Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in industrialized countries. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Iron is an essential nutrient for cell growth. Iron overload caused by hereditary mutations or excess dietary iron uptake has been identified as a risk factor for CRC. Intestinal iron is tightly controlled by iron transporters that are responsible for iron uptake, distribution, and export. Dysregulation of intestinal iron transporters are observed in CRC and lead to iron accumulation in tumors. Intratumoral iron results in oxidative stress, lipid peroxidation, protein modification and DNA damage with consequent promotion of oncogene activation. In addition, excess iron in intestinal tumors may lead to increase in tumor-elicited inflammation and tumor growth. Limiting intratumoral iron through specifically chelating excess intestinal iron or modulating activities of iron transporter may be an attractive therapeutic target for CRC.
References
[1]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics. CA Cancer J. Clin. 2012, 62, 10–29.
[2]
Karim-Kos, H.E.; de Vries, E.; Soerjomataram, I.; Lemmens, V.; Siesling, S.; Coebergh, J.W. Recent trends of cancer in Europe: A combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur. J. Cancer 2008, 44, 1345–1389, doi:10.1016/j.ejca.2007.12.015.
[3]
Bray, F.; Sankila, R.; Ferlay, J.; Parkin, D.M. Estimates of cancer incidence and mortality in Europe in 1995. Eur. J. Cancer 2002, 38, 99–166, doi:10.1016/S0959-8049(01)00350-1.
[4]
Yasui, H.; Yoshino, T.; Boku, N.; Onozawa, Y.; Hironaka, S.; Fukutomi, A.; Yamazaki, K.; Taku, K.; Kojima, T.; Machida, N. Retrospective analysis of S-1 monotherapy in patients with metastatic colorectal cancer after failure to fluoropyrimidine and irinotecan or to fluoropyrimidine, irinotecan and oxaliplatin. Jpn. J. Clin. Oncol. 2009, 39, 315–320, doi:10.1093/jjco/hyp014.
Qiao, L.; Feng, Y. Intakes of heme iron and zinc and colorectal cancer incidence: A meta-analysis of prospective studies. Cancer Causes Control 2013, 24, 1175–1183.
Han, O.; Failla, M.L.; Hill, A.D.; Morris, E.R.; Smith, J.C., Jr. Reduction of Fe(III) is required for uptake of nonheme iron by Caco-2 cells. J. Nutr. 1995, 125, 1291–1299.
[9]
Ma, Q.; Kim, E.Y.; Han, O. Bioactive dietary polyphenols decrease heme iron absorption by decreasing basolateral iron release in human intestinal Caco-2 cells. J. Nutr. 2010, 140, 1117–1121, doi:10.3945/jn.109.117499.
[10]
Roughead, Z.K.; Zito, C.A.; Hunt, J.R. Inhibitory effects of dietary calcium on the initial uptake and subsequent retention of heme and nonheme iron in humans: Comparisons using an intestinal lavage method. Am. J. Clin. Nutr. 2005, 82, 589–597.
[11]
Theil, E.C. Iron homeostasis and nutritional iron deficiency. J. Nutr. 2011, 141, 724S–728S, doi:10.3945/jn.110.127639.
[12]
Shayeghi, M.; Latunde-Dada, G.O.; Oakhill, J.S.; Laftah, A.H.; Takeuchi, K.; Halliday, N.; Khan, Y.; Warley, A.; McCann, F.E.; Hider, R.C.; et al. Identification of an intestinal heme transporter. Cell 2005, 122, 789–801, doi:10.1016/j.cell.2005.06.025.
[13]
Qiu, A.; Jansen, M.; Sakaris, A.; Min, S.H.; Chattopadhyay, S.; Tsai, E.; Sandoval, C.; Zhao, R.; Akabas, M.H.; Goldman, I.D. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 2006, 127, 917–928, doi:10.1016/j.cell.2006.09.041.
[14]
Raffia, S.B.; Woo, C.H.; Roost, K.T.; Price, D.C.; Schmid, R. Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase. J. Clin. Investig. 1974, 54, 1344–1352.
[15]
McKie, A.T.; Barrow, D.; Latunde-Dada, G.O.; Rolfs, A.; Sager, G.; Mudaly, E.; Mudaly, M.; Richardson, C.; Barlow, D.; Bomford, A.; et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 2001, 291, 1755–1759, doi:10.1126/science.1057206.
[16]
Gunshin, H.; Mackenzie, B.; Berger, U.V.; Gunshin, Y.; Romero, M.F.; Boron, W.F.; Nussberger, S.; Gollan, J.L.; Hediger, M.A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997, 388, 482–488.
[17]
Gunshin, H.; Fujiwara, Y.; Custodio, A.O.; Direnzo, C.; Robine, S.; Andrews, N.C. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Investig. 2005, 115, 1258–1266.
[18]
Theil, E.C. Ferritin: At the crossroads of iron and oxygen metabolism. J. Nutr. 2003, 133, 1549S–1553S.
[19]
Donovan, A.; Brownlie, A.; Zhou, Y.; Shepard, J.; Pratt, S.J.; Moynihan, J.; Paw, B.H.; Drejer, A.; Barut, B.; Zapata, A.; et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000, 403, 776–781, doi:10.1038/35001596.
