Structure, tissue distribution and function of Clusterin in tumorigenesis

Structure, tissue distribution and function of Clusterin in tumorigenesis

Clusterin (CLU) is a heterodimeric glycoprotein with nearly ubiquitous tissue distribution and an active role in many biological processes including tissue differentiation, cell proliferation, DNA repair and cell death. CLU also plays important roles in many human neurodegenerative diseases and cancer. A general consensus concerning the function of CLU was reached recently. The consensus has a starting point the different CLU isoforms, products of the same gene through mechanisms which have not yet been clarified.

CLU expression is dysregulated in many types of cancer, including colorectal, prostate and mammary carcinoma. Specific modulation of expression/localization of CLU isoforms has been associated with both neoplastic transformation and progression of tumours. Although literature data appear contradictory, discrepancies in the report findings may derive from the fact that the studies may have contemplated different CLU isoforms. There is a growing awareness of the possibility that biological functions of CLU may also be linked to its localization inside and outside the cell. In particular, the cytoplasmic CLU/nuclear CLU ratio is a key player in cell survival: an increase in nuclear CLU is clearly linked to apoptosis, whereas cytoplasmic CLU may exert a cytoprotective effect.

Since CLU may exert different function depending upon the components with which it interacts, investigations on the complex mechanisms of regulation of CLU expression (falling under epigenetic control) are complemented with efforts to identify putative molecular ligands of CLU. In vitro, and in animal models of prostate cancer and neuroblastoma, we have found that CLU acts as a tumour suppressor gene, inhibiting lesion growth and metastasis formation, and controlling the fate of the transformed cells. On this basis, CLU is now regarded as a possible molecular target of new gene therapies aimed at killing cells along the pathway of transformation, or cells becoming resistant to standard drugs in advanced cancers.

We are actively addressing the potential of CLU as a prognostic factor and as a factor preventing metastatic spread of prostate carcinoma cells. The studies are now being extended to a number of other tumour types in which we have identified a biological significance of CLU in their progression. Our mid- and long-term goal is to pave the way to novel CLU-directed therapeutic targeting of multiple cancer types.