- Prof. Renty B. Franklin
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, MD, USA.
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- Prof. Leslie C. Costello
Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, MD, USA.
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Special Issue Introduction
Zinc is an essential metal that is required for the normal function of all cells. It is important to the structure and function of many cellular proteins. Zinc plays an important role in the regulation of complex cellular processes such as proliferation, apoptosis, regulation of gene expression, regulation of the immune system, bioenergetic metabolic pathways, signal transduction and many other systemic effects. Zinc is not toxic, even at high concentrations. This is represented by Wilson’s disease, in which patients are treated with 500 mg Zn/day, often for many years. Thus, the risk of zinc overload and adverse effects from zinc treatment for cancer is extremely unlikely.
Zinc dyshomeostasis has been linked to the development of cancers. Malignant cells are characterized as “decreased zinc” malignancies. The reason is that the higher zinc concentration in the normal cells is cytotoxic in malignant cells. It has been reported that zinc protects malignant cells from apoptosis induced by other factors and is also cytotoxic to malignant cells. The only way to establish the implications of zinc is with zinc-stained human tissue sections, and the comparison of the malignant cells vs. the normal cells. The normal cells exhibit high zinc stain, and the malignant cells exhibit major loss of zinc; to the extent that they are not distinguished from the stromal cells. Moreover, the treatment of malignant cells with physiological concentrations of zinc results in the inhibition of cell cycle and cell growth, and it promotes apoptosis, inhibits cell mobility, and inhibits cell invasion. With such conditions, no corroborated report of increased zinc in malignancy exists. In addition, the various experimental conditions applied in zinc studies, especially in vitro, have undoubtedly contributed to the confusion surrounding the effects of zinc on malignant cells. To be physiologically relevant, the concentration of zinc used must be within the range of the extracellular zinc concentration present in situ. Moreover, one must also recognize that zinc is relatively impermeable to cells and that it must enter through the activity of zinc transporters on the plasma membrane. Thus, relevant studies of zinc effects must ensure that zinc enters the cell under concentration conditions comparable to the in-situ plasma zinc level. Studies to manipulate the intracellular zinc level present a different set of concerns. Generally, these studies involve cell permeable chelators to bind and lower intracellular zinc followed by zinc replacement. Since the chelator zinc complex is another diffusible species, one must be aware that the chelator may either bind the zinc and lower reactive zinc or act as an ionophore and transport zinc out of the cell. In this special issue of Journal of Cancer Metastasis and Treatment, we request reports that (1) help to establish associations between cancers and zinc homeostasis, (2) that explore mechanisms involved in zinc dysregulation related to transformation to malignancy and (3) zinc related treatments for cancer.
Zinc, cancer, zinc homeostasis, malignancies, intracellular zinc
Submission Deadline30 Nov 2022