Trace Elements and Cancer

The role of the trace elements in humans has increased during the last 20 years. It seems that they play a signifi cant role in maintaining the healthy state of the organism. These minerals are present in small levels, but their role is vital. Although they account for only 0.02% of the total body weight, it has highlighted that they play significant roles, either as active centers of enzymes or as trace bioactive substances. Their excess or defi ciency may influence the homeostasis and potentially can lead to several chronic diseases, including cancer. It is already known that certain elements in the free or combined state can be primary causative agents, or risk factors for human cancer. Nevertheless, it is important to underline that the carcinogenic elements are fewer than it was expected in studies. Copper, cobalt, chromium, zinc, selenium, are involved in many biochemical processes supporting life. However, their concentrations may play an important role in developing cancer, by influencing proliferation or apoptosis. Disruption of the balance between free radicals and antioxidants may cause a cellular damage and trigger carcinogenesis.


INTRODUCTION
Essential trace elements of the human body include zinc (Zn), copper (Cu), selenium (Se), chromium (Cr), cobalt (Co), iodine (I), manganese (Mn), and molybdenum (Mo) 1 . Although these elements account for only 0.02% of the total body weight, they play significant roles, e.g., as active centers of enzymes or as trace bio-Recent evidence has suggested the role of Se in reducing the risk of a variety of malignancies. Proposed mechanisms for anti-cancer actions of Se include antioxidant protection, enhanced carcinogen detoxifi cation, enhanced immune surveillance, modulation of cell cycle, inhibition of tumor cell invasion and inhibition of angiogenesis 13 . Additionally, studies showed that Zn supplement may protect against free radical damage 14 , or that Zn levels are decreased in patients with certain malignancies 15 . Se and Zn levels have been correlated to prostate cancer risk 16 . Higher Se levels are related to a lower risk of many types of neoplasms, including lung, colorectal, prostate and possibly bladder 17,18 .
Natural trace elements such as zinc and copper have some dictatorial functions that may aff ect immune reactions and free radical generation 19,20 . Zinc (Zn), copper (Cu), and iron (Fe) have been also implicated in various types of malignancies 21 .
Copper, zinc, selenium, and molybdenum are involved in important biochemical processes. Th e most important of these are cellular respiration, cellular utilization of oxygen, DNA and reproduction, maintenance of cell membrane integrity and sequestration of free radicals. In the same time, these elements are involved in destruction of free radicals through a cascade of enzyme systems (superoxide dismutase), in the presence of copper and zinc cofactors. Form this process hydrogen peroxide results, which is then reduced to water by the selenium-glutathione peroxidase couple. When the removal of these superoxide free radicals is effi cient, the integrity of membranes is maintained and thus, the aging process and the risk of cancer decreases 22 .
Some studies showed elevated levels of Cu in bladder, breast, prostate, and liver cancers, and the Cu/Zn ratio is proposed to be used as a biomarker,to assess patient's prognosis 23 . Oxidative stress is defi ned as animbalance between oxidant-antioxidant balance, in favor of the oxidant process. Chemical and physical agents, including those that induce reactive oxygen species (ROS), can induce and modulate this multistep activity. Th e human body produces certain antioxidants (scavenging enzymes) such as glutathione, superoxide dismutase (SOD) and catalase (CAT) that can counteract the harmful eff ects of ROS and protect against cellular and molecular damages. Breaking the balance between free radicals and antioxidants may cause a cellular damage which triggers the carcinogenesis 24,25 .
Some trace metals are supposed to play a carcinogenic role, inducing a toxic eff ect through the formation of ROS and acting as cofactors in the oxidative dama-combination of metals may be necessary for enzymatic function, such as magnesium and manganese in phosphorylase, and iron and molybdenum for xanthine oxidase in a ratio of 8:1:4. Metals, therefore, do interact in biological systems 4 .
