Biobehavioral Influences and the Ovarian Tumor Microenvironment

描述（由申请人提供）：卵巢癌是第二常见的妇科癌症。由于大多数卵巢癌患者的生存率较低，因此确定导致肿瘤进展的因素至关重要。流行病学研究表明，生活压力、抑郁和社会支持等生物行为因素与癌症进展之间存在关联。这项研究探讨了一种新的途径，可能是卵巢癌中这些联系的基础，特别是生物行为因素与肿瘤微环境中常驻巨噬细胞的关系。现在人们认识到，肿瘤微环境在支持或抑制肿瘤进展方面至关重要。我们以前曾报道过卵巢癌患者在肿瘤微环境中抑郁和低社会支持与细胞免疫反应较差的相关性。我们还证明了生物行为因子和支持血管生成的细胞因子之间的直接联系，新血管的形成促进了肿瘤的生长和进展。巨噬细胞是肿瘤微环境的主要组成部分，它们主要从抗肿瘤表型转化为促肿瘤表型，并在支持炎症和肿瘤进展中发挥关键作用。然而，关于生物行为因素是否以有利于肿瘤生长的方式影响肿瘤相关巨噬细胞（TAM）以及TAM与肿瘤细胞之间的相互作用知之甚少。基于令人信服的初步数据，我们提出肿瘤微环境中TAM和肿瘤细胞的生物行为影响对支持肿瘤生长和进展的因子的产生有显着影响。我们关注TAM是因为它们在肿瘤微环境中的关键作用，也是因为在心血管文献和我们的初步数据中表明巨噬细胞对应激因素敏感。因此，该提案的首要目标是研究生物行为因素有助于促进驻留细胞（TAM）和肿瘤细胞之间相互作用的容许局部环境的途径，这些细胞有利于卵巢癌中的肿瘤生长。该项目将前瞻性地研究206例卵巢癌患者肿瘤微环境中生物行为因素（生活压力、抑郁和社会支持）与TAM产物（炎性细胞因子和肿瘤生长因子）的关系。还将检查生物行为因素与肿瘤细胞中与炎症和增殖相关的基因转录物上调的关联。基于初步的数据，我们将研究肾上腺素能信号在这些关系中作为介质的作用。为了确定这些生物学改变的临床意义，研究将评估诊断后24个月内的无进展生存期和总生存期。研究结果将对卵巢癌患者的创新行为和药物干预策略产生影响。

DESCRIPTION (provided by applicant): Ovarian cancer is the second most common gynecologic cancer. Because of low rates of survival for the majority of ovarian cancer patients, identification of factors contributing to tumor progression is of paramount importance. Epidemiologic studies have suggested an association between biobehavioral factors such as life stress, depression, and social support and cancer progression. This study examines a novel pathway that may underlie these links in ovarian cancer, specifically, the relationship of biobehavioral factors with resident macrophages within the tumor microenvironment. It is now acknowledged that the tumor microenvironment is critical in supporting or inhibiting tumor progression. We have previously reported associations of depression and low social support with a poorer cellular immune response in ovarian cancer patients in the tumor microenvironment. We have also demonstrated direct links between biobehavioral factors and cytokines supporting angiogenesis, the formation of new blood vessels that enhance tumor growth and progression. Macrophages are major components of the tumor microenvironment where they are predominantly converted from an anti-tumor phenotype to a pro-tumor phenotype and play a key role in supporting inflammation and tumor progression. However, little is known regarding whether biobehavioral factors influence tumor associated macrophages (TAM) and interactions between TAM and tumor cells in a way that favors tumor growth. Based on compelling preliminary data, we propose that biobehavioral influences on both TAM and tumor cells in the tumor microenvironment have significant effects on production of factors supporting tumor growth and progression. We focus on TAM because of their key role in the tumor microenvironment, and because of indications of macrophage sensitivity to stress factors in the cardiovascular literature and in our preliminary data. Thus, the overarching goal of this proposal is to examine pathways by which biobehavioral factors contribute to a permissive local environment for interactions between resident cells (TAM) and tumor cells that favor tumor growth in ovarian cancer. The proposed project will prospectively examine the relationship of biobehavioral factors (life stress, depression, and social support) and TAM products (inflammatory cytokines and tumor growth factors) in the tumor microenvironment in 206 ovarian cancer patients. Association of biobehavioral factors with upregulation of gene transcripts related to inflammation and proliferation in tumor cells will also be examined. Based on preliminary data we will examine the role of adrenergic signaling as a mediator in these relationships. To determine the clinical significance of these biological alterations, the investigation will assess progression-free and overall survival during the 24 months following diagnosis. Findings will have implications for innovative behavioral and pharmacological intervention strategies for ovarian cancer patients.