Discovery of Gene Expression Signatures in Cancer Stroma

癌症基质中基因表达特征的发现

• 批准号: 8197004
• 负责人: Robert B West
• 金额: $ 37.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-10 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197004
• 关键词: Adipocytes; Affect; Applications Grants; Behavior; Breast Carcinoma; Carcinoma; Cataloging; Catalogs; Cells; Clinical; Connective Tissue; Connective Tissue Cells; Data; Data Set; Development; Diagnosis; Endothelial Cells; Epithelial; Fibroblasts; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; Growth; Immunohistochemistry; In Situ Hybridization; Lead; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mesenchymal; Molecular Profiling; Myofibroblast; Operative Surgical Procedures; Outcome; Ovarian Carcinoma; Pathologic; Pathologist; Pathway interactions; Patients; Pattern; Play; Process; Prognostic Marker; Publishing; Reaction; Research; Role; Series; Signal Transduction; Soft Tissue Neoplasms; Specimen; Stromal Cells; Stromal Neoplasm; Tissue Microarray; Tissues; Tumor Tissue; Variant; cancer cell; cancer therapy; cell type; experience; field study; follow-up; genome-wide; lymph nodes; malignant breast neoplasm; neoplastic cell; novel; novel marker; prognostic; response; sarcoma; therapeutic target; therapy resistant; tool; tumor; tumor growth; tumor progression

PROJECT SUMMARY/ABSTRACT A growing body of research has shown that the stroma plays a significant role in the maintenance and growth of carcinomas, but little is known about the different types of stroma that exist in tumors. Moreover, as the stromal cells within the tumor are thought to be "normal" and less genetically labile than the neoplastic cells, development of acquired resistance to therapy is thought to be less likely and as such, the tumor stroma may be an excellent target for directed therapy. Tumor stroma contains a variety of mesenchymal cell types that include fibroblasts, myofibroblasts, endothelial cells, and adipocytes. The expression profiles of these lineages are only partially known and it is likely that several currently unrecognized subtypes of these cells exist. We hypothesize that within a particular group of tumors (e.g. breast carcinoma) there exist distinct types of stroma that affect tumor growth in different ways. We further hypothesize that soft tissue tumors (STTs), thought to be derived from different stromal precursors, could function as discovery tools for the various stroma types. Soft tissue tumors (including the malignant variants called sarcomas) are derived from a wide variety of normal connective tissue cells and can be thought of as clonal outgrowths of different subtypes of mesenchymal cells such as fibroblasts and myofibroblasts, and other, as yet undiscovered, stromal components. We propose to use STTs as "discovery tools" in a genome-wide search to discover groups of novel markers that identify distinct types of tumor stroma and that recognize the normal connective tissue counterparts from which these types of stroma are derived. By identifying subsets of genes that distinguish different STT, our project will examine how these gene sets can differentiate between carcinomas with distinct stroma types. In two separate studies we have shown that this is feasible and that in fact the different stroma types are associated with different clinical outcomes. In the proposed project, we will perform gene expression profiling on additional STTs to discover further new types of carcinoma stroma. Subsequently, we will verify and extend our findings on tissue micro arrays containing hundreds of specimens of several carcinomas from patients with known clinical follow-up. Finally, we will identify epithelial-stromal gene-pairs involved in the "cross-talk" between cancer and stromal cells. This grant proposal aims to expand our understanding of stromal responses to cancer and, by finding new genes and pathways involved in this response, identify new targets for tumor microenvironment-targeted therapy. In addition to their use as prognostic markers, we believe that potential therapeutic targets may also be discovered in the group of genes, especially those involved in "cross-talk" between cancer and stromal cells. Our studies will also help identify which subsets of cancers would response to these stroma-targeted therapies. The fact that different carcinomas share expression of these targets would mean that large groups of patients suffering from a variety of tumors could benefit.

项目总结/摘要 越来越多的研究表明，基质在维持和生长中起着重要作用， 癌，但鲜为人知的是，不同类型的间质存在于肿瘤。而且随着 肿瘤内的基质细胞被认为是“正常的”并且比肿瘤细胞遗传上更不稳定， 对治疗产生获得性耐药性的可能性较小，因此，肿瘤间质可能 成为定向治疗的绝佳目标肿瘤间质含有多种间充质细胞类型， 包括成纤维细胞、肌成纤维细胞、内皮细胞和脂肪细胞。这些谱系的表达谱 仅仅是部分已知的，并且很可能存在这些细胞的几种目前未被识别的亚型。我们 假设在一组特定的肿瘤（如乳腺癌）中存在不同类型的间质 以不同的方式影响肿瘤的生长。我们进一步假设，软组织肿瘤（STTs），被认为是 来源于不同的基质前体，可以作为各种基质类型的发现工具。软 组织肿瘤（包括称为肉瘤的恶性变体）来源于多种正常组织， 结缔组织细胞，可以认为是不同亚型间充质细胞的克隆产物 如成纤维细胞和肌成纤维细胞以及其它尚未发现的基质成分。我们建议 在全基因组搜索中使用STT作为“发现工具”，以发现识别 不同类型的肿瘤间质，并认识到正常结缔组织对应，这些 基质的类型被导出。通过识别区分不同STT的基因子集，我们的项目将 研究这些基因组如何区分具有不同间质类型的癌。在两 我们的独立研究表明，这是可行的，事实上，不同的基质类型是相关的 不同的临床结果。在拟议的项目中，我们将进行基因表达谱， 额外的STT以发现更多的新类型的癌间质。随后，我们将核实并延长 我们在组织微阵列上的发现包含了数百个来自患有癌症的患者的几种癌症样本， 已知的临床随访。最后，我们将确定上皮基质基因对参与的“串扰”， 癌症和基质细胞之间的联系 这项拨款提案旨在扩大我们对癌症间质反应的理解， 参与这种反应的基因和途径，确定肿瘤微环境靶向的新靶点， 疗法除了作为预后标志物外，我们认为潜在的治疗靶点也可能 在一组基因中发现，特别是那些参与癌症和基质之间的“串扰”的基因。 细胞我们的研究还将有助于确定哪些癌症亚群会对这些基质靶向治疗产生反应。 治疗不同的癌症共享这些靶点的表达这一事实意味着， 各种肿瘤的患者都能从中受益。