Reducing oxidative stress, or enhancing the repair capacity of trace elements (such as Se, Zn, Mn) relies on ability to act as essential cofactors for antioxidant enzymes such as Cu, Zn-superoxide dismutase, Mn-superoxide dismutase, catalase (Cu, Fe), and the diff erent types of glutathione peroxidases (Se). Th ese enzymes are mandatory for limiting oxidation of lipids, nucleic acids or proteins, which are involved in chronic diseases, such as cancers and cardiovascular disorders and also in ageing 5 .
Trace elements play a signifi cant role in maintaining the healthy state of an organism. Consequently, disturbances in trace element homeostasis may result in the development of pathologic states and diseases. Th e defi ciency occurs due to insuffi cient trace element content in diets or increased requirements of an organism. Nevertheless, the diff erence between "enough" and "too much" of these minerals is often tiny 6,7 . Furthermore, massive intake of one trace element will infl uence the absorption of others: molybdenum will aff ect copper retention; a defi ciency of copper will limit the requirement for iron; copper may counteract zinc or molybdenum toxicity 8 . Th ere is also the phenomenon of competition of one element with another for a site in a specifi c biological tissue. Both strontium and beryllium have an affi nity for bone and can cause rickets, whereas all group VII elements of the periodic chart go to the thyroid gland.
Many epidemiological surveys and animal studies have demonstrated that health problems are caused by deficiency or excess of trace elements. Trace element deficiency or excess is one of the most difficult diagnosis 9 . Th e defi ciencies show some general rules of development. All of them are followed by a decrease of immune response. Th e defi ciency is never isolated and is always followed by a considerable disturbance of metabolism (mineral, lipid, carbohydrate and protein). As a result, there may be weight gain, reduced immune resistance, atherosclerosis or endocrine gland pathologies. All of these can favor the development of various malignancies 10 . Further on, the chronic defi ciency leads to considerable metabolic disturbances and distinct clinical and morphological changes 11 . Both processes result in endocrinopathies, infl ammations and neoplastic diseases 12 .
ge of biological macromolecules and DNA 26 . However, their exact role in carcinogenesis is still unclear 27 .
Worldwide, there are more than 10 million new cancer cases each year, and cancer is the cause of approximately 12% of all deaths. A large number of epidemiologic studies have been made to identify the risk factors for cancer. Among these, an association with trace elements has received considerable attention 28 . Elements like selenium, zinc, arsenic, cadmium, and nickel, are found naturally in the environment, and human exposure derives from a variety of sources, including air, drinking water, and food. It has been also underlined that trace elements' levels of exposure are potentially modifi able 29 .
A hundred years ago, it was suggested that cancer is a disease linked with chromosomes, based on the observations that whole chromosomes or chromosome arms are missing or duplicated in the genomes of cells in a tumor (aneuploidy). Furthermore, based on basic researches, another observation was made, highlighting that the concentrations of some trace elements, especially zinc, copper and iron are changed in tumor cells 30 . It is highlighted that the tumor zinc level, for example, is consistently elevated in some cancers (e.g., breast) and consistently decreased in others (e.g., prostate, pancreatic, liver). Th e eff ects of trace elements on proliferation and apoptosis are supposed to be cell type specifi c and may diff er in normal and malignant cells 31,32 .
With regard to their concentrations, it was observed that they may have an infl uence on metastasis. Diff erent types of metastases show deregulated trace element concentrations, compared to surrounding normal tissue 33 . Cancer is a leading cause of death worldwide, accounting for an estimated 9.6 million deaths in 2018. Th e most common cancers are: lung (2.09 million cases), breast (2.09 million cases), colorectal (1.80 million cases), prostate (1.28 million cases). Th e most common causes of cancer death are cancers of: lung (1.76 million deaths), colorectal (862 000 deaths), stomach (783 000 deaths), liver (782 000 deaths) and breast (627 000 deaths) 34 .

