Iron and Esophageal Cancer
August 1, 1999
Iron and Esophageal Cancer
By Chung S. Yang, PhD, and Xiaoxin Chen
Iron, one of the essential chemical elements of life, exists in hemoglobin, myoglobin, and other heme and non-heme proteins that are involved in many important cellular functions. Iron can be very toxic in that it catalyzes the formation of reactive oxygen species (ROS) and, thus, leads to irreversible damage of various cellular structures. Whether iron is "nutritious" or "noxious" is determined by its concentration and the ligands it is bound to. It has been well established that iron can promote the growth of neoplastic cells and induce rapid neoplastic transformation of cell lines. Suppression of the ability of neoplastic cells to assimilate iron can inhibit their growth. The growth-stimulatory effect of iron may be largely due to iron’s effect on ribonucleotide reductase activity, an essential enzyme in DNA synthesis.1 Iron may induce cancers in animals, and promote carcinogenesis in various animal cancer models.1 In humans, increased body stores of iron are associated with an increased risk and poor prognosis of many human cancers.2 Patients with genetic hemochromatosis, an iron overload disorder, also have increased incidence of cancers.3
History
Esophageal cancer is comprised of two histological types: squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). EAC is the most rapidly increasing cancer in the United States. During the past three decades, the incidence rate of EAC and gastric cardia adenocarcinoma in the United States increased by 5-6 fold, with a yearly increase of approximately 4-10%.4 Several human epidemiological studies have identified some risk factors for human EAC, including obesity, insufficient dietary intake of fruits and fibers, increased use of relaxative agents of the lower esophageal sphincter, alcohol, smoking, etc. Most of these are related to gastroesophageal reflux disease (GERD), which is clinically manifested by regurgitation, heartburn, etc. It has been well established that most EACs originate from GERD.4 Iron overload was recently identified as a risk factor for human esophageal cancer. Patients with hemochromatosis had a high risk for esophageal cancer (standardized incidence ratio, 42.9), according to an epidemiological study in Denmark.3 One study indicated that occupational exposure to silica dust in a large iron-steel complex in northern China increased the risk of esophageal cancer by 2.8-fold; however, other epidemiological studies have found no association between iron overload and EAC.5
Esophagoduodenal Anastomosis
Recently, we studied the effect of iron supplementation on a rat surgical model of EAC, known as esophagoduodenal anastomosis (EDA), in our lab.6 The distal end of the esophagus was cut from the gastroesophageal junction, and anastomosed end-to-side to the duodenum. Mixed reflux of gastric and duodenal contents into the esophagus was induced to mimic human GERD. Iron was supplemented (50 mg/kg/mo, intraperitoneal [IP]) to prevent postoperative iron-deficiency anemia. To our surprise, esophageal adenocarcinogenesis was greatly enhanced, since EDA itself in the absence of iron supplementation only induced a low incidence of EAC.7,8 Apparently, IP iron injection after EDA is the most important causative factor for esophageal adenocarcinogenesis in the EDA model. (See Table.) EDA was complicated by various nutritional problems. One possible explanation was that anemic EDA rats might not have sufficient metabolic energy for the tumor to develop. Iron supplementation merely provided that metabolic energy. Therefore, we developed a new surgical model, known as esophaogastroduodenal anastomosis (EGDA), by anastomosing the gastroesophageal junction with the duodenum, side-to-side. Nutritional problems were not observed with EGDA, but again, iron supplementation promoted EAC formation.9 A linear, time-dependent iron deposition was observed in the esophagus after surgery and iron supplementation. Positive staining for EAC was not uniformly distributed in the esophagus; rather, it was associated with severe inflammation, especially at the squamocolumnar junction where all the EACs arose.9,10 Interestingly, although EDA rats had iron deposited in the esophagus after IP supplementation of 4 mg/kg/wk Fe, their iron nutritional status was still below normal. This suggested that, specifically, esophageal iron overload, instead of overall iron overload, was related to the increased incidence of EAC. In the esophagi of EDA or EGDA rats without iron supplementation, we also observed some positive iron staining. Iron administered IP simply loaded the esophagi of EGDA rats with more free iron, which expedited the development and increased the incidence of EAC.
Iron Dextran
Iron dextran, a complex of ferric hydroxide and low molecular mass dextran, was used in our studies. After IP injection, most of the iron was absorbed within 12-24 hours. On the other hand, the body’s ability to excrete parenterally administered iron is very limited, and the reticuloendothelial system sequesters excess iron. During inflammation, however, macrophages in the reticuloendothelial system incorporate the "free" iron into siderophore, and then carry the iron to the site of inflammation. Iron deposited in the reticuloendothelial system is hardly reused. This phenomenon accounts for the finding that the EGDA and EDA rats had excess iron deposition in the esophagi, regardless of their overall iron nutritional status. In addition to "free" iron in the premalignant columnar cells, we observed overexpression of transferrin receptor in cells at the squamocolumnar junction, which facilitated loading of these cells with excess iron.9 We observed overexpression of inducible nitric oxide synthase and nitrotyrosine in the rat esophagus after surgery, which was augmented with iron supplementation. Levels of oxidative damage to DNA (8-hydroxydeoxyguanosine), lipid (lipid peroxidation), and protein (carbonyl content) were significantly higher in the esophagi of EDA rats than those in the non-operated control rats. Moreover, the premalignant columnar cells were targeted by ROS, since they overexpressed heme oxygenase 1 and metallothionein, both known to be responsive to oxidative damage. Taken together, these pieces of evidence suggest that oxidative damage resulting from chronic GERD and esophageal iron overload is a major causative factor for EAC formation in the EDA or EGDA model.9,10 This may partially account for the drastic increase of EAC incidence observed during the past two decades.
