and defensible MOA for carcinogenicity, or would there need to be other tangential/correlative data (e.g., tumors) available.  In other words, is OS sufficient by itself as an indicator and compelling basis for a carcinogenic concern? 
Carcinogenesis Environmental health Epigenetics Genetics Genomics
Carcinogenesis is multistep process and OS is not sufficient by itself as an indicator and compelling basis for a carcinogenic concern
K. Kannan
No, OS is a global marker of stress and is not specific to exposure to chemicals or chemical classes.  Dietary factors can affect oxidative stress levels as well.  Many disease conditions can affect oxidative stress.  Therefore oxidative stress markers alone cannot predict carcinogenicity.
Maria Dagli
 Indirectly YES, because "Oxidative stress is viewed as an imbalance between the production of reactive oxygen species (ROS) and their elimination by protective mechanisms, which can lead to chronic inflammation.". "A substantial body of evidence supports the conclusion that chronic inflammation can predispose an individual to cancer, as demonstrated by the association between chronic inflammatory bowel diseases and the increased risk of colon carcinoma. Chronic inflammation is caused by a variety of factors, including bacterial, viral, and parasitic infections, chemical irritants, and nondigestible particles. The longer the inflammation persists, the higher the risk of associated carcinogenesis". Tumor promoting inflammation has been classified as an enabling characteristic in Hanahan and Weinberg's  "Hallmarks of Cancer: the Next Generation" (DOI: 
I understand that if a compound increases oxidative stress, this must cause chronic inflammation and may lead to cancer. Of course, risk/safety assessments can be performed to detect the most suitable dose for the compound, that does not lead to chronic inflammation. 
Amal Saad-Hussein
No, OS is not sufficient by itself as an indicator and compelling basis for a carcinogenic concern. There are many other factors could have an importance in considering the susceptibility to develop cancers; such as exposure to carcinogenic substances and gene susceptibility …etc.
Rafia Azmat
Oxidative stress results from the generation of highly reactive species like OH, O etc, which react with compounds and degenerate, consequently having carcinogenic effects on the body.
It is also an imbalance between the production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability to disturb the physiological system of the body
Mohd. Iqbal
Oxidative stress reflects disturbances in oxidants and antioxidants; that disturbance can be attributed to any disease or condition and not merely to cancers......Oxidative indices cannot be confirmatory markers for cancer diagnosis though they may indicate degree of severity to some extent.
Mohammad Asaduzzaman Chowdhury
Numerous theories about the mode of action of carcinogens have been advanced for more than half a century. This review examines a wide range of evidence that links oxidative stress (OS) to a variety of aspects of oncology, including the formation of reactive oxygen species (ROS) by major and minor carcinogens, cancer stages, oncogene activation, aging, genetic and infectious diseases, nutrition, and the role of antioxidants (AOs). ROS are frequently generated by redox cycling via electron transfer (ET) groups, such as quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced products), and conjugated imines, despite the fact that they can come from a variety of sources, including both endogenous and exogenous agents (or iminium species). The OS unifying theme represents a method for integrating disparate data on carcinogenesis. Because this theoretical framework aids in the knowledge of cancer beginning, it can be helpful in the fight against cancer, especially in terms of prevention. The electron transfer - oxidative stress (ET-OS) scenario can be applied to a variety of medication classes, poisons, enzymes, and hormones.
Andres Trostchansky
Carcinogenesis is a multifactorial process, and cannot be ascribed solely to Oxidative Stress a key responsibility in the process. It's a relevant player in idiopathic carcinogenesis and an adjuvant process that stimulates carcinogenesis. In fact, can support the stimulation of harmful processes and decrease oxidative stress in some types of tumor progression should aid in retarding metastasis formation. But per se it´s not the cause of the carcinogenesis process.    
Dr. N. Rajendra Prasad
Oxidative Stress plays a major role in carcinogenesis. Several carcinogenic chemicals and radiations induce cancer via oxidative stress. The oxidative stress in the blood plasma/serum or tissue homogenates can be easily estimated. Enzymatic antioxidants such as superoxide dismutase, catalase, peroxidase, and reduced glutathione along with elevated lipid peroxidative products are commonly measured to understand oxidative stress during carcinogen treatment. The oxidative stress products like hydroxyl radicals (a major ROS) attack DNA and cause oxidative DNA damage which contributes to DNA double-strand breaks and single-strand breaks resulting in mutagenesis and carcinogenesis. The oxidative DNA damage during oxidative stress conditions can be measured by 8-deoxy guanosine antibodies and double-strand DNA breaks can be measured by gamma-h2ax antibodies. 
DMBA like hydrocarbon chemical carcinogens were used for experimental carcinogenesis which induces cancer in animals through oxidative stress.
Oxidative stress is only one of many factors that contribute to carcinogenicity. It by itself is not sufficient to cause cancer, therefore it should not be used as an absolute indication of a carcinogen. Plus oxidative stress can lead to many different non-neoplastic pathologies. Identifying carcinogens requires data from multiple studies looking at several different things. The most obvious is tumor induction, but other mechanistic data combined can be used to give a high probability that a chemical is a carcinogen. Studies were done with Vitamin E looking to reduce the number of lung tumors and it ended up having the exact opposite effect and increased lung tumors in smokers. So, oxidative and anti-oxidative effects are not so straight forward and simple as it may initially seem. 
You have asked at least three questions, each of which have different answers.

