Investigating the Role of Adipocytes on Leukemia Relapse

描述(申请人提供)：肥胖会增加多种癌症的发病率和死亡率。最近的一项回顾研究发现，与瘦小的儿童相比，诊断为高危急性淋巴细胞白血病(ALL)时肥胖的儿童复发风险增加50%。这种较高的死亡率可能是由于肥胖对白血病本身的直接影响，可能是由某些脂肪细胞衍生的激素或细胞因子介导的。或者，这可能是肥胖的影响，混淆了白血病的治疗，可能是由于化疗药物的药代动力学改变。鉴于ALL和肥胖症的高患病率，我们必须调查这两种疾病之间的联系。因此，我们开发了肥胖和ALL的小鼠模型。我们发现，患有急性淋巴细胞白血病的肥胖小鼠在长春新碱治疗后更有可能复发，即使剂量与体重成正比。此外，我们的体外数据表明，脂肪细胞具有多种影响ALL化疗的作用：它们分泌迄今尚未确定的导致地塞米松全部耐药的因子，它们将长春新碱浓缩在细胞外环境之外，使ALL细胞无法获得长春新碱。本研究旨在以这些结果为基础。在我们的第一个目标中，我们将使用蛋白质组学的方法来鉴定导致地塞米松耐药的脂肪细胞衍生因子(S)。我们还将研究它们的合成和分泌的调节，以及它们对白血病细胞的作用机制(S)。在我们的第二个目标中，我们将在肥胖小鼠身上进行长春新碱和地塞米松的药代动力学实验，以量化肥胖如何改变白血病对这些药物的暴露。最后，在我们的第三个目标中，我们将使用一种新的免疫抑制小鼠饮食诱导肥胖的模型，NOD/SCID IL2R 3c-/-小鼠，以探索肥胖对体内人类白血病细胞的影响。通过这个模型，我们还将研究白血病如何渗入脂肪组织可能导致对治疗的抵抗。这些研究将增加我们对白血病及其与肥胖的关系的理解，它们有可能改变我们日益超重人口治疗癌症的方式。他们还将提供对白血病细胞利基的洞察，并确定所有糖皮质激素耐药的潜在靶点。这些研究可能直接导致癌症治疗的改进，并拯救瘦削和超重的儿童和成年人的生命。与公共卫生相关：患有白血病的超重儿童在治疗后复发的几率高出50%。白血病是儿童中最常见的癌症类型。目前的研究将探讨超重使白血病更难治愈的原因，并探索逆转这些影响的方法。由于世界各地的人口变得越来越肥胖，了解肥胖如何影响癌症结果和治疗将对制定更有效地治疗这些癌症的战略产生重大影响。

DESCRIPTION (provided by applicant): Obesity increases both the incidence and mortality of numerous types of cancer. A recent retrospective study found that children who are obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a 50% increased risk of relapse compared to lean children. This higher mortality may be due to a direct effect of obesity on the leukemia itself, perhaps mediated by some adipocyte-derived hormone or cytokine. Alternatively, it may be an effect of obesity to confound the leukemia treatment, possibly due to altered pharmacokinetics of chemotherapeutic agents. Given the high prevalence of both ALL and obesity, it is imperative that we investigate the link between these two conditions. Therefore, we have developed mouse models of obesity and ALL. We have found that obese mice with ALL are more likely to relapse after treatment with vincristine, even when it is dosed proportional to body weight. Also, we have in vitro data demonstrating that adipocytes have multiple effects to impair chemotherapy of ALL: they secrete as yet unidentified factors which cause ALL resistance to dexamethasone, and they concentrate vincristine out of the extracellular environment, making it inaccessible to the ALL cells. The present studies are designed to build on these results. In our first Aim, we will use a proteomics approach to identify the adipocyte-derived factor(s) responsible for causing dexamethasone resistance. We will also investigate the regulation of their synthesis and secretion, and their mechanism(s) of action on leukemia cells. In our second Aim, we will perform pharmacokinetics experiments in obese mice with vincristine and dexamethasone to quantify how obesity alters the leukemia exposure to these agents. Finally, in our third Aim, we will use a novel model of diet-induced obesity in an immunosuppressed mouse, the NOD/SCID IL2R 3c -/- mouse, to explore the effects of obesity on human leukemia cells in vivo. With this model we will also investigate how leukemia infiltration into adipose tissue may lead to resistance to therapy. These studies will increase our understanding of leukemia and its relation to obesity, and they have the potential to change the way we treat cancer in our increasingly overweight population. They will also provide insight into the leukemia cell niche and identify potential targets for ALL glucocorticoid resistance. These studies could lead directly to improvements in cancer treatment and saved lives in both lean and overweight children and adults. PUBLIC HEALTH RELEVANCE: Overweight children who get leukemia, the most common type of cancer in children, have a 50% higher chance of having the cancer come back after treatment. The present studies will examine the reasons why being overweight makes leukemia more difficult to cure and investigate ways to reverse these effects. Since populations around the world are becoming more obese, finding out how obesity affects cancer outcome and treatment will have a significant impact on the development of strategies to more effectively treat these cancers.