The Role of Stromal Fibroblast Hypoxic Response in Mammary Tumor Progression

简介（由申请人提供）：Randall Johnson博士是乳腺癌生物学领域的杰出科学家。Johnson博士实验室已经建立了许多转基因小鼠模型，用于研究低氧（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Johnson博士的科学指导，在Johnson实验室的培训将为我提供一个理想的机会来获得利用动物模型的经验，这将补充我之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Johnson实验室的培训和我立志成为一名优秀科学家的目标，将为我作为一名独立的癌症生物学家的研究生涯奠定基础。癌细胞依赖于它的微环境。肿瘤微环境是肿瘤细胞产生、繁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。成纤维细胞已被证明能加速乳腺癌的生长和转移性扩散（6,24）。然而，成纤维细胞促进肿瘤生长和转移的分子机制尚不清楚。缺氧或缺氧是肿瘤微环境中的另一个重要因素（26）。缺氧区的形成是由于血管形成不足导致血液灌注不足，从而导致肿瘤快速生长。在缺氧的癌症组织中，低氧诱导因子-1 (HIF-1)，一种对肿瘤缺氧适应至关重要的低氧反应蛋白被发现过度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，以及最重要的是它如何促进乳腺癌的进展，尚未得到研究。这项研究将利用基因工程小鼠模型，在成纤维细胞中特异性地切除HIF-1a基因，并与MMTV-PyMT转基因小鼠一起在乳腺中发生乳腺癌（19）。我们提出的实验将验证HIF-1在成纤维细胞中的表达在乳腺癌的进展和转移扩散中发挥关键作用，通过为肿瘤进展产生更支持性的微环境。我们在此提出的研究计划可能揭示乳腺癌进展过程中肿瘤缺氧微环境中肿瘤相关成纤维细胞的潜在分子意义。

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.