Role of phosphate availability in lung cancer invasion and bone metastasis

项目总结 转移转移是癌症死亡的主要原因，骨转移是一种 预后特别差。不幸的是，骨转移是最常见的转移部位之一。 乳腺癌、前列腺癌和肺癌等癌症。在肺癌方面，近一半的晚期病例发生转移到 骨质疏松症严重影响患者的发病率和生存率。其潜在的机制还不完全清楚。 限制治疗选择，以减少诊断后的疼痛和骨折风险。因此，解决这一问题的研究 服务不足的区域将标志着在预防和治疗骨转移方面的重大进步。越来越多 肿瘤微环境的不同成分已被确定为癌症进展的调节器。 我们和其他人已经确定了一种这样的成分是无机磷(PI)，它在 美国人的饮食是由加工食品造成的。据推测，高膳食PI与癌症进展和 攻击性。我们的数据表明，高PI可以增加局部侵袭、血管生成和骨转换 潜在地推动了肿瘤的扩散，并启动了骨中转移的缝隙。此外，使用基于FRET的 PI传感器，我们观察到单个肺癌细胞内胞浆PI水平的显着差异。 这表明肿瘤细胞对PI水平的变化有不同程度的感知和反应。 因此，导致假设肿瘤细胞亚群对PI和AS的波动更敏感 其结果是推动肿瘤的进展和骨转移。这里提出的研究将使用最先进的 小鼠肿瘤转移模型及PI荧光传感器实时监测PI代谢的作用 磷酸盐的有效性在促进肺癌侵袭和骨骼定植方面的作用。具体地说，我们将测试 肺癌中高PI利用率是侵袭和转移的假说， 影响骨骼中的转移负荷。此外，我们将检查PI在肺内转运的异质性 癌细胞系促进肿瘤细胞向骨骼归巢。为了验证这一假设，我们将：1)确定血清 磷酸盐水平促进肺癌侵袭和骨转移，2)决定细胞需求 磷酸盐在肿瘤侵袭和骨转移中的作用。当前提案的结果将提供新的 PI在改变细胞行为和肿瘤转移机制中的作用 骨骼的移民化。

PROJECT SUMMARY Metastatic dissemination is a leading cause of death from cancer with metastasis to bone represents a particularly poor prognosis. Unfortunately, metastasis to bone is one of the most common sites of metastases in cancers such as breast, prostate and lung. In lung cancer, near half of advanced cases develop metastasis to the bone significantly impacting morbidity and survival. The underlying mechanisms are incompletely understood limiting treatment options to reducing pain and fracture risk after diagnosis. Therefore, studies addressing this underserved area would mark a significant advance in preventing and treating bone metastasis. Increasingly different components of the tumor microenvironment have been identified as modulators of cancer progression. Ourselves and others have identified one such component to be inorganic phosphate (Pi), which is elevated in the American diet due to processed foods. High dietary Pi has putatively been linked to cancer progression and aggression. Our data suggests that high Pi could increase local invasion, angiogenesis and bone turnover potentially driving tumor dissemination and priming the metastatic niche in bone. Further, using a FRET-based Pi sensor we have observed marked differences in cytosolic Pi levels within individual lung cancer cells. Suggesting that tumor cells have varying degrees to which they can sense and respond to changes in Pi levels. Thus, leading to the postulation that a subpopulation of tumor cells is more sensitive to fluctuations in Pi and as a result drive tumor progression and metastasis to the bone. Studies proposed herein will use a state-of-the-art mouse metastasis model and a fluorescent Pi sensor to monitor Pi metabolism in real-time to examine the role of phosphate availability in promoting lung cancer invasion and colonization of the bone. Specifically, we will test the hypothesis that high Pi availability in lung cancer is pro-invasion and pro-metastatic, and specifically influences the metastatic burden in the bone. Further, we will examine if heterogeneity in Pi transport within lung cancer cell lines promotes tumor cell homing to bone. To test this hypothesis, we will: 1) Determine if serum phosphate levels promote lung cancer invasion and bone metastasis and 2) Determine the cellular requirement of phosphate for tumor invasion and metastasis to bone. Results from the current proposal will provide new information about the role of Pi in altering cell behavior and mechanisms underlying tumor dissemination and colonization of the skeleton.