Osteopontin as a target for cancer therapy.

Osteopontin (OPN) is a glycophosphoprotein cytokine that has multiple functions. OPN is expressed and secreted by various cells, and has a role in cell adhesion, chemotaxis, prevention of apoptosis, invasion, migration and anchorage-independent growth of tumor cells. Extensive research has demonstrated the pivotal participation of OPN in the regulation of cell signaling which controls neoplastic and malignant transformation. The elevated expression of OPN has been observed in a variety of cancers. OPN has been linked with tumor metastasis and signifies a poor prognosis for the patient. This review details the mechanisms by which OPN facilitates these pathological events. It will also show that gaining an understanding of the mechanism of OPN's action at a cellular level has led to the development of a number of therapeutic strategies against the cytokine. These include inhibiting its expression, antagonizing cell surface receptor activation and blocking downstream cell signaling pathways. In addition to the potential of these therapies, serum levels of OPN could be used as a diagnostic and prognostic marker. The authors propose that with further research and development, osteopontin directed treatment could greatly enhance outcomes for cancer patients.

The role of LEF/TCF factors in neoplastic transformation.

The T cell factor 4 (Tcf-4) interacts with beta-catenin in the Wnt signalling pathway and coactivates downstream target genes in diverse systems including the breast. This activity is important during normal development but its deregulation plays a pivotal role in cancer progression. In a rat model for breast cancer it has been shown that metastasis-inducing DNA (Met-DNA) sequesters the endogenous inhibitory Tcf-4 and thereby promotes transcription of the secreted extracellular matrix glycophosphoprotein, osteopontin, the direct effector of metastasis in this model system. Permanent transfection of the benign rat mammary cell line with a fragment from the Met-DNA containing the Tcf recognition sequence CAAAG induces the cells to metastasize in syngeneic rats in vivo. Tcf-4 expression in human breast carcinomas is inversely associated with osteopontin protein levels. High Tcf-4 expression impedes both OPN promoter activity and protein expression in rat mammary carcinoma cells. Understanding the role of Tcf-4 in cancer development and its transcription regulation should lay the foundation for novel therapeutic approaches in the future.