[20]
McKie, A.T.; Marciani, P.; Rolfs, A.; Brennan, K.; Wehr, K.; Barrow, D.; Miret, S.; Bomford, A.; Peters, T.J.; Farzaneh, F.; et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell 2000, 5, 299–309, doi:10.1016/S1097-2765(00)80425-6.
[21]
Hahn, P.; Qian, Y.; Dentchev, T.; Chen, L.; Beard, J.; Harris, Z.L.; Dunaief, J.L. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc. Natl. Acad. Sci. USA 2004, 101, 13850–13855.
[22]
Cherukuri, S.; Potla, R.; Sarkar, J.; Nurko, S.; Harris, Z.L.; Fox, P.L. Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab. 2005, 2, 309–319, doi:10.1016/j.cmet.2005.10.003.
[23]
Vulpe, C.D.; Kuo, Y.M.; Murphy, T.L.; Cowley, L.; Askwith, C.; Libina, N.; Gitschier, J.; Anderson, G.J. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat. Genet. 1999, 21, 195–199.
[24]
Laurell, C.B. What is the function of transferrin in plasma? Blood 1951, 6, 183–187.
[25]
Hentze, M.W.; Muckenthaler, M.U.; Andrews, N.C. Balancing acts: Molecular control of mammalian iron metabolism. Cell 2004, 117, 285–297, doi:10.1016/S0092-8674(04)00343-5.
[26]
Gatter, K.C.; Brown, G.; Trowbridge, I.S.; Woolston, R.E.; Mason, D.Y. Transferrin receptors in human tissues: Their distribution and possible clinical relevance. J. Clin. Pathol. 1983, 36, 539–545, doi:10.1136/jcp.36.5.539.
[27]
Blachier, F.; Vaugelade, P.; Robert, V.; Kibangou, B.; Canonne-Hergaux, F.; Delpal, S.; Bureau, F.; Blottiere, H.; Bougle, D. Comparative capacities of the pig colon and duodenum for luminal iron absorption. Can. J. Physiol. Pharmacol. 2007, 85, 185–192, doi:10.1139/Y07-007.
[28]
Tako, E.; Glahn, R.P.; Welch, R.M.; Lei, X.; Yasuda, K.; Miller, D.D. Dietary inulin affects the expression of intestinal enterocyte iron transporters, receptors and storage protein and alters the microbiota in the pig intestine. Br. J. Nutr. 2008, 99, 472–480.
[29]
Mole, D.R. Iron homeostasis and its interaction with prolyl hydroxylases. Antioxid. Redox. Signal. 2010, 12, 445–458, doi:10.1089/ars.2009.2790.
[30]
Simpson, R.J.; McKie, A.T. Regulation of intestinal iron absorption: The mucosa takes control? Cell Metab. 2009, 10, 84–87, doi:10.1016/j.cmet.2009.06.009.
[31]
Ganz, T.; Nemeth, E. Hepcidin and iron homeostasis. Biochim. Biophys. Acta 2012, 1823, 1434–1443, doi:10.1016/j.bbamcr.2012.01.014.
[32]
Ganz, T.; Nemeth, E. Hepcidin and disorders of iron metabolism. Annu. Rev. Med. 2011, 62, 347–360.
[33]
Knutson, M.D. Iron-sensing proteins that regulate hepcidin and enteric iron absorption. Annu. Rev. Nutr. 2010, 30, 149–171, doi:10.1146/annurev.nutr.012809.104801.
[34]
Eisenstein, R.S. Iron regulatory proteins and the molecular control of mammalian iron metabolism. Annu. Rev. Nutr. 2000, 20, 627–662, doi:10.1146/annurev.nutr.20.1.627.
[35]
Pigeon, C.; Ilyin, G.; Courselaud, B.; Leroyer, P.; Turlin, B.; Brissot, P.; Loreal, O. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J. Biol. Chem. 2001, 276, 7811–7819.
[36]
Lesbordes-Brion, J.C.; Viatte, L.; Bennoun, M.; Lou, D.Q.; Ramey, G.; Houbron, C.; Hamard, G.; Kahn, A.; Vaulont, S. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood 2006, 108, 1402–1405, doi:10.1182/blood-2006-02-003376.
[37]
Nemeth, E.; Tuttle, M.S.; Powelson, J.; Vaughn, M.B.; Donovan, A.; Ward, D.M.; Ganz, T.; Kaplan, J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004, 306, 2090–2093, doi:10.1126/science.1104742.
[38]
Chua, A.C.; Klopcic, B.; Lawrance, I.C.; Olynyk, J.K.; Trinder, D. Iron: An emerging factor in colorectal carcinogenesis. World J. Gastroenterol. 2010, 16, 663–672, doi:10.3748/wjg.v16.i6.663.
[39]
Nelson, R.L. Iron and colorectal cancer risk: Human studies. Nutr. Rev. 2001, 59, 140–148, doi:10.1111/j.1753-4887.2001.tb07002.x.
