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.

Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function

“…In particular, decades of epidemiological and experimental studies have established that iron excess, due to either genetic factors or excessive dietary intake, is implicated in multiple types of human cancers (Torti and Torti, 2013; Toyokuni, 2009). Hereditary hemochromatosis (HH) is a genetic disorder of iron overload, with clinical complications including liver cirrhosis and a 20- to 200-fold increased risk for hepatocellular carcinoma (Elmberg et al, 2003; Niederau et al, 1985) or other cancer types (Osborne et al, 2010; Pietrangelo, 2010; Radulescu et al, 2012). Meanwhile, tumors reprogram iron metabolism to achieve a growth advantage or metastasis, resulting in the emergence of iron deprivation, via iron chelation or application of transferrin receptor-neutralizing antibodies, as a major chemotherapeutic strategy.…”

Nanoparticulate iron(III) oxo-hydroxide delivers safe iron that is well absorbed and utilised in humans

“…A negative impact on the commensal flora, especially suppression of Lactobacillus , 7 and an enhancement of systemic infection for at-risk populations 8,9 have been convincingly demonstrated in oral iron supplementation/fortification studies in humans. Most recently, a marked enhancement of colonic carcinogenesis by soluble luminal (chelated) iron has been demonstrated in mice, 10 including those with Apc mutations, the commonest gene mutation in sporadic colon cancer in humans 11 …”

Systemic and tumor level iron regulation in men with colorectal cancer: a case control study

“…Beyond impaired iron status and red blood cell production, the ACD may be relevant for persons with CRC given that hepcidin-induced reductions in dietary iron absorption in the proximal gut may increase colonic iron exposure. Colonic tumors may benefit from this alteration since iron is a substrate for cell proliferation, cancer progression and metastasis [1,2,5,6]. The primary aims of this case–control study were to simultaneously examine systemic and tumor level iron status and regulation in men with CRC compared to controls and determine if systemic or tumor level hepcidin expression was associated with tumor iron accumulation.…”

“…suggests that a subset of persons with CRC have increased expression of systemic hepcidin, which may precipitate greater intestinal iron exposure, and promote tumor iron retention [1]. In a murine model of CRC, animals had increased tumor growth when fed a high iron diet compared to a low iron diet [5]. Also, in persons with ulcerative colitis (UC), who have co-existing systemic and colonic inflammation and hepcidin-mediated dietary iron malabsorption, luminal iron exposure is associated with greater colonic inflammation and mucosal proliferation [40-42].…”