Causes and Consequences of Acid pH in Tumors

描述(由申请人提供)： 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。这个研究项目的重点是肿瘤的pH值，尽管也包括对肿瘤氧合的研究。寻求更新资金，以继续改进肿瘤pH成像方法(目标1)，并了解在这种不利的微环境中酸堆积的原因(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。新的方法被开发和输出，揭示了有氧糖酵解和酸中毒之间的基本关系，并表征了酸堆在增强对可电离药物的抗性方面的作用。根据这些最新的发现，一项临床试验正在计划中，以提高米托蒽醌代谢碱化治疗的疗效。一本书和27份手稿已经出版、正在印刷或已经提交。在下一个支持阶段的目标1中，我们建议开发一类令人兴奋的新的MRI敏感的含Gd的pH报告器，它们有望以非常高的时空分辨率成像pH。将花费大量的努力来开发最终适用于临床的定量方法。AIMS 2和3的实验将集中于测试一种新的模型，该模型将肿瘤中的缺氧和酸度视为驱动肿瘤表型从良性向转移性演变的选择性压力。该模型提出，暂时性低氧--缺氧反应元件的失调，HIF-1α-&GT；有氧糖酵解--高酸度-蛋白水解酶这些联系中的每一个都已经在文献中观察到了，但还没有在一个单一的系统中进行测试。这样的模型可以解释为什么在转移性癌症中经常观察到氟脱氧葡萄糖摄取增加。目的2将利用原代和已建立的人乳腺癌细胞来确定HIF-1α、有氧糖酵解升高、转移潜能和高酸堆积之间是否存在功能联系。目的3将在渗出和定植水平上确定糖酵解、酸堆和转移之间是否存在功能联系。虽然具体的假设将得到检验，但即使假设不是真的，实验也是为了提供重要信息而设计的。

DESCRIPTION (provided by applicant): 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-1alpha-> 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-1alpha, 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.