Comparison of the elemental alterations of solid and hematopoietic tumors in children and adolescents after completion of antitumor therapy

doi:10.21203/rs.3.rs-3414164/v1

As medical research develops, more and more attention is being focused on the study of elemental alterations in cancer patients, not only as a marker of the disease, but also as a possible complication of the disease. This study aims to investigate changes in the levels of essential and toxic trace elements in patients who completed antitumor therapy for malignant neoplasms. A retrospective study was conducted among children and adolescents aged 4 to 17 years at a single center. A total of 214 patients were enrolled in this study, with an equal distribution of 107 patients in both the remission group after undergoing therapy for hematologic malignancies and the group who completed therapy for solid tumors. The results of the study of hair samples and blood serum showed that the elemental profile of patients after antitumor therapy has both similar patterns and distinctive features depending on the histological type of tumor. Our data demonstrate that patients with solid tumors showed somewhat higher accumulation of toxic metals compared to samples from patients with hematopoietic tumors, and neoplasms of the hematopoietic system are characterized by more pronounced alterations in the composition of essential elements in hair and blood serum. Nevertheless, serious specific alterations in elemental homeostasis depending on the histologic structure have not been reported. The findings obtained highlight the importance of careful monitoring of homeostasis parameters to prevent the development of complications of antitumor therapy associated with elementary homeostasis.

Trace elements

Solid tumors

Hematopoietic tumors

Hair

Serum

Antitumor therapy

Modern theory of carcinogenesis attracts more and more attention to the role of elemental alterations in the induction of tumor growth [1]. Thus, associations of essential and toxic chemical elements with several types of malignant neoplasms have been revealed [2]. In studies on the role of elemental alterations in experimental or clinical models, toxic elements are most associated with carcinogenic activity [3, 4]. Additionally, imbalance of essential elements promotes either metabolic rearrangement of proteins, providing activation or inhibiting enzymatic reactions, affecting cell membrane permeability [5, 6], or changes in cellular microenvironment and immune status [7], which can also modulate cancer progression. Some organic and inorganic metal compounds, such as selenium (Se) or zinc (Zn), can affect the redox status of cells [8, 9] by provoking the formation of reactive oxygen species (ROS), interfering with proapoptotic signaling pathways [10], an appropriate amount of ROS can promote carcinogenesis and support the transformation and proliferation of tumor cells [11].

Unfortunately, antitumor therapy is also very toxic and some of its component could create different early onset and late-onset metabolic complications [12]. The direct cytotoxic effect of chemotherapeutic agents, along with potential iron overload from blood transfusions [13] and accumulation of heavy toxic metals [14], can result in detrimental impacts to the nervous, cardiovascular, and renal systems [15]. Nutritional imbalances [16], including essential micronutrients, and impaired metabolic homeostasis can also occur as a result of antitumor therapy, leading to clinical manifestations such as osteoporosis [17], iron deposition and malnutrition [18, 19]. Many other body systems are also affected by the side effects of chemotherapy [20, 21]. Thus, excessive accumulation of toxic elements commonly recognized as possible carcinogens may be observed after treatment with anticancer drugs, directly leading to disruption of mitochondrial function, cell growth processes and DNA damage [22]. It has also been shown that changes in the concentration of some essential elements can influence oxidative stress and suppress or intensify cancer processes due to abnormal redox balance [23]. Many elements show correlation with oxidative stress in blood of cancer patients [24, 25], so even excessive accumulation of essential elements affecting redox status in tissues should be considered as a factor associated with oncogenesis. On this basis, elemental imbalance after antitumor therapy should also be considered as a factor preventing or provoking cancer recurrence.

Available data indicate possible specificity of elemental status in patients with tumors of different histological affiliation. For example, hematopoietic tumors differ from solid tumors not only by the variant of cell differentiation but also by other consequent features: biochemical and tissue atypism, metastatic activity, signaling pathways, etc. [26], which can affect the metabolism in different ways, contributing to the appearance of specific disease biomarkers [27]. Features of microenvironment related to activation of matrix metalloproteinases [28], distribution of metals in tissues due to their participation in ion transport [29], their action as cofactors [30] can change elemental profile in biosubstrates of solid tumors, different in comparison with hemoblastoses. In the current literature, the profile of trace and macronutrients often appears as a possible application point for targeted diagnosis, treatment or prevention of cancer [31], however it is necessary to consider specificity of cancer histology and features of anticancer therapy for this cancer type in exposure to the element composition.

