Mucins and immune cell interactions in ovarian cancer pathogenesis & progression

 描述（由申请人提供）：在本R35中，我回顾了癌症预防和早期发现的障碍，包括以下需求：1）协调卵巢癌的个体风险因素 与流行病学证据的整体; 2）找到不同癌症常见的风险因素的统一解释; 3）证明粘蛋白肿瘤抗原水平不仅由肿瘤而且由肿瘤的风险因素改变;和4）能够在白色血细胞计数（WBC）的背景下考虑血清生物标志物。我们的研究表明，卵巢癌的发病机制涉及急性和慢性事件，这些事件影响与粘蛋白（MUC）家族蛋白质CA15.3（MUC 1）和CA 125（MUC 16）相关的免疫。这些线上皮束和过度表达的炎症，激素，或肿瘤事件影响这些组织。急性事件，如腮腺炎或输卵管结扎释放肿瘤样MUC 1和MUC 16，使其暴露于免疫系统，并产生抗MUC 1或抗MUC 16抗体，保护免受表达粘蛋白的卵巢癌。慢性事件如子宫内膜异位症、反复排卵和在生殖器区域使用滑石粉会导致持续暴露于粘蛋白、免疫力下调、抗体水平降低和卵巢癌风险增加。免疫力也可以解释风险因素，如衰老，肥胖，吸烟，儿童感染，以及许多不同癌症常见的生殖因素。我们一直在努力推广这样一种观点，即它不仅是一种可以影响粘蛋白抗原（或抗粘蛋白抗体）水平的癌症，而且还可以影响癌症的风险因素，如年龄，种族，BMI，奇偶性和吸烟。在癌症病例和对照组中都可以看到风险因素和粘蛋白标记物之间的关联。一个主要的障碍是缺乏数据集，允许粘蛋白抗原（或抗体）水平的白细胞计数的情况下进行检查。我们研究了卵巢癌诊断时的CA 125、流行病学因素和WBC计数，并计算了炎症生物标志物嗜中性粒细胞与淋巴细胞比率（NLR）。较高的NLR和较低的淋巴细胞计数与较高的肿瘤分期和分级、较高的CA 125和较差的生存率相关。NLR与风险因素相关，包括犹太种族，身高较高，排卵周期较多，癌症家族史和滑石粉使用。为了进一步研究，我们建议：1）检测诊断时卵巢癌病例和全国调查妇女血清中的CA 125、CA 15. 3、抗CA 125和抗CA 15.3抗体，包括WBC和危险因素数据; 2）开发一种新的检测方法来定量CA 125的结合（或CA 15.3）与WBC亚类结合的功能性免疫效应;和4）开始“下一代”病例对照研究，该研究在治疗前招募病例和良性疾病对照，并收集基线WBC，危险因素数据，和手术标本三十年来，我一直致力于通过流行病学和生物标志物研究来促进卵巢癌的预防和早期检测，并获得了广泛的视野，将癌症的常见风险因素，粘蛋白肿瘤抗原以及体液和细胞免疫反应与之联系起来。只有通过R35机制才能迅速推进这项研究。

 DESCRIPTION (provided by applicant): In this R35, I review obstacles to cancer prevention and early detection including the needs: 1) to reconcile individual risk factors for ovarian cancer with the totality of epidemiologic evidence; 2) to find unifying explanations for risk factors common to different cancers; 3) to demonstrate that mucin tumor antigen levels are changed not only by the tumor but also by risk factors for the tumor; and 4) to be able to consider serum biomarkers in the context of the white blood count (WBC). Our research suggests ovarian cancer pathogenesis involves acute and chronic events that affect immunity related to the mucin (MUC) family of proteins, CA15.3 (MUC1) and CA125(MUC16). These line epithelial tracts and are over expressed during inflammatory, hormonal, or neoplastic events affecting these tissues. Acute events like mumps or a tubal ligation release tumor-like MUC1 and MUC16, expose them to the immune system, and create anti-MUC1 or anti-MUC16 antibodies protective against mucin-expressing ovarian cancer. Chronic events like endometriosis, repeated ovulation, and talc use in the genital area cause persistent exposure to mucins, down regulation of immunity, lower antibody levels, and increased risk for ovarian cancer. Immunity may also explain risk factors like aging, obesity, smoking, childhood infections, and reproductive factors that are common to many different cancers. We have sought to promote the idea that it is not only a cancer that can affect mucin antigen (or anti-mucin antibody) levels but also risk factors for cancer such as age, ethnicity, BMI, parity, and smoking. Associations between risk factors and mucin markers can be seen in both cancer cases and controls. A major obstacle is a paucity of datasets that allow mucin antigen (or antibody) levels to be examined in the context of the WBC count. We studied CA125, epidemiologic factors, and WBC counts at diagnosis of ovarian cancer and calculated the neutrophil-to-lymphocyte ratio (NLR), a biomarker of inflammation. Greater NLR and lower lymphocyte count was associated with higher tumor stage and grade, higher CA125, and poorer survival. NLR correlated with risk factors including Jewish ethnicity, taller height, more ovulatory cycles, family history of cancer, and talc use. To move forward, we propose to: 1) assay CA125, CA15.3, anti-CA125 and anti-CA15.3 antibodies in sera from ovarian cancer cases at diagnosis and women from national surveys, both with WBC and risk factor data; 2) develop a novel assay to quantify binding of CA125 (or CA15.3) to WBC subclasses; 3) study the functional immune effects of CA125-binding to WBCs; and 4) begin a "next generation" case control study that enrolls cases and benign disease controls prior to therapy and collects baseline WBC, risk factor data, and operative specimens. For three decades, I have sought to advance the prevention and early detection of ovarian cancer through epidemiologic and biomarker research and gained a broad vision inter- relating common risk factors for cancer, mucin tumor antigens, and humoral and cellular immune reactions to them. Taking this research forward expeditiously can only be accomplished by an R35 mechanism.