BREAST CANCER
Breast cancer is the most frequent cancer among women, impacting 2.1 million women each year, and also causes the greatest number of cancer-related deaths among women. In 2018, it is estimated that 627,000 women died from breast cancer -that is approximately 15% of all cancer deaths among women. While breast cancer rates are higher among women in more develo-ped regions, rates are increasing in nearly every region globally 34 . It is also the most commonly diagnosed one, widespread aff ecting 1 in 8 women 35 . Th e offi cial WHO data show that the risk of breast cancer rises with age, reaching the highest point in postmenopausal women.
Although the mechanisms of breast cancer disease are better understood, it is still the most frequent malignant tumor in women and one of the leading causes of cancer death 36 . Th e relationship between serum levels of trace elements and breast cancer remainsunclear 37 . Nevertheless, they play important roles in biological processes relevant to breast cancer, especially by infl uencing the elements that are essential antioxidants components. Although several articles tried to identify associations between trace element levels and breast cancer in diff erent populations, using diff erent samples, like hair, toenails, or blood, their conclusions have been inconsistent 38 . Several analytical methods have been used to identify and measure trace elements. X-ray fl uorescence spectroscopy, atomic absorption spectroscopy (AAS), inductively coupled plasma mass spectrometry (ICP-MS), and inductively coupled plasma atomic emission spectroscopy (ICP-AES) are the most used methods 39 .
A comparative analysis of epidemiological data for breast cancer in the USA, Canada, India, China, Taiwan, Japan, South Korea, and Sweden showed notable diff erences in the median age at diagnosis; the peak age at diagnosis being 40-50 years in Asian countries, and 60-70 years in Western countries 40 . Th e major known risk factors for breast cancer include female sex, age, and family history, as well as reproductive factors, including early age at menarche, later menopause, nulliparity, and fi rst childbirth after age 30. All of these are independent risk factors 41 .
Th ere are some studies that show that lower iron level is linked to colorectal, or breast cancer. Some, did not found any link between iron levels and the risk of breast cancer 42 . Changes in calcium, copper, iron, magnesium and zinc concentrations were also detected in breast cancer patients, compared with the healthy population. Th e ratios of Ca/Mg, Cu/Zn and Cu/Fe could be used as biochemical markers in these patients 43 .
Most data have reported no association between selenium and risk of breast, colorectal, and stomach cancer, and between zinc and prostate cancer risk. Th ere is compelling evidence in support of positive associations between arsenic and risk of both lung and bladder cancers, and between cadmium and lung cancer risk 44 .
play an important role in the pathogenesis of this kind of cancer. Very few reports are available on the concentration of trace elements in colon cancer patients 58 .
Although Ca levels seemed to be high, it did not reach statistical signifi cance. It was also found low iron concentrations in comparison with healthy controls, but with no statistical signifi cance. On the other hand, serum Zn levels were signifi cantly reduced. Th ese decreased serum levels in in colon cancer patients may be due to the mobilization of circulating Zn to the colon cancer tissue. Th erefore its involvement in the antioxidant defense since the patients might be under higher oxidative stress 59 .

LUNG CANCER
Copper, arsenic, chromium, lead, nickel and beryllium, are trace elements with possible implication in the cause of lung cancer. A high incidence of lung cancer has been demonstrated as an occupational disease among workers engaged in the chromate production process in Germany and the United States. Th is excess risk is believed to be the result of exposure to hexavalent chromium and not linked with smoking status 60 . As in other cancer causes, Zn levels seem to play a protective role also in lung cancer. In addition, it is suggested that low levels of zinc can facilitate the pathogenesis of lung cancer.
Copper is a mineral found in trace amounts in all tissues in the body. Although only a small amount is needed, copper is an essential nutrient that plays a role in the production of hemoglobin, myelin, collagen, and melanin. In one clinical study that followed over 1,600 patients with lung cancer found that dietary zinc and copper intakes are associated with reduced risk of lung cancer 61 . Exposure to potentially carcinogenic traceelements can occur as a result of both occupational and environmental sources. As, Cd, Ni and other trace elements have been consistently linked to lung cancer in ecologic, cohort, and case-control studies 62 .
Another case-control study compared the results withother cancer patients from the same region. Contrary to initial hypothesis, based on previous studies, the authors found that there was no positive association between trace-element concentrations, in toenails and lung cancer 63 .