In this study, we sought to identify the specificity of elemental alterations following chemotherapy treatment depending on the histological structure of the tumor. Increased attention should be focusing on the inclusion of carcinogenic elements: cadmium (Cd), nickel (Ni), arsenic (As), beryllium (Be) and chromium (Cr) already known and described in the literature [32]. The noninvasiveness and rapidity of the screening method using the analysis of chemical elements in blood serum and hair make it very promising in relation to oncology.

To compare the elemental composition of biological substrates such as hair and serum depending on the histological types of the tumor in children and adolescents who were in remission after completion of antitumor therapy.

3.1. Ethical Statement

The study was approved by the the Ethics Committee of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) and fulfilled the requirements of The Declaration of Helsinki and its later amendments. Informed consent was obtained from the parents of the examined children before inclusion into the study.

3.2. Study Design

A single-center cross-sectional retrospective study included patients of the Clinical Research and Rehabilitation Center "Russian Field" of the Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology 2019-2021 (Moscow, Russia), these were children and adolescents of both sexes aged 4 to 17 years. The study group consisted of 214 children, of which 107 were patients (1 group) who had completed treatment and were in remission, International Classification of Diseases Version 10 (ICD) disease codes C 91; C 92; C 81-84, and 107 patients (2 group) who received antitumor therapy for solid tumors ICD disease codes C 22-76, excluding central nervous system tumors. The ages of the children and adolescents included in the study ranged from 4.2 to 17.6. The median age was 11.4 years. Duration of tumor remission ranged from 2.6 to 8.0 years, median 3.9 ± 1.1 years on average. The treatment of hemoblastosis included BFM, MB, DAL-HD protocols, solid neoplasms was in accordance with the international protocols approved by the Russian Ministry of Health (SIOP, EURAMOS et al.). The structure of the used chemotherapeutic agents excludes the use of the studied chemical elements in patients included in the study.

Inclusion criteria for the study: (i) confirmed remission of malignant tumors according to ICD 10: C 91; C 92, C 81-84, C 22-76; (ii) patients under 18 years of age; (iii) signed informed consent by teenagers over 14 years old or parents. The exclusion criteria were: (i) the somatic or psychological condition of the patient preventing the study, (ii) specific dietary behavior (including vegetarian diet), (iii) metallic implants (including dental amalgam fillings), (iv) surgical and traumatic diseases, (v) acute inflammatory and infectious diseases. The occurrence of any of exclusion criterion during the study resulted in withdrawal of the patient from the trial. The control group was based in the Center for Biotic Medicine (Moscow, Russia). It comprised 213 children from 4 to 17 years with no cancer history and other chronic somatic diseases. In addition, all participants in the control group reported no use of macro- and micronutrient preparations in the last year before the study. Appropriate exclusion criteria were applied to participants in the control group.

3.3. Sample collection and preparation

The biosubstrates were used for comprehensive assessment by mass spectrometry: hair and blood serum. Only proximal parts of strands less susceptible to exogenous contamination were used for the investigation. The preparation of the samples included washing procedures and microwave digestion in order to removal of contaminants. Hair samples were degreased with acetone (Chimmed, Russia) for 10-15 min, washed three times with 18.2 MΩ • cm deionized water (Labconco Corp., Kansas City, MO, USA), and dried at 60 °C. Dry hair samples were digested in Teflon tubes with 5 mL of concentrated (65%) nitric acid (Sigma-Aldrich Co., St. Louis, MO, USA) for 20 min at 170–180 ◦C. Also hair samples were subjected to microwave-assisted acid digestion in Berghof SpeedWave-4 DAP-40 system (Berghof Products + Instruments GmbH, 72800 Eningen, Germany) at microwave frequency, 2.46 GHz; power, 1450 W. Afterwards, the obtained solutions were added to a total volume of 15 ml with distilled deionized water. The resulting solution was used for the subsequent ICP-MS analysis.

Blood samples obtained from the ulnar vein using Vacutest tubes (Greiner Bio-One International AG, Austria) with clotting activator. Serum was obtained by centrifugation of blood for 10 min at 1800 rpm. Analysis was conducted only on serum samples that did not show any evidence of hemolysis. All samples were diluted 1:15 with an acidified (pH = 2.0) diluent containing (v/v) 1-Butanol 1% (Merck KGaA, Darmstadt, Germany), Triton X-100 0.1% (Sigma-Aldrich, Co., St. Louis, MO USA), and HNO3 0.07% (Sigma-Aldrich, Co., St. Louis, MO, USA) in distilled deionized water.

