Editors' ChoiceCancer

Iron fuels glioblastoma growth

Sci. Signal.  27 Oct 2015:
Vol. 8, Issue 400, pp. ec311
DOI: 10.1126/scisignal.aad7099

Some cells in glioblastomas have properties similar to stem cells and are thus called cancer stem-like cells (CSCs). CSCs tend to thrive in nutrient-poor and oxygen-deprived environments and are particularly resistant to chemotherapeutics. Schonberg et al. found that glioblastoma CSCs exhibited a mechanism of iron scavenging typically observed for liver cells and this iron uptake promoted their proliferation. RNA sequencing revealed that the expression of the gene encoding transferrin, a protein typically synthesized by the liver to scavenge iron from the blood, was among the most increased in glioblastoma CSCs compared with either glioblastoma cells lacking CSC properties or normal brain cell progenitors. Epigenetic profiling in these same cell populations indicated that the CSCs had the transferrin-encoding gene within an enhancer region that was normally limited to hepatocytes and that the gene encoding transferrin receptor (TfR) was transcriptionally active in CSCs. TfR abundance was increased on the surface of CSCs compared with TfR abundance on nonCSC glioblastoma cells in culture and patient-derived xenografts, the amount of transferrin that colocalized with tumor cells was greater in brain slices implanted ex vivo with CSCs than with slices implanted with nonCSC glioblastoma cells, and cultured CSCs took up more transferrin-conjugated iron than did nonCSC gliobastoma cells. Once trafficked into the cell, iron is either used or stored in ferritin, the synthesis of which is stimulated by free intracellular iron. As expected from increased iron uptake observed in CSCs, ferritin synthesis was increased in CSCs cultured with iron. Likewise, the expression of the genes encoding the two ferritin subunits was greater in glioblastoma CSCs than in nonCSC glioblastoma cells or normal brain tissue. The expression of the genes encoding the two ferritin subunits and the abundance of TfR correlated with advanced tumor grade and poor survival in glioblastoma patients. Knocking down ferritin decreased the abundance of TfR at the surface of and decreased proliferation of cultured CSCs, and xenografted tumors of CSCs in which ferritin was knocked down exhibited reduced growth. Although loss of ferritin also slowed proliferation of normal adult brain cells in culture, the effect was much less than that observed in ferritin-deficient CSCs. The abundance of the transcription factor STAT3 and its target FOXM1, which is increased in glioblastoma and promotes cell proliferation, correlated with that of ferritin. FOXM1 overexpression restored proliferation in ferritin-deficient CSCs. Iron is critical to normal brain function, thus rather than use traditional iron chelators, these findings suggest that targeting ferritin may be a more selective therapy to target glioblastoma, particularly the stubborn CSCs that drive its growth.

D. L. Schonberg, T. E. Miller, Q. Wu, W. A. Flavahan, N. K. Das, J. S. Hale, C. G. Hubert, S. C. Mack, A. M. Jarrar, R. T. Karl, A. M. Rosager, A. M. Nixon, P. J. Tesar, P. Hamerlik, B. W. Kristensen, C. Horbinski, J. R. Connor, P. L. Fox, J. D. Lathia, J. N. Rich, Preferential iron trafficking characterizes glioblastoma stem-like cells. Cancer Cell 28, 441–455 (2015). [PubMed]