Calcium role in human carcinogenesis: a comprehensive analysis and critical review of literature

The central role played by calcium ion in biological systems has generated an interest for its potential implication in human malignancies. Thus, lines of research, on possible association of calcium metabolism regulation with tumorigenesis, implying disruptions and/or alterations of known molecular pathways, have been extensively researched in the recent decades. This paper is a critical synthesis of these findings, based on a functional approach of the calcium signaling toolkit. It provides strong support that this ubiquitous divalent cation is involved in cancer initiation, promotion, and progression. Different pathways have been outlined, involving equally different molecular and cellular structures. However, if the association between calcium and cancer can be described as constant, it is not always linear. We have identified several influencing factors among which the most relevant are (i) the changes in local or tissular concentrations of free calcium and (ii) the histological and physiological types of tissue involved. Such versatility at the molecular level may probably account for the conflicting findings reported by the epidemiological literature on calcium dietary intake and the risk to develop certain cancers such as the prostatic or mammary neoplasms. However, it also fuels the hypothesis that behind each cancer, a specific calcium pathway can be evidenced. Identifying such molecular interactions is probably a promising approach for further understanding and treatment options for the disease.