Tumor metastasis: Biobehavioral mechanisms

描述（由申请人提供）：摘要参考NOT-OD-09-058（通知标题：NIH宣布恢复法案资金用于竞争性修订申请的可用性），我们将此竞争性修订提交给题为“肿瘤转移：生物行为机制（R 01 CA 110793）”的母基金。心理社会压力可以引起免疫、神经化学和内分泌功能的改变。迄今为止，大多数关于压力和肿瘤生长的研究都集中在抑制免疫上;然而，癌症的进行性生长受到许多其他因素的影响，包括肿瘤细胞的迁移和侵袭。很少有人研究应激激素如去甲肾上腺素和肾上腺素对转移所需的这些关键过程的影响。粘着斑激酶（Focal adhesion kinase，FAK）是参与肿瘤细胞迁移和侵袭的关键因子之一。我们有令人信服的初步数据表明，应激激素之一去甲肾上腺素可以直接激活FAK并促进肿瘤生长，这些作用可以通过使用β-肾上腺素能受体抑制剂来阻断。此外，我们的初步数据表明，FAK在卵巢癌的迁移和侵袭中起着关键作用。父母补助金已经确定了潜在的机制和途径，应激激素可以影响卵巢癌的迁移和侵袭使用体外测定，我们已经实验性地确定了体内慢性应激对卵巢癌进展的影响使用一个良好的表征卵巢癌的小鼠模型，并正在研究人类卵巢癌中心理社会因素和FAK之间的关联。在这项工作中，我们有了新的观察，慢性应激和相关的增加，儿茶酚胺保护肿瘤细胞进行失巢凋亡，但确切的机制还不清楚。在本增刊中，我们试图确定慢性应激和相关的神经内分泌动力学是否可以保护卵巢癌细胞免受失巢凋亡，并确定潜在的信号通路。拟议的补充将通过允许我们检查去甲肾上腺素介导的抗失巢凋亡保护作用的体外机制，并确定应激对腹水中肿瘤细胞抗凋亡保护的体内作用（肿瘤细胞避免失巢凋亡的体内反映），推进母基金的目标和目的。这项研究的发现可能导致识别一种全新的机制，慢性应激通过这种机制影响肿瘤细胞的存活和生长，因此可能导致新的行为和药理学治疗方法。 公共卫生相关性：已知FAK可促进肿瘤细胞存活，并可能在避免失巢凋亡方面发挥重要作用。我们以前已经证明，儿茶酚胺通过刺激血管生成途径促进卵巢癌的生长。然而，入侵的肿瘤细胞在失巢凋亡中存活的机制在很大程度上仍然未知。这里提出的工作将通过允许我们检查去甲肾上腺素介导的对失巢凋亡的保护作用的体外机制，并确定应激对FAK和Src的体内影响，以及保护腹水中的细胞免受凋亡（肿瘤细胞避免失巢凋亡的体内反映），来推进母基金的目标和目的。

DESCRIPTION (provided by applicant): Abstract In reference to NOT-OD-09-058 (Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications), we submit this Competitive Revision to the parent grant entitled "Tumor metastasis: Biobehavioral mechanisms (R01CA110793)." Psychosocial stress can elicit alterations of immunological, neurochemical, and endocrinological functions. To date, most of the research dealing with stress and tumor growth has focused on suppressed immunity; however, progressive growth of cancer is influenced by many other factors including tumor cell migration and invasion. There has been little investigation of the effect of stress hormones such as norepinephrine and epinephrine on these key processes that are required for metastasis. Focal adhesion kinase (FAK) is one of the key factors involved in tumor cell migration and invasion. We have compelling preliminary data that one of the stress hormones, norepinephrine, can directly activate FAK and promote tumor growth and these effects can be blocked by using inhibitors of beta-adrenergic receptors. Furthermore, our preliminary data suggest that FAK plays a key role in ovarian cancer migration and invasion. The parent grant has determined the underlying mechanisms and pathways by which stress hormones can affect ovarian cancer migration and invasion using in vitro assays and we have experimentally identified the in vivo effects of chronic stress on ovarian cancer progression using a well-characterized mouse model of ovarian carcinoma and are examining the associations between psychosocial factors and FAK in human ovarian cancers. During this work, we have made novel observations that chronic stress and associated increases in catecholamines protect tumor cells from undergoing anoikis, but the exact mechanisms are not well known. In the present supplement, we seek to determine whether chronic stress and associated neuroendocrine dynamics could protect ovarian cancer cells from anoikis, and to identify the underlying signaling pathways. The proposed supplement will advance the goals and objectives of the parent grant by allowing us to examine in vitro mechanisms of norepinephrine mediated protective effects against anoikis and determine in vivo effects of stress on protection of tumor cells in ascites against apoptosis (in vivo reflection of anoikis avoidance by tumor cells). Findings of this study could lead to identification of a completely new mechanism by which chronic stress affects tumor cell survival and growth, and therefore may lead to new behavioral and pharmacological therapeutic approaches. PUBLIC HEALTH RELEVANCE: Project narrative FAK is known to promote tumor cell survival and may play a significant role in avoidance of anoikis. We have previously demonstrated that catecholamines promote ovarian carcinoma growth via stimulation of angiogenic pathways. However, the mechanism by which invading tumor cells survive anoikis remains largely unknown. The proposed work here will advance the goals and objectives of the parent grant by allowing us to examine in vitro mechanisms of norepinephrine mediated protective effects against anoikis and determine in vivo effects of stress on FAK and Src and protection of cells in ascites against apoptosis (in vivo reflection of anoikis avoidance by tumor cells).