Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

Plasminogen activators, tissue degradation, and cancer.

The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues.

Considerable advances have been made in recent years in our understanding of the biochemistry of mucin-type glycoproteins. This class of compounds is characterized mainly by a high level of O-linked oligosaccharides. Initially, the glycoproteins were solely known as the major constituents of mucus. Recent studies have shown that mucins from the gastrointestinal tract, lungs, salivary glands, sweat glands, breast, and tumor cells are structurally related to high-molecular-weight glycoproteins, which are produced by epithelial cells as membrane proteins. During mucin synthesis, an orchestrated sequence of events results in giant molecules of Mr 4 to 6 x 10(6), which are stored in mucous granules until secretion. Once secreted, mucin forms a barrier, not only to protect the delicate epithelial cells against the extracellular environment, but also to select substances for binding and uptake by these epithelia. This review is designed to critically examine relations between structure and function of the different compounds categorized as mucin glycoproteins.

Mucin-type glycoproteins.

To determine whether tumors containing carcinoembryonic antigen could be detected by administration of a Radio-labeled, affinity-purified, goat IgG having 70 per cent immunoreactivity against carcinoembryonic antigen, 18 patients with a history of cancer of diverse histopathology received an average total dose of 1.0 mCi of 131l-labeled IgG. Total-body photoscans were performed with a gamma scintillation camera at various intervals after administration of the radioactive antibody. Ordinary photoscans proved difficult to interpret because of blood-pool background radioactivity, thus necessitating the computer subtraction of radioactive blood-pool agents from the antibody's 131I activity. Tumor location could be demonstrated at 48 hours after injection in almost all cases studied. The scans were negative in patients without demonstrable tumors or with tumors apparently devoid of carcinoembryonic antigen. Circulating antigen levels of up to 350 ng per milliliter did not prevent successful tumor imag...

Use of Radiolabeled Antibodies to Carcinoembryonic Antigen for the Detection and Localization of Diverse Cancers by External Photoscanning

Colorectal carcinomas (CRC) that arise proximal (right) or distal (left) to the splenic flexure exhibit differences in incidence according to geographic region, age and gender. Together with observations that tumours in the hereditary cancer syndromes HNPCC and FAP occur predominantly in the right and left colon, respectively, the existence of 2 categories of CRC based on site of origin in the large bowel was proposed more than a decade ago. Differences between normal right and left colonic segments that could favour progression through different tumourigenic pathways are summarized in this review. Accumulating evidence suggests that the risk of CRC conferred by various environmental and genetic factors is different for proximal and distal tumours. Right- and left-sided tumours also exhibit different sensitivities to fluorouracil-based chemotherapy. Such differences are probably related to the molecular characteristics of the tumours, with the microsatellite instability and CpG island methylator phenotypes being associated with right-sided tumours and chromosomal instability with left-sided tumours. Future molecular-based classification systems for CRC that rely upon distinctive gene expression patterns may allow a clearer discrimination of subgroups than that provided by tumour site alone. Until then however, the existence of 2 broadly different groups of cancer defined by site of origin in the colon should be considered in the design of future epidemiologic studies as well as in the design of new clinical trials aimed at testing novel adjuvant therapies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.10635

Are there two sides to colorectal cancer

A glycoprotein present in normal human tissue is characterized that is neither organ- nor tumor-specific (nonspecific crossreacting antigen) and that crossreacts (by the Ouchterlony double-diffusion technique) with the carcinoembryonic antigen. This immunological relationship indicates common determinants on the molecules of both antigens. We demonstrate that the nonspecific crossreacting antigen is not a fragment of the carcinoembryonic antigen molecule.

https://www.pnas.org/content/pnas/69/9/2492.full.pdf

Identification of an Antigen from Normal Human Tissue That Crossreacts with the Carcinoembryonic Antigen

The antigenic surface pattern of a continuous cell line (HT29) derived from a human primary carcinoma of the colon was studied by the immunofluorescence technique. Monovalent and polyvalent immune sera were used. The cells of this long-term culture kept the ability to synthesize the three principal colon tumor antigens: carcinoembryonic and nonspecific cross-reacting antigens, and the membrane-associated tissular autoantigen. On the HT29 cells, which still carry the original blood group of the tumor donor, no receptors for human Ig's were detected.

Immunohistology of the Antigenic Pattern of a Continuous Cell Line From a Human Colon Tumor

Using immunofluorescence methods, 3 antisera respectively stain 3 groups of mucous cells of the human gastrointestinal tract, showing specific antigens for each group of cells. The antigens of the first group, the M1 antigens, were principally associated with columnar cells of the gastric epithelium, the M2 antigens with mucous cells of gastric and Brunner's glands, and the M3 antigen with the goblet cells of the intestinal mucosa. The gastric M antigens normally detectable in stomach and duodenum (but not in colon) were expressed in certain colonic tumours (benign or malignant) and in adjacent mucosa. They are always present with the intestinal M3 antigen. In 100 colonic adenocarcinomas, the intestinal M3 antigen was found in 53 cases, gastric M1 antigens in 29 cases, and gastric M2 antigens in 10 cases, always with the two other M antigens. A good correlation could be established between the association of M antigens and the histological type of tumour.

Antigens of gastric and intestinal mucous cells in human colonic tumours.

This study concerns the immunohistologic distribution of carcino-embryonic antigen (CEA) in tissues and organs from 86 legal abortions, stillborn fetuses and perinatal deaths and from 5 adults without

Immunohistochemistry of Carcino-Embryonic Antigen in the Embryo, Fetus and Adult

Twenty colonic adenocarcinomas were studied by immunofluorescence with antisera against components of the basement membrane: type IV collagen, laminin and heparan sulfate-rich proteoglycan, as well as antisera against antigens of the connective tissue: type-III collagen, fibronectin and hyaluronectin. Marked alterations of the basement membranes were consistently observed on staining with each one of the first three antisera. In contrast, staining of the normal components of connective tissue was in most cases as intense as in normal colonic mucosa. Hyaluronectin, a marker of peritumoral stroma, was found to be present in 12 out 15 tumors studied.

Pierre Burtin

Papers

Identification of an Antigen from Normal Human Tissue That Crossreacts with the Carcinoembryonic Antigen

Immunohistology of the Antigenic Pattern of a Continuous Cell Line From a Human Colon Tumor

Antigens of gastric and intestinal mucous cells in human colonic tumours.

Immunohistochemistry of Carcino-Embryonic Antigen in the Embryo, Fetus and Adult

Antigens of the basement membrane and the peritumoral stroma in human colonic adenocarcinomas: an immunofluorescence study.