[40]
Chan, A.T.; Ma, J.; Tranah, G.J.; Giovannucci, E.L.; Rifai, N.; Hunter, D.J.; Fuchs, C.S. Hemochromatosis gene mutations, body iron stores, dietary iron, and risk of colorectal adenoma in women. J. Natl. Cancer Inst. 2005, 97, 917–926, doi:10.1093/jnci/dji165.
[41]
Bridle, K.R.; Frazer, D.M.; Wilkins, S.J.; Dixon, J.L.; Purdie, D.M.; Crawford, D.H.; Subramaniam, V.N.; Powell, L.W.; Anderson, G.J.; Ramm, G.A. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003, 361, 669–673.
[42]
Schmidt, P.J.; Toudjarska, I.; Sendamarai, A.K.; Racie, T.; Milstein, S.; Bettencourt, B.R.; Hettinger, J.; Bumcrot, D.; Fleming, M.D. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia. Blood 2013, 121, 1200–1208, doi:10.1182/blood-2012-09-453977.
[43]
Osborne, N.J.; Gurrin, L.C.; Allen, K.J.; Constantine, C.C.; Delatycki, M.B.; McLaren, C.E.; Gertig, D.M.; Anderson, G.J.; Southey, M.C.; Olynyk, J.K.; et al. HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology 2010, 51, 1311–1318, doi:10.1002/hep.23448.
[44]
Shi, Z.; Johnstone, D.; Talseth-Palmer, B.A.; Evans, T.J.; Spigelman, A.D.; Groombridge, C.; Milward, E.A.; Olynyk, J.K.; Suchy, J.; Kurzawski, G.; et al. Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age. Int. J. Cancer 2009, 125, 78–83, doi:10.1002/ijc.24304.
[45]
Shaheen, N.J.; Silverman, L.M.; Keku, T.; Lawrence, L.B.; Rohlfs, E.M.; Martin, C.F.; Galanko, J.; Sandler, R.S. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J. Natl. Cancer Inst. 2003, 95, 154–159, doi:10.1093/jnci/95.2.154.
[46]
Aune, D.; Chan, D.S.; Vieira, A.R.; Navarro Rosenblatt, D.A.; Vieira, R.; Greenwood, D.C.; Kampman, E.; Norat, T. Red and processed meat intake and risk of colorectal adenomas: A systematic review and meta-analysis of epidemiological studies. Cancer Causes Control 2013, 24, 611–627, doi:10.1007/s10552-012-0139-z.
[47]
Norat, T.; Bingham, S.; Ferrari, P.; Slimani, N.; Jenab, M.; Mazuir, M.; Overvad, K.; Olsen, A.; Tjonneland, A.; Clavel, F.; et al. Meat, fish, and colorectal cancer risk: The European Prospective Investigation into cancer and nutrition. J. Natl. Cancer Inst. 2005, 97, 906–916, doi:10.1093/jnci/dji164.
[48]
Cross, A.J.; Ferrucci, L.M.; Risch, A.; Graubard, B.I.; Ward, M.H.; Park, Y.; Hollenbeck, A.R.; Schatzkin, A.; Sinha, R. A large prospective study of meat consumption and colorectal cancer risk: An investigation of potential mechanisms underlying this association. Cancer Res. 2010, 70, 2406–2414, doi:10.1158/0008-5472.CAN-09-3929.
[49]
Sesink, A.L.; Termont, D.S.; Kleibeuker, J.H.; van der Meer, R. Red meat and colon cancer: Dietary haem, but not fat, has cytotoxic and hyperproliferative effects on rat colonic epithelium. Carcinogenesis 2000, 21, 1909–1915, doi:10.1093/carcin/21.10.1909.
[50]
Sesink, A.L.; Termont, D.S.; Kleibeuker, J.H.; van der Meer, R. Red meat and colon cancer: The cytotoxic and hyperproliferative effects of dietary heme. Cancer Res. 1999, 59, 5704–5709.
[51]
Noortje, I.J.; Rijnierse, A.; de Wit, N.; Jonker-Termont, D.; Dekker, J.; Muller, M.; van der Meer, R. Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon. Gut 2012, 61, 1041–1049, doi:10.1136/gutjnl-2011-300239.
[52]
Bastide, N.M.; Pierre, F.H.; Corpet, D.E. Heme iron from meat and risk of colorectal cancer: A meta-analysis and a review of the mechanisms involved. Cancer Prev. Res. (Phila.) 2011, 4, 177–184.
[53]
Joosen, A.M.; Kuhnle, G.G.; Aspinall, S.M.; Barrow, T.M.; Lecommandeur, E.; Azqueta, A.; Collins, A.R.; Bingham, S.A. Effect of processed and red meat on endogenous nitrosation and DNA damage. Carcinogenesis 2009, 30, 1402–1407, doi:10.1093/carcin/bgp130.
[54]
Baradat, M.; Jouanin, I.; Dalleau, S.; Tache, S.; Gieules, M.; Debrauwer, L.; Canlet, C.; Huc, L.; Dupuy, J.; Pierre, F.H.; et al. 4-Hydroxy-2(E)-nonenal metabolism differs in Apc(+/+) cells and in Apc(Min/+) cells: It may explain colon cancer promotion by heme iron. Chem. Res. Toxicol. 2011, 24, 1984–1993, doi:10.1021/tx2003036.
