Role of the Sex Hormones and Insulin/IGF-Axes in Endometrial Cancer Recurrence

性激素和胰岛素/IGF-轴在子宫内膜癌复发中的作用

• 批准号: 8271330
• 负责人: HOWARD D STRICKLER
• 金额: $ 39.51万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271330
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Biological Factors; Blood Circulation; Cancer Patient; Cancerous; Cells; Cessation of life; Clinical; Cohort Studies; Collaborations; Cross-Sectional Studies; Data; Development; Endometrial; Endometrial Carcinoma; Endometrioid Carcinoma; Enrollment; Estradiol; Estrogen Receptors; Estrogens; Estrone; Etiology; Fasting; Free Association; Gonadal Steroid Hormones; Growth; Growth Factor; Gynecologic; Gynecologic Oncology Group; Histocytochemistry; Hyperinsulinism; Hysterectomy; Immunohistochemistry; Insulin; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth-Factor Binding Protein 1; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like-Growth Factor I Receptor; Lead; Malignant Neoplasms; Measurement; Measures; Messenger RNA; Metabolic; Obesity; Observational Study; Pathway interactions; Patients; Play; Postmenopause; Production; Progesterone; Progesterone Receptors; Prospective Studies; Recurrence; Residual Tumors; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Sequence Homology; Serological; Serum; Serum Proteins; Sex Hormone-Binding Globulin; Signal Pathway; Site; Source; Specimen; Staging; Subcategory; Testing; Tissues; Triage; Uterine Prolapse; Uterus; Woman; Women' s Health; aggressive therapy; base; cancer recurrence; carcinogenesis; cohort; follow-up; hazard; improved; novel therapeutic intervention; prognostic; prospective; public health relevance; tumor; tumorigenic

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy in US women, with more than 39,000 new cases each year. Stage II or higher endometrial cancers recur in more than 30% of cases, and most recurrent cases result in death. However, little is known regarding the biologic factors that underlie endometrial cancer recurrence. We reason that many of the same risk factors associated with the initial development of endometrial cancer may also represent risk factors for recurrence (e.g., by stimulating the growth of residual tumor and pre-cancerous cells). Two of the strongest risk factors for endometrioid adenocarcinoma (EA), the most common form of endometrial cancer, are estrogen exposure and obesity. In fact, high estrogen levels are common in obese postmenopausal women, and are thought to partly explain the obesity-EA relationship. Hyperinsulinemia is also common in obese patients, and our recent prospective study in the Women's Health Initiative (WHI) found that insulin - which has mitogenic/anti-apoptotic activity - was significantly associated with risk of incident EA (hazard ratio, highest to lowest quartile = 2.33; 1.13-4.82), after controlling for estradiol. We also studied insulin-like growth factor-I (IGF-I). IGF-I shares sequence homology with insulin and is mitogenic. However, uterine and serum IGF-I levels are regulated by different mechanisms, and it is not known whether they are at all correlated. It is notable, therefore, that we found an inverse relation of EA with free IGF- I levels in serum, results that are in keeping with most prior cross-sectional studies, and could reflect the known anti-inflammatory activity of IGF-I in serum. An indirect effect such as this is consistent with there being little correlation between serum and uterine IGF-I levels or activity, a possibility that requires further study. Determining the role of insulin, the IGF-axis and sex hormones in EA recurrence has important clinical implications. First, it could provide a means of differentiating EA into prognostic subcategories (e.g., to triage patients into more or less aggressive therapy), and second, improved understanding of these tumorigenic pathways could lead to novel therapeutic approaches. Therefore, in collaboration with the Gynecologic Oncology Group (GOG), we propose the first large prospective study of the insulin, IGF and sex hormone axes and their associations with recurrence of stage II-IV EA. Subjects will include all of the 815 stage II-IV EA expected to be enrolled in GOG-0210, a study of endometrial cancer patients enrolled prior to treatment. More than 170 of the stage II-IV EA cases are expected to recur. Pretreatment specimens will be used to address the following aims. To study the associations of EA recurrence with: (i) fasting serum levels of insulin, total and free IGF-I, IGF-II, IGFBP-1 and -3, estradiol, estrone, progesterone and sex hormone binding globulin (SHBG); (ii) tumor expression of IGF-I, IGF-II, IGFBP-1 and -3 mRNA (based on RT-PCR), and of the insulin receptor, IGF-I receptor, estrogen receptor, progesterone receptor (based on immuno-histochemistry). Lastly, we will (iii) measure the correlations of serum and tissue IGF-I, IGF-II, IGFBP-1 and -3 in women with and without cancer. PUBLIC HEALTH RELEVANCE: Endometrial cancer is the most common gynecologic malignancy in women, and higher stage endometrial cancer is associated with high rates of recurrence and subsequent death. The proposed application will investigate the prognostic value of both serologic and tissue levels of sex hormones and insulin/IGF axis components in relation to endometrial cancer recurrence. The study will be conducted in a large, prospective cohort study of endometrial cancer (GOG-0210).

