Role of phosphate availability in lung cancer invasion and bone metastasis

项目摘要 转移性播散是癌症死亡的主要原因，骨转移是癌症死亡的主要原因。 尤其是预后不良。不幸的是，骨转移是骨转移瘤中最常见的转移部位之一。 乳腺癌、前列腺癌和肺癌。在肺癌中，近一半的晚期病例发生转移， 骨骼严重影响发病率和生存率。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，针对这一问题的研究 这将标志着预防和治疗骨转移的重大进展。日益 肿瘤微环境的不同组分已被鉴定为癌症进展的调节剂。 我们自己和其他人已经确定了一种这样的成分是无机磷酸盐（Pi），它在体内升高。 美国人的饮食习惯膳食中高含量的Pi与癌症进展有关， 侵略我们的数据表明，高磷可以增加局部侵袭，血管生成和骨转换 潜在地驱动肿瘤扩散并引发骨中的转移性小生境。此外，使用基于FRET的 我们已经观察到单个肺癌细胞内细胞溶质Pi水平的显著差异。 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，导致肿瘤细胞的亚群对Pi的波动更敏感的假设， 结果导致肿瘤进展并转移到骨。本文提出的研究将使用最先进的 小鼠转移模型和荧光Pi传感器来实时监测Pi代谢，以检查其作用 磷酸盐的有效性促进肺癌的侵袭和骨的定植。具体来说，我们将测试 肺癌中高磷利用率是促侵袭和促转移的假设， 影响骨转移的负荷。此外，我们将研究肺内Pi转运的异质性， 癌细胞系促进肿瘤细胞归巢到骨。为了验证这一假设，我们将：1）确定血清是否 磷酸盐水平促进肺癌侵袭和骨转移; 2）确定细胞需求 磷酸盐对肿瘤侵袭和转移到骨的作用。目前提案的结果将提供新的 关于Pi在改变细胞行为和肿瘤扩散机制中的作用的信息， 骨骼的殖民化。

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.