Most initiated cells that contain genetic alterations by carcinogens can remain dormant and will not develop into tumors or progress to malignancies unless further internal or external factors, called tumor promoters, persistently stimulate these cells. Therefore, malignancies commonly develop much later in life. The mechanism of tumor promotion is not well understood. Identification of cellular and molecular participants involved in the promotion stage of carcinogenesis is a subject of importance as such information could provide the key to preventing certain malignancies. Our long-term goal is to understand how matrix proteins stimulated by tumor promoters participate in the process of tumorigenesis. Specifically, we will study the secreted, adhesive protein, osteopontin (OPN). OPN expression is elevated in several types of human cancers and premalignant tumors. Experimental evidences support the role of OPN as a mediator of tumor promotion. Thus, we hypothesize that OPN acts as an autocrine stimulus for tumor promotion of initiated cells. To test this hypothesis, we will use both in vitro and in vivo tumor promotion models. Specifically, we intend to determine the extent to which OPN induction is required for tumor promotion in JB6 cells, model for tumor promotion studies. We have developed unique genetic tools, antisense OPN JB6 clones and sense OPN JB6 clones, to determine OPN's effect on colony formation on soft agar and tumorigenicity in immunodeficient mice. We will evaluate the cellular and molecular mechanism(s) whereby OPN transforms JB6 cells. In addition, the importance of OPN in tumor promotion in vivo will be addressed by the lack of OPN expression and targeted expression of OPN in epidermis. Together, these studies will provide a better understanding of the role of OPN in tumor promotion and may contribute to the design of a mechanism-based strategy for cancer prevention.
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