[55]
Corpet, D.E. Red meat and colon cancer: Should we become vegetarians, or can we make meat safer? Meat Sci. 2011, 89, 310–316, doi:10.1016/j.meatsci.2011.04.009.
[56]
Pierre, F.; Santarelli, R.; Tache, S.; Gueraud, F.; Corpet, D.E. Beef meat promotion of dimethylhydrazine-induced colorectal carcinogenesis biomarkers is suppressed by dietary calcium. Br. J. Nutr. 2008, 99, 1000–1006.
[57]
Balder, H.F.; Vogel, J.; Jansen, M.C.; Weijenberg, M.P.; van den Brandt, P.A.; Westenbrink, S.; van der Meer, R.; Goldbohm, R.A. Heme and chlorophyll intake and risk of colorectal cancer in the Netherlands cohort study. Cancer Epidemiol. Biomarkers Prev. 2006, 15, 717–725, doi:10.1158/1055-9965.EPI-05-0772.
[58]
De Vogel, J.; Jonker-Termont, D.S.; van Lieshout, E.M.; Katan, M.B.; van der Meer, R. Green vegetables, red meat and colon cancer: Chlorophyll prevents the cytotoxic and hyperproliferative effects of haem in rat colon. Carcinogenesis 2005, 26, 387–393.
[59]
Lee, D.H.; Jacobs, D.R., Jr.; Folsom, A.R. A hypothesis: Interaction between supplemental iron intake and fermentation affecting the risk of colon cancer. The Iowa Women’s Health Study. Nutr. Cancer 2004, 48, 1–5.
[60]
Lund, E.K.; Wharf, S.G.; Fairweather-Tait, S.J.; Johnson, I.T. Oral ferrous sulfate supplements increase the free radical-generating capacity of feces from healthy volunteers. Am. J. Clin. Nutr. 1999, 69, 250–255.
[61]
Rosenberg, D.W.; Giardina, C.; Tanaka, T. Mouse models for the study of colon carcinogenesis. Carcinogenesis 2009, 30, 183–196, doi:10.1093/carcin/bgn267.
[62]
Siegers, C.P.; Bumann, D.; Baretton, G.; Younes, M. Dietary iron enhances the tumor rate in dimethylhydrazine-induced colon carcinogenesis in mice. Cancer Lett. 1988, 41, 251–256, doi:10.1016/0304-3835(88)90285-6.
[63]
Radulescu, S.; Brookes, M.J.; Salgueiro, P.; Ridgway, R.A.; McGhee, E.; Anderson, K.; Ford, S.J.; Stones, D.H.; Iqbal, T.H.; Tselepis, C.; et al. Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo. Cell Rep. 2012, 2, 270–282.
[64]
Xue, X.; Taylor, M.; Anderson, E.; Hao, C.; Qu, A.; Greenson, J.K.; Zimmermann, E.M.; Gonzalez, F.J.; Shah, Y.M. Hypoxia-inducible factor-2α activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res. 2012, 72, 2285–2293, doi:10.1158/0008-5472.CAN-11-3836.
[65]
Besarab, A.; Horl, W.H.; Silverberg, D. Iron metabolism, iron deficiency, thrombocytosis, and the cardiorenal anemia syndrome. Oncologist 2009, 14, 22–33, doi:10.1634/theoncologist.2009-S1-22.
[66]
Merk, K.; Mattsson, B.; Mattsson, A.; Holm, G.; Gullbring, B.; Bjorkholm, M. The incidence of cancer among blood donors. Int. J. Epidemiol. 1990, 19, 505–509, doi:10.1093/ije/19.3.505.
[67]
Zacharski, L.R.; Chow, B.K.; Howes, P.S.; Shamayeva, G.; Baron, J.A.; Dalman, R.L.; Malenka, D.J.; Ozaki, C.K.; Lavori, P.W. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: Results from a randomized trial. J. Natl. Cancer Inst. 2008, 100, 996–1002.
[68]
Brookes, M.J.; Hughes, S.; Turner, F.E.; Reynolds, G.; Sharma, N.; Ismail, T.; Berx, G.; McKie, A.T.; Hotchin, N.; Anderson, G.J.; et al. Modulation of iron transport proteins in human colorectal carcinogenesis. Gut 2006, 55, 1449–1460, doi:10.1136/gut.2006.094060.
[69]
Jiang, X.P.; Elliott, R.L.; Head, J.F. Manipulation of iron transporter genes results in the suppression of human and mouse mammary adenocarcinomas. Anticancer Res. 2010, 30, 759–765.
[70]
Pinnix, Z.K.; Miller, L.D.; Wang, W.; D’Agostino, R., Jr.; Kute, T.; Willingham, M.C.; Hatcher, H.; Tesfay, L.; Sui, G.; Di, X.; et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2010, 2, 43ra56, doi:10.1126/scisignal.3001127.
[71]
Takeuchi, K.; Bjarnason, I.; Laftah, A.H.; Latunde-Dada, G.O.; Simpson, R.J.; McKie, A.T. Expression of iron absorption genes in mouse large intestine. Scand. J. Gastroenterol. 2005, 40, 169–177, doi:10.1080/00365520510011489.