3.4. ICP-MS Analysis

Hair and serum levels of macro- and trace elements including Na, P, K, Mg, Ca, Al, As, Be, Co, Cr, Cu, Fe, Hg, I, Mn, Ni, Pb, Se, Sn, V, Zn, Li, Mo, Rb, Tl, Cd, Bi, B were assessed by means of inductively coupled plasma mass spectrometry at NexION 300D (PerkinElmer Inc., Shelton, CT 06484, USA) equipped with ESI SC-2 DX4 autosampler (Elemental Scientific Inc., Omaha, NE 68122, USA). The use of Dynamic Reaction Cell (DRC) technology allowed to remove the majority of polyatomic interferences by the system. The system was calibrated using Universal Data Acquisition Standards Kit (PerkinElmer Inc., Shelton, CT 06484, USA) diluted with distilled deionized water (acidified with 1% HNO3) to the final concantrations of 0.5, 5, 10, and 50 μg/l. 10 μg/l yttrium solution prepared from Yttrium (Y) Pure Single-Element Standard (PerkinElmer Inc., Shelton, CT 06484, USA) was used as the internal online standard prepared on a matrix containing 8% 1-butanol (Merck KGaA, Darmstadt, Germany), 0.8% Triton X-100 (Sigma-Aldrich, Co.), 0.02% tetramethylammonium hydroxide (Alfa-Aesar, Ward Hill, MA 01835 USA), and 0.02% ethylenediaminetetraacetic acid (Sigma-Aldrich, St Louis, MO, USA).

3.5. Laboratory Quality Control

Laboratory quality control was performed using control analysis of certified reference material of human hair GBW09101 (Shanghai Institute of Nuclear Research, Shanghai, China) and ClinCheck Plasma Controls (lot 129, levels 1 and 2, RECIPE Chemicals + Instruments GmbH, Germany). The recovery rates for all analyzed trace elements were within the limit of 90–110%. Moreover, the obtained values for all metals and metalloids were within limits estimated as allowable by the manufacturer of the reference materials. The laboratory is also involved in the system of External Quality Assessment Schemes in the field of Occupational and Environmental Medicine (EQAS OELM).

3.6. Statistical Analysis

Search and calculations of statistically significant deviations in elemental status of patients were performed using Jupyter Notebook software development environment in Python 3.9. The basis for algorithm implementation were open-source libraries: pandas, numpy, and pingouin. The nature of the data distribution was assessed by applying the Shapiro-Wilk criterion. Significance of intergroup differences was assessed using the nonparametric Mann-Whitney test for data with a non-normal distribution. The median (Me) and interquartile range (IQR) boundaries were also calculated to compare the statistical significance of the observations. The difference between the group values was considered significant at p<0.05.

Trace elements composition in patients with hematopoietic tumors was characterized by a significant decrease in Co, Mn, I, Fe, Al, Ni, Pb (p-value <0.05). It is noteworthy that elemental imbalance with predominantly decreased concentration in hair was detected much more frequently in the cohort of patients with hematopoietic tumors than in the group of solid tumors.

In patients with solid tumors, the spectrum of manifestations of elements composition in the hair is different: decreased values of Na, P, Mg, with unchanged concentrations of Ca and K. As for trace elements, the level of Mn decreased significantly (p-value <0.05), and the concentration of V, Cr, I, Sn, Se, Co was on the contrary increased (Table 1).

