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: 8394921
• 负责人: Robert B West
• 金额: $ 35.66万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394921
• 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 microenvironment; 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.

项目摘要/摘要 越来越多的研究表明，间质在维持和生长过程中发挥着重要作用 但对肿瘤中存在的不同类型的间质知之甚少。此外，作为 肿瘤内的间质细胞被认为是“正常的”，与肿瘤细胞相比遗传不稳定， 获得性耐药的发生被认为不太可能，因此，肿瘤间质可能 成为定向治疗的极佳靶点。肿瘤间质含有多种类型的间充质细胞， 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 只有部分已知，很可能存在目前无法识别的这些细胞的几个亚型。我们 假设在特定的肿瘤组(例如乳腺癌)中存在不同类型的间质 以不同的方式影响肿瘤生长。我们进一步假设软组织肿瘤(STT)被认为是 来源于不同的基质前体，可作为各种基质类型的发现工具。软的 组织肿瘤(包括称为肉瘤的恶性变种)来源于各种各样的正常组织。 结缔组织细胞，可被认为是不同亚型间充质细胞的克隆性生长 如成纤维细胞和肌成纤维细胞，以及其他尚未发现的间质成分。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，并识别来自这些组织的正常结缔组织 得出了基质的类型。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不同间质类型的癌。分成两份 单独的研究表明，这是可行的，事实上，不同的基质类型是相关的 有着不同的临床结果。在建议的项目中，我们将对 更多的STT以发现更多新类型的癌间质。随后，我们将验证和扩展 我们在组织微阵列上的发现包含了数百个来自癌症患者的癌组织样本 已知的临床随访。最后，我们将确定与“串扰”有关的上皮-间质基因对。 癌症和间质细胞之间的关系。 这项拨款提案旨在扩大我们对癌症间质反应的理解，并通过寻找新的 参与这种反应的基因和途径，识别肿瘤微环境的新靶点-靶向 心理治疗。除了用作预后标记物外，我们认为潜在的治疗靶点也可能 在这组基因中被发现，特别是那些与癌症和间质之间的“串扰”有关的基因 细胞。我们的研究还将有助于确定哪些癌症亚型会对这些间质靶向的肿瘤产生反应 治疗。不同的癌症共享这些靶点的表达这一事实将意味着大的群体 患有各种肿瘤的患者都能从中受益。

项目成果

Expression of subtype-specific group 1 leiomyosarcoma markers in a wide variety of sarcomas by gene expression analysis and immunohistochemistry.

• DOI: 10.1097/pas.0b013e318211abd6
• 发表时间: 2011-04
• 期刊: The American journal of surgical pathology
• 作者: Mills AM;Beck AH;Montgomery KD;Zhu SX;Espinosa I;Lee CH;Subramanian S;Fletcher CD;van de Rijn M;West RB
• 通讯作者: West RB

Stromal responses among carcinomas--response.

癌症间的基质反应——反应。

• DOI: 10.1158/1078-0432.ccr-13-3238
• 发表时间: 2014
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: West,RobertB;vandeRijn,Matt;Chen,JuliaL
• 通讯作者: Chen,JuliaL

Variations in stromal signatures in breast and colorectal cancer metastases.

• DOI: 10.1002/path.2738
• 发表时间: 2010-10
• 期刊: JOURNAL OF PATHOLOGY
• 影响因子: 7.3
• 作者: Webster, Jonathan A.;Beck, Andrew H.;Sharma, Mimansa;Espinosa, Inigo;Weigelt, Britta;Schreuder, Marthe;Montgomery, Kelli D.;Jensen, Kristin C.;van de Rijn, Matt;West, Robert
• 通讯作者: West, Robert

Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ.

• DOI: 10.1007/s10549-009-0654-0
• 发表时间: 2010-09
• 期刊: BREAST CANCER RESEARCH AND TREATMENT
• 影响因子: 3.8
• 作者: Sharma, M.;Beck, A. H.;Webster, J. A.;Espinosa, I.;Montgomery, K.;Varma, S.;van de Rijn, M.;Jensen, K. C.;West, R. B.
• 通讯作者: West, R. B.

The macrophage colony-stimulating factor 1 response signature in breast carcinoma.

• DOI: 10.1158/1078-0432.ccr-08-1283
• 发表时间: 2009-02-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Beck AH;Espinosa I;Edris B;Li R;Montgomery K;Zhu S;Varma S;Marinelli RJ;van de Rijn M;West RB
• 通讯作者: West RB