Modulation of different clusterin isoforms in human colon tumorigenesis

Abstract

Clusterin is a ubiquitous secretory heterodimeric disulfidelinked 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.

Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer

“…We favour the recent proposal that tumour cell survival is connected with overexpression of sCLU and loss of nCLU. 3 This theory has been supported by recent data which suggest that cells must suppress sCLU to stimulate cell death. One proposed mechanism for this death process is through the activation of the p53 tumour suppressor gene.…”

“…17 This would apparently explain how progression towards high-grade and metastatic carcinoma leads to a shift from nCLU to sCLU expression, and that the role of CLU for tumour growth may be related to a pattern shift in its isoform production. 3 It is well known that apoptotic pathways are regulated via an orchestrated interplay of multiple activators (e.g. tumour necrosis factor, Fas ligand, Bax, and p53) and suppressors (e.g.…”

“…[1][2][3][4] It is involved in numerous physiological processes important for carcinogenesis and tumour growth, including apoptotic cell death, cell cycle regulation, DNA repair, cell adhesion, tissue remodelling, lipid transportation, membrane recycling, and immune system regulation. [1][2][3] Increased CLU mRNA and protein levels have been consistently detected in various tissues undergoing stress, including heart, brain, liver, kidney, breast, and retinal tissues both in vivo and in vitro. Early studies seemed to establish that CLU gene expression was a marker of apoptotic cell loss.…”

“…Early studies seemed to establish that CLU gene expression was a marker of apoptotic cell loss. 5 Importantly, CLU upregulation has been reported in various human malignancies, including bladder, 6 kidney, 7 prostate, [8][9][10][11] colon, 3 breast, 12,13 and lung 14 tumours.…”

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

“…Moreover, in colon carcinoma28 and prostate cancer,29 the CLU levels reflect disease progression and the biological aggressiveness of the tumor. Although serum CLU levels increased with tumor stage in our group of melanoma patients and it seems to be associated with advanced tumor stages, the multivariate analysis did not show any clear relationship with metastatic progression in early stage I–II melanoma patients (Table 4).…”