Multiple hepatic receptors cooperate to eliminate secretory mucins aberrantly entering the bloodstream: are circulating cancer mucins the "tip of the iceberg"?

Hollow organs lined by columnar epithelial cells normally secrete mucins and their proteolytic fragments vectorially into the lumen. These heterogeneously O-glycosylated molecules are known to aberrantly enter the bloodstream in the setting of epithelial carcinomas and possibly during injury or inflammation. We have recently shown that carcinoma mucin fragments can trigger the rapid formation of platelet-rich microthrombi in vivo. Thus, mechanisms to clear such aberrantly secreted mucins must exist. Indeed, we found that i.v. injected carcinoma mucin fragments had an approximately 1 minute half-life in mice, which was primarily due to rapid clearance by hepatic reticuloendothelial cells. Inhibition of known glycan-recognizing hepatic clearance receptors showed involvement of multiple partially overlapping clearance systems. Studies of genetically deficient mice and incomplete competition between different mucins confirmed this result. Thus, multiple hepatic clearance receptors cooperate to eliminate secretory mucins entering the circulation, limiting potential pathology. This may also explain why mucin-type clustered O-glycosylation is rare on plasma proteins. Notably, small subsets of injected carcinoma mucins remained unrecognized by clearance systems, had a much longer half-life, and carried highly sialylated O-glycans. Similar circulating mucins were found in tumor-bearing mice despite lack of saturation of hepatic clearance mechanisms. Thus, circulating cancer mucins currently used as clinical diagnostic markers likely represent only the clearance-resistant "tip of the iceberg." Such aberrantly circulating mucins could play pathologic roles not only in cancer but also during injury or inflammation of hollow organs and in liver disease.