CONCLUSIONS
In recent years, the analysis of trace elements inhuman tissues has gained great interest due to the role that

PROSTATE CANCER
Prostate cancer is one of the most prevalent male cancer all over the world. Globally, prostate cancer ranks second in incidence and the fi fth in mortality in men, and represents an important public health issue 45 . Prostate cancer incidence is rising rapidly in Asia too, probably because of the aging population, westernized dietary habits and increasing use of prostate-specifi c antigen (PSA) testing [46][47][48] .
It was also revealed that in the prostatic fl uid of cancerous prostate Zn was signifi cantly lower, compared with those in the prostatic fl uid of hyperplastic prostate 49 . Th e decrease in levels of Zn in the prostatic fl uid of cancerous prostate might demonstrate an involvement of these trace elements in the etiology and pathogenesis of malignant prostate tumors. It is supposed that the changes of Zn levels can be used as tumor markers 50,51 .
Cadmium (Cd) is recognized as a carcinogen 52 , based particularly on studies made on individuals having substantial occupational exposure via the respiratory system. Once absorbed, Cd binds to metallothionein and is stored mainly in the kidneys and liver. Prostate tissue has also been identifi ed as a target for Cd deposition 53 . In a recent populational prospective study, dietary Cd exposure was associated with a slightly increased overall risk of prostate cancer and for localized disease, the risk was more marked in smokers and lean men 54 .
Magnesium (Mg) is the second most abundant intracellular cation in the body, involved with numerous biological activities, particularly related to its interaction with Ca. Serum Mg levels, and Ca/Mg ratio have been shown to be associated with high-grade prostate cancer 55 . Mg defi ciency is linked to chronic infl ammation, possibly due to the concurrent Ca levels. Furthermore, it is speculated that Ca may play a key role in the progression of prostate cancer 56 .
Copper (Cu) appears to play also an important role in the carcinogenic process. Th is fact is evident through the Cu high levels observed in cancerous tissues 57 .

COLON CANCER
Colorectal cancer is still the third leading cause of the cancer causes in the world, with an increased incidence in the developing countries. A number of studies have shown that dietary calcium intake is associated with a reduced incidence of colon cancer among middle-aged subjects. Other observations suggested that alterations in essential trace elements like Cu, Fe, Zn and Ca may which integrates selenium as selenocysteine, an infrequently incident amino acid, to its active center 69 .
A better understanding and application of traditional tumor biomarkers and the identifi cation of new markers is essential since they improve the patients' quality of life, sparing them from going under toxic treatments that are unlikely to benefi t from, and also by making possible to diff erentiate an appropriate individualized treatment for each type of tumor 64 .
More studies must be expected to enlighten the certain role of certain trace elements in cancer development. Knowing already that the era of biomarkers has an important development, it is challenging to establish some new reliable biomarkers based on the variations of the trace elements in diff erent type of cancers. Th is possibility could represent a brighter future.
Compliance with ethics requirements: Th e authors declare no confl ict of interest regarding this article. Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study. they play in biochemical and physiological processes. Although trace elements constitute a minor part of the tissue's compounds, they are important for almost all vital processes 64 .
However, in abnormal amount, they seem to contribute in several pathological processes, including tumor growth, invasion and metastasis 66 .
Arsenic levels have been found linked with cancer risk, focusing on the detection from drinking water. Some articles highlighted the role of Cd and Ni exposure levels in diff erent workplaces. Also, the role of Zn in several cancer sites has been examined as well, while Se did not show a direct relation to cancer risk 67 . Other studies highlighted the eff ective role of Se in preventing cancers 68 . Th e mechanism of prevention include selenium role in arresting the cell cycle, decreasing cell proliferation, inducing apoptosis, DNA repair by p53 activation, disruption of androgen receptor indications, and acting as a core component of selenoenzymes,