Mechanisms of Disease: Carcinogenesis in Barrett's Esophagus
Mechanisms of Disease: Carcinogenesis in Barrett's Esophagus
The pathogenesis of cancer in Barrett's esophagus is multifactorial. Gastroesophageal reflux seems to be important in the initiation of Barrett's esophagus, but its role in promoting carcinogenesis has yet to be established. Diet, lifestyle and carcinogens, especially the nitrates, may be important in the development of carcinogenesis, and require further investigation. Inhibition of reflux-stimulated inflammatory changes, for example by inhibiting cyclooxygenase, holds promise for decreasing cancer progression. Similarly, dietary and lifestyle modification used in the management of reflux may also help to prevent the development of esophageal cancer. The molecular changes that are associated with the development of cancer in Barrett's esophagus offer several potential areas of intervention to prevent and manage esophageal cancer. Limiting cell growth, increasing apoptosis of damaged cells, limiting cell invasion and angiogenesis factors could be useful to accomplish this goal. Having a greater understanding of the pathogenesis of this condition can only help to develop more management options in the future.
In Barrett's esophagus, normal esophageal squamous epithelium is replaced by a specialized columnar epithelium.The condition is widespread and incurs patients with a 125-fold greater risk of developing adenocarcinoma. Most patients with Barrett's esophagus, however, never develop carcinoma -- cancer incidence is only 1 out of every 227 patient-years of follow-up. For this reason, and for optimal management of the condition, it is important to define the mechanisms of carcinogenesis in Barrett's esophagus.
In the past decade, we have gained significant insight into the pathophysiology and molecular pathways associated with carcinogenesis. Epidemiological studies suggest that there is a strong association between chronic gastroesophageal reflux disease (GERD) and esophageal adenocarcinoma. Indeed, reflux of gastroduodenal contents can promote chronic mucosal injury resulting in inflammation, which is known to promote carcinogenesis. In addition, the geographic distribution of esophageal adenocarcinoma indicates that dietary habits, obesity, upper gastrointestinal infections and exposure to carcinogens might interact and be responsible for the development of carcinogenesis in Barrett's esophagus. Current concepts of the possible roles of host and environmental factors in the development of cancer in Barrett's esophagus are outlined in Figure 1 and discussed below.
(Enlarge Image)
Putative risk factors promoting carcinogenesis in Barrett's esophagus. Various risk factors associated with carcinogenesis in Barrett's esophagus are outlined in this figure. The strongest risk factor that promotes carcinogenesis in the esophagus is the reflux of gastroduodenal contents into the esophagus, which causes chronic esophageal injury. Epidemiological studies also point to an increased risk of esophageal cancer in patients who are obese. Obesity-associated increased circulating growth factors may have a role in cancer progression in Barrett's esophagus. Carcinogen exposure related to tobacco smoking and production of carcinogenic nitroso compounds as well as nitric oxide by oral and gastric flora may also have an important role in cancer development in the esophagus. A positive association of hypergastrenemia, which has a pro-survival effect on Barrett's mucosa, and a negative association of Helicobacter pylori infection that can potentially decrease esophageal reflux is also proposed in esophageal carcinogenesis.
The pathogenesis of cancer in Barrett's esophagus is multifactorial. Gastroesophageal reflux seems to be important in the initiation of Barrett's esophagus, but its role in promoting carcinogenesis has yet to be established. Diet, lifestyle and carcinogens, especially the nitrates, may be important in the development of carcinogenesis, and require further investigation. Inhibition of reflux-stimulated inflammatory changes, for example by inhibiting cyclooxygenase, holds promise for decreasing cancer progression. Similarly, dietary and lifestyle modification used in the management of reflux may also help to prevent the development of esophageal cancer. The molecular changes that are associated with the development of cancer in Barrett's esophagus offer several potential areas of intervention to prevent and manage esophageal cancer. Limiting cell growth, increasing apoptosis of damaged cells, limiting cell invasion and angiogenesis factors could be useful to accomplish this goal. Having a greater understanding of the pathogenesis of this condition can only help to develop more management options in the future.
In Barrett's esophagus, normal esophageal squamous epithelium is replaced by a specialized columnar epithelium.The condition is widespread and incurs patients with a 125-fold greater risk of developing adenocarcinoma. Most patients with Barrett's esophagus, however, never develop carcinoma -- cancer incidence is only 1 out of every 227 patient-years of follow-up. For this reason, and for optimal management of the condition, it is important to define the mechanisms of carcinogenesis in Barrett's esophagus.
In the past decade, we have gained significant insight into the pathophysiology and molecular pathways associated with carcinogenesis. Epidemiological studies suggest that there is a strong association between chronic gastroesophageal reflux disease (GERD) and esophageal adenocarcinoma. Indeed, reflux of gastroduodenal contents can promote chronic mucosal injury resulting in inflammation, which is known to promote carcinogenesis. In addition, the geographic distribution of esophageal adenocarcinoma indicates that dietary habits, obesity, upper gastrointestinal infections and exposure to carcinogens might interact and be responsible for the development of carcinogenesis in Barrett's esophagus. Current concepts of the possible roles of host and environmental factors in the development of cancer in Barrett's esophagus are outlined in Figure 1 and discussed below.
(Enlarge Image)
Putative risk factors promoting carcinogenesis in Barrett's esophagus. Various risk factors associated with carcinogenesis in Barrett's esophagus are outlined in this figure. The strongest risk factor that promotes carcinogenesis in the esophagus is the reflux of gastroduodenal contents into the esophagus, which causes chronic esophageal injury. Epidemiological studies also point to an increased risk of esophageal cancer in patients who are obese. Obesity-associated increased circulating growth factors may have a role in cancer progression in Barrett's esophagus. Carcinogen exposure related to tobacco smoking and production of carcinogenic nitroso compounds as well as nitric oxide by oral and gastric flora may also have an important role in cancer development in the esophagus. A positive association of hypergastrenemia, which has a pro-survival effect on Barrett's mucosa, and a negative association of Helicobacter pylori infection that can potentially decrease esophageal reflux is also proposed in esophageal carcinogenesis.
