Mucins — large extracellular proteins that are heavily glycosylated with complex oligosaccharides — establish a selective molecular barrier at the epithelial surface and engage in morphogenetic signal transduction. Alterations in mucin expression or glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion and immune surveillance. Mucins are used as diagnostic markers in cancer, and are under investigation as therapeutic targets for cancer.

Mucins in cancer: Protection and control of the cell surface

Publisher Summary Aberrant glycosylation is the most common phenomenon associated with oncogenic transformation expressed in cell membranes of animal and human cancer cells. Such aberrant structures at the surface membranes may well be effective targets in prevention, diagnosis, and treatment of human cancer. Many of the aberrant glycosylation products can be recognized by specific MAbs as tumor-associated carbohydrate antigens. Many of these antigens have been identified as carbohydrates, thus there is increasing evidence that essentially all human cancers are characterized by aberrant glycosylation. Aberrant glycosylation as such may be the basis of inappropriate cell/cell and cell/matrix interactions that may be reflected in the abnormal cell social behavior of tumor cells, such as uncontrolled cell growth, invasiveness, and metastatic potential. Whatever the genetic or epigenetic basis of expression of aberrant glycosylation is, the phenomenon is of crucial importance in understanding the antisocial behavior of tumor cells as well as in practical applications in diagnosis and treatment of human cancer.

Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens

Only women with symptoms need to have their breast implants removed, says government

A monoclonal antibody-defined antigen associated with gastrointestinal cancer is a ganglioside containing sialylated lacto-N-fucopentaose II.

A current trend in cell biology is to study the mechanisms of regulatory cellular function through specific structural and func tional molecules, i.e., growth factors, their receptors, membrane transporters, cytoskeletal systems, surface membrane and pericellular components, etc., rather than classical enzymes. The key molecules involved in such functional regulation are modified by 2 major chemical processes, phosphorylation and glycosylation. A greal deal of interest has been focused on phosphorylation as a ubiquitous and essential modulatory mechanism of cellular function. This idea has been greatly reinforced by the fact that many transforming genes (cellular as well as viral oncogenes) encode phosphoproteins, which by themselves are protein kinases, although the functions of many of their substrates have not been identified (see, for a review, Ref. 9). Less attention has been paid to the functional significance of glycosylation than to that of phosphorylation; nevertheless, the changes in glycosylation occur as quickly and dramatically as the process of phosphorylation at various stages of develop ment, differentiation, and oncogenesis (see, for a review, Ref. 38). While phosphorylation patterns are few, the patterns of glycosylation are numerous; over 100 types of glycosylated structures have been characterized among those bound to lipids (ceramides), i.e., glycolipids (see, for a review, Ref. 39). Similar variation of glycosylation can also be found in the peripheral region of carbohydrates in glycoproteins, in addition to the structural variation in the core region of carbohydrate chains bound to proteins through Nor O-glycosides (see, for reviews, Refs. 42 and 65). In contrast to phosphorylation, which directly modulates pro tein function, glycosylation affects the conformation, localization, and organization of functional and structural proteins; thus, glycosylation determines the turnover and organizational frame work of proteins within cytoplasm, membranes, and the pericellular matrix (see, for reviews, Refs. 42 and 87). LJpidglycosylation in membranes, particularly cell surface membranes, offers cell recognition sites for cell-social events and may regulate the function of membrane proteins such as receptors and adhesive proteins (38, 115) (Table 1). With the functional significance of

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Aberrant glycosylation in cancer cell membranes as focused on glycolipids: overview and perspectives.

The binding of monoclonal antibody specific for colon carcinoma was inhibited by serum from patients with adenocarcinoma of the colon but not by serum from patients with other bowel diseases or from healthy volunteers. Of other malignancies studied, serum from two patients with gastric carcinoma and two patients with pancreatic carcinoma also inhibited the specific binding of monoclonal antibody. The levels of carcinoembryonic antigen in these serum samples were not correlated with their levels of binding inhibition. Such monoclonal antibodies may prove useful for the detection of colorectal carcinoma.

Specific antigen in serum of patients with colon carcinoma

A monosialoganglioside antigen of gastrointestinal adenocarcinomas defined by murine monoclonal antibody was demonstrated by immunoperoxidase (IP) assay in fixed paraffinembedded tumors in 59% of colonic adenocarcinomas, 86% of pancreatic adenocarcinomas, and 89% of all gastric adenocarcinomas. In all patients with detectable levels of antigen in circulation, the resected tumors also expressed the antigen in IP assay. Six of eight individuals with no detectable levels of antigen in their serum samples expressed the antigen in the tumor tissue. Removal of the sialic acid residue of the antigen abolished the IP reaction. The successful use of the IP assay on fixed tissue to demonstrate the specific sites of gastrointestinal cancer antigen localization in human tumors and normal tissues provides an important tool for the study of developing neoplasia.

https://cancerres.aacrjournals.org/content/canres/42/11/4820.full.pdf

Gastrointestinal cancer-associated antigen in immunoperoxidase assay.

Inoculation of human subjects with mouse monoclonal antibody results in the production of anti-idiotype antibody that reacts with the binding site of the monoclonal antibody. This reaction is hapten-inhibited, suggesting that an internal image of the antigen is produced by the anti-idiotype response. The anti-idiotype antibody isolated from sera of three patients showed significant crossreactivity. Patients who developed the anti-idiotype antibody improved clinically and had long remission from their disease. The possible presence of the internal image of cancer antigen on the human immunoglobulin molecule may change the conditions under which the immune system reacts to the tumor antigen and may open new approaches to the control of tumor growth.

http://www.pnas.org/content/81/1/216.full.pdf

Human anti-idiotype antibodies in cancer patients: Is the modulation of the immune response beneficial for the patient?

Hybridoma-secreted monoclonal anti-colorectal carcinoma antibodies 19-9, 52a, and C4 14 bind specifically to cells of colorectal, gastric, and pancreatic carcinoma in tissue culture. The assay for the detection of antigen in human sera is based on the inhibition of binding of monoclonal antibodies to target preparations of colorectal carcinoma cells. Binding of monoclonal antibody 52a was inhibited more than 12% by 163 of 255 sera from patients from various stages of carcinoma of colon and rectum, by 45 of 49 sera from patients with pancreatic carcinoma, and by 8 of 11 sera from patients with gastric carcinoma. By contrast, only 7 of 89 sera from patients with other malignancies and 2 of 108 sera from healthy donors inhibited binding of this monoclonal antibody by more than 12%. These studies show the potential usefulness of monoclonal antibodies in the diagnosis of human malignancy.

Monoclonal antibody detection of a circulating tumor-associated antigen. I. Presence of antigen in sera of patients with colorectal, gastric, and pancreatic carcinoma.

A murine monoclonal antibody (MAb) which binds to human metastatic gastrointestinal adenocarcinomas can be administered safely and has tumor effects in some patients Its therapeutic effect was assessed in 20 patients with measurable advanced colorectal carcinoma that was refractory to prior surgical resection, chemotherapy, and/or radiotherapy All patients had agreed to receive no other therapy at the time of MAb administration and follow-up evaluation In one patient, tumor at all known sites responded after a single iv injection of antibody One other patient had a marked reduction in a hepatic metastasis where binding of 131I-labeled F(ab')2 MAb fragments was demonstrated but not in his abdominal wall metastases where no MAb binding could be demonstrated In a third patient, stabilization persisting for 12 mo of an aggressively growing tumor was observed The antibody was well tolerated in all patients, although 10 patients mounted an anti-murine immunoglobulin antibody response

https://cancerres.aacrjournals.org/content/canres/45/11_Part_2/5910.full.pdf

Henry F. Sears

Papers

Specific antigen in serum of patients with colon carcinoma

Gastrointestinal cancer-associated antigen in immunoperoxidase assay.

Human anti-idiotype antibodies in cancer patients: Is the modulation of the immune response beneficial for the patient?

Monoclonal antibody detection of a circulating tumor-associated antigen. I. Presence of antigen in sera of patients with colorectal, gastric, and pancreatic carcinoma.

Phase II clinical trial of a murine monoclonal antibody cytotoxic for gastrointestinal adenocarcinoma.