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

在模拟人类乳腺癌发生的WAP-T小鼠中，肿瘤的发生和发展的特点是低级别肿瘤(G0和G1级)的早期血管生成增强，随后中低分化腺癌(G2和G3级)血管生成不足，从而导致肿瘤中心肿块的肿瘤坏死。然而，血管生成在未分化和间变性肿瘤(G4级)中再次增加(血管生成开关)。因此，WAP-T小鼠系统非常适合测试血管生成调节剂对肿瘤进展和转移的影响。我们想要分析血管生成因子CEACAM1在WAP-T小鼠肿瘤发生发展中的作用，WAP-T小鼠将分别与内皮细胞中CEACAM1过表达的小鼠(CEACAM1endo+小鼠)或内皮细胞中CEACAM1功能被显性负CEACAM1过表达阻断的小鼠(CEACAM1endo+小鼠)杂交。通过对WAP-T和WAP-T x CEACAM1小鼠的表型和分子水平的比较分析，我们将阐明内皮CEACAM1在肿瘤发生发展不同阶段对肿瘤血管形成和基质形成的影响，并揭示CEACAM1与其他血管生成因子之间的相互作用。我们将利用WAP-T x CEACAM1K0小鼠，分析肿瘤形成和发展过程中内皮和上皮CEACAM1表达之间可能的相互关系。我们计划研究的一个重要总体目标是确定影响高级别WAP-T肿瘤血管生成开关的分子参数，因为这种开关可能与这些肿瘤的转移潜力有关。

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.