Blood Donation and Colorectal Cancer Incidence and Mortality in Men

Background: Although blood donations may reduce body iron stores, to date, prospective data on frequent blood donation and colorectal cancer risk are limited. Methodology/Principal Findings: We tested whether frequent blood donation is associated with a lower risk of colorectal cancer in the Health Professionals Follow-up Study. We prospectively followed 35,121men who provide the information on lifetime number of blood donations in 1992 through 2008. Serum ferritin levels were measured in a random sample of 305 men. Cox proportional hazard regression models were used to calculate the multivariable relative risks (RRs, 95%CIs) after adjusting for age and other established colorectal cancer risk factors. We documented 684 incident colorectal cancer cases and 224 deaths from colorectal cancer. The mean serum ferritin levels varied from 178 µg/L for men who did not donate blood to 98 µg/L for men who had at least 30 donations. Age-adjusted results for both incidence and mortality were essentially the same as the multivariable-adjusted results. Comparing with non-donors, the multivariable RRs (95%CIs) for colorectal cancer incidence were 0.92 (0.77, 1.11) for 1–5 donation, 0.85 (0.64, 1.11) for 6–9 donations, 0.96 (0.73, 1.26) for 10–19 donations, 0.91 (0.63, 1.32) for 20–29 donations, and 0.97 (0.68, 1.38) for at least 30 donations (Ptrend = 0.92). The multivariable RRs for colorectal cancer mortality were 0.99 (0.72, 1.36) for 1–5 donation, 0.93 (0.57, 1.51) for 6–9 donations, 0.85 (0.50, 1.42) for 10–19 donations, and 1.14 (0.72, 1.83) for at least 20 donations (Ptrend = 0.82). The results did not vary by cancer sub-sites, intake levels of total iron, heme iron, or family history of colorectal cancer. Conclusions/Significance: Frequent blood donations were not associated with colorectal cancer incidence and mortality in men. Our results do not support an important role of body iron stores in colorectal carcinogenesis

Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice

Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk