Clusterin is a ubiquitous secretory heterodimeric
disulfide-linked
glycoprotein, which is implicated in several physiological processes, including immune regulation, cell adhesion and morphological transformation,
lipid transportation, tissue remodelling, membrane recycling and cell-cell interactions. A large number of studies have focused their interest on
clusterin gene products as mediators of cell cycle progression and cell death induction, although data on the different
isoforms and their role in the different cell processes are still obscure. Recently, an increased
clusterin expression in
breast cancer has been reported. In order to elucidate the role of
clusterin in
tumor progression and whether one of its
isoforms is preferentially expressed in
tumorigenesis, we examined its presence throughout the different steps of human colon
carcinoma, one of the best-characterized models of human
tumor progression. The immunohistochemical observation of 30 bioptic and surgical colon specimens demonstrated a cell compartment
clusterin translocation from the nucleus to the cytoplasm directly related to
tumor progression. In fact, a nuclear localization found in healthy colonic mucosa is consistent with the involvement of the proapoptotic nuclear form in the regulation of cell cycle progression and in cell death induction. The progression towards high-grade and metastatic
carcinoma leads to cytoplasmic
clusterin distribution.
Protein extracts from freshly isolated cells of the same patients confirm in high-grade
carcinomas with metastatic nodes the complete loss of the proapoptotic nuclear form and a cytoplasmic overexpression of the highly glycosylated form. Data obtained from in vitro experiments confirm that this form is released in the extracellular space and corresponded to the fully glycosylated one. These data suggest that the controversial data on
clusterin function in
tumors may be related to the pattern shift of its
isoform production. As the secreted form of
clusterin is correlated to cell matrix formation, cell membrane remodeling and cell-cell adhesion, the overexpression of this form in highly aggressive
tumors and metastatic nodes could be a potential new prognostic and predictive marker for colon
carcinoma aggressiveness.