title: Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo.
abstract: It is clear from epidemiological studies that excess iron is associated with increased risk of colorectal cancer; however, questions regarding the mechanism of how iron increases cancer risk, the source of the excess iron (circulating or luminal), and whether iron reduction represents a potential therapeutic option remain unanswered. In this study, we show that after Apc deletion, the cellular iron acquisition proteins TfR1 and DMT1 are rapidly induced. Conversely, restoration of APC reduces cellular iron due to repression of these proteins. To test the functional importance of these findings, we performed in vivo investigations of the impact of iron levels on intestinal tumorigenesis. Strikingly, depletion of luminal (but not systemic) iron strongly suppressed murine intestinal tumorigenesis, whereas increased luminal iron strongly promoted tumorigenesis. Taken together, our data definitively delineate iron as a potent modifier of intestinal tumorigenesis and have important implications for dietary iron supplementation in patients at high risk of colorectal cancer.
authors.affiliation: Beatson Institute of Cancer Research, Glasgow, UK.
authors.forename: Sorina
authors.initials: S
authors.lastname: Radulescu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brookes
authors.forename: Pedro
authors.initials: P
authors.lastname: Salgueiro
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.forename: Ewan
authors.initials: E
authors.lastname: McGhee
authors.forename: Kurt
authors.initials: K
authors.lastname: Anderson
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Ford
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Stones
authors.forename: Tariq H
authors.initials: TH
authors.lastname: Iqbal
authors.forename: Chris
authors.initials: C
authors.lastname: Tselepis
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D019587:Dietary Supplements; D017353:Gene Deletion; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D027682:Cation Transport Proteins; D007501:Iron; D011990:Receptors, Transferrin; D000099236:Solute Carrier Family 11, Member 2; C480029:Tfrc protein, mouse