Luminal Iron Levels Govern Intestinal Tumorigenesis after Apc Loss In Vivo

• Published in: Cell reports (Cambridge) Vol. 2; no. 2; pp. 270 - 282
• Main Authors: Radulescu, Sorina, Brookes, Matthew J., Salgueiro, Pedro, Ridgway, Rachel A., McGhee, Ewan, Anderson, Kurt, Ford, Samuel J., Stones, Daniel H., Iqbal, Tariq H., Tselepis, Chris, Sansom, Owen J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.08.2012; Elsevier
• Subjects: Adenomatous Polyposis Coli Protein; Animals; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Colorectal Neoplasms - prevention & control; Dietary Supplements; Gene Deletion; Humans; Intestinal Mucosa - metabolism; Intestines - pathology; Iron - metabolism; Iron - pharmacology; Mice; Mice, Knockout; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.07.003

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. [Display omitted] ► APC-deficient cells accumulate iron ► Dietary iron levels govern the survival of APC-deficient cells ► High iron induces expression of WNT target genes, including c-MYC and LGR5 ► Modulation of iron is a potential therapeutic opportunity for colon cancer Colorectal cancer has a dietary component, and although excess iron has been associated with colon tumors, it is not clear whether it is a cause or an effect. In this study, Tselepis, Sansom, and colleagues report that dietary (but not systemic) iron levels are crucial for the fate of cells that have lost the APC tumor suppressor. An iron-rich diet promotes tumorigenesis by expanding the stem cell compartment and increasing proliferation, whereas a diet lacking iron promotes apoptosis and slows tumor growth.