Table 1

Hair elemental status according to the main diagnosis

Trace elements, μg/g	Me(Q1-Q3) Tumors of the hematopoietic tissues (n=107)	P-value	Me(Q1-Q3) Solid tumors (n=107)	P-value	Me(Q1-Q3) Control group (n=213)
Trace elements, μg/g	Me(Q1-Q3) Tumors of the hematopoietic tissues (n=107)	P-value	Me(Q1-Q3) Solid tumors (n=107)	P-value	Me(Q1-Q3) Control group (n=213)
Al	3,632 (2,303-5,398)	0.0291	4,51 (3,05-7,57)	0.524	4,202 (2,839-6,882)
As	0,029 (0,020-0,044)	0.846	0,029 (0,018-0,041)	0.582	0,029 (0,019-0,046)
Be	0,00048 (0,0001-0,001)	0.146	0,0003 (0,0002-0,0009)	0.161	0,00039 (0,0001-0,0007)
Co	0,0089 (0,004-0,014)	0.039	0,015 (0,007-0,027)	0.0102	0,0105 (0,006-0,016)
Cr	0,123 (0,059-0,241)	0.553	0,835 (0,469-0,90)	0.000	0,1291 (0,082-0,269)
Cu	11,007 (8,69-14,47)	0.805	11,98 (9,38-15,51)	0.064	10,76 (8,74-13,76)
Fe	12,86 (9,01-18,21)	0.0008	16,73 (12,62-26,04)	0.372	17,038 (11,28-24,02)
Hg	0,089 (0,03-0,15)	0.083	0,108 (0,05-0,18)	0.668	0,1145 (0,05-0,18)
I	0,341 (0,21-0,55)	0.029	0,793 (0,33-1,64)	0.004	0,4776 (0,26-0,94)
Mn	0,241 (0,15-0,43)	0.000	0,343 (0,19-0,68)	0.041	0,4702 (0,22-1,52)
Ni	0,148 (0,101-0,239)	0.015	0,173 (0,118-0,407)	0.959	0,173 (0,132-0,282)
Pb	0,293 (0,155-0,651)	0.0001	0,533 (0,235-1,12)	0.325	0,566 (0,268-1,33)
Se	0,4704 (0,382-0,56)	0.003	0,441 (0,381-0,572)	0.044	0,409 (0,369-0,491)
Si	23,3 (14,2-36,66)	0.152	23,13 (12,99-34,86)	0.099	25,45 (17,94-36,35)
Sn	0,092 (0,054-0,238)	0.104	0,167 (0,087-0,472)	0.030	0,1208 (0,07-0,282)
V	0,025 (0,015-0,047)	0.111	0,045 (0,026-0,08)	0.000	0,021 (0,013-0,035)
Zn	175,84 (128,94-216,16)	0.217	179 (127-227)	0.373	189,63 (153,1-225,61)

An increase of trace elements Al, Mn, Ni, V, Tl, Cu, Zn, Fe, B, Bi and a decrease of Co, Rb, Mo (p-value <0.05) was observed in hematopoietic tumors. Deviations from the reference values were observed for the metals of toxic and essential groups: increased levels of P, Al, Mn, Ni, V, Tl, Cd, Be, Bi (p-value <0.05) and decreased values of Co, Cr, Rb, Mo in solid tumors (Table 2).

