Overexpression of MUC1 reconfigures the binding properties of tumor cells

Abstract

Although it is known that adhesion and antiadhesion are essential to the metastatic spread of tumor cells, little is known about the molecules that regulate these processes. Key words: selectin; metastasis; ICAM-1; pancreatic cancer; colon cancerHuman MUC1 1-4 is a large, type I transmembrane protein normally expressed on the apical surface of ductal epithelia. 5 MUC1 is synthesized as a single polypeptide chain but exists on the cell surface as a heterodimer. Proteolytic cleavage of the full-length protein results in 2 associated fragments: a large extracellular polypeptide containing the tandem repeat domain that can be released from the cell surface and a polypeptide consisting of the short extracellular domain, the transmembrane domain and the cytoplasmic tail that exists as an integral membrane protein. 6 -8 The tandem repeat domain of MUC1 is rich in serines and threonines and is heavily glycosylated with complex O-linked oligosaccharides. Fully processed forms of MUC1 produced by different secretory epithelia (e.g., pancreas, mammary gland, kidney, lung) are distinct in part because of differential glycosylation. 6,9 -12 Levels of expression and types of posttranslational modifications of MUC1 by transformed epithelial cells often differ from forms produced by corresponding normal epithelia. [13][14][15][16][17][18][19] The appearance of novel oligosaccharide structures on MUC1 expressed by tumors (compared with normal epithelia) or differential glycosylation at different positions on the MUC1 core protein may confer new properties of adhesion that contribute to the ability of tumor cells to metastasize. For example, certain glycoforms of MUC1 have been shown to associate with intracellular adhesion molecule 1 (ICAM-1), 20 and it is predicted that certain oligosaccharide structures present on MUC1, such as sialyl Lewis A (sLe a ) or sialyl Lewis X (sLe x ) 15,21 interact with different lectin-like molecules 22 that influence general properties of cell adhesion.There is also evidence for a seemingly opposing hypothesis: that MUC1 can have "antiadhesive" properties at the cell surface. Some allelic forms of MUC1 extend 200 -500 nm above the plasma membrane, 23 which implies that the extracellular domain of MUC1 can extend more than 150 -450 nm above the estimated length of other cell surface adhesion molecules. These physical properties, together with observed differences in morphologic properties of cells overexpressing MUC1, have led to the proposal of an antiadhesion function for MUC1. One line of supporting evidence comes from the normal cellular expression pattern: MUC1 is expressed at the apical surface of ductal epithelia, in contrast to adhesion molecules found on the basal and lateral surfaces that are in tight contact with surrounding cells or stromal elements. 24 Specific localization of MUC1 to the apical surface of the ductal lumen may contribute to establishment and maintenance of the zone of cell surface that is exposed to the lumen and is not in contact with adjoining cells. Loss of cellu...

Nuclear Association of the Cytoplasmic Tail of MUC1 and β-Catenin

“…Studies 2 from our group have shown that similar carbohydrate structures are expressed on both the full-length and CT3 forms (data not shown), although it is not known if the extracellular domains are glycosylated to the same density. Similar to previous studies (2,4), the tandem repeat domain deleted MUC1F(⌬ TR) protein trafficked to the cell surface and was detected as a broad band with an apparent molecular mass of 60 kDa.…”

“…1A. DNA encoding the FLAG epitope was added to different MUC1 cDNA con- structs, as described previously (4,31). This insertion yields recombinant product with the epitope tag on the extracellular domain of the protein.…”

“…Full-length MUC1 is synthesized as a single polypeptide chain, which undergoes an early proteolytic cleavage (probably in the endoplasmic reticulum) creating two subunits that remain associated during its post-translational processing and transport to the cell surface (2). The larger of the two fragments contains most of the extracellular domain, including the signal sequence and a tandem repeat domain (3)(4)(5). The smaller subunit contains a short extracellular domain, transmembrane domain, and cytoplasmic tail (CT), 1 which are highly conserved across species (88% identity with murine transmembrane and CT sequence) (6).…”

Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein

“…17 Moreover, in vitro studies showed that increasing MUC1 expression results in decreased adhesion between adjacent cells and between cells and extracellular matrix (ECM). [18][19][20] It also results in contraction of collagen type I matrix and altered expression of epithelial cytokeratins. 21 Therefore, the consistent expression of MUC1 in invasive micropapillary carcinoma on the stromafacing rather than the apical surface of the cellsindependent of the location of the tumor-may be responsible at least in part, for the detachment of the cells from the stroma, one of the main entity-defining features of invasive micropapillary carcinoma.…”

Immunoliposomes: A Multipurpose Strategy in Breast Cancer Targeted Therapy

“…The most used and characterized antigens belong to the HER family. Moreover, other targets have been used and well characterized: EpCAM in breast and gastric cancers (Cimino, Halushka et al, 2009;Wenqi, Li et al, 2009), PSMA in prostate cancer (Ikegami, Tadakuma et al, 2005;Ikegami, Yamakami et al, 2006) or MUC1 in colon and prostate cancer (McDermott, Crocker et al, 2001;Papadopoulos, Sivridis et al, 2001). The continuous discovery of new tumor specific and/or tumor overexpressed antigens by many research groups working in this field will enormously contribute to the development of these treatments, by generating a constant increase in the number of potential antibodies.…”