Role of Fibroblasts in Cancer

成纤维细胞在癌症中的作用

• 批准号: 7848919
• 负责人: RAGHU KALLURI
• 金额: $ 25.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-10 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848919
• 关键词: Ablation; Address; Alleles; Angiogenic Switch; Applications Grants; Attenuated; Biochemical; Biological; Breast Cancer Cell; Cancer Model; Carcinoma; Cells; Cytoskeletal Proteins; Data; Endothelial Cells; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Protein; Family; Fibroblasts; Genetic; Growth; Growth Factor; Healed; Knowledge; Laboratories; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mediator of activation protein; Metastatic Lesion; Metastatic Neoplasm to the Liver; Methods; Modeling; Mus; Mutant Strains Mice; Neoplasm Metastasis; Nodule; Pericytes; Phenotype; Play; Population; Population Heterogeneity; Primary Neoplasm; Production; Proteins; Research; Rest; Role; Seeds; Smooth Muscle Actin Staining Method; Soil; Stromal Cell-Derived Factor 1; Techniques; Tenascin; Testing; Thymidine Kinase; Time; Transgenic Mice; Vascular Endothelial Growth Factors; Vascular Permeabilities; angiogenesis; cancer cell; cell motility; chemokine; density; design; healing; insight; mouse Fsp1 protein; mouse model; promoter; reconstitution; research study; response to injury; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Tumors are known as wounds that do not heal - implying that cells involved in angiogenesis and injury response, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Our knowledge regarding the role of the resting and the activated fibroblasts (also known as carcinoma-associated fibroblasts, CAF) in cancer is still evolving. Fibroblast production of growth factors, chemokines and extracellular matrix likely facilitates the angiogenic recruitment of endothelial cells and pericytes. Moreover, the precise role of fibroblasts in the recruitment and the formation of metastasis is completely unknown. Therefore, this grant application is focused on the role of fibroblast in cancer progression, with specific emphasis on metastasis. Emerging data from other laboratories and our own preliminary data suggest that fibroblasts are a heterogeneous population. In the tumor microenvironment, we have now identified a population of CAF that are positive for fibroblast specific protein-1 (FSP1) but not for alpha-smooth muscle actin (aSMA). Our studies demonstrate for the first time that not all CAF are aSMA+. Additionally, specific ablation of FSP1+/alphaSMA- fibroblasts using transgenic mice, which harbor FSP1 promoter driven thymidine kinase protein (FSP1-tk), demonstrate that FSP1+ fibroblasts are critical for the formation of metastasis without a significant impact on the growth of angiogenic primary tumors. Furthermore, we demonstrate that VEGF, SDF-1 and Tenascin-C, might mediate the formation of metastatic nodules. To further evaluate the role of these fibroblasts in the formation of metastasis, we propose the following aims in this proposal: 1. To evaluate the contribution of FSP1+ fibroblasts in the growth of primary tumors and recruitment of metastasis, 2. To address the contribution of VEGF produced by FSP1+ fibroblasts in the growth of primary tumors and the formation of metastasis, 3. To investigate the contribution of SDF-1, produced by FSP1+ fibroblasts, a downstream effector of VEGF, in the formation of metastasis, and 4. To study the contribution of Tenascin-C, a FSP1+ fibroblast-produced extracellular matrix protein, in the organization of metastasis nodules. Successful completion of experiments proposed in this grant application will provide crucial insights into the role of FSP1+ fibroblasts as key determinants for the organization of metastasis. PUBLIC HEARLTH RELEVANCE: Cancer cells are not the only constituent cells within a primary tumor and secondary metastasis. Other cells including fibroblasts are found inside the primary tumor and secondary metastatic nodules. The role of such fibroblasts in cancer progression and metastasis is unknown. This proposal addresses the role of fibroblasts in facilitating metastasis.

描述（由申请人提供）：肿瘤被称为无法愈合的伤口——这意味着参与血管生成和损伤反应的细胞，如内皮细胞和成纤维细胞，在癌症的进展、生长和扩散中发挥着重要作用。 我们对静息和活化成纤维细胞（也称为癌相关成纤维细胞，CAF）在癌症中的作用的认识仍在不断发展。 成纤维细胞产生生长因子、趋化因子和细胞外基质可能促进内皮细胞和周细胞的血管生成募集。 此外，成纤维细胞在招募和转移形成中的确切作用尚不清楚。 因此，这项拨款申请的重点是成纤维细胞在癌症进展中的作用，特别是转移。 来自其他实验室的新数据和我们自己的初步数据表明，成纤维细胞是一个异质群体。 在肿瘤微环境中，我们现已鉴定出一群对成纤维细胞特异性蛋白 1 (FSP1) 呈阳性但对 α-平滑肌肌动蛋白 (aSMA) 呈阳性的 CAF 群体。 我们的研究首次证明并非所有 CAF 都是 aSMA+。 此外，使用含有 FSP1 启动子驱动的胸苷激酶蛋白 (FSP1-tk) 的转基因小鼠对 FSP1+/αSMA- 成纤维细胞进行特异性消融，表明 FSP1+ 成纤维细胞对于转移的形成至关重要，而对血管原发性肿瘤的生长没有显着影响。 此外，我们证明 VEGF、SDF-1 和 Tenascin-C 可能介导转移结节的形成。 为了进一步评估这些成纤维细胞在转移形成中的作用，我们在本提案中提出以下目标： 1. 评估 FSP1+ 成纤维细胞在原发肿瘤生长和转移灶招募中的贡献， 2. 解决FSP1+成纤维细胞产生的VEGF在原发肿瘤的生长和转移形成中的作用，3.研究FSP1+成纤维细胞产生的SDF-1的贡献，SDF-1是下游VEGF 效应子在转移形成中的作用，以及 4. 研究 Tenascin-C（一种 FSP1+ 成纤维细胞产生的细胞外基质蛋白）在转移结节组织中的作用。 成功完成本资助申请中提出的实验将为 FSP1+ 成纤维细胞作为转移组织的关键决定因素的作用提供重要的见解。 公众健康相关性：癌细胞并不是原发性肿瘤和继发性转移瘤中的唯一组成细胞。 包括成纤维细胞在内的其他细胞存在于原发性肿瘤和继发性转移结节内。 这种成纤维细胞在癌症进展和转移中的作用尚不清楚。 该提案阐述了成纤维细胞在促进转移中的作用。