How Does Exercise Counteract Stress-Induced Tumor Growth

描述（由申请人提供）：运动如何对抗应激诱导的肿瘤生长？癌症诊断后增加体力活动已被证明可以显著减少癌症复发。此外，运动已被证明具有抗抑郁作用，对长期承受压力的人有益，包括卵巢癌患者。由于慢性应激有助于肿瘤的侵袭性生长，导致癌症患者预后不良，我们预测减少慢性应激的行为改变也应该防止应激诱导的肿瘤生长。我们提出，运动可以作为抗抑郁药提高癌症患者的总体生存率，并假设运动和抗抑郁药激活的相同分子途径可以减轻压力，也可以抑制压力介导的肿瘤生长。我们进一步预测，这些影响是由细胞内的回路调节的，这些回路受到一种叫做BDNF的物质的影响。这种物质通常是在抗抑郁药物或运动的反应中产生的，是抗抑郁行为效果所必需的。目的1。确定运动和抗抑郁药对应激诱导小鼠卵巢肿瘤生长的影响，并确定这些影响是否由BDNF/TrkB通路介导。我们已经证明，在我们的卵巢癌小鼠模型中，定期运动和抗抑郁药都可以逆转压力介导的肿瘤生长。我们首先计划用其他卵巢肿瘤类型来证实这些发现。为了确定BDNF/TrkB信号是否影响卵巢肿瘤的生长，我们将评估应激小鼠在运动和抗抑郁药的作用下循环proBDNF和mBDNF水平的变化。我们将进一步尝试将proBDNF和mBDNF的血浆水平与暴露于日常压力下的运动和抗抑郁治疗的动物的肿瘤生长和转移联系起来。我们期望mBDNF水平的增加对运动或抗抑郁药物的反应应该反映在较小的，侵袭性较低的肿瘤上。目标2。为了确定BDNF/TrkB激活对卵巢癌细胞的影响：我们已经证明BDNF前体蛋白proBDNF是由卵巢癌细胞系和肿瘤分泌的。运动和抗抑郁药物导致proBDNF转化为成熟的BDNF (mBDNF)，这两种分子被认为对细胞生长和行为产生相反的影响。这两种分子的受体p75NTR和TrkB也在卵巢肿瘤中表达。我们将描述培养细胞中proBDNF和mBDNF对卵巢癌细胞生长和扩散的影响。我们预计，在卵巢癌动物模型中，培养细胞对proBDNF和mBDNF的反应将反映肿瘤对运动和抗抑郁药的反应。为了与“癌症控制行为研究探索性资助”的目标保持一致，我们预计这些实验可能会阐明运动对癌症进展和复发有益作用的生物学机制。公共卫生相关性：在这项提议中，我们希望揭示运动如何减少癌症复发的分子生物学基础。在诊断出癌症后，行为的改变会对患者的生存和生活质量产生重大影响。通过抵消压力的影响，运动可以显著改善卵巢癌患者的临床预后。此外，对于因化疗而感到疲劳和压力的患者，抗抑郁药可能会替代运动的有益效果，直到身体活动可以舒适地恢复。了解运动产生有益效果的机制可能会导致开发更有效的治疗策略，这将提高所有癌症患者的生活质量。

DESCRIPTION (provided by applicant): How does exercise counteract stress-induced tumor growth? Increased physical activity following the diagnosis of cancer has been demonstrated to significantly reduce cancer recurrence. Furthermore, exercise has been demonstrated to have antidepressant effects, benefiting individuals who are chronically stressed, including ovarian cancer patients. Because chronic stress contributes to aggressive tumor growth, resulting in a poor outcome for cancer patients, we predict that changes in behavior that reduce chronic stress should also prevent stress-induced tumor growth. We propose that exercise improves the overall survival of cancer patients by acting as an antidepressant, and hypothesize that the same molecular pathways activated by exercise and antidepressants that reduce stress, will also inhibit stress- mediated tumor growth. We further predict that these effects are modulated by the circuits inside the cells that are affected by a substance called BDNF. This substance is frequently produced in response to either antidepressant drugs or exercise and is required for antidepressant behavioral effects. AIM 1. To determine the effects of exercise and antidepressants on stress-induced ovarian tumor growth in mice, and to determine if these effects are mediated by the BDNF/TrkB pathway. We have already shown that both regular exercise and antidepressants can reverse stress-mediated tumor growth in our mouse model of ovarian cancer. We first plan to confirm these findings with additional ovarian tumor types. To determine if BDNF/TrkB signaling impacts ovarian tumor growth, we will evaluate changes in circulating proBDNF and mBDNF levels in stressed mice in response to exercise and antidepressants. We will further attempt to correlate plasma levels of proBDNF and mBDNF to tumor growth and metastasis in exercising and antidepressant-treated animals, who are exposed to daily stress. We expect that increasing levels of mBDNF in response to exercise or antidepressants should be reflected by smaller, less aggressive tumors. AIM 2. To determine the effects BDNF/TrkB activation in ovarian cancer cells: We have shown that the BDNF precursor protein, proBDNF, is secreted by ovarian cancer cell lines and tumors. Exercise and antidepressants result in the conversion of proBDNF to mature BDNF (mBDNF), and the two molecules are thought to produce opposing effects on cell growth and behavior. The receptors for these two molecules, p75NTR and TrkB respectively, are also expressed by ovarian tumors. We will characterize changes in ovarian cancer cell growth and spread in response to proBDNF versus mBDNF in cultured cells. We anticipate that the response of cultured cells to proBDNF and mBDNF will reflect the response of tumors to exercise and antidepressants in an animal model of ovarian cancer. In keeping with the goals of "Exploratory Grants for Behavioral Research in Cancer Control" we anticipate that these experiments may clarify the biological mechanisms underlying the beneficial effects of exercise on cancer progression and recurrence. PUBLIC HEALTH RELEVANCE: In this proposal, we hope to unravel the molecular biology underlying how exercise reduces cancer recurrence. Changes in behavior can have a significant impact on patient survival and quality of life following the diagnosis of cancer. By counteracting the effects of stress, exercise could significantly improve the clinical outcome of ovarian cancer patients. Furthermore, in patients fatigued and stressed by chemotherapy, antidepressants may provide a substitute for the beneficial effects of exercise until physical activity can be comfortably resumed. An understanding of the mechanisms responsible for the beneficial effects of exercise may lead to the development more effective treatment strategies, which will improve the quality of life for all cancer patients.