Studies over the past few years have established important roles for cyclooxygenase expression and prostaglandin production in tumorigenesis in a variety of human malignancies particularly colon cancer. There is great interest in the potential role of NSAIDs and selective Cox-2 inhibitors as chemopreventive agents. Although impressive progress has been made in this area a number of fundamental questions remain unanswered: 1. What specific biologic events are affected by prostaglandins to mediate their effects on tumorigenesis? 2. Are the relevant prostaglandins made by the host or the tumor? 3. What intracellular signaling events mediate the effects of prostaglandins? Our central hypothesis is that PGE2 promotes tumorigenesis by suppressing tumor cell apoptosis, by promoting escape from cell cycle arrest and by suppressing immune rejection. To test this hypothesis we will pursue three Specific Aims: 1. To define the effects of prostaglandins on apoptosis, cell cycle events, and angiogenesis in cancer in vivo and to determine if the prostaglandins that affect these events are derived from the tumor itself or surrounding stromal ceils. 2. To define the intracellular signaling events that mediate the effects of PGE2 on apoptosis and the cell cycle in cancer cells. 3. To define the role of prostaglandins in regulating the immune rejection of cancers. To address these Specific Aims we have developed a series of sarcomas induced by injecting methylcholanthrene in WT, Cox-1-/- and Cox-2-/- mice. In the proposed studies WT, Cox-1-/- and Cox-2-/- sarcomas will be injected into WT, Cox-1-/- and Cox-2-/- mice in """"""""mix and match"""""""" in vivo growth studies. Similarly we have identified a Cox-2-expressing mouse colon cancer cell line (MCA38-LD) and a Cox-2- non-expressing mouse colon cancer cell line (MCA38). These cell lines will also be injected into WT, Cox- 1-/- and Cox-2-/- mice and their growth assessed. Preliminary data from in vitro studies suggests that the effects of PGE2 on apoptosis are mediated through Akt activation and inhibition of Bax translocation. In vivo growth studies of Cox-1-/- and Cox-2-/- sarcomas in WT and Rag-1-/- mice suggest that suppression of the host immune response by tumor PGE2 markedly enhances tumor growth.
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