Expression of Cyclo-oxygenase-2 in Gastrointestinal Carcinoid Tumors
Expression of Cyclo-oxygenase-2 in Gastrointestinal Carcinoid Tumors
Background: Cyclo-oxygenase (COX)-2 overexpression is observed in various neoplasms and COX-2 inhibition has been attempted as prevention and/or therapy in these neoplasms. Carcinoid tumors are thought to arise from neuroendocrine cells and originate mainly in the gastrointestinal tract. Cyclo-oxygenase-2 is reportedly expressed in neuroendocrine cells of normal colorectal mucosa. The role of COX in carcinoids has not previously been investigated. The aim of the present paper was to clarify the expression of COX-1 and -2, and their role in human gastrointestinal carcinoids.
Methods: Expression of COX-1 and -2 was studied immunohistochemically in 38 gastrointestinal carcinoids. Five bronchopulmonary and seven metastatic carcinoids were also examined, for comparison with gastrointestinal carcinoids. The immunohistochemical score (IHS) was calculated from staining intensity and immunoreactive cell population, and ranked according to four grades (negative to strong).
Results: Cyclo-oxygenase-2 was expressed in all gastrointestinal carcinoids (weak, 1; moderate, 13; strong, 24) and bronchopulmonary carcinoids (weak, 1; moderate, 4), as well as their metastases (moderate, 3; strong, 4). The IHS of COX-2 in larger tumors was significantly lower than that in smaller tumors. However, the IHS of COX-2 at the advancing tumor edge was significantly higher than that at the centers of tumors ≥10 mm in size. Faint COX-1 expression was detected in only one duodenal, one rectal and four bronchopulmonary carcinoids.
Conclusions: Enhanced COX-2 expression was observed in gastrointestinal as well as bronchopulmonary carcinoids and their metastases, especially at the advancing edges of the tumors. Cyclo-oxygenase-2 may play a role in carcinoid progression.
Carcinoid tumors are uncommon and originate mainly in the gastrointestinal (GI) tract. These tumors are considered to be of endodermal origin and to arise in the deep portion of the GI mucosa, from cells known as disperse endocrine cells, basal granular cells, enterochromaffin-like cells or neuroendocrine cells. These cells have neuroendocrine granules, and have characteristic silver staining and reactivity with immuno-markers such as chromogranin A and neuron-specific enolase (NSE). Although carcinoid tumors are generally indolent and slow-growing compared to carcinomas, metastases can occur and the prognosis is poor in some cases. Tumor removal, if possible, remains the best treatment for primary carcinoid tumors and their metastases. Synthetic analogs of somatostatin, ischemic liver therapy, chemotherapy and interferon-α are used to relieve the symptoms of patients suffering from carcinoid syndrome and/or to reduce tumor aggressiveness. These approaches are not always sufficient to treat carcinoid tumors, however, especially those with local progression and extended metastases. It is important to clarify the molecular mechanisms of tumorigenesis and progression in carcinoid tumors in order to develop effective therapeutic strategies.
Cyclo-oxygenase (COX) is the key enzyme in the formation of prostaglandins (PG) and other eicosanoids from arachidonic acid, and there are at least two major isoforms, COX-1 and -2. Cyclo-oxygenase-1 is constitutively expressed in most tissues and appears to be responsible for the production of eicosanids that control normal physiological functions, such as regulation of renal blood flow and maintenance of the gastric mucosa. By contrast, COX-2 is induced by various stimuli and is important in a variety of pathophysiological conditions, such as inflammation and tumorigenesis. Cyclo-oxygenase-2 overexpression is observed in various malignancies, including lung, breast, uterine, prostate, gastric and colorectal cancer· Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the biological activity of COX, and COX-2 selective inhibitors reportedly inhibit tumor growth in various premalignant and malignant lesions, such as colorectal adenoma and carcinoma.
Cyclo-oxygenase-2 is reportedly expressed in neuroendocrine cells of human colonic mucosa. However, the pathophysiological role of COX-2 in neuroendocrine cells remains unknown. Cellular metabolism was reported to be inhibited by NSAIDs in a cell line derived from a human bronchial carcinoid tumor, suggesting the presence of COX activity. High PG levels were demonstrated in two bronchial carcinoid tumor cases. Enhancement of COX-2 expression is reportedly observed in malignant and borderline pancreatic endocrine tumors. Recently, COX expression was found in cell lines derived from human neuroendocrine tumors. However, to our knowledge, there are no previous reports on COX expression status in carcinoid tumors. We have already reported the first evidence that rectal carcinoid tumors have COX-2 but not COX-1 immunoreactivity. Herein we demonstrate, using immunohistochemistry, COX-1 and -2 expression in GI carcinoid tumors. We also examined metastatic and bronchopulmonary carcinoid tumors to determine whether their COX expression differ in origin and/or behavior among tumors.
