THE BIOLOGY OF HUMAN PROSTATE CANCER METASTASIS

背景资料：前列腺癌死亡的主要原因是对常规治疗如雄激素消融和细胞毒性化疗具有抗性的转移。针对人前列腺癌骨转移的有效新疗法的设计需要在系统、细胞和分子水平上更好地理解该过程。转移的结果取决于肿瘤细胞的独特亚群和特定宿主因子之间的多种连续相互作用，包括器官微环境，如血管生成所例示的。假设和具体目标：这些数据表明了这样的假设，即前列腺癌的进行性生长和转移依赖于与促血管生成分子如白介素（IL）-8和抗血管生成分子如干扰素（IFN）-β之间的不平衡相关的器官特异性血管生成的诱导。因此，平衡的恢复应该抑制血管生成并导致肿瘤消退。为了验证这一假设，我们将使用裸鼠原位模型来选择来自不同人前列腺癌的非转移性和转移性细胞，并分离和培养来自不同器官（骨、肺和皮肤）的内皮细胞。我们将确定变异细胞的转移基因型和表型，并确定调节骨特异性血管生成的机制。我们将确定IL-8在人前列腺癌进行性生长和转移中的作用，以及是否将确定IL-8在人前列腺癌进行性生长和转移中的作用，以及器官微环境是否调节IL-8的表达。最近的数据表明，肿瘤血管生成与IFN（α和β）的组织水平的降低有关，因此，我们将确定长期全身性给予IFN是否抑制原发性前列腺癌和骨转移的血管生成，以及IFN和化疗的组合是否可以根除前列腺癌转移。最后，在使用低剂量IFN的临床试验的准备中，我们将确定个体患者的前列腺癌中的转移/血管生成调节基因的表达水平是否验证了实验数据，并且可以作为抗血管生成治疗的替代标志物。重要性：从系统、细胞和分子水平上了解前列腺癌血管生成和骨转移的过程对于设计新的有效治疗方法将是非常宝贵的。

Background: The major cause of death from prostate cancer is metastases that are resistant to conventional therapies such as androgen ablation and cytotoxic chemotherapy. The design of effective new therapies against human prostate cancer bone metastasis requires a better understanding of the process at the systemic, cellular, and molecular levels. The outcome of metastasis depends on multiple continuous interactions between unique subpopulations of tumor cells and specific host factors, including the organ microenvironment, as exemplified by angiogenesis. Hypotheses and Specific Aims: These data suggest the hypothesis that the progressive growth and metastasis of prostate cancer are dependent on the induction of organ-specific angiogenesis associated with an imbalance between the pro-angiogenic molecules, such as interleukin (IL)-8 and ant- angiogenic molecules, such as interferon (IFN)-beta. Restoration of the balance, therefore, should inhibit angiogenesis and lead to tumor regression. To test this hypothesis, we shall use a nude mouse orthotopic model to select non-metastatic and metastatic cells from different human prostate cancers and to isolate and culture endothelial cells from different organs (bone, lung, and skin). We shall determine the metastatic genotypes and phenotypes of the variant cells and determine the mechanisms that regulate bone-specific angiogenesis. We shall determine the role of IL-8 in the progressive growth and metastasis of human prostate cancer and whether shall determine the role of IL-8 in the progressive growth and metastasis of human prostate cancer and whether the organ microenvironment regulates expression of IL-8. Recent data showed that neoplastic angiogenesis is associated with a decrease in tissue levels of IFN (alpha and beta), so we shall therefore determine whether chronic systemic administration of IFN inhibits angiogenesis of primary prostate cancer and bone metastases and whether the combination of IFN and chemotherapy can eradicate prostate cancer metastases. Finally, in preparation for clinical trials using low-dose IFN, we shall determine whether the expression levels of metastasis/angiogenesis-regulating genes in the prostate cancers of individual patients validate the experimental data and can serve as a surrogate marker for anti-angiogenic therapy. Significance: Understanding the process of prostate cancer angiogenesis and bone metastasis on the systemic, cellular, and molecular levels will be invaluable in designing new effective therapy.