Table 2

Serum elemental status according to the main diagnosis

Trace elements, μg/g	Me(Q1-Q3) Tumors of the hematopoietic tissues (n=38)	P-value	Me(Q1-Q3) Solid tumors (n=38)	P-value	Control group (n=213)
Trace elements, μg/g	Me(Q1-Q3) Tumors of the hematopoietic tissues (n=38)	P-value	Me(Q1-Q3) Solid tumors (n=38)	P-value	Control group (n=213)
Al	0,0338 (0,024-0,095)	0.0003	0,0336 (0,027-0,036)	0.0003	0,0151 (0,008-0,024)
As	0,0018 (0,001-0,001)	0.98	0,0016 (0,001-0,002)	0.66	0,0018 (0,001-0,006)
Be	0,00004 (0,000-0,00007)	0.052	0,0001 (0,00007-0,0001)	0.0000	0,00001 (0,000-0,00002)
Co	0,00069 (0,0005-0,0009)	0.0000	0,00062 (0,0004-0,0008)	0.0000	0,0054 (0,001-0,011)
Cr	0,0026 (0,001-0,002)	0.1	0,0025 (0,001-0,002)	0.01	0,0351 (0,001-0,13)
Cu	1,196 (1,093-1,386)	0.0002	1,079 (0,99-1,24)	0.11	0,991 (0,9-1,082)
Fe	2,59 (1,78-3,574)	0.0000	1,69 (1,44-1,845)	0.06	1,37 (1,153-1,699)
Hg	0,00018 (0,0001-0,0001)	0.72	0,00018 (0,0001-0,0001)	0.29	0,00018 (0,0001-0,0001)
I	0,059 (0,051-0,069)	0.78	0,058 (0,053-0,067)	0.47	0,05 (0,052-0,066)
Mn	0,0024 (0,001-0,003)	0.0000	0,0018 (0,001-0,002)	0.02	0,0014 (0,001-0,001)
Ni	0,0054 (0,003-0,006)	0.0000	0,0051 (0,003-0,006)	0.0000	0,0019 (0,001-0,002)
Pb	0,0005 (0,0002-0,001)	0.57	0,0004 (0,0002-0,001)	0.46	0,0005 (0,0004-0,0007)
Se	0,084 (0,072-0,098)	0.57	0,091 (0,073-0,099)	0.68	0,087 (0,08-0,095)
Sn	0,0001 (0,00006-0,0004)	0.46	0,0001 (0,00003-0,0001)	0.07	0,00017 (0,0001-0,0002)
V	0,0029 (0,0004-0,004)	0.0000	0,00525 (0,0005-0,006)	0.0000	0,00008 (0,0000-0,0004)
Zn	1,809 (1,636-1,981)	0.0000	1,12 (0,967-1,54)	0.25	1,09 (1,013-1,21)
Li	0,0014 (0,0009-0,001)	0.8	0,0014 (0,0008-0,002)	0.46	0,0014 (0,0009-0,001)
Mo	0,0009 (0,0006-0,001)	0.0005	0,00095 (0,0007-0,001)	0.0002	0,0015 (0,001-0,001)
Rb	0,169 (0,134-0,22)	0.0088	0,187 (0,161-0,227)	0.03	0,251 (0,191-0,35)
Tl	0,00002 (0,000-0,00003)	0.03	0,00002 (0,000-0,00002)	0.003	0,00001 (0,000-0,00001)
Cd	0,00002 (0,000-0,00007)	0.21	0,00008 (0,000-0,0001)	0.0066	0,00002 (0,000-0,00003)
Bi	0,00002 (0,000-0,00002)	0.004	0,00001 (0,000-0,00002)	0.018	0,000006 (0,00-0,0000)
B	0,0531 (0,023-0,082)	0.018	0,0202 (0,011-0,037)	0.53	0,0242 (0,012-0,033)

In addition, we presented a table showing more clearly the statistically significant change in concentration in all three analyzed biosubstrates depending on the histological nature of the tumor (table 3).

Table 3

Changes of elemental status depending on substrate and tumor nature (p<0.05)

Significant change in the concentration of elements	Tumors of the hematopoietic tissues		Solid tumors
Significant change in the concentration of elements	Hair	Serum	Hair	Serum
‘↑‘	Se	Al, Mn, Ni, V, Tl, Cu, Zn, Fe, B, Bi	V, Cr, I, Sn, Se, Co	Al, Mn, Ni, V, Tl, Cd, Be, Bi
‘↓‘	Al, Co, Fe, I, Mn, Ni, Pb	Co, Rb, Mo	Mn	Co, Cr, Rb, Mo

Note: signs '↓' and '↑' denote elements with statistically significant (p<0.05) change in concentration.

In the present study, the levels of 23 trace elements in serum and hair were compared between 107 patients after antitumor therapy with tumors of the hematopoietic tissues and 213 healthy controls, as well as 107 patients after antitumor therapy with solid tumors and 213 healthy controls. The results showed that both groups of patients had the significantly changes in trace element concentrations. Thus, in a cohort of patients who have completed treatment for hematopoietic tumors were found higher serum concentrations of Al, Mn, Ni, V, Tl, Cu, Zn, Fe, B, Bi (p<0.05), but lower serum concentrations of Co, Rb, Mo (p<0.05). Besides, in the same patients, the hair was found to contain higher levels of Se (p<0.05), and lower levels of Al, Co, Fe, I, Mn, Ni, Pb (p<0.05). Additionally, patients received treatment for solid tumors demonstrated higher serum levels of Al, Mn, Ni, V, Tl, Cd, Be, Bi (p<0.05), and lower serum levels Co, Cr, Rb, Mo (p<0.05), but there were levels detected in the hair higher levels of V, Cr, I, Sn, Se, Co (p<0.05), and lower levels of Mn (p<0.05).

