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)：肿瘤间质微环境具有作为治疗靶点的令人兴奋的潜力。实体肿瘤间质的主要成分是肿瘤相关成纤维细胞(CAF)，它能产生结构基质，刺激生长，支持新生血管形成，促进肿瘤转移。研究表明，CAF的来源有多种，包括组织成纤维细胞、上皮向间充质转分化(EMT)和骨髓(即间充质干细胞)。我们开发了一种新的移植模型，在该模型中，受致死性照射的受体小鼠的骨髓由来自单个EGFP+造血干细胞(HSC)的克隆性细胞群重建。我们使用该模型的研究表明，CAF和循环中的成纤维细胞前体(CFPs)起源于HSC并促进肿瘤生长。这一新的成纤维细胞前体和CAF的HSC来源是拟议研究的基础。我们的假设是，HSC来源的CFF和CAF在肿瘤的增殖、侵袭、迁移和转移中发挥关键作用；然而，这些HSC来源的CAF和CFP在肿瘤进展中的具体作用尚未被研究。也没有对来源于HSC的CAF与非来源于HSC的“常驻”人群进行直接比较。这项拟议的研究将结合我们的克隆细胞移植模型和Lewis肺癌(LLC)肿瘤模型，通过以下特定目的来描述这一独特的细胞群体，并确定它们对肿瘤进展的影响：1)确定HSC来源的CFPs和CAF促进肿瘤进展的机制。这个目标的第一个目标是通过流式细胞术、免疫组织化学和分子图谱来比较来源于HSC的EGFP+CAF和EGFP“驻留”CAF。然后将在体外检测HSC来源的CFPs对肿瘤增殖、迁移和侵袭的影响，并在功能获得和/或功能丧失研究中确定和验证相关的促肿瘤因子。2)确定调节HSC来源的CFP在肿瘤微环境中的募集、归巢、分化和成熟的因素。研究将通过体外功能实验来检查调节HSC来源的CFPs对肿瘤的贡献的因素。3)确定HSC来源的CFPs和CAF在体内对肿瘤的贡献。这些研究将检验HSC来源的CFPs增强LLC的致瘤性、进展和转移的能力。目标1和目标2中确定的蛋白质/基因的功能重要性也将使用遗传缺陷模型或siRNA方法进行评估。总之，这些研究不仅将有助于更好地了解基本的肿瘤生物学，而且有可能导致识别独特的癌症相关分子特征和HSC衍生的CFP/CAF特异性因子，这些因子可能是以抑制实体瘤生长和进展为目标的。 公共卫生相关性：我们的目标是确定造血干细胞(HSC)、肿瘤相关成纤维细胞(CAF)及其循环成纤维细胞前体(CFP)如何直接影响肿瘤进展，并确定这些细胞在肿瘤中的作用机制。这些研究的结果将有助于更好地了解基础肿瘤生物学，以及基于HSC来源的CFP/CAF参与肿瘤微环境的新的潜在治疗靶点。此外，这些研究有可能导致识别独特的癌症相关分子特征，这些特征可能被证明对患者分层、预测转移和临床结果有用，最终导致改善诊断和预后价值。