Humoral Immune Response to MUC5AC - Patients With CRC and Polyps
Humoral Immune Response to MUC5AC - Patients With CRC and Polyps
Background: MUC5AC is a secreted mucin aberrantly expressed by colorectal polyps and carcinoma. It has been hypothesized that aberrant expression of MUC5AC in colorectal carcinoma tissues increased the overall survival of patients with colorectal carcinoma. The present study investigates the incidence of naturally occurring MUC5AC antibodies in the sera of normal individuals, patients with colonic polyps and patients with advanced colorectal carcinoma. A second aim was to determine the relationship of MUC5AC antibody with the prognosis of colorectal carcinoma.
Methods: Free circulating MUC5AC antibodies were measured using an enzyme-linked immunosorbent assay with a synthetic peptide corresponding to an 8 aa. segment of MUC5AC tandem repeat region. Immunohistochemical analysis was completed to demonstrate MUC5AC expression in the polyp specimens.
Results: MUC5AC antibodies were detected in 6 of 22 (27.3%) healthy subjects, 9 of 20 (45%) polyp patients, 18 of 30 (60%) patients with colorectal cancer. The presence of circulating free MUC5AC antibody levels was significantly correlated with expression of MUC5AC in polyp sections. Serum MUC5AC antibody positivity was higher in patients with colon located tumors, advanced stage and poorly differentiated tumors were found negatively affecting patient survival in our study. MUC5AC antibody positivity was higher in patients with poor prognostic parameters. Disease free survival and overall survival were shorter in this group of patients. In the multivariate analysis MUC5AC antibody positivity didn't find an independent prognostic factor on prognosis.
Conclusion: Decreased survival in colorectal carcinoma patients with MUC5AC antibody positivity may be due to a decrease in the MUC5AC expression in tumor tissues of surviving carcinoma patients.
Mucins are high molecular weight glycoproteins with O-linked oligosaccharides attached to serine or threonine residues of the apomucin protein backbone. To date, 19 genes coding for apomucin have been identified. Mucins are expressed with a cell and tissue-specific pattern in normal tissues. There are two structurally and functionally distinct classes of mucins; secreted gel-forming mucins and transmembrane mucins. Secreted gel-forming mucins include the products of the MUC2, MUC5AC, MUC5B and MUC6 genes on chromosome 11p15.5. Each has a central region with a variable number of tandem repeat (VNRT), but there is a little similarity. MUC5AC was cloned from tracheobronchial and stomach cDNA libraries. Tandem repeat units have eight amino acid residues.
MUC5AC expression is found on apical epithelial cells of the mucus glands of gastric antrum and body, tracheobronchial epithelium, superficial epithelium of the gallbladder and endocervix epithelium. MUC5AC is found in fetal and precancerous colonic mucosa but < 20% of normal colon tissue. De novo expression was shown in > 55% of colonic polyps. MUC5AC is highly expressed in adenoma. Levels decrease with increasing degree of dysplasia in polyps Less than 30% of colorectal carcinomas expressed MUC5AC. However, in another study, there was de novo expression of MUC5AC in 23/36 colorectal carcinomas. In our previous study, we reported 34.1% of colorectal carcinomas expressed MUC5AC. We emphasized that MUC5AC expression decreases with increased malignancy pathology and MUC5AC negative tumors had a more malignant potential, as shown by a more aggressive behavior. These patients had a significantly shorter survival in our study. We suggested that the absence of MUC5AC expression in colorectal carcinomas might be a negative prognostic factor.
Humoral and cellular immune responses to other mucin core proteins have been described in cancer patients. Tumor reactive cytotoxic T-lymphocytes specific for MUC-1 core peptides have been described in breast, pancreatic and ovarian cancer patients. Circulating immune complexes and free anti-mucin antibody against the MUC 1 tandem repeat also have been identified in patients with benign and malignant tumors.
The specific aims of the present study are to investigate the incidence of humoral immune response against MUC5AC core protein in healthy individuals, patients with colorectal polyps and colorectal carcinoma, and the possible clinical importance of this antigen for the diagnosis and prognosis of colorectal carcinoma.
