Causes and Consequences of Acid pH in Tumors

肿瘤的微环境可能是一个不利的地方，有大量的低氧和酸性区域。 这项研究计划的重点是肿瘤的pH值，尽管对肿瘤氧合的研究也是 包括在内。寻求更新资金，以继续改进肿瘤pH成像方法(目标1)，并 了解在这种恶劣的微环境中堆酸的原因(目标2)和后果(目标3)。 在上一次支助期间，我们在所有三个目标方面都取得了重大进展。已经有了新的方法 开发和输出，有氧糖酵解和高酸血症之间的基本关系是 并对酸堆对电离药物的抗性进行了表征。从… 这些最新的发现，一项临床试验正在计划中，以提高米托蒽醌治疗的疗效 代谢性碱化。一本书和27份手稿已经出版、正在印刷或已经出版 已提交。 在下一个支持阶段的目标1中，我们建议开发一种令人兴奋的新类别的核磁共振敏感 含Gd的pH报告器有望以非常高的时空分辨率成像pH。一个 将花费大量的努力来开发最终适合于 诊所。AIMS 2和AIMS 3的实验将集中于测试一种新的模型，该模型可以在 肿瘤作为选择性压力，驱动肿瘤表型从良性向转移性的演变。这个 模型认为，短暂低氧-的调节失调之间存在着功能上的联系。 缺氧反应元件，HIF-1_有氧糖酵解_高酸度_蛋白水解酶-外渗 殖民时期的生存。这些联系中的每一个都在文献中被观察到，但还没有 在单一系统中进行了测试。这样的模型可以解释为什么氟脱氧葡萄糖的摄取增加 通常见于转移性癌症。目标2将确定之间是否存在功能联系 HIF-1或，肿瘤中升高的有氧糖酵解，转移潜能和高酸堆积 已建立的人类乳腺癌细胞。目标3将确定之间是否存在功能联系 糖酵解、酸堆和外渗、定植水平的转移。虽然具体 假设将被测试，实验被设计为产生重要信息，即使假设是 不是这样的。

The microenvironment of tumors can be a hostile place, with significant regions that are hypoxic and acidic. The focus of this research program is on the tumor pH, although studies of tumor oxygenation are also included. Renewal funding is sought to continue improving methods for imaging tumor pH (Aim 1), and.to understand the causes (Aim 2) and consequences (Aim 3) of acid pile in this hostile microenvironment. During the last period of support we made significant advances in all three aims. New methods have been developed and exported, a fundamental relationship between aerobic glycolysis and hyperacidosis was uncovered, and the effect of acid pile in conferring resistance to ionizable drugs was characterized. From these last findings, a clinical trial is being planned to enhance the efficacy ofmitoxantrone therapy with metabolic alkalinization. One book and 27 manuscripts have been published, are in press or have been submitted. In Aim 1 of the next period of support, we propose to develop an exciting new class of MRI-sensitive Gd-containing pH reporters which hold promise for imaging pH with very high spatio-temporal resolution. A significant effort will be spent developing quantitative methods that would eventually be appropriate for the clinic. Experiments in aims 2 & 3 will focus on testing a novel model which treats the hypoxia and acidity in tumors as selective pressures that drive the evolution of the tumor phenotype from benign to metastatic. The model proposes that there are functional connections between transient hypoxia --_ dysregulation of the hypoxia response element, HIF-la _ aerobic glycolysis _ hyperacidity _ proteases --_ extravasation survival during colonization. Each of these connections has been observed in the literature, but has not been tested in a single system. Such a model could explain why elevated uptake of flurodeoxyglucose is commonly observed in metastatic cancers. Aim 2 will determine if there are functional connections between HIF-1 or, elevated aerobic glycolysis, metastatic potential and hyperacidic pile in tumors using primary and established human breast cancer cells. Aim 3 will determine if there are functional connections between glycolysis, acid pile and metastasis at the levels of extravasation and colonization. Although specific hypotheses will be tested, experiments are designed to yield important information even if the hypotheses are not true.