The Role of Stromal Fibroblast Hypoxic Response in Mammary Tumor Progression

基质成纤维细胞缺氧反应在乳腺肿瘤进展中的作用

• 批准号: 8061263
• 负责人: Jung-whan Kim
• 金额: $ 4.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061263
• 关键词: Ablation; Address; Affect; Animal Model; Biochemical; Blood Vessels; Cancer Biology; Cancer Cell Growth; Cancer Patient; Characteristics; Communication; Complement; Cytotoxic agent; Data; Development; Fibroblasts; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Goals; Growth; Growth Factor; Human; Hypoxia; Indium; Inflammation; Inflammatory; Lead; Length; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Myeloid Cells; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Nutrient; Oncogenic; Outcome; Oxygen; Oxygen measurement, partial pressure, arterial; Pathology; Pathway interactions; Phenotype; Play; Proteins; Reporting; Research; Research Infrastructure; Resources; Role; Scientist; Source; Stromal Cells; Supporting Cell; Testing; Therapeutic; Tissues; Training; Transgenic Mice; Tumor Angiogenesis; Vascular Endothelial Growth Factors; angiogenesis; blood perfusion; cancer cell; career; chemotherapeutic agent; density; experience; hypoxia inducible factor 1; improved; insight; malignant breast neoplasm; mouse model; neoplastic cell; overexpression; research study; response; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Dr. Randall Johnson is a distinguished scientist in the fields of breast cancer biology. Dr. Johnson lab has established a number of transgenic mouse models, which have been employed for the studies demonstrating the critical role of hypoxic (low oxygen tension) response in progression and pulmonary metastasis from mammary gland cancers(13, 16, 20, 25). Taking advantage of these available resources as well as Dr. Johnson's scientific guidance, training in Johnson lab will provide me an ideal opportunity to obtain experience of utilizing animal models, which will complement my previous research experience in the cellular and biochemical analysis of cancer progression. I believe that training in Johnson lab and my determined goal to become a good scientist will synergistically construct an infrastructure for my research career as an independent cancer biologist. A cancer cell is dependent on its microenvironment. The tumor microenvironment is the host microenvironment in which cancer cells originate, multiply and spread. Recent studies have shown that the tumor microenvironment plays a pivotal role in a cancer cell's growth, malignant progression and metastasis(22). However, little is known about the characteristics of the tumor microenvironment, and how a cancer cell interacts with its microenvironment. Fibroblasts (supporting cells) are key components of the tumor microenvironment. Fibroblasts have been shown to accelerate breast cancer growth and metastatic spread(6, 24). However, the molecular mechanism underlying the role of fibroblasts in the promotion of tumor growth and metastasis is poorly understood. Hypoxia, or a shortage of oxygen, is another prominent element in the tumor microenvironment(26). The formation of hypoxic regions results from the insufficient blood vessel formation that then leads to inadequate blood perfusion to rapidly growing tumors. In hypoxic cancer tissue, the hypoxia- inducible factor-1 (HIF-1), a hypoxia-responsive protein that is essential for hypoxic adaptation of tumors has been found to be overexpressed and to contribute to tumor progression(23, 25). Yet, how hypoxia and HIF-1 expression affect fibroblasts in mammary tumors, and most importantly how this contributes to the progression of breast cancer, have not been studied. This study will take advantage of genetically engineered mouse models, in which the HIF-1a gene is specifically ablated in fibroblasts in conjunction with MMTV-PyMT transgenic mice that develop breast cancer in the mammary glands(19). We propose experiments that will test the hypothesis that HIF-1 expression in fibroblasts plays a pivotal role in the breast cancer progression and metastatic spread by generating a more supportive microenvironment for tumor progression. Our research plan proposed here may reveal potential molecular implications of tumor-associated fibroblasts in the hypoxic microenvironment of tumors during breast cancer progression. PUBLIC HEALTH RELEVANCE: Research plan proposed here will determine how tumor-associated fibroblasts, a prominent host component of tumor microenvironment affect breast cancer progression. This will provide insight into potentials for targeting cross-communication between cancer cells and their microenvironment, which may be exploited for more effective therapeutic tactics in treating breast cancer.

描述（由申请人提供）：Randall约翰逊博士是乳腺癌生物学领域的杰出科学家。约翰逊博士实验室建立了许多转基因小鼠模型，这些模型已用于研究，证明缺氧（低氧张力）反应在乳腺癌进展和肺转移中的关键作用（13，16，20，25）。利用这些可用的资源以及约翰逊博士的科学指导，在约翰逊实验室的培训将为我提供一个理想的机会，获得利用动物模型的经验，这将补充我以前在癌症进展的细胞和生化分析方面的研究经验。我相信，在约翰逊实验室的培训和我成为一名优秀科学家的坚定目标将协同作用，为我作为一名独立的癌症生物学家的研究生涯奠定基础。 癌细胞依赖于其微环境。肿瘤微环境是癌细胞起源、增殖和扩散的宿主微环境。最近的研究表明，肿瘤微环境在癌细胞的生长，恶性进展和转移中起着关键作用（22）。然而，人们对肿瘤微环境的特征以及癌细胞如何与其微环境相互作用知之甚少。成纤维细胞（支持细胞）是肿瘤微环境的关键组成部分。已显示成纤维细胞加速乳腺癌生长和转移扩散（6，24）。然而，成纤维细胞在促进肿瘤生长和转移中的作用的分子机制知之甚少。缺氧或缺氧是肿瘤微环境中的另一个重要因素（26）。缺氧区域的形成是由于血管形成不足，然后导致快速生长的肿瘤的血液灌注不足。在缺氧癌组织中，已发现缺氧诱导因子-1（HIF-1）（一种对肿瘤的缺氧适应至关重要的缺氧响应蛋白）过表达并促进肿瘤进展（23，25）。然而，缺氧和HIF-1表达如何影响乳腺肿瘤中的成纤维细胞，以及最重要的是如何促进乳腺癌的进展，尚未研究。本研究将利用基因工程小鼠模型，其中HIF-1a基因在成纤维细胞中特异性消融，与乳腺中发生乳腺癌的MMTV-PyMT转基因小鼠结合（19）。我们提出的实验将测试的假设，即HIF-1在成纤维细胞中的表达发挥了关键作用，在乳腺癌的进展和转移扩散，产生一个更支持肿瘤进展的微环境。我们的研究计划可能揭示乳腺癌进展过程中肿瘤相关成纤维细胞在肿瘤缺氧微环境中的潜在分子意义。 公共卫生关系：本文提出的研究计划将确定肿瘤相关成纤维细胞（肿瘤微环境的主要宿主成分）如何影响乳腺癌进展。这将为靶向癌细胞及其微环境之间的交叉通信提供深入了解，这可能被用于治疗乳腺癌的更有效的治疗策略。