Hematopoietic Stem Cell-Derived Carcinoma Associated Fibroblasts in Tumor

肿瘤中造血干细胞衍生的癌相关成纤维细胞

• 批准号: 8040183
• 负责人: AMANDA C. LARUE
• 金额: $ 26.15万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040183
• 关键词: Address; Affect; Bone Marrow; CCL21 gene; CSF3 gene; CXCL12 gene; Carcinoma; Cell Differentiation process; Cell Proliferation; Cell Transplantation; Cell surface; Cells; Clinical; Diagnostic; Epithelial; Extracellular Matrix Degradation; Fibroblasts; Gene Proteins; Genes; Genetic Models; Goals; Granulocyte Colony-Stimulating Factor; Growth; Hematopoietic stem cells; Homing; Image; In Vitro; Lead; Lewis Lung Carcinoma; Longitudinal Studies; Lymphoid; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mesenchymal; Mesenchymal Stem Cells; Methods; Modeling; Molecular Profiling; Morphology; Mus; Myofibroblast; Neoplasm Metastasis; Outcome; Pathology; Patients; Pericytes; Platelet-Derived Growth Factor; Play; Population; Production; Proteins; Proto-Oncogene Proteins c-sis; RNA; Role; Small Interfering RNA; Solid; Solid Neoplasm; Source; Stromal Neoplasm; Testing; Tissues; Transforming Growth Factor beta; Transplantation; Tumor Angiogenesis; Tumor Biology; Tumorigenicity; base; cell stroma; chemokine; cytokine; gain of function; improved; in vivo; insight; loss of function; macrophage; migration; monocyte; monocyte colony stimulating factor; neoplastic cell; neovascularization; novel; population based; prognostic; reconstitution; research study; therapeutic target; transdifferentiation; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The tumor stromal microenvironment holds exciting potential as a therapeutic target. The major component of solid tumor stroma is the carcinoma associated fibroblast (CAF), which generates structural matrix, stimulates growth, supports neovascularization and promotes metastasis of tumor. Studies suggest various sources for CAFs including tissue fibroblasts, epithelial-to-mesenchymal transdifferentiation (EMT) and bone marrow (i.e., mesenchymal stem cells). We have developed a novel transplantation model in which the bone marrow of lethally irradiated recipient mice is reconstituted by a clonal population of cells derived from a single EGFP+ hematopoietic stem cell (HSC). Our studies using this model demonstrate that CAFs and circulating fibroblast precursors (CFPs) are of HSC origin and promote tumor growth. This novel HSC source for both fibroblast precursors and CAFs is the basis for the proposed studies. It is our hypothesis that HSC-derived CFPs and CAFs play a critical role in tumor proliferation, invasion, migration and metastasis; however the specific role of these HSC-derived CAFs and CFPs in tumor progression has not yet been investigated. Nor has direct comparison of HSC-derived CAFs to non-HSC-derived "resident" populations been conducted. The proposed studies will profile this unique population of cells and determine their influence on tumor progression using our clonal cell transplantation model in conjunction with Lewis lung carcinoma (LLC) tumor models through the following Specific Aims: 1) To determine the mechanisms by which HSC-derived CFPs and CAFs promote tumor progression. The first goal of this Aim is to compare HSC-derived EGFP+ CAFs and EGFP- "resident" CAFs via flow cytometric, immunohistochemical and molecular profiling. The effects of HSC-derived CFPs on tumor proliferation, migration and invasion will then be examined in vitro and the tumor-promoting factors responsible identified and validated in gain of function and/or loss of function studies. 2) To identify factors which regulate HSC-derived CFP recruitment, homing, differentiation and maturation in the tumor microenvironment. Studies will examine factors regulating the contribution of HSC-derived CFPs to tumor via functional in vitro experiments. 3) To determine the contributions of HSC-derived CFPs and CAFs to tumor in vivo. These studies will examine the ability of HSC-derived CFPs to enhance LLC tumorigenicity, progression and metastasis. The functional importance of proteins/genes identified in Aims 1 and 2 will also be evaluated using models of genetic deficiency or siRNA methods. Together these studies will not only lead to a better understanding of basic tumor biology, but have the potential to lead to the identification of unique cancer associated molecular signatures and HSC-derived CFP/CAF-specific factors that may be targeted to inhibit solid tumor growth and progression. PUBLIC HEALTH RELEVANCE: Our goal is to determine how hematopoietic stem cell (HSC) carcinoma associated fibroblasts (CAFs) and their circulating fibroblast precursors (CFPs) directly influence tumor progression and identify mechanisms that regulate the contribution of these cells to tumor. Findings from these studies will lead to a better understanding of basic tumor biology as well as identify novel potential therapeutic targets based on HSC-derived CFP/CAF participation in tumor microenvironment. Furthermore, these studies have the potential to lead to the identification of unique cancer associated molecular signatures that may prove useful for stratifying patients and predicting metastasis and clinical outcomes, eventually leading to improved diagnostic and prognostic values.

