Biobehavioral Influences and the Ovarian Tumor Microenvironment

描述(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存活率较低，识别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。这项研究考察了卵巢癌中可能存在这些联系的一种新途径，特别是生物行为因素与肿瘤微环境中驻留巨噬细胞的关系。现已认识到，肿瘤微环境在支持或抑制肿瘤进展中起着关键作用。我们以前曾报道，在肿瘤微环境中，卵巢癌患者的抑郁和低社会支持与较差的细胞免疫反应有关。我们还证明了生物行为因素和支持血管生成的细胞因子之间的直接联系，血管生成是促进肿瘤生长和进展的新血管的形成。巨噬细胞是肿瘤微环境的主要组成部分，在肿瘤微环境中，巨噬细胞主要由抗肿瘤表型转变为亲肿瘤表型，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影响肿瘤相关巨噬细胞()以及与肿瘤细胞之间的相互作用是否有利于肿瘤生长，我们知之甚少。基于令人信服的初步数据，我们认为肿瘤微环境中对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具有显著影响。我们之所以关注，是因为他们在肿瘤微环境中的关键作用，以及心血管文献和我们的初步数据中显示巨噬细胞对应激因素敏感的迹象。因此，这项建议的首要目标是研究生物行为因素通过何种途径有助于为卵巢癌中有利于肿瘤生长的驻留细胞()和肿瘤细胞之间的相互作用提供允许的局部环境。该项目将前瞻性地检测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)与产品(炎性细胞因子和肿瘤生长因子)的关系。生物行为因素与肿瘤细胞炎症和增殖相关基因转录上调的关系也将被研究。基于初步数据，我们将研究肾上腺素能信号在这些关系中的中介作用。为了确定这些生物学改变的临床意义，这项研究将评估诊断后24个月内的无进展和总存活率。这一发现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.