Immune Status and Tumor Regression Upon Oncogene Inactivation

癌基因失活后的免疫状态和肿瘤消退

• 批准号: 7616159
• 负责人: DEAN W FELSHER
• 金额: $ 36.56万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7616159
• 关键词: Address; Appendix; BCL-2 Protein; BCL2 gene; Bioluminescence; Blood; Cancer Immunology Science; Cells; Chromosomal translocation; Collaborations; Data; Dependence; Development; Disease regression; Event; Gene Expression; Genes; Genetic; Genetic Transcription; Hematopoietic; Hematopoietic Neoplasms; Image; Immune; Kinetics; Localized; Luciferases; Lymphocyte Count; Malignant Neoplasms; Mediating; Methods; Microarray Analysis; Modeling; Molecular Abnormality; Mus; Nature; Neoplasm Transplantation; Neoplasms; Oncogene Activation; Oncogenes; Phosphoproteins; Play; Population; Process; Proteins; Proto-Oncogenes; Reagent; Research Personnel; Role; Transgenic Model; Transgenic Organisms; Tumor Escape; Tumor Suppressor Genes; cDNA Arrays; cancer immunology function; cancer therapy; expectation; in vivo; neoplastic cell; novel; programs; repaired; response; transcription factor; tumor; tumorigenesis

Cancer is a multi-step process caused by genetic abnormalities in proto-oncogenes and tumor suppressor genes. A highly specific and effective form of cancer therapy may be to target the repair, replacement or inactivation of oncogenes. Indeed, we and others have shown that the inactivation of a single oncogene can induce sustained tumor regression. However, we have also shown that tumors can escape dependence upon oncogenes. Now, to better interrogate the mechanisms by which oncogenes initiate and sustain tumorigenesis, we have generated a transgenic model in which we can temporally regulate, alone or in combination the expression of oncogenes, to study in vivo the kinetics of oncogene induced tumor regression upon oncogene inactivation. We have begun to use this strategy to examine how oncogene inactivation induces tumor regression, the role of host immune mechanisms to mediate this tumor regression and the genetic mechanisms by which cancers escape dependence upon oncogenes. We have obtained several potentially important preliminary results. First, we have found that when tumors are transplanted into immune compromised hosts, oncogene inactivation is much less capable of inducing tumor regression. These results suggest that immune mechanisms play a key role in mediating tumor regression upon oncogene inactivation. Second, we have used Spectral Karyotypic Analysis (SKY) and CGH Microarrays to demonstrate that tumors that escape dependence upon oncogenes have acquired novel chromosomal translocations. Our expectation is that both cell extrinsic and intrinsic mechanisms are involved tumor escape from oncogene dependence. In some cases, these mechanisms may converge. Thus, there are likely to be genetic events that impair the response of tumor cells to a host mediated suppression of tumorigenesis.

癌症是由原癌基因和肿瘤抑制剂的遗传异常引起的多步骤过程 基因。癌症治疗的一种高度特异性和有效的形式可能是针对维修，更换或 失活的癌基因。确实，我们和其他人表明，单一癌基因的失活可以 诱导持续的肿瘤回归。但是，我们还表明肿瘤可以逃脱依赖性 在癌基因上。现在，更好地询问癌基因启动和维持的机制 肿瘤发生，我们已经产生了一个转基因模型，在该模型中，我们可以单独或中间调节 结合癌基因的表达，在体内研究癌基诱导肿瘤的动力学 癌基因灭活后的回归。我们已经开始使用这种策略来研究如何 灭活诱导肿瘤消退，宿主免疫机制介导这种肿瘤回归的作用 以及癌症逃脱对癌基因的遗传机制。我们已经获得了 几个潜在的重要初步结果。首先，我们发现当肿瘤移植到 免疫受损的宿主，癌基因失活的能力降低了诱导肿瘤消退的能力。 这些结果表明，免疫机制在介导肿瘤回归时起着关键作用 癌基因失活。其次，我们使用光谱核型分析（SKY）和CGH微阵列 证明逃避依赖对癌基因的肿瘤已经获得了新型染色体 易位。我们的期望是细胞外在和内在机制涉及肿瘤 逃脱癌细胞的依赖。在某些情况下，这些机制可能会融合。因此，有 可能是遗传事件会损害肿瘤细胞对宿主介导的抑制的反应 肿瘤发生。