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

• 批准号: 8266328
• 负责人: Eric Alejandro Sweet-Cordero
• 金额: $ 33.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266328
• 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; 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; 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; 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

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）：用标准化疗的实体瘤的治疗通常仅导致部分反应。因此，由肿瘤重新定性细胞（TRIC）驱动的化学疗法后的肿瘤复发是癌症治疗中的核心问题。尽管它的重要性，但对可变治疗反应和体内肿瘤重新定脂的解释的机制知之甚少。在人类中了解这种现象的一个重要问题是在同一患者化学疗法之前和之后匹配的临床样本的无法访问。紧密模仿人类疾病的癌症小鼠模型是研究化学疗法后肿瘤再进行过程的有用工具。但是，很少有研究系统地利用这些模型来了解化学疗法反应。使用人类肺癌的小鼠模型，我们已经确定了可以通过细胞表面标记分离的肿瘤细胞的子集，并且对化学疗法的内在耐药性增加。我们利用了越过条件转基因报告基因（TDRFP）的KRAS驱动的肺肿瘤模型，以促进FACS分离肿瘤细胞。这些小鼠的顺铂治疗导致CD44+; TDRFP+细胞的数量急剧减少，这表明CD44-细胞具有耐化学疗法。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提高有关。体外球体形成能力进一步富含CD44-/CD24+亚群。因此，我们发现了化学抗性与与癌症干细胞相关的特征之间的关系（细胞表面标记异质性，球体形成）。在此提案中，我们将利用小鼠遗传学，功能性基因组学和原发性人类肺癌样本来阐明非小细胞肺癌中化学耐药机制及其与癌症干细胞表型的关系。