Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like Cells

Abstract

Cholangiocarcinoma (CCA) is a devastating liver tumour arising from malignant transformation of bile duct epithelial cells. Cancer stem cells (CSC) are a subset of tumour cells endowed with stem-like properties, which play a role in tumour initiation, recurrence and metastasis. In appropriate conditions, CSC form 3D spheres (SPH), which retain stem-like tumour-initiating features. Here, we found different expression of iron proteins indicating increased iron content, oxidative stress and higher expression of CSC markers in CCA-SPH compared to tumour cells growing as monolayers. Exposure to the iron chelator desferrioxamine decreased SPH forming efficiency and the expression of CSC markers and stem-like genes, whereas iron had an opposite effect. Microarray profiles in CCA samples (n = 104) showed decreased H ferritin, hepcidin and ferroportin expression in tumours respect to surrounding liver, whereas transferrin receptor was up-regulated. Moreover, we found a trend toward poorer outcome in CCA patients with elevated expression of ferritin and hepcidin, two major proteins of iron metabolism. These findings, which represent the first evidence of a role for iron in the stem cell compartment as a novel metabolic factor involved in CCA growth, may have implications for a better therapeutic approach.

Ferroptosis: Final destination for cancer?

“…Correspondingly, iron chelation can inhibit the stemness of CSCs, whereas iron supplementation can have the reverse effect. In other words, iron may function as a protective factor in CSCs . However, iron deprivation has also been found to halt cell proliferation in mouse‐induced pluripotent cells and inhibit the expression of stemness markers .…”

“…These findings indicate that iron may have a dual function in CSCs. Studies have shown that levels of both the iron storage protein ferritin and the iron exporter ferroportin (FPN) are decreased in cholangiocarcinoma CSCs and ovarian CSCs . In addition, low H ferritin levels and high TFRC expression were detected in cholangiocarcinoma cells when grown in monolayers; however, when the same cell lines formed tumour spheres, there were high H ferritin levels and low TFR1 expression levels.…”

Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma

“…The higher iron content may affect the redox status of CSCs, but information to this regard is still limited. Iron chelation treatment inhibited the stemness, as shown by the decreased expression typical surface markers or the decrease capacity to form spheres, whereas the reverse effect was observed upon iron supplementation . Accordingly, iron deprivation obtained by overexpressing Fpn in breast cancer cells significantly decreased the expression of specific markers and impaired metastatic capacity .…”

“…123,125 Notably, dysregulated expression of iron proteins in CSCs has been found to be a negative prognostic factor in human tumours. 39,123,124,130 All these findings prompt metabolic plasticity as a central force that enables CSCs to modify their replicative capabilities according to specific needs. Furthermore, emerging evidence suggests that CSCs may adopt specific metabolic phenotypes based on their location within the tumour mass.…”

“…It has been shown that CSCs of different types of tumours are iron‐rich in comparison with tumour cells. In particular, ferroportin, the iron exporter protein, is down‐modulated in CSCs associated to different tumours, and the expression of H ferritin, the iron storage protein, is increased and seems to correlate closely with CSCs features like the capacity to form spheres . The higher iron content may affect the redox status of CSCs, but information to this regard is still limited.…”