Causes and Consequences of Acid pH in Tumors

肿瘤中酸性 pH 值的原因和后果

• 批准号: 7225411
• 负责人: Robert J. Gillies
• 金额: $ 11.84万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225411
• 关键词: Krebs' cycle; SCID mouse; acid base balance; bioimaging /biomedical imaging; breast neoplasms; cell line; contrast media; endopeptidases; female; gadolinium; human tissue; hypoxia; hypoxia inducible factor 1; magnetic resonance imaging; metastasis; neoplasm /cancer classification /staging; neoplastic process; patient oriented research; technology /technique development

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.

描述（由申请人提供）： 肿瘤的微环境可能是一个充满敌意的地方，其中很大一部分区域处于缺氧和酸性状态。该研究项目的重点是肿瘤 pH 值，但也包括肿瘤氧合作用的研究。寻求更新资金以继续改进肿瘤 pH 成像方法（目标 1），并了解这种恶劣微环境中酸堆积的原因（目标 2）和后果（目标 3）。在过去的支持期间，我们在所有三个目标方面都取得了重大进展。新方法已被开发和输出，有氧糖酵解和酸中毒之间的基本关系被揭示，并且酸堆在赋予对可电离药物的抗性中的作用被表征。根据这些最新发现，正在计划进行一项临床试验，以提高米托蒽醌代谢碱化疗法的疗效。已出版、正在出版或已提交一本书和27篇手稿。在下一期支持的目标 1 中，我们建议开发一种令人兴奋的新型 MRI 敏感的含 Gd pH 记录仪，它有望以非常高的时空分辨率对 pH 进行成像。我们将投入大量精力开发最终适合临床的定量方法。目标 2 和 3 的实验将重点测试一种新模型，该模型将肿瘤中的缺氧和酸性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，短暂性缺氧——缺氧反应元件失调、HIF-1α->有氧糖酵解->胃酸过多->蛋白酶->外渗->定植期间的存活之间存在功能联系。这些连接中的每一个都已在文献中观察到，但尚未在单个系统中进行测试。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代脱氧葡萄糖的摄取升高。目标 2 将使用原代和已建立的人类乳腺癌细胞来确定肿瘤中 HIF-1α、升高的有氧糖酵解、转移潜能和高酸堆之间是否存在功能联系。目标 3 将确定糖酵解、酸堆和转移之间在外渗和定植水平上是否存在功能联系。尽管将测试特定的假设，但即使假设不正确，实验的目的也是为了产生重要的信息。