Modulation of Tumor Angiogenesis by CEACAM1 in a Mouse Model for Mammary Carcinogenesis (WAP-T Mice)

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Tumor development and progression in WAP-T mice, modelling human mammary carcinogenesis, is characterized by an initial phase of enhanced angiogenesis in low grade tumors (G0 and G1 grade), followed by insufficient angiogenesis in moderately and poorly differentiated adenocarcinoma (G2 and G3 grade), thereby leading to tumor necrosis in the central mass of the tumor. However, angiogenesis increases again in undifferentiated and anaplastic tumors (G4 grade) ( angiogenic switch ). The WAP-T mouse system thus is extremely well suited to test the effects of modulators of angiogenesis on tumor progression and metastasis. We want to analyze the effects of the angiogenic factor CEACAM1 on tumor development and progression in WAP-T mice, WAP-T mice will be crossed with mice overexpressing CEACAM1 in endothelial cells (CEACAM1endo+ mice), or with mice in which functional CEACAM1 expression in endothelial cells is blocked by overexpression of a dominant-negative CEACAM1 (CEACAM1endo+ mice), respectively. Comparative phenotypic and molecular analyses of WAP-T and WAP-T x CEACAM1 mice will elucidate the influence of endothelial CEACAM1 on tumor vascularization and stroma formation at different stages of tumor development and progression, and reveal the cross-talk between CEACAM1 and other angiogenic factors, Using WAP-T x CEACAM1K0 mice, we will analyze the possible mutual relationship between endothelial and epithelial CEACAM1 expression during tumor formation and progression. An important general goal of our planned investigations is to define molecular parameters influencing the angiogenic switch in high-grade WAP-T tumors, as this switch might relate to the metastatic potential of these tumors.