Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.

Connecting copper and cancer: from transition metal signalling to metalloplasia.

Although it has been reported that selenium (Se) deficiency can trigger inflammation, however, there are few reports on the effect of Se on the function of mouse peritoneal macrophages. Herein, we examined the expression of inflammatory factors, oxidative stress levels, and phagocytosis for primary-cultured peritoneal macrophages using control and Se-deficient groups. Our results revealed that Se deficiency induced the accumulation of oxygen free radicals and weakened antioxidant capacity. Se deficiency also significantly increased the expression of inflammation factors including iNOS, IL-1β, IL-12, IL-10, PTGe, and NF-κB. Meanwhile, Se suppression restrained macrophage production of TNF-α. The results of the phagocytosis assay demonstrated that Se deficiency inhibited the phagocytosis of macrophages. In conclusion, Se-deficient macrophages undergo severe inflammation through the NF-κB pathway due to the accumulation of oxygen free radicals and are hindered in their phagocytic capacity.

Impact of Selenium Deficiency on Inflammation, Oxidative Stress, and Phagocytosis in Mouse Macrophages.

Colorectal cancer has increased in Middle Eastern countries and exposure to environmental pollutants such as heavy metals has been implicated. However, data linking them to this disease are generally lacking. This study aimed to explore the spatial pattern of age-standardized incidence rate (ASR) of colon cancer and its potential association with the exposure level of the amount of heavy metals existing in rice produced in north-eastern Iran. Cancer data were drawn from the Iranian population-based cancer registry of Golestan Province, north-eastern Iran. Samples of 69 rice milling factories were analysed for the concentration levels of cadmium, nickel, cobalt, copper, selenium, lead and zinc. The inverse distance weighting (IDW) algorithm was used to interpolate the concentration of this kind of heavy metals on the surface of the study area. Exploratory regression analysis was conducted to build ordinary least squares (OLS) models including every possible combination of the candidate explanatory variables and chose the most useful ones to show the association between heavy metals and the ASR of colon cancer. The highest concentrations of heavy metals were found in the central part of the province and particularly counties with higher amount of cobalt were shown to be associated with higher ASR of men with colon cancer. In contrast, selenium concentrations were higher in areas with lower ASR of colon cancer in men. A significant regression equation for men with colon cancer was found (F(4,137) = 38.304, P < .000) with an adjusted R2 of 0.77. The predicted ASR of men colon cancer was − 58.36 with the coefficients for cobalt = 120.33; cadmium = 80.60; selenium = − 6.07; nickel = − 3.09; and zinc = − 0.41. The association of copper and lead with colon cancer in men was not significant. We did not find a significant outcome for colon cancer in women. Increased amounts of heavy metals in consumed rice may impact colon cancer incidence, both positively and negatively. While there were indications of an association between high cobalt concentrations and an increased risk for colon cancer, we found that high selenium concentrations might instead decrease the risk. Further investigations are needed to clarify if there are ecological or other reasons for these discrepancies. Regular monitoring of the amount of heavy metals in consumed rice is recommended.

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Association between heavy metals and colon cancer: an ecological study based on geographical information systems in North-Eastern Iran

The purpose of this study was to analyze the existing studies and to investigate the relationship between the risk of colorectal cancer (CRC) and intakes of four individual dietary elements calcium (Ca), iron (Fe), magnesium (Mg), and potassium (K). All relevant articles in both Chinese and English were searched and collected from PubMed, Web of Science, and Chinese National Knowledge Infrastructure databases up to December 17, 2017. There were 29 eligible literatures selected for further meta-analysis, including 14 cohort studies and 15 case-control studies. The meta-analysis of cohort studies indicated that the high intakes of dietary Ca and Mg were negatively associated with the risk of CRC, as the hazard ratios (HR) were 0.76 (95% confidence interval (CI) 0.72, 0.80) and 0.80 (95% CI 0.73, 0.87), respectively. Nevertheless, high intake of dietary heme Fe was positively correlated to the incidence of colon cancer (HR = 1.01, 95% CI 0.82, 1.19) and rectal cancer (HR = 1.04, 95% CI 0.67, 1.42). A meta-analysis of case-control studies indicated that high intakes of dietary Ca, Mg, and K were negatively related with the occurrence of CRC, because the odds ratios (OR) were 0.36 (95% CI 0.32, 0.40), 0.80 (95% CI 0.63, 0.98) and 0.97 (95% CI 0.74, 1.21), respectively. However, high Fe intake from diet was positively correlated with the rising increasing of CRC (OR = 1.04, 95% CI 0.91, 1.18). More research is needed to indicate the risk relationship between element intake and CRC.

Dietary Intakes of Calcium, Iron, Magnesium, and Potassium Elements and the Risk of Colorectal Cancer: a Meta-Analysis

Colorectal cancer and trace elements alteration

Cases of colorectal cancer (CRC) have increased dramatically in Middle Eastern and other Asian countries. Many studies indicate an important role of environmental factors, including trace elements as an etiology of cancer. This study aims to assess the concentration of eight trace elements in cancerous and adjacent non-cancerous tissues in case of CRC. In a cross-sectional study, conducted between March 2015 and February 2016, zinc (Zn), chromium (Cr), manganese (Mn), tin (Sn), copper (Cu), aluminum (Al), lead (Pb), and iron (Fe) levels were evaluated among patients suffering from CRC. All the patients underwent a full colonoscopy. Multiple samples were taken from cancerous lesions and adjacent healthy tissues that kept a minimum distance of 10 cm from the lesions. These specimens were kept at −80 °C. The classic flame atomic absorption spectroscopy (FAAS) method was applied in this study. The mean age of the study population was 55.6 ± 12.8. The median of Zn, Cr, Cu, Al, and Pb in cancerous tissues was significantly higher than that of healthy tissues (P < 0.05). Nevertheless, the median of Mn, Sn, and Fe was significantly lower than that of non-cancerous tissues (P < 0.05). Between colon and rectal specimens, we did not find a difference between Cr and Al levels and Zn, Sn, and Cu levels in cancerous and healthy tissues, respectively. We revealed that gender and history of smoking may influence the level of some trace elements. We revealed that the levels of eight elements were significantly different for cancerous and healthy tissues. This may play a role in developing CRC. These findings reflect the importance of environmental pollution in this setting.

Gholamrez Hemmasi

Papers

Trace Element and Heavy Metal Levels in Colorectal Cancer: Comparison Between Cancerous and Non-cancerous Tissues