Discovery of Gene Expression Signatures in Cancer Stroma

描述（由申请人提供）：越来越多的研究表明，间质在癌的维持和生长中起着重要作用，但对肿瘤中存在的不同类型的间质知之甚少。 此外，由于肿瘤内的基质细胞被认为是“正常的”并且比肿瘤细胞更少遗传不稳定，因此认为对治疗的获得性抗性的发展不太可能，因此，肿瘤基质可能是定向治疗的极好靶点。 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部分已知，并且很可能存在这些细胞的几种目前未识别的亚型。 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），被认为是来自不同的基质前体，可以作为发现工具的各种基质类型。 软组织肿瘤（包括称为肉瘤的恶性变体）来源于多种正常结缔组织细胞，并且可以被认为是不同亚型的间充质细胞（如成纤维细胞和肌成纤维细胞）以及其他尚未发现的基质成分的克隆产物。 我们建议在全基因组搜索中使用STTs作为“发现工具”，以发现识别不同类型的肿瘤间质并识别这些类型的间质所来源的正常结缔组织对应物的新型标记物组。 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集如何区分具有不同基质类型的癌。 在两项独立的研究中，我们已经证明这是可行的，事实上，不同的基质类型与不同的临床结果相关。 在拟议的项目中，我们将对其他STT进行基因表达谱分析，以发现更多新类型的癌间质。 随后，我们将验证和扩展我们的研究结果的组织微阵列包含数百例标本的几种癌患者已知的临床随访。 最后，我们将确定上皮间质基因对参与癌症和间质细胞之间的“串扰”。 这项拨款提案旨在扩大我们对癌症基质反应的理解，并通过寻找参与这种反应的新基因和途径，确定肿瘤微环境靶向治疗的新靶点。 除了它们作为预后标志物的用途外，我们认为还可以在基因组中发现潜在的治疗靶点，特别是那些参与癌症和基质细胞之间“串扰”的基因。 我们的研究还将有助于确定哪些癌症子集会对这些基质靶向治疗产生反应。 不同的癌症共享这些靶点的表达这一事实意味着患有各种肿瘤的大量患者可以受益。 公共卫生相关性：这项拨款提案旨在扩大我们对癌症基质反应的理解，并通过寻找参与这种反应的新基因和途径，确定肿瘤微环境靶向治疗的新靶点。 除了它们作为预后标志物的用途外，我们认为还可以在基因组中发现潜在的治疗靶点，特别是那些参与癌症和基质细胞之间“串扰”的基因。 不同的癌症共享这些靶点的表达这一事实意味着患有各种肿瘤的大量患者可以受益。

DESCRIPTION (provided by applicant): 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 microarrays 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 respond 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. PUBLIC HEALTH RELEVANCE: 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. 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.