Secreted mucins in pseudomyxoma peritonei: pathophysiological significance and potential therapeutic prospects

Abstract

Pseudomyxoma peritonei (PMP, ORPHA26790) is a clinical syndrome characterized by progressive dissemination of mucinous tumors and mucinous ascites in the abdomen and pelvis. PMP is a rare disease with an estimated incidence of 1-2 out of a million. Clinically, PMP usually presents with a variety of unspecific signs and symptoms, including abdominal pain and distention, ascites or even bowel obstruction. It is also diagnosed incidentally at surgical or non-surgical investigations of the abdominopelvic viscera. PMP is a neoplastic disease originating from a primary mucinous tumor of the appendix with a distinctive pattern of the peritoneal spread. Computed tomography and histopathology are the most reliable diagnostic modalities. The differential diagnosis of the disease includes secondary peritoneal carcinomatoses and some rare peritoneal conditions. Optimal elimination of mucin and the mucin-secreting tumor comprises the current standard of care for PMP offered in specialized centers as visceral resections and peritonectomy combined with intraperitoneal chemotherapy. This multidisciplinary approach has reportedly provided a median survival rate of 16.3 years, a median progression-free survival rate of 8.2 years and 10- and 15-year survival rates of 63% and 59%, respectively. Despite its indolent, bland nature as a neoplasm, PMP is a debilitating condition that severely impacts quality of life. It tends to be diagnosed at advanced stages and frequently recurs after treatment. Being ignored in research, however, PMP remains a challenging, enigmatic entity. Clinicopathological features of the PMP syndrome and its morbid complications closely correspond with the multifocal distribution of the secreted mucin collections and mucin-secreting implants. Novel strategies are thus required to facilitate macroscopic, as well as microscopic, elimination of mucin and its source as the key components of the disease. In this regard, MUC2, MUC5AC and MUC5B have been found as the secreted mucins of relevance in PMP. Development of mucin-targeted therapies could be a promising avenue for future research which is addressed in this article.

Figure 1

Schematic representation of the events resulting in the development of PMP. The pathologic process starts with a neoplastic transformation of the appendiceal goblet cells and development of a primary mucinous tumor (1). Overproduction of mucin and obstruction of the appendiceal lumen lead to the development, and subsequent rupture, of a mucocele (2). Shredded tumor cells gain access to the peritoneal cavity and circulate with the peritoneal fluid (3). Accordingly, tumor cells redistribute and accumulate within the dependent portions of the peritoneal cavity (3*, downward arrows) as well as at the peritoneal fluid reabsorption sites (3**, upward arrows).

Figure 2

MUC2 in colonic mucosa. A Synthesis, secretion and organization of colonic mucosa. The first stage in the biosynthesis of MUC2 is the formation of MUC2 monomer as an N-glycosylated apoprotein in the endoplasmic reticulum. Subsequently, MUC2 dimers are formed when intermolecular disulfide bonds bridge between the C-terminal cysteine knot domains. During transit through the Golgi apparatus, MUC2 dimers become heavily O-glycosylated. Complete glycosylation of the dimers occurs in Golgi where trimerization through disulfide bonds at the N-terminus forms protease-resistant trimers. The fully glycosylated and processed MUC2 is densely packed and stored in secretory granules/vesicles and released through constitutive or stimulated secretory mechanisms. Once released, MUC2 is organized into the firmly adherent inner layer. At a certain distance from the epithelium, this layer is converted into the loose outer layer through proteolytic cleavage and expansion. Mucus also contains immunoglobulins and other proteins. B MUC2 structure. The protein core consists of five different regions. Segment (a) and (b) are two central repetitive regions rich in potential O-glycosylation sites, to which branched carbohydrate chains of 4–12 sugars are O-glycosidically linked to form a closely packed sheath around the central protein core. Segment (a), also known as VNTR domain, is a large domain that contains 50–100 “variable number of tandem repeats (VNTRs)” of 23 amino acids, in particular, threonine. Segment (b), also called PTS domain, is a 347 amino acid domain, containing irregular repeats rich in proline, threonine and serine (PTS). These two segments are linked together by segment (c) which is a 148 amino acid, cysteine containing region. Segments (d) and (e) are extensive peptide chains rich in cysteine located at the C and N terminal ends, respectively, containing D domains with sequence homology to von Willebrand factor. These regions are the presumed sites for end to end polymerization of mucin subunits.