描述(申请人提供)：子宫内膜癌是美国女性最常见的妇科恶性肿瘤，每年新增病例超过39,000例。超过30%的病例会复发II期或更高级别的子宫内膜癌，大多数复发病例会导致死亡。然而，人们对子宫内膜癌复发的生物学因素知之甚少。我们推测，许多与子宫内膜癌最初发展相关的危险因素也可能是复发的危险因素(例如，通过刺激残留肿瘤和癌前细胞的生长)。子宫内膜样腺癌(EA)是最常见的子宫内膜癌，其最大的两个危险因素是雌激素暴露和肥胖。事实上，高雌激素水平在肥胖的绝经后女性中很常见，人们认为这在一定程度上解释了肥胖与EA的关系。高胰岛素血症在肥胖患者中也很常见，我们最近在妇女健康倡议(WHI)上进行的前瞻性研究发现，在控制雌二醇后，具有促分裂/抗凋亡活性的胰岛素与发生EA的风险显著相关(风险比，最高到最低四分位=2.33；1.13-4.82)。我们还研究了胰岛素样生长因子-I(IGF-I)。IGF-I与胰岛素序列同源，具有促有丝分裂作用。然而，子宫和血清IGF-I水平受到不同机制的调节，目前尚不清楚它们是否存在相关性。因此，值得注意的是，我们发现EA与血清中游离IGF-I水平呈负相关，这一结果与大多数先前的横断面研究一致，并可以反映已知的血清中IGF-I的抗炎活性。像这样的间接影响与血清和子宫IGF-I水平或活性之间几乎没有相关性是一致的，这一可能性需要进一步研究。确定胰岛素、IGF轴和性激素在EA复发中的作用具有重要的临床意义。首先，它可以提供一种方法来区分EA的预后亚类(例如，对患者进行或多或少的积极治疗)，其次，对这些肿瘤发生途径的更好理解可能导致新的治疗方法。因此，我们与妇科肿瘤学小组(GOG)合作，提出了第一项关于胰岛素、IGF和性激素轴及其与II-IV期EA复发的关系的大型前瞻性研究。受试者将包括所有预计将在GOG-0210中登记的815名II-IV期EA患者，这是一项在治疗前登记的子宫内膜癌患者的研究。预计超过170例II-IV期EA病例将复发。将使用前处理样品来实现以下目标。(1)空腹血清胰岛素、总和游离IGF-I、IGF-II、IGFBP-1和-3、雌二醇、雌酮、孕酮和性激素结合球蛋白(SHBG)水平；(2)肿瘤组织中IGF-I、IGF-II、IGFBP-1和-3mRNA的表达(RT-PCR法)，以及胰岛素受体、IGF-I受体、雌激素受体、孕激素受体(免疫组化法)的表达。最后，我们将(III)测量患有和不患有癌症的妇女血清和组织中IGF-I、IGF-II、IGFBP-1和-3的相关性。 公共卫生相关性：子宫内膜癌是女性最常见的妇科恶性肿瘤，分期较高的子宫内膜癌与较高的复发率和随后的死亡率有关。这项拟议的应用将调查血清学和组织性激素水平以及胰岛素/胰岛素样生长因子轴成分与子宫内膜癌复发的预后价值。这项研究将在一项关于子宫内膜癌的大型前瞻性队列研究中进行(GOG-0210)。