The results obtained confirm the presence of an imbalance of trace elements in patients with oncologic diseases, including the period after the completion of antitumor therapy. Elemental imbalance was slightly different depending on neoplasm type, though there were similar trends. The trends of chemical elements concentration in serum of the patients of both groups partially coincided: increase of manganese (Mn), aluminum (Al), vanadium (V), nickel (Ni), thallium (Tl) and decrease of magnesium (Mg), cobalt (Co), rubidium (Rb) and molybdenum (Mo). Concentration of Mn decreased in the hair in both solid and hematopoietic tumors; likewise Se concentration increased (table 3).

Trace elements with significant alterations can be divided into 2 categories: essential trace elements and toxic trace elements. It has been reported that exposure to certain toxic elements may contribute to cancer development [33]. Elevation of toxic elements can be considered as agents of unfavorable prognosis after anticancer therapy, since it has been noted that toxic metals can affect processes related to mutagenic reactions of cells (apoptosis, proliferation, neoplastic transformation) [34]. In our study of patients with hematopoietic tumors, we observed changes of toxic elements in the levels of Al, Tl, Bi, and Pb. Also, hair and serum of patients with solid tumors detected changes levels of Al, Tl, Cd, Be, and Bi.

An increase in the content of toxic elements can be considered as a factor of unfavorable prognosis after anticancer therapy, since it has been noted that toxic metals can affect processes associated with mutagenic reactions of cells (apoptosis, proliferation, neoplastic transformation) [35]. In our study of patients with hematopoietic tumors, we observed changes in toxic elements in the levels of Al, Be, Cd Tl, Bi, and Pb. Also, changes in the levels of Al, Tl, Cd, Be and Bi were detected in the hair and blood serum of patients with solid tumors.

A number of publications have shown that high serum Al levels are also characteristic of patients with breast tumor tissue, but there is no evidence that this is directly related to carcinogenic effects [36]. No information was found on increased Al levels in the hair and blood serum of patients with tumors of the hematopoietic system.

It cannot be excluded that the increase in Tl content is a consequence of previously implemented mechanisms of carcinogenesis. Tl can carry out procanceroogenic activity by interfering with important processes, replacing potassium, in particular, in the (Na+/K+)-ATPase. But the antitumor role of thallium salts is described and shown in individual cell cultures [37]. Participation in oncogenes is confirmed by the effectiveness of Tl-scintigraphy to detect malignant tumors such as breast cancer and lymphoma [38].

It has also been reported that Bi nanoparticles (BisBAL NPs), derived from the compound bis(p-aminophenyl)lumazine, can inhibit the growth of breast cancer cells, with the effectiveness directly depending on the dosage used [39]. This is an important discovery because it suggests that BisBAL nanoparticles may have potential as a targeted therapy for breast cancer, specifically targeting cancer cells while sparing healthy cells. Interestingly, our data showed a decrease in serum Bi levels after chemotherapy.

Exposure to Pb (lead) is also associated with various health risks, including harmful effects on the nervous system, reproductive system, and kidneys. However, the relationship between Pb exposure and cancer development is less clear. Pb is associated with the formation of free radicals, which leads to the destruction of cells and tissues, increasing the risk of health problems such as cardiovascular disease and cancer [40]. It should be noted that our data indicate a low level of Pb in the hair of patients with tumors of the hematopoietic system.

In addition, the cohort of patients with solid tumors had elevated concentrations of Cd and Be, which recognized as human or animal carcinogens by International Agency for Research on Cancer (IARC). Numerous studies have noted that chronic exposure to these metals is associated with the development of solid tumors [41, 42]. Perhaps this is due to their ability to disrupt nucleotide excision repair, leading to genomic instability [43], which leads to tumor growth. Notably, high levels of Cd and Be were found only in serum of patients with solid tumors. Patients in the group of tumors of the hematopoietic system were characterized by no change in these toxic metals in serum.

It has been reported that too high concentration of essential elements can be a cause of toxicity, as too low concentration leads to disturbance of homeostasis. Among essential and probably essential trace elements, changes in the levels of Se, Mn, Ni, V, Cu, Zn, Fe, B, Co, I, Rb, Mo were found in the group with tumors of the hematopoietic system, and V, Cr, I, Sn, Se, Co, Mn, Ni, V, Co, Rb, Mo were found in the group with solid tumors. The described essential elemental imbalance in group with tumors of the hematopoietic tissues in serum largely coincides with the data obtained by other authors.