[72]
Zou, T.T.; Selaru, F.M.; Xu, Y.; Shustova, V.; Yin, J.; Mori, Y.; Shibata, D.; Sato, F.; Wang, S.; Olaru, A.; et al. Application of cDNA microarrays to generate a molecular taxonomy capable of distinguishing between colon cancer and normal colon. Oncogene 2002, 21, 4855–4862, doi:10.1038/sj.onc.1205613.
[73]
Skrzypczak, M.; Goryca, K.; Rubel, T.; Paziewska, A.; Mikula, M.; Jarosz, D.; Pachlewski, J.; Oledzki, J.; Ostrowski, J. Modeling oncogenic signaling in colon tumors by multidirectional analyses of microarray data directed for maximization of analytical reliability. PLoS One 2010, 5, e13091.
[74]
Sabates-Bellver, J.; van der Flier, L.G.; de Palo, M.; Cattaneo, E.; Maake, C.; Rehrauer, H.; Laczko, E.; Kurowski, M.A.; Bujnicki, J.M.; Menigatti, M.; et al. Transcriptome profile of human colorectal adenomas. Mol. Cancer Res. 2007, 5, 1263–1275, doi:10.1158/1541-7786.MCR-07-0267.
[75]
Knekt, P.; Reunanen, A.; Takkunen, H.; Aromaa, A.; Heliovaara, M.; Hakulinen, T. Body iron stores and risk of cancer. Int. J. Cancer 1994, 56, 379–382, doi:10.1002/ijc.2910560315.
[76]
Prutki, M.; Poljak-Blazi, M.; Jakopovic, M.; Tomas, D.; Stipancic, I.; Zarkovic, N. Altered iron metabolism, transferrin receptor 1 and ferritin in patients with colon cancer. Cancer Lett. 2006, 238, 188–196, doi:10.1016/j.canlet.2005.07.001.
[77]
Okazaki, F.; Matsunaga, N.; Okazaki, H.; Utoguchi, N.; Suzuki, R.; Maruyama, K.; Koyanagi, S.; Ohdo, S. Circadian rhythm of transferrin receptor 1 gene expression controlled by c-Myc in colon cancer-bearing mice. Cancer Res. 2010, 70, 6238–6246, doi:10.1158/0008-5472.CAN-10-0184.
[78]
Tacchini, L.; Bianchi, L.; Bernelli-Zazzera, A.; Cairo, G. Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J. Biol. Chem. 1999, 274, 24142–24146.
[79]
Lok, C.N.; Ponka, P. Identification of a hypoxia response element in the transferrin receptor gene. J. Biol. Chem. 1999, 274, 24147–24152, doi:10.1074/jbc.274.34.24147.
[80]
O’Donnell, K.A.; Yu, D.; Zeller, K.I.; Kim, J.W.; Racke, F.; Thomas-Tikhonenko, A.; Dang, C.V. Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol. Cell. Biol. 2006, 26, 2373–2386.
[81]
Habeshaw, J.A.; Lister, T.A.; Stansfeld, A.G.; Greaves, M.F. Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma. Lancet 1983, 1, 498–501.
[82]
Wrba, F.; Ritzinger, E.; Reiner, A.; Holzner, J.H. Transferrin receptor (TrfR) expression in breast carcinoma and its possible relationship to prognosis. An immunohistochemical study. Virchows Arch. A 1986, 410, 69–73.
[83]
Kawabata, H.; Yang, R.; Hirama, T.; Vuong, P.T.; Kawano, S.; Gombart, A.F.; Koeffler, H.P. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J. Biol. Chem. 1999, 274, 20826–20832.
[84]
Calzolari, A.; Oliviero, I.; Deaglio, S.; Mariani, G.; Biffoni, M.; Sposi, N.M.; Malavasi, F.; Peschle, C.; Testa, U. Transferrin receptor 2 is frequently expressed in human cancer cell lines. Blood Cells Mol. Dis. 2007, 39, 82–91, doi:10.1016/j.bcmd.2007.02.003.
[85]
Calzolari, A.; Deaglio, S.; Maldi, E.; Cassoni, P.; Malavasi, F.; Testa, U. TfR2 expression in human colon carcinomas. Blood Cells Mol. Dis. 2009, 43, 243–249, doi:10.1016/j.bcmd.2009.08.001.
[86]
Andrews, N.C. Ferrit(in)ing out new mechanisms in iron homeostasis. Cell Metab. 2010, 12, 203–204, doi:10.1016/j.cmet.2010.08.011.
[87]
Harrison, P.M.; Arosio, P. The ferritins: Molecular properties, iron storage function and cellular regulation. Biochim. Biophys. Acta 1996, 1275, 161–203.
[88]
Nelson, R.L.; Davis, F.G.; Sutter, E.; Sobin, L.H.; Kikendall, J.W.; Bowen, P. Body iron stores and risk of colonic neoplasia. J. Natl. Cancer Inst. 1994, 86, 455–460, doi:10.1093/jnci/86.6.455.
[89]
Bird, C.L.; Witte, J.S.; Swendseid, M.E.; Shikany, J.M.; Hunt, I.F.; Frankl, H.D.; Lee, E.R.; Longnecker, M.P.; Haile, R.W. Plasma ferritin, iron intake, and the risk of colorectal polyps. Am. J. Epidemiol. 1996, 144, 34–41, doi:10.1093/oxfordjournals.aje.a008852.