描述（由申请人提供）：肿瘤基质微环境具有令人兴奋的潜力作为治疗靶标。 实体瘤基质的主要成分是癌相关的成纤维细胞（CAF），该成纤维细胞（CAF）产生结构基质，刺激生长，支持新血管形成并促进肿瘤的转移。 研究表明，包括组织成纤维细胞，上皮到间质转分化（EMT）和骨髓（即间充质干细胞）在内的CAF的各种来源。我们已经开发了一种新型的移植模型，其中源自单个EGFP+造血干细胞（HSC）的细胞（HSC）的细胞（HSC），将致命的受体小鼠的骨髓骨髓重构。 我们使用该模型的研究表明，CAF和循环成纤维细胞前体（CFP）是HSC起源的，并促进了肿瘤的生长。 成纤维细胞前体和CAFS的新型HSC来源是拟议研究的基础。 我们的假设是，HSC衍生的CFP和CAF在肿瘤增殖，入侵，迁移和转移中起着至关重要的作用。但是，尚未研究这些HSC衍生的CAF和CFP在肿瘤进展中的具体作用。 也没有直接比较HSC衍生的CAF与非HSC衍生的“居民”人群的直接比较。 拟议的研究将介绍这种独特的细胞群，并使用我们的克隆细胞移植模型与刘易斯肺癌（LLC）肿瘤模型通过以下特定目的确定它们对肿瘤进展的影响：1）确定HSC衍生的CFP和CAF促进肿瘤进展的机制。 该目的的第一个目标是通过流式细胞仪，免疫组织化学和分子分析比较HSC衍生的EGFP+ CAF和EGFP-“居民” CAF。 然后，将在体外检查HSC衍生的CFP对肿瘤增殖，迁移和侵袭的影响，并在功能获得和/或功能研究丧失方面识别和验证的肿瘤促进因素。 2）确定肿瘤微环境中调节HSC衍生的CFP募集，归因，分化和成熟的因素。 研究将研究通过功能性实验的功能性的HSC衍生CFP对肿瘤的贡献的因素。 3）确定HSC衍生的CFP和CAF对体内肿瘤的贡献。 这些研究将研究HSC衍生的CFP增强LLC肿瘤性，进展和转移的能力。 在目标1和2中鉴定的蛋白质/基因的功能重要性也将使用遗传缺乏或siRNA方法的模型进行评估。 这些研究共同使对基本肿瘤生物学的了解不仅会更好地理解，而且有可能导致鉴定与癌症相关的分子特征和HSC衍生的CFP/CAF特异性因素，这些因素可能旨在抑制实体瘤的生长和进展。 公共卫生相关性：我们的目标是确定造血性干细胞（HSC）癌相关的成纤维细胞（CAF）及其循环成纤维细胞前体（CFP）如何直接影响肿瘤进展并确定调节这些细胞对肿瘤贡献的机制。 这些研究的发现将使人们更好地了解基本肿瘤生物学，并基于HSC衍生的CFP/CAF参与肿瘤微环境的新型潜在治疗靶标。 此外，这些研究有可能导致鉴定独特的癌症相关分子特征，这些分子特征可能证明对分层患者和预测转移和临床结果有用，最终导致诊断和预后值改善。