Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like Cells

Chiara Raggi; Elena Gammella; Margherita Correnti; Paolo Buratti; Elisa Forti; Jesper B. Andersen; Gianfranco Alpini; Shannon Glaser; Domenico Alvaro; Pietro Invernizzi; Gaetano Cairo; Stefania Recalcati

doi:10.1038/s41598-017-17804-1

Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like Cells

Chiara Raggi, Elena Gammella, Margherita Correnti, Paolo Buratti, Elisa Forti, Jesper B. Andersen, Gianfranco Alpini, Shannon Glaser, Domenico Alvaro, Pietro Invernizzi^*, Gaetano Cairo, Stefania Recalcati

^*Corresponding author for this work

27 Citations (Scopus)

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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.

Original language	English
Article number	17667
Journal	Scientific Reports
Volume	7
Issue number	1
Number of pages	12
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-017-17804-1
Publication status	Published - 1 Dec 2017

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Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like CellsFinal published version, 1.82 MBLicence: CC BY

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title = "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.",

author = "Chiara Raggi and Elena Gammella and Margherita Correnti and Paolo Buratti and Elisa Forti and Andersen, {Jesper B.} and Gianfranco Alpini and Shannon Glaser and Domenico Alvaro and Pietro Invernizzi and Gaetano Cairo and Stefania Recalcati",

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AU - Raggi, Chiara

AU - Gammella, Elena

AU - Correnti, Margherita

AU - Buratti, Paolo

AU - Forti, Elisa

AU - Andersen, Jesper B.

AU - Alpini, Gianfranco

AU - Glaser, Shannon

AU - Alvaro, Domenico

AU - Invernizzi, Pietro

AU - Cairo, Gaetano

AU - Recalcati, Stefania

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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AN - SCOPUS:85038250095

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VL - 7

JO - Scientific Reports

JF - Scientific Reports

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Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like Cells

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