Thus, we found similar patterns of elevated serum Fe, Cu, and Ni levels known from previous studies [44, 45]. It was observed that Ni could stimulate cancer stem cells proliferation through NADPH oxidase/ROS-dependent mechanism [46]. It has been also reported that high Ni levels were associated with breast cancer, and it might be a risk factor for carcinogenesis [47]. Some authors have noted the predominance of epigenetic modulation in nickel carcinogenesis, which may include changes in the histone acetylation, methylation, ubiquitylation, and alterations in DNA methylation causing to affect gene expression [48]. Also, Ni may be involved in the hypoxic signaling pathway leading to nickel-induced carcinogenesis due to Ni was found to be a strong inducer of HIF-1α protein and an activator of HIF-dependent transcription [49], which may provide the conditions of resistant to apoptosis. Although Ni and Fe are quite similar and can alter each other's metabolism [50], the effects of Fe are more based on the regulation of oxidative stress and subsequent carcinogenesis [51]. Excess Fe, which is a cofactor for hematopoietic cell proliferation, can also stimulate cancer cell growth [52]. Caroline L. et al. showed that patients with acute leukemia have elevated serum Fe levels [53].

Copper (Cu) is an essential trace element playing a significant role in cellular functioning. However, elevated serum Cu levels may increase oxidative stress associated with the PI3K/Akt pathway, which may be a favorable factor for the development of oncogenic processes [54], and this is consistent with our results, as serum Cu was elevated among patients with hematopoietic tumors. Numerous studies have unequivocally confirmed a significant increase in Cu levels in both tumors and serum of cancer patients, which is significantly higher than in healthy individuals [55]. Thus, Li Y. et al. showed that elevated serum copper levels increase the risk of colorectal cancer, thus high serum copper levels may be considered as an indicator of a risk factor for the disease [56].

We also can note a higher concentration of V in serum compared to controls. Vanadium can affect many enzyme systems - phosphatases, ATPases, peroxidases, ribonucleases, protein kinases and oxidoreductases, and V has been shown in a number of animal cancer models to provide protection against all stages of carcinogenesis [57]. However, V promotes cell mutation in some cells, induces phosphorylation of tyrosine kinases and thus may affect oncogenes [58]. Due to its physiological duality, V becomes toxic at excessive levels, and can probably pro-carcinogenic properties [59]. Multiple studies have shown that a range of B derivatives have proven to be effective in combating cancer [60]. Various types of B compounds and structures possess the ability to hinder the progression of cancer and have been linked to lower cancer incidence in a variety of cancer types. B exhibits its anticancer effects through the involvement of specific molecular mechanisms, such as apoptosis induction and cell cycle arrest [61]. Nevertheless, many aspects of this effect remain unclear. We found an increase in serum B content in patients with hematopoietic tumors.

Besides that, patients with solid tumors had lower serum Cr concentrations, which was not seen in patients with hematopoietic tumors. Cr(VI)-associated carcinogenesis has been described in the literature and includes mutational inactivation of p53, base substitutions at A/T pairs and double missense mutations [62]. Cr(VI) is also listed as a Group 1 carcinogen by the IARC. Changes in Cr content were observed in hair and serum from patients with solid tumors, with Cr decreasing in serum while its concentration increased in hair. Zekavat et al. were shown that levels of serum Cr decreased after completion of combined chemotherapy [63], which correlates with our findings. The same study recorded a decrease in serum Mn concentration. On the other hand, Diez et al. found higher levels of Mn in patients with lung cancer [64]. Our results indicate reduced Mn levels in hair, but serum Mn levels are elevated compared to controls. Mn 2+ induces apoptosis in cells, which promotes capsize activation and participates in the antitumor immune response via the cGAS-STING signaling pathway, and is therefore characterised by a normally antitumor element [65].

Iodine (I) is one of the major antioxidants. Antitumor, antiproliferative and cytotoxic effects of iodine in cancer have been described [66]. Antitumor, antiproliferative and cytotoxic effects of iodine in cancer have been described. We found a decrease in hair I in a cohort of patients with hematopoietic tumors, and an increase in serum I in a group of solid tumors. Tin (Sn) compounds also have the described anticancer properties. It has been reported, that Sn-DBPTF-1 is effective against cancer or tumorigenic cell lines due to Sn-DBPTF-1 (dibenzyl phosphinoyldithioformate) may induce apoptosis and double-strand DNA breaks [67]. Notably, we found elevated Sn levels in hair from patients with solid tumors.

