THE BIOLOGY OF HUMAN PROSTATE CANCER METASTASIS

背景：前列腺癌的主要死亡原因是对雄激素消融术和细胞毒性化疗等常规治疗具有耐药性的转移灶。设计针对人类前列腺癌骨转移的有效新疗法需要更好地了解系统，细胞和分子水平的过程。转移的结果取决于肿瘤细胞独特亚群与特定宿主因子之间的多种持续相互作用，包括器官微环境，如血管生成。假设和具体目的：这些数据表明，前列腺癌的进行性生长和转移依赖于器官特异性血管生成的诱导，这与促血管生成分子（如白细胞介素(IL)-8）和促血管生成分子（如干扰素(IFN)- β）之间的失衡有关。因此，平衡的恢复应该会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类前列腺癌的非转移和转移细胞，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性基因型和表型，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，是否确定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。最近的数据显示，肿瘤血管生成与组织中IFN （α和β）水平的降低有关，因此我们将确定慢性全身给药IFN是否能抑制原发性前列腺癌和骨转移的血管生成，以及IFN联合化疗是否能根除前列腺癌转移。最后，在准备使用低剂量IFN进行临床试验时，我们将确定个体患者前列腺癌中转移/血管生成调节基因的表达水平是否验证实验数据，并可作为抗血管生成治疗的替代标志物。意义：在系统、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设计新的有效治疗方法具有重要意义。

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.