[90]
Tseng, M.; Greenberg, E.R.; Sandler, R.S.; Baron, J.A.; Haile, R.W.; Blumberg, B.S.; McGlynn, K.A. Serum ferritin concentration and recurrence of colorectal adenoma. Cancer Epidemiol. Biomarkers Prev. 2000, 9, 625–630.
[91]
Vaughn, C.B.; Weinstein, R.; Bond, B.; Rice, R.; Vaughn, R.W.; McKendrick, A.; Ayad, G.; Rockwell, M.A.; Rocchio, R. Ferritin content in human cancerous and noncancerous colonic tissue. Cancer Investig. 1987, 5, 7–10, doi:10.3109/07357908709020300.
[92]
Cermak, J.; Balla, J.; Jacob, H.S.; Balla, G.; Enright, H.; Nath, K.; Vercellotti, G.M. Tumor cell heme uptake induces ferritin synthesis resulting in altered oxidant sensitivity: Possible role in chemotherapy efficacy. Cancer Res. 1993, 53, 5308–5313.
[93]
Wu, K.J.; Polack, A.; Dalla-Favera, R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science 1999, 283, 676–679, doi:10.1126/science.283.5402.676.
[94]
Frazer, D.M.; Vulpe, C.D.; McKie, A.T.; Wilkins, S.J.; Trinder, D.; Cleghorn, G.J.; Anderson, G.J. Cloning and gastrointestinal expression of rat hephaestin: Relationship to other iron transport proteins. Am. J. Physiol. Gastrointest. Liver Physiol. 2001, 281, G931–G939.
[95]
Rhodes, D.R.; Chinnaiyan, A.M. Integrative analysis of the cancer transcriptome. Nat. Genet. 2005, 37, S31–S37, doi:10.1038/ng1570.
[96]
Gaedcke, J.; Grade, M.; Jung, K.; Camps, J.; Jo, P.; Emons, G.; Gehoff, A.; Sax, U.; Schirmer, M.; Becker, H.; et al. Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas. Genes Chromosomes Cancer 2010, 49, 1024–1034, doi:10.1002/gcc.20811.
[97]
Hong, Y.; Downey, T.; Eu, K.W.; Koh, P.K.; Cheah, P.Y. A “metastasis-prone” signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin. Exp. Metastasis 2010, 27, 83–90, doi:10.1007/s10585-010-9305-4.
[98]
Hinoi, T.; Gesina, G.; Akyol, A.; Kuick, R.; Hanash, S.; Giordano, T.J.; Gruber, S.B.; Fearon, E.R. CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium. Gastroenterology 2005, 128, 946–961, doi:10.1053/j.gastro.2005.01.003.
Pantopoulos, K.; Porwal, S.K.; Tartakoff, A.; Devireddy, L. Mechanisms of mammalian iron homeostasis. Biochemistry 2012, 51, 5705–5724, doi:10.1021/bi300752r.
[101]
Le, N.T.; Richardson, D.R. The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim. Biophys. Acta 2002, 1603, 31–46.
[102]
Jomova, K.; Valko, M. Importance of iron chelation in free radical-induced oxidative stress and human disease. Curr. Pharm. Des. 2011, 17, 3460–3473, doi:10.2174/138161211798072463.
[103]
Ribeiro, M.L.; Priolli, D.G.; Miranda, D.D.; Arcari, D.P.; Pedrazzoli, J., Jr.; Martinez, C.A. Analysis of oxidative DNA damage in patients with colorectal cancer. Clin. Colorectal Cancer 2008, 7, 267–272.
[104]
Knobel, Y.; Weise, A.; Glei, M.; Sendt, W.; Claussen, U.; Pool-Zobel, B.L. Ferric iron is genotoxic in non-transformed and preneoplastic human colon cells. Food Chem. Toxicol. 2007, 45, 804–811.
[105]
Glei, M.; Latunde-Dada, G.O.; Klinder, A.; Becker, T.W.; Hermann, U.; Voigt, K.; Pool-Zobel, B.L. Iron-overload induces oxidative DNA damage in the human colon carcinoma cell line HT29 clone 19A. Mutat. Res. 2002, 519, 151–161, doi:10.1016/S1383-5718(02)00135-3.
Rainis, T.; Maor, I.; Lanir, A.; Shnizer, S.; Lavy, A. Enhanced oxidative stress and leucocyte activation in neoplastic tissues of the colon. Dig. Dis. Sci. 2007, 52, 526–530.
[108]
Younes, M.; Trepkau, H.D.; Siegers, C.P. Enhancement by dietary iron of lipid peroxidation in mouse colon. Res. Commun. Chem. Pathol. Pharmacol. 1990, 70, 349–354.
[109]
Stone, W.L.; Papas, A.M.; LeClair, I.O.; Qui, M.; Ponder, T. The influence of dietary iron and tocopherols on oxidative stress and ras-p21 levels in the colon. Cancer Detect. Prev. 2002, 26, 78–84.
