Cancer Cell Adaptation to Hypoxia and/or Nutrient Deprivation

癌症生长失调的早期影响是恶性细胞的积累超过现有血管系统可以支持的生理数量。因此，发展中的肿瘤受到氧气限制和营养剥夺的组合。在这样的条件下，非转化细胞的积累是有限的，因为缺氧和/或营养耗尽导致细胞凋亡的开始。相比之下，大多数肿瘤细胞在其凋亡反应中是有缺陷的，因此， 不能通过细胞凋亡对缺氧和/或营养限制作出反应。该项目的目标是确定允许肿瘤细胞在营养和/或氧气限制条件下适应和生长的代谢途径。设想了两个具体目标。在第一个具体目标中，我们将研究在葡萄糖耗尽条件下脂质合成和降解的调节。在这个目标中，我们希望深入了解在葡萄糖限制下生长的肿瘤细胞如何同时激活脂肪酸氧化以支持ATP的产生，同时保持细胞生长所需的净脂肪酸合成。同时参与脂肪酸的合成和催化，使细胞处于可能致命的徒劳循环的风险中。在第二个具体目标中，我们希望确定支持缺氧细胞存活和脂质合成的代谢适应。我们将研究低氧肿瘤细胞如何维持活力和脂质合成，尽管事实上，HIF-1 α激活导致可利用的葡萄糖转向无氧糖酵解。对具体目标1的研究应提供有助于成功实现以下目标的信息： 项目2和3。拟议的研究将提供深入了解的分子机制，细胞保持一个可行的ATP/ADP比例，同时保持大分子合成葡萄糖可用性的次优条件下。反过来，具体目标2中提议的研究能否成功，部分取决于项目2和项目3提供的专门知识和试剂，也可能受益于这些项目正在取得的成果。通过这些合作研究，我们希望深入了解转化和非转化细胞如何不仅生存，而且在条件下生长。 氧气和/或营养缺乏。作为拟议研究的结果，我们希望确定削弱/增强这些生存策略的方法，以提高现有癌症治疗的疗效，同时保留非转化细胞的存活和恢复。

An early effect of dysregulated cancer growth is the accumulation of malignant cells in excess of the physiological numbers that can be supported by the existing vascular system. As a result, developing tumors are subject to a combination of oxygen limitation and nutrient deprivation. Under such conditions, the accumulation of non-transformed cells is limited because hypoxia and/or nutrient depletion leads to the initiation of apoptosis. In contrast, most tumor cells are defective in their apoptotic response and, as a result, fail to respond to hypoxia and/or nutrient limitations through apoptosis. The goal of this project is to identify metabolic pathways that allow tumor cells to adapt and grow under conditions of nutrient and/or oxygen limitation. Two Specific Aims are envisioned. In the first Specific Aim, we will examine the regulation of lipid synthesis and degradation under conditions of glucose depletion. In this Aim, we hope to gain insight into how tumor cells growing under glucose limitation can simultaneously activate fatty acid oxidation to support ATP production while maintaining the net fatty acid synthesis required for cell growth. Engaging in the simultaneous synthesis and catabolism of fatty acids puts the cell at risk of engaging in a potentially fatal futile cycle. In the second Specific Aim, we hope to determine the metabolic adaptations that support hypoxic cell survival and lipid synthesis. We will investigate how hypoxic tumor cells maintain viability and lipid synthesis despite the fact that HIF-1 a activation results in diversion of available glucose into anaerobic glycolysis. The studies of Specific Aim 1 should provide information that will contribute to the success of Projects 2 and 3. The proposed studies will provide insights into the molecular mechanisms by which cells maintain a viable ATP/ADP ratio while maintaining macromolecular synthesis under suboptimal conditions of glucose availability. In turn, the success of the studies proposed in Specific Aim 2 are dependent in part on the expertise and reagents available from Projects 2 and 3, and are also likely to benefit from insights derived from the ongoing results of these projects. Through these collaborative studies, we wish to gain insight into how both transformed and non-transformed cells not only survive but grow under conditions of oxygen and/or nutrient deprivation. As a result of the proposed investigations, we hope to identify ways to impair/augment these survival strategies to enhance the efficacy of existing cancer therapy while preserving the survival and recovery of non-transformed cells.