Note also the common patterns of decreased serum Co, Rb, Mo levels in patients with both solid and hematopoietic tumors. Cao G.H. et al. reported that hair and serum Mo contents of gastric cancer cases were lower than those of healthy controls [68]. The introduction of Mo compounds promotes apoptosis and the generation of reactive oxygen species, thus demonstrating their potential use for treating metastatic cancer cells [69]. A case-control study of Yetişgin F. et al. have shown that levels of Co were increase in the patient group with myeloproliferative neoplasms [70]. Several studies have shown that Co(II) ions are genotoxic due to production of active oxygen species and DNA repair inhibition [71]. Also, it is worth noting the finding by Wang X. et al. that Rb levels correlated with the lifetime cancer risks, which may be related to possible involvement in cancer etiology [72].

The effect of such trace elements as selenium (Se) and zinc (Zn) should be considered specifically, as it is believed that among the trace elements they have the maximum antitumor effect. Zn was assessed as a marker for predicting response to chemotherapy. It has been also reported that Zn deficiency is common in hematopoietic and solid tumors [73]. Apparently, this relationship can be explained by the properties of zinc to inhibit MT expression and further induce ROS content increase [74]. Some studies suggest that disruption of redox activity can lead to cancer progression by affecting signal transduction pathways that cause expression of anti-apoptotic genes that regulate cell death [75, 76]. Nevertheless, redox active trace elements may be useful in antitumor therapy. Thus, Se-based compounds are considered as chemotherapeutic agents that mediate the activation of death receptors expressed on the cell surface and the production of ROS, leading to necroptosis [77]. Elevated Se levels in hair are inconsistent with other studies of decreased Se levels in patients with leukemia and lymphoma [78]. Since our study considered the delayed effects of chemotherapy, an increase in Se levels can be interpreted as a disruption of the excretion process. Additionally, essential trace elements could have therapeutic applications when used synergistically with antitumor therapy, especially in their ability to modulate the toxicity of anticancer therapies and promote repair of healthy tissue [79]. It is important to consider this because an imbalance of essential trace elements can lead to impaired immune function, increased risk of side effects of therapy, and deteriorated quality of life.

Our study has some limitations, such as the number of participants, lack of measurement of elemental profile before treatment and lack of follow-up after elemental measurement after induction of antitumor therapy, which makes it impossible to accurately determine whether the apparent disturbances in elemental status are due to disease or treatment. We did not aim to differentiate between elemental disturbances induced by antitumor therapy and delayed metabolic disturbances of the tumor process. This should be evaluated in subsequent studies.

In conclusion, we found a statistically significant difference between the elemental profile in serum, hair in patients with different tumor histological structure and controls. As clinical data accumulate, it is reasonable to consider metabolic changes in essential and toxic element levels. Our data suggest that neoplasms of the hematopoietic system are characterized by more pronounced alterations in the composition of essential elements in hair and serum, and solid tumors show a somewhat higher accumulation of certain toxic metals compared with tumors of the hematopoietic system. However, no major and specific differences were found between the cohorts. A more differentiated approach to correcting nutritional status may be necessary depending on the type of tumor and treatment. Further studies are needed to evaluate the causes of elemental imbalance, associated toxic effects and the possible role of supplementation as supportive therapy. A study of the long-term effects of antitumor therapy on alterations in trace element homeostasis and associated impairment of general health, the consequences treatment, and the risk of tumor recurrence is required.

Funding: This work was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers "Digital biodesign and personalized healthcare" №075-15-2022-304

Authors' Contributions:

Skalny AV, Zhukovskaya EV - study concept and design;
Zhukovskaya EV - collection and processing of the material;
Savko SA, Zhukovskaya EV - writing text;
Savko SA - statistical processing;
Skalny AV, Karelin AF, Korobeynikova TV, Rumyantsev AG - text editing. All authors have made a significant contribution to the search, analysis, and preparation of the article, read and approved the final version before publication, and accepted responsibility for the integrity of all parts of the article.

Conflict of Interest. The authors declare no conflict of interest in relation to the manuscript.

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No competing interests reported.

Comparison of the elemental alterations of solid and hematopoietic tumors in children and adolescents after completion of antitumor therapy

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Abstract

1. Introduction

2. Objectives

3. Materials and Methods

4. Results and Discussion

Conclusion

Declarations

References

Additional Declarations

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Version 1