[110]
Lund, E.K.; Fairweather-Tait, S.J.; Wharf, S.G.; Johnson, I.T. Chronic exposure to high levels of dietary iron fortification increases lipid peroxidation in the mucosa of the rat large intestine. J. Nutr. 2001, 131, 2928–2931.
Seril, D.N.; Liao, J.; Ho, K.L.; Warsi, A.; Yang, C.S.; Yang, G.Y. Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig. Dis. Sci. 2002, 47, 1266–1278, doi:10.1023/A:1015362228659.
[113]
Seril, D.N.; Liao, J.; Ho, K.L.; Yang, C.S.; Yang, G.Y. Inhibition of chronic ulcerative colitis-associated colorectal adenocarcinoma development in a murine model by N-acetylcysteine. Carcinogenesis 2002, 23, 993–1001, doi:10.1093/carcin/23.6.993.
[114]
Kinzler, K.W.; Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 1996, 87, 159–170.
[115]
Dongiovanni, P.; Fracanzani, A.L.; Cairo, G.; Megazzini, C.P.; Gatti, S.; Rametta, R.; Fargion, S.; Valenti, L. Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. Am. J. Pathol. 2010, 176, 1006–1017, doi:10.2353/ajpath.2010.090249.
[116]
Fukuchi, K.; Tomoyasu, S.; Watanabe, H.; Kaetsu, S.; Tsuruoka, N.; Gomi, K. Iron deprivation results in an increase in p53 expression. Biol. Chem. Hoppe Seyler. 1995, 376, 627–630, doi:10.1515/bchm3.1995.376.10.627.
[117]
Liang, S.X.; Richardson, D.R. The effect of potent iron chelators on the regulation of p53: Examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1. Carcinogenesis 2003, 24, 1601–1614.
[118]
Reya, T.; Clevers, H. Wnt signalling in stem cells and cancer. Nature 2005, 434, 843–850.
[119]
Nishisho, I.; Nakamura, Y.; Miyoshi, Y.; Miki, Y.; Ando, H.; Horii, A.; Koyama, K.; Utsunomiya, J.; Baba, S.; Hedge, P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991, 253, 665–669.
[120]
Bodmer, W.F.; Bailey, C.J.; Bodmer, J.; Bussey, H.J.; Ellis, A.; Gorman, P.; Lucibello, F.C.; Murday, V.A.; Rider, S.H.; Scambler, P.; et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 1987, 328, 614–616, doi:10.1038/328614a0.
[121]
Leppert, M.; Dobbs, M.; Scambler, P.; O’Connell, P.; Nakamura, Y.; Stauffer, D.; Woodward, S.; Burt, R.; Hughes, J.; Gardner, E.; et al. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science 1987, 238, 1411–1413.
[122]
He, T.C.; Sparks, A.B.; Rago, C.; Hermeking, H.; Zawel, L.; da Costa, L.T.; Morin, P.J.; Vogelstein, B.; Kinzler, K.W. Identification of c-MYC as a target of the APC pathway. Science 1998, 281, 1509–1512.
[123]
Tetsu, O.; McCormick, F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999, 398, 422–426, doi:10.1038/18884.
[124]
Brookes, M.J.; Boult, J.; Roberts, K.; Cooper, B.T.; Hotchin, N.A.; Matthews, G.; Iqbal, T.; Tselepis, C. A role for iron in Wnt signalling. Oncogene 2008, 27, 966–975, doi:10.1038/sj.onc.1210711.
[125]
Song, S.; Christova, T.; Perusini, S.; Alizadeh, S.; Bao, R.Y.; Miller, B.W.; Hurren, R.; Jitkova, Y.; Gronda, M.; Isaac, M.; et al. Wnt inhibitor screen reveals iron dependence of beta-catenin signaling in cancers. Cancer Res. 2011, 71, 7628–7639.
[126]
Coombs, G.S.; Schmitt, A.A.; Canning, C.A.; Alok, A.; Low, I.C.; Banerjee, N.; Kaur, S.; Utomo, V.; Jones, C.M.; Pervaiz, S.; et al. Modulation of Wnt/beta-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer. Oncogene 2012, 31, 213–225, doi:10.1038/onc.2011.228.
[127]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674, doi:10.1016/j.cell.2011.02.013.
[128]
Prior, P.; Gyde, S.N.; Macartney, J.C.; Thompson, H.; Waterhouse, J.A.; Allan, R.N. Cancer morbidity in ulcerative colitis. Gut 1982, 23, 490–497, doi:10.1136/gut.23.6.490.
[129]
Wang, D.; DuBois, R.N. The role of anti-inflammatory drugs in colorectal cancer. Annu. Rev. Med. 2013, 64, 131–144, doi:10.1146/annurev-med-112211-154330.
[130]
Elliott, R.L. Cancer immunothearapy more than vaccines “psychoneuro-immunooncology: Cancer, the host, and the surgeon”. J. Cancer Ther. 2011, 2, 401–407.
[131]
Wang, L.; Harrington, L.; Trebicka, E.; Shi, H.N.; Kagan, J.C.; Hong, C.C.; Lin, H.Y.; Babitt, J.L.; Cherayil, B.J. Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. J. Clin. Investig. 2009, 119, 3322–3328.
