Popular Science: Cancer “supercells” helped by iron to escape therapy?
Iron represents a pivotal component of cellular oxidation-reduction processes, during which it shuffles between ferrous and ferric form. It also facilitates a wide range of enzymatic reactions. Cellular iron levels are tightly controlled through several mechanisms, for example, the transferrin receptor is responsible for iron uptake while the sphere-shaped protein ferritin participates in iron storage inside the cell. The production of both these proteins is regulated by the intracellular iron level – a deficiency or excess amount of iron brings about the binding of specific proteins to the non-coding region of the particular mRNA, affecting its stability. Apart from this, many other cellular processes are involved in iron metabolism. Free iron is known to generate reactive oxygen species (along with hydrogen peroxide) and is toxic to the cells.
Scientists have remarked on the increased iron uptake rates in cancer cells in the past, resulting from extensive proliferation. Likewise, the deregulation of iron uptake has been proposed to drive the development of cancer and to correlate with the prognosis of oncologic patients. These findings have been successfully used in the therapy of certain tumour types. The results of a recent study by Dr. Jaroslav Truksa from the Institute of Biotechnology, Czech Academy of Sciences, in cooperation with Sandra Lettlová and Veronika Tomková from the Faculty of Science, show that changes in iron metabolism also occur in tumour-initiating cells (TICs). These cells have been defined as a small subpopulation of tumour cells exhibiting characteristics of stem cells that are resistant to chemotherapeutic agents and possess the ability to initiate tumour growth. TICs are likely to make a major contribution to the relapse of cancer. Therapy aimed at the elimination of TICs could thus efficiently prevent the recurrence of the disease.
In order to shed more light on the role of iron in the biology of TICs, scientists from Dr. Truksa´s group have assessed the level of iron in their mitochondria as well as the intracellular labile iron content. They have also investigated iron uptake and storage together with the expression profile of selected genes involved in iron metabolism. The results of this study suggest that TICs have higher iron requirements in comparison to control cells – they exhibit a higher intracellular labile iron pool, higher iron uptake rate, mitochondrial iron accumulation and reduced ferritin protein level. The authors have also identified a set of ten genes (e.g. ABCB10, ACO1, CYBRD1, EPAS1, GLRX5, HEPH, HFE, IREB2, QSOX1 a TFRC), an expression of which is able to specifically distinguish the subpopulation of TICs from tumour cells.
The importance of this principle, as well as the significance of deregulated iron metabolism in TICs, is further supported by the finding that the same gene set expression pattern is also associated with the leukemia-initiating cells (LICs) phenotype. These cells represent a subset of leukemic cells that serve as a reservoir for disease persistence and relapse. Understanding the changes in iron utilization in both studied cell types could thus be crucial for the development of novel therapeutic approaches that will further complicate the well-being of these cells.
Rychtarcikova Z, Lettlova S, Tomkova V, Korenkova V, Langerova L, Simonova E, Zjablovskaja P, Alberich-Jorda M, Neuzil J, Truksa J. (2017), Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism. Oncotarget, 8(4), 6376–6398. http://doi.org/10.18632/oncotarget.14093