Background: MUC5AC is a secreted mucin aberrantly expressed by colorectal polyps and carcinoma. It has been hypothesized that aberrant expression of MUC5AC in colorectal carcinoma tissues increased the overall survival of patients with colorectal carcinoma. The present study investigates the incidence of naturally occurring MUC5AC antibodies in the sera of normal individuals, patients with colonic polyps and patients with advanced colorectal carcinoma. A second aim was to determine the relationship of MUC5AC antibody with the prognosis of colorectal carcinoma.
Methods: Free circulating MUC5AC antibodies were measured using an enzyme-linked immunosorbent assay with a synthetic peptide corresponding to an 8 aa. segment of MUC5AC tandem repeat region. Immunohistochemical analysis was completed to demonstrate MUC5AC expression in the polyp specimens.
Results: MUC5AC antibodies were detected in 6 of 22 (27.3%) healthy subjects, 9 of 20 (45%) polyp patients, 18 of 30 (60%) patients with colorectal cancer. The presence of circulating free MUC5AC antibody levels was significantly correlated with expression of MUC5AC in polyp sections. Serum MUC5AC antibody positivity was higher in patients with colon located tumors, advanced stage and poorly differentiated tumors were found negatively affecting patient survival in our study. MUC5AC antibody positivity was higher in patients with poor prognostic parameters. Disease free survival and overall survival were shorter in this group of patients. In the multivariate analysis MUC5AC antibody positivity didn't find an independent prognostic factor on prognosis.
Conclusion: Decreased survival in colorectal carcinoma patients with MUC5AC antibody positivity may be due to a decrease in the MUC5AC expression in tumor tissues of surviving carcinoma patients.
Mucins are high molecular weight glycoproteins with O-linked oligosaccharides attached to serine or threonine residues of the apomucin protein backbone. To date, 19 genes coding for apomucin have been identified. Mucins are expressed with a cell and tissue-specific pattern in normal tissues. There are two structurally and functionally distinct classes of mucins; secreted gel-forming mucins and transmembrane mucins. Secreted gel-forming mucins include the products of the MUC2, MUC5AC, MUC5B and MUC6 genes on chromosome 11p15.5. Each has a central region with a variable number of tandem repeat (VNRT), but there is a little similarity. MUC5AC was cloned from tracheobronchial and stomach cDNA libraries. Tandem repeat units have eight amino acid residues.
MUC5AC expression is found on apical epithelial cells of the mucus glands of gastric antrum and body, tracheobronchial epithelium, superficial epithelium of the gallbladder and endocervix epithelium. MUC5AC is found in fetal and precancerous colonic mucosa but < 20% of normal colon tissue. De novo expression was shown in > 55% of colonic polyps. MUC5AC is highly expressed in adenoma. Levels decrease with increasing degree of dysplasia in polyps Less than 30% of colorectal carcinomas expressed MUC5AC. However, in another study, there was de novo expression of MUC5AC in 23/36 colorectal carcinomas. In our previous study, we reported 34.1% of colorectal carcinomas expressed MUC5AC. We emphasized that MUC5AC expression decreases with increased malignancy pathology and MUC5AC negative tumors had a more malignant potential, as shown by a more aggressive behavior. These patients had a significantly shorter survival in our study. We suggested that the absence of MUC5AC expression in colorectal carcinomas might be a negative prognostic factor.
Humoral and cellular immune responses to other mucin core proteins have been described in cancer patients. Tumor reactive cytotoxic T-lymphocytes specific for MUC-1 core peptides have been described in breast, pancreatic and ovarian cancer patients. Circulating immune complexes and free anti-mucin antibody against the MUC 1 tandem repeat also have been identified in patients with benign and malignant tumors.
The specific aims of the present study are to investigate the incidence of humoral immune response against MUC5AC core protein in healthy individuals, patients with colorectal polyps and colorectal carcinoma, and the possible clinical importance of this antigen for the diagnosis and prognosis of colorectal carcinoma.