Abstract
Background: We investigated the effects of the frequently polymorphic high iron gene (HFE), on tumor growth in a novel mouse model. We hypothesized that host mutations in the HFE protein modify tumor progression. Methods: C57BL/6 mice possessing either H67D/H67D or WT/WT HFE genotype, aged 18 months, were injected subcutaneously with 4x106 cells of the B16F10 mouse melanoma cell line. After 2 weeks, mice were sacrificed and the tumors and plasma were collected. Animal methods were approved by our IACUC, (04-166). Tumors were analyzed by RT-PCR. In parallel, bone marrow derived macrophages were cultured to determine how B16F10 cell cultures react to conditioned media from macrophages of each genotype. ELISAs were performed for ferroportin, ferritin, secreted cytokine and chemokine content of macrophage media. Results: H67D mice had significantly smaller tumors (t-test, P = 0.02) after two weeks. Exploratory qRT-PCR analysis of tumors revealed that the H67D host may suppress angiogenesis and growth. In culture, macrophages derived from H67D mice secrete higher levels of monocyte chemoattractant protein 1 (MCP1), suggesting a change in chemotactic signaling (p = 0.02). When conditioned media from the H67D macrophages were placed onto B16F10 cells in culture there was significantly less growth compared to conditioned media from WT macrophages (p < 0.01 MTT, p < 0.01 BrdU). In macrophage cell lysates, H67D is associated with lower levels of Ferroportin (p = 0.03). Conclusions: Macrophages from H67D mice do not support tumor cell proliferation as well as WT controls. Our data reveal the importance of HFE genotype on tumor growth that may be related to macrophage function.
Highlights
We investigated the effects of the frequently polymorphic high iron gene (HFE), on tumor growth in a novel mouse model
Incubation of B16F10 cells in the H67D/H67D mouse yields a smaller subcutaneous tumor compared to its wild type littermate (P < 0.001, Figure 1)
The results of the present study demonstrate that tumors formed from B16F10 Luc G5 melanoma cells are smaller in mice carrying the H67D HFE gene variant compared to wild type
Summary
We investigated the effects of the frequently polymorphic high iron gene (HFE), on tumor growth in a novel mouse model. Much clinical evidence exists to support a relationship between cancer and HFE genotype, the nature of this relationship and the mechanisms by which HFE function affect tumor progression are still unclear. HFE is an atypical MHC class I molecule that affects immune function [1,2] and HFE polymorphisms disrupt iron metabolism. It is already known that iron metabolism affects tumor progression [3]. We have previously reported that elevated ferritin, iron storage and transport protein, in serum are associated with poor prognosis in breast cancer [5]. Hereditary hemochromatosis most often arises from mutations in the HFE gene and it has been commonly assumed that the cancers associated with the HFE mutation are related to excess iron accumulation [7]
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