Iron Overload
Esophageal iron overload depends on several factors. Excessive dietary iron intake tends to build up overall iron overload in the body. In the United States during the past two decades, there was a remarkable increase of dietary iron intake. The daily iron intake per capita from 1970 to 1990 climbed from 15.5 to 19.3 mg, an increase by 24.5%. In fact, adult males, post-menopausal females, and the elderly only require 10 mg/d.2 Heme iron, primarily from hemoglobin and myoglobin in red meat, is more readily taken up into the duodenal mucosa than non-heme iron. It can enhance the absorption of non-heme iron.3 Route of administration affects the bioavailability of iron. Absorption of dietary iron is subject to the regulation by the overall body iron store. Parenteral iron bypasses this control. This is why we observed esophageal iron overload in the EDA and EGDA rats that were given IP iron supplementation.4 Iron absorption can be enhanced by other dietary constituents. Alcohol drinking can facilitate the absorption of iron by stimulating the secretion of gastric acid. Ascorbic acid and citric acid, which are common food additives and are present in high quantities in orange juice, increase the absorption of nonheme iron by converting it into ferrous iron.
In this country, there has been a dramatic increase of orange juice consumption during the past few decades, while the intake of inhibitors of iron absorption (milk, eggs, and grains) has decreased. Bantu blacks of South Africa, who consume a traditional low-pH drink containing a high concentration of dissolved iron, have high body iron stores and a high incidence of cancer.5 Idiopathic hemochromatosis is an HLA-associated genetic defect associated with increased duodenal and intestinal iron absorption. About 5-10% of the U.S. population is heterozygous for idiopathic hemochromatosis and, thus, develops relatively high body iron stores if regularly given a diet high in absorbable iron.6 Even in the absence of overall iron overload, local iron overload may still result when iron is not properly distributed.
Once iron enters the circulation, it is usually delivered to the liver, the spleen, and bone marrow, which express large numbers of transferrin receptors. This may account for the finding that overall iron overload or hemochromatosis is related to a higher incidence of hepatic cancer. In the presence of local inflammation, reticuloendothelial cells may carry excess iron to the site of inflammation. In the esophagus, chronic inflammation resulting from GERD tends to cause esophageal iron overload. In fact, GERD is a commonly seen clinical entity, with more than 30% of the general population in western countries experiencing the symptoms at least once every month. Since patients who have undergone gastrectomy are at a higher risk of developing EAC, caution should be taken when iron supplementation is considered for iron-deficiency anemia after surgery.
Conclusion
Further research is warranted to clarify the mechanisms of esophageal iron overload in the formation of EAC. Considering the increasing tendency toward esophageal iron overload in this country, we make the following general suggestions: 1) patients with symptoms of GERD should see their primary physician or gastroenterologist; 2) decrease iron intake by quitting smoking, cutting back on red meat, and avoiding iron-enriched food, unless they are anemic; 3) avoid taking vitamin C in combination with iron-rich food; 4) avoid alcohol; 5) consume more plant fiber or grains; and 6) consider donating blood one or two times every year to reduce iron overload. (Dr. Yang is Professor and Associate Chair, and Mr. Chen is a Graduate Student, Department of Chemical Biology, Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ.)
Table 1-Rat Esophageal Cancer Induced by EDA or EGDA, with or without Iron Supplementation |
|||||
| Treatment | Diet | Weeks after surgery | Incidence of Cancer | Tumor Volume (cm3) | References |
| EDA | Lab chow | 22 | 14% (1/7) EAC | n.d.* | 7 |
| EDA | Lab chow | 26 | 0/13 | n.d. | 8 |
| EDA | AIN76 | 0/14 | n.d. | 8 | |
| EDA | AIN76+ high fat | 8% (1/12) ESCC | n.d. | 8 | |
| EDA | Lab chow | 30 | 0/4 | n.d. | 6 |
| EDA+ 50 mg/kg/wk Fe IP | Lab chow | 73% (8/11) EAC | n.d. | 6 | |
| EDA+ 50 mg/kg/wk Fe IP | Lab chow | 35 | 60% (20/33) EAC | n.d. | Unpublished |
| EDA | AIN93M | 40 | 35% (9/26) EAC | 0.29 ± 0.23 | Unpublished |
| EDA+12 mg/kg/wk Fe IP | AIN93M | 68% (19/28) EAC | 0.55 ± 0.26 | Unpublished | |
| EGDA | AIN93M | 40 | 26% (11/43) EAC | 0.37 ± 0.10 | 9 |
| * n.d. = not determined,/td> | |||||
References
1. Weinberg ED. Biol Trace Element Res 1992;34:123-140.
2. Knekt P, Reunanen H, et al. Int J Cancer 1994;56:379-382.
3. Hsing AW, McLaughlin JK, et al. Int J Cancer 1995;60: 160-162.
4. Altorki NK, Oliveria S, et al. Sem Surg Oncol 1997;13:270-280.
5. Zhang ZF, Kurtz RC, et al. Nutri Cancer 1997;27:298-309.
6. Goldstein SR, Yang GY, et al. Carcinogenesis 1997;11:2265-2270.
7. Attwood SE, Smyrk TC, et al. Surgery 1992;111:503-510.
8. Clark GWB, Smyrk TC, et al. Ann Surg Oncol 1994;1:252-261.
9. Chen X, Yang GY, et al. Carcinogenesis 1999 (in press).
10. Goldstein SR, Yang GY, et al. Carcinogenesis 1998;19:1445-1449.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content