[132]
Zhang, F.; Tao, Y.; Zhang, Z.; Guo, X.; An, P.; Shen, Y.; Wu, Q.; Yu, Y.; Wang, F. Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses. Haematologica 2012, 97, 1826–1835, doi:10.3324/haematol.2012.063974.
[133]
Zhang, Z.; Zhang, F.; An, P.; Guo, X.; Shen, Y.; Tao, Y.; Wu, Q.; Zhang, Y.; Yu, Y.; Ning, B.; et al. Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 2011, 118, 1912–1922.
[134]
Klimesova, K.; Kverka, M.; Zakostelska, Z.; Hudcovic, T.; Hrncir, T.; Stepankova, R.; Rossmann, P.; Ridl, J.; Kostovcik, M.; Mrazek, J.; et al. Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice. Inflamm. Bowel Dis. 2013, 19, 1266–1277, doi:10.1097/MIB.0b013e318281330a.
[135]
Arthur, J.C.; Jobin, C. The complex interplay between inflammation, the microbiota and colorectal cancer. Gut Microbes 2013, 4, 253–258, doi:10.4161/gmic.24220.
[136]
Zhu, Q.; Gao, R.; Wu, W.; Qin, H. The role of gut microbiota in the pathogenesis of colorectal cancer. Tumor Biol. 2013, 34, 1285–1300.
[137]
Engle, S.J.; Ormsby, I.; Pawlowski, S.; Boivin, G.P.; Croft, J.; Balish, E.; Doetschman, T. Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res. 2002, 62, 6362–6366.
Sobhani, I.; Tap, J.; Roudot-Thoraval, F.; Roperch, J.P.; Letulle, S.; Langella, P.; Corthier, G.; Tran van Nhieu, J.; Furet, J.P. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One 2011, 6, e16393.
[140]
Vipperla, K.; O’Keefe, S.J. The microbiota and its metabolites in colonic mucosal health and cancer risk. Nutr. Clin. Pract. 2012, 27, 624–635, doi:10.1177/0884533612452012.
[141]
Marchesi, J.R.; Dutilh, B.E.; Hall, N.; Peters, W.H.; Roelofs, R.; Boleij, A.; Tjalsma, H. Towards the human colorectal cancer microbiome. PLoS One 2011, 6, e20447.
[142]
Kau, A.L.; Ahern, P.P.; Griffin, N.W.; Goodman, A.L.; Gordon, J.I. Human nutrition, the gut microbiome and the immune system. Nature 2011, 474, 327–336.
[143]
Dostal, A.; Fehlbaum, S.; Chassard, C.; Zimmermann, M.B.; Lacroix, C. Low iron availability in continuous in vitro colonic fermentations induces strong dysbiosis of the child gut microbial consortium and a decrease in main metabolites. FEMS Microbiol. Ecol. 2013, 83, 161–175, doi:10.1111/j.1574-6941.2012.01461.x.
[144]
Dostal, A.; Chassard, C.; Hilty, F.M.; Zimmermann, M.B.; Jaeggi, T.; Rossi, S.; Lacroix, C. Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats. J. Nutr. 2012, 142, 271–277, doi:10.3945/jn.111.148643.
[145]
Noortje, I.J.; Derrien, M.; van Doorn, G.M.; Rijnierse, A.; van den Bogert, B.; Muller, M.; Dekker, J.; Kleerebezem, M.; van der Meer, R. Dietary heme alters microbiota and mucosa of mouse colon without functional changes in host-microbe cross-talk. PLoS One 2012, 7, e49868, doi:10.1371/journal.pone.0049868.
[146]
Tompkins, G.R.; O’Dell, N.L.; Bryson, I.T.; Pennington, C.B. The effects of dietary ferric iron and iron deprivation on the bacterial composition of the mouse intestine. Curr. Microbiol. 2001, 43, 38–42.
[147]
Buhnik-Rosenblau, K.; Moshe-Belizowski, S.; Danin-Poleg, Y.; Meyron-Holtz, E.G. Genetic modification of iron metabolism in mice affects the gut microbiota. Biometals 2012, 25, 883–892, doi:10.1007/s10534-012-9555-5.
[148]
Werner, T.; Wagner, S.J.; Martinez, I.; Walter, J.; Chang, J.S.; Clavel, T.; Kisling, S.; Schuemann, K.; Haller, D. Depletion of luminal iron alters the gut microbiota and prevents Crohn’s disease-like ileitis. Gut 2011, 60, 325–333, doi:10.1136/gut.2010.216929.
[149]
Zimmermann, M.B.; Chassard, C.; Rohner, F.; N’Goran, E.K.; Nindjin, C.; Dostal, A.; Utzinger, J.; Ghattas, H.; Lacroix, C.; Hurrell, R.F. The effects of iron fortification on the gut microbiota in African children: A randomized controlled trial in Cote d’Ivoire. Am. J. Clin. Nutr. 2010, 92, 1406–1415.
[150]
O’Keefe, S.J.; Chung, D.; Mahmoud, N.; Sepulveda, A.R.; Manafe, M.; Arch, J.; Adada, H.; van der Merwe, T. Why do African Americans get more colon cancer than Native Africans? J. Nutr. 2007, 137, 175S–182S.
