Mechanisms of chemotherapy response and tumor re-initiation in lung cancer

肺癌化疗反应和肿瘤再启动的机制

基本信息

批准号：
8838054
负责人：
Eric Alejandro Sweet-Cordero
金额：
$ 34.06万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8838054
关键词：
Accounting Address Antibodies Biochemical Biological Assay CD44 gene Cell Line Cell surface Cells Cellular biology Characteristics Cisplatin Clinical DNA Adducts DNA Damage DNA Repair DNA Repair Pathway Epigenetic Process Genes Genetic Genome Genomic approach Genomics Heterogeneity Human In Vitro Link Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Modeling Mus Mutation Non-Small-Cell Lung Carcinoma Pathway interactions Patients Phenotype Platinum Population Process Recurrence Reporter Residual Tumors Resistance Role Sampling Solid Neoplasm Testing Therapeutic Intervention Transgenic Organisms Tumor-Associated Process cancer cell cancer stem cell cancer therapy chemotherapy cisplatin-DNA adduct functional genomics human disease in vivo injury and repair knock-down mouse model neoplastic cell partial response programs response self-renewal stemness therapy resistant tool tumor

项目摘要

DESCRIPTION (provided by applicant): Treatment of solid tumors with standard chemotherapy often leads only to partial response. Thus, tumor recurrence after chemotherapy driven by tumor-reinitiating cells (TRICs) is a central problem in cancer therapy. Despite its importance, the mechanisms accounting for variable therapy response and tumor re-initiation in vivo are poorly understood. A significant problem in understanding this phenomenon in humans is the inaccessibility of matched clinical samples before and after chemotherapy from the same patient. Mouse models of cancer that closely mimic the human disease are useful tools to study the process of tumor re- initiation after chemotherapy. However, few studies have systematically utilized these models to understand chemotherapy response. Using a mouse model of human lung cancer, we have identified a subset of tumor cells that can be isolated by their cell surface markers and have an increased intrinsic resistance to chemotherapy. We utilized a Kras-driven lung tumor model crossed to a conditional transgenic reporter (tdRFP) in order to facilitate isolation of tumor cells by FACs. Cisplatin treatment of these mice leads to a dramatic decrease in the number of CD44+;tdRFP+ cells, suggesting that CD44- cells are chemotherapy resistant. Using an antibody that detects cisplatin-DNA adducts, we find that CD44- and CD44+ tumor cells have distinct DNA repair capacities. Chemoresistance in this model is associated with a dramatic increase in sphere-forming ability in vitro. In vitro sphere-forming ability is further enriched in a CD44-/CD24+ subpopulation. Thus, we have uncovered a relationship between chemoresistance and characteristics associated with cancer stem cells (cell surface marker heterogeneity, sphere formation). In this proposal, we will utilize mouse genetics, functional genomics and primary human lung cancer samples to elucidate the mechanism of chemoresistance and its relationship to the cancer stem cell phenotype in non-small cell lung cancer.

描述（由申请人提供）：用标准化疗治疗实体瘤通常只能产生部分反应。因此，肿瘤再启动细胞（TRIC）驱动的化疗后肿瘤复发是癌症治疗的核心问题。尽管它很重要，但人们对体内不同治疗反应和肿瘤重新启动的机制知之甚少。理解人类这一现象的一个重要问题是无法获得同一患者化疗前后的匹配临床样本。与人类疾病极为相似的小鼠癌症模型是研究化疗后肿瘤重新启动过程的有用工具。然而，很少有研究系统地利用这些模型来了解化疗反应。利用人类肺癌的小鼠模型，我们鉴定出了肿瘤细胞的一个子集，这些细胞可以通过其细胞表面标记物进行分离，并且对化疗具有增强的内在抵抗力。我们利用 Kras 驱动的肺肿瘤模型与条件转基因报告基因 (tdRFP) 交叉，以促进 FAC 分离肿瘤细胞。对这些小鼠进行顺铂治疗导致 CD44+;tdRFP+ 细胞数量急剧减少，表明 CD44- 细胞对化疗具有抗性。使用检测顺铂-DNA 加合物的抗体，我们发现 CD44- 和 CD44+ 肿瘤细胞具有不同的 DNA 修复能力。该模型中的化学抗性与体外球体形成能力的显着增加相关。 CD44-/CD24+ 亚群的体外成球能力进一步增强。因此，我们发现了化疗耐药性与癌症干细胞相关特征（细胞表面标志物异质性、球体形成）之间的关系。在本提案中，我们将利用小鼠遗传学、功能基因组学和原发性人类肺癌样本来阐明非小细胞肺癌的化疗耐药机制及其与癌症干细胞表型的关系。