Abstract and Introduction
Abstract
Background: Cyclo-oxygenase (COX)-2 overexpression is observed in various neoplasms and COX-2 inhibition has been attempted as prevention and/or therapy in these neoplasms. Carcinoid tumors are thought to arise from neuroendocrine cells and originate mainly in the gastrointestinal tract. Cyclo-oxygenase-2 is reportedly expressed in neuroendocrine cells of normal colorectal mucosa. The role of COX in carcinoids has not previously been investigated. The aim of the present paper was to clarify the expression of COX-1 and -2, and their role in human gastrointestinal carcinoids.
Methods: Expression of COX-1 and -2 was studied immunohistochemically in 38 gastrointestinal carcinoids. Five bronchopulmonary and seven metastatic carcinoids were also examined, for comparison with gastrointestinal carcinoids. The immunohistochemical score (IHS) was calculated from staining intensity and immunoreactive cell population, and ranked according to four grades (negative to strong).
Results: Cyclo-oxygenase-2 was expressed in all gastrointestinal carcinoids (weak, 1; moderate, 13; strong, 24) and bronchopulmonary carcinoids (weak, 1; moderate, 4), as well as their metastases (moderate, 3; strong, 4). The IHS of COX-2 in larger tumors was significantly lower than that in smaller tumors. However, the IHS of COX-2 at the advancing tumor edge was significantly higher than that at the centers of tumors ≥10 mm in size. Faint COX-1 expression was detected in only one duodenal, one rectal and four bronchopulmonary carcinoids.
Conclusions: Enhanced COX-2 expression was observed in gastrointestinal as well as bronchopulmonary carcinoids and their metastases, especially at the advancing edges of the tumors. Cyclo-oxygenase-2 may play a role in carcinoid progression.
Introduction
Carcinoid tumors are uncommon and originate mainly in the gastrointestinal (GI) tract. These tumors are considered to be of endodermal origin and to arise in the deep portion of the GI mucosa, from cells known as disperse endocrine cells, basal granular cells, enterochromaffin-like cells or neuroendocrine cells. These cells have neuroendocrine granules, and have characteristic silver staining and reactivity with immuno-markers such as chromogranin A and neuron-specific enolase (NSE). Although carcinoid tumors are generally indolent and slow-growing compared to carcinomas, metastases can occur and the prognosis is poor in some cases. Tumor removal, if possible, remains the best treatment for primary carcinoid tumors and their metastases. Synthetic analogs of somatostatin, ischemic liver therapy, chemotherapy and interferon-α are used to relieve the symptoms of patients suffering from carcinoid syndrome and/or to reduce tumor aggressiveness. These approaches are not always sufficient to treat carcinoid tumors, however, especially those with local progression and extended metastases. It is important to clarify the molecular mechanisms of tumorigenesis and progression in carcinoid tumors in order to develop effective therapeutic strategies.
Cyclo-oxygenase (COX) is the key enzyme in the formation of prostaglandins (PG) and other eicosanoids from arachidonic acid, and there are at least two major isoforms, COX-1 and -2. Cyclo-oxygenase-1 is constitutively expressed in most tissues and appears to be responsible for the production of eicosanids that control normal physiological functions, such as regulation of renal blood flow and maintenance of the gastric mucosa. By contrast, COX-2 is induced by various stimuli and is important in a variety of pathophysiological conditions, such as inflammation and tumorigenesis. Cyclo-oxygenase-2 overexpression is observed in various malignancies, including lung, breast, uterine, prostate, gastric and colorectal cancer· Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the biological activity of COX, and COX-2 selective inhibitors reportedly inhibit tumor growth in various premalignant and malignant lesions, such as colorectal adenoma and carcinoma.
Cyclo-oxygenase-2 is reportedly expressed in neuroendocrine cells of human colonic mucosa. However, the pathophysiological role of COX-2 in neuroendocrine cells remains unknown. Cellular metabolism was reported to be inhibited by NSAIDs in a cell line derived from a human bronchial carcinoid tumor, suggesting the presence of COX activity. High PG levels were demonstrated in two bronchial carcinoid tumor cases. Enhancement of COX-2 expression is reportedly observed in malignant and borderline pancreatic endocrine tumors. Recently, COX expression was found in cell lines derived from human neuroendocrine tumors. However, to our knowledge, there are no previous reports on COX expression status in carcinoid tumors. We have already reported the first evidence that rectal carcinoid tumors have COX-2 but not COX-1 immunoreactivity. Herein we demonstrate, using immunohistochemistry, COX-1 and -2 expression in GI carcinoid tumors. We also examined metastatic and bronchopulmonary carcinoid tumors to determine whether their COX expression differ in origin and/or behavior among tumors.
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