CANCER METASTASIS--BIOLOGY AND TREATMENT

因为大多数死于癌症的人都是由于对 传统疗法，了解基本的肿瘤细胞 控制肿瘤转移的特性和宿主因素及其设计 寻找新的治疗方法是我们研究计划的主要目标。 我们将继续发展相关的原位动物模型进行研究 人类肿瘤转移生物学及分离新的非转移和非转移基因 人前列腺器官特异性(淋巴、骨)转移变异体 癌症。我们将研究器官特异性的分子机制 内脏器官和大脑的转移。为了预测转移 对于个别患者肿瘤的潜在可能性，我们将开发一种 利用多个分子探针进行多参数检测 调节不同基本步骤的基因的上调(MRNA) 人类肿瘤转移的发病机制。因为这个器官 环境影响肿瘤细胞的特性，包括对 治疗，我们将确定正常的分子机制 组织调控P-糖蛋白在器官中的表达 转移瘤。我们还将尝试抑制药物在体内的诱导 干扰生长磷酸化在肿瘤细胞中的耐药性 因子受体。我们建立的体内转移模型 实验室非常适合于确定基因治疗的潜力。 我们计划开展一系列合作研究IRF-1基因转移以诱导 转移性人结肠癌细胞产生干扰素-β(因此， 减少血管生成和侵袭性)和通过引入 单纯疱疹病毒tk基因(自杀基因)进入人结肠和前列腺 在裸鼠体内生长的癌症。 肿瘤的生物多样性意味着成功的治疗 必须包括一种规避以下问题的方式 异质性和对传统疗法的抵抗力。因为巨噬细胞 用含有人工合成物质的脂质体系统激活 免疫调节剂摧毁对常规药物具有抵抗力的肿瘤细胞 化疗和生物疗法，我们将继续研究它们的 转移治疗的潜力。我们计划识别出有效的分子 对巨噬细胞的系统激活和对分子的理解 使单核细胞具有杀瘤作用的过程变得均匀。这个 从这些研究中获得的知识将转化为临床 使用脂质体/免疫调节剂的试验是我们实验室开发的。

Since most deaths from cancer are due to metastases that are resistant to conventional therapies, understanding the fundamental tumor cell properties and host factors that control cancer metastasis and the design of new approaches to therapy are the major goals of our research program. We shall continue to develop relevant orthotopic animal models to study the biology of human cancer metastasis and isolate new nonmetastatic and organ-specific (lymph node, bone) metastatic variants from human prostate cancers. We shall investigate the molecular mechanisms for organ-specific metastasis in visceral organs and the brain. To predict the metastatic potential of individual patients' tumors, we shall develop a multiparametric assay using several molecular probes to detect upregulation (mRNA) of genes that regulate different essential steps in the pathogenesis of metastasis by human neoplasms. Since the organ environment influences tumor cell properties that include sensitivity to therapy, we shall determine the molecular mechanism by which normal tissues modulate expression of P-glycoprotein in organ-specific metastases. We shall also attempt to inhibit the in vivo induction of drug resistance in tumor cells by interfering with phosphorylation of growth factor receptors. The in vivo metastatic models developed in our laboratory are ideally suited to determine the potential of gene therapy. We plan a series of collaborations to study IRF-1 gene transfer to induce production of IFN-beta in metastatic human colon cancer cells (and, hence, decrease angiogenesis and invasiveness) and gene therapy by introducing the Herpes Simplex-tk gene ("suicide gene") into human colon and prostate cancers growing in nude mice. The biologic diversity of neoplasms implies that the successful treatment of metastasis must include a modality that circumvents the problems of heterogeneity and resistance to conventional therapies. Since macrophages activated systemically with liposomes containing synthetic immunomodulators destroy tumor cells that are resistant to conventional chemo- and biological therapies, we shall continue to study their potential for therapy of metastasis. We plan to identify potent molecule for systemic activation of macrophages and to understand on a molecular level the processes by which monocytes are rendered tumoricidal. The knowledge gained from these studies will be translated into clinical trials using liposomes/immunomodulators developed in our laboratory.