Determining mode of action (MOA) implies one has already established a causal link between  a carcinogen and the associated malignancy and want to establish which of the many observed biological responses  are the key events that led to malignancy.  The tumors are primary, not "correlative data" when establishing MOA.

Perhaps what you mean to ask is whether observations of oxidative stress can be a reliable marker for hazard identification for carcinogens.  Several of the previous replies note cases in which the ROS generation has been mechanistically linked to carcinogenesis.  However, there are many ways of measuring "oxidative stress" and I am unaware of convincing arguments that any one of those tests can reliably distinguish carcinogens from non carcinogens, particularly as a stand-alone measure of carcinogenic risk.

Muhammad Ayaz
Free radicals are frequently generated from endogenous as well as exogenous aerobic metabolism. These free radicals are normally neutralized by human immune system antioxidant system including catalase, hydroperoxidases and glutathione. In situation where these free radicals are liberated in excessive amount of the immune system is compromised then these free radicals initiate chain reactions thus damaging cells, nuclear materials, proteins, lipids and accelerate inflammatory disorders. These radicals attack DNA thus causing mutations as well as breakage of DNA strands. Changes in the genetic materials leads to excessive tumor growth as a result of loss of control on cell cycle arrest. These free radicals also act as signaling molecules and participate in regulation of cells signaling processes. The process of mutagenesis via free radicals induced DNA damage is well established and evidences indicate that free radicals are implicated in the expansion of tumor clones as well as acquirement of malignant characteristics. Subsequently, free radicals are considered as a vital group of carcinogens 

W. Foster
Not at all. Oxidative stress (OS) is general marker of cell or tissue stress; however, enzymatic pathways are unregulated in response to OS obviating any adverse outcome. Moreover, OS is not specific to chemicals or to any chemical exposure or class of chemicals. Evidence of oxidative stress is present within the electron transport chain, in cells during steroidogenesis and is multiple disease conditions. Therefore, in my opinion, on its own evidence of oxidative stress cannot predict carcinogenicity. It must be accompanied by other indicators. 
mkgoodness (Khatami, Mahin)
Yes, we described in details that loss of balance in tumoricidal and tumorigenic properties of effective immunity (Yin-Yang of immune surveillance) were described to be involved in growth promoting and anabolic properties of immune system in multistep tumorigenesis and angiogenesis.  The following recent articles are extension of Khatami et al accidental discoveries on the role of inflammation in experimental models of acute and chronic inflammatory diseases. The results describe a series of first evidence on direct role of inflammation-induced time-course kinetics of immune dysfunction in multistep tumorigenesis and angiogenesis.

4th book: Khatami M: In Inflammation, Aging and Cancer: Biological Injustices to Molecular Village that Guard Health. Berlin: Springer; 2017: 1‐ 389. 

Unresolved inflammation: ‘immune tsunami’ or erosion of integrity in immune‐privileged and immune‐responsive tissues and acute and chronic inflammatory diseases or cancer. Exp Opin Biol Ther. 2011; 11: 1419‐ 1432

Chronic inflammation: synergistic interactions of recruiting macrophages (TAMs) eosinophils (Eos) with host mast cells (MCs) and tumorigenesis in CALTs. MCSF, suitable biomarker for cancer diagnosis! Cancers. 2014; 6: 297‐ 322. 

“Yin and Yang” in inflammation: duality in innate immune cell function and tumorigenesis. Exp Opin Biol Ther. 2008; 8: 1461‐ 1472.

Inflammation, aging, and cancer: tumoricidal versus tumorigenesis of immunity: a common denominator mapping chronic diseases. Cell Biochem Biophys. 2009; 55: 55‐ 79.

Singh Z
Oxidative stress (OS) can be a key factor responsible for many disease pathologies. MDA estimations or similar compound elevations may be associated with different disease conditions. But, OS cannot be directly and absolutely taken as an indicator and compelling basis for cancer concern. 

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