Mucins and immune cell interactions in ovarian cancer pathogenesis & progression

 描述(申请人提供)：在这本R35中，我回顾了癌症预防和早期发现的障碍，包括需要：1)协调卵巢癌的个体危险因素 这些研究包括：1)收集所有流行病学证据；2)为不同癌症常见的风险因素找到统一的解释；3)证明粘蛋白肿瘤抗原水平不仅受肿瘤的影响，还受肿瘤的风险因素的影响；4)能够在白细胞计数(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CA15.3(MUC1)和CA125(MUC16)相关的免疫。这些细胞排列在上皮区，在影响这些组织的炎症、激素或肿瘤事件中过度表达。腮腺炎或输卵管结扎术等急性事件会释放类似肿瘤的MUC1和MUC16，使它们暴露在免疫系统中，并产生抗MUC1或抗MUC16抗体，以防止粘蛋白表达的卵巢癌。子宫内膜异位症、反复排卵和生殖器区域使用滑石粉等慢性事件会导致持续接触粘蛋白、免疫调节下降、抗体水平降低，并增加患卵巢癌的风险。免疫也可以解释许多不同癌症常见的风险因素，如衰老、肥胖、吸烟、儿童感染和生殖因素。我们试图宣传这样一种观点，即癌症不仅会影响粘蛋白抗原(或抗粘蛋白抗体)水平，而且还会影响癌症的危险因素，如年龄、种族、BMI、产次和吸烟。风险因素和粘蛋白标记物之间的关联在癌症病例和对照组中都可以看到。一个主要的障碍是缺乏允许在白细胞计数的背景下检查粘蛋白抗原(或抗体)水平的数据集。我们研究了CA125、流行病学因素和卵巢癌诊断时的WBC计数，并计算了中性粒细胞/淋巴细胞比率(NLR)，这是炎症的生物标志物。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CA125和较差的生存有关。NLR与风险因素相关，包括犹太种族、身高、排卵周期、癌症家族史和滑石粉使用。为了进一步发展，我们建议：1)检测卵巢癌确诊病例和来自全国调查的妇女血清中的CA125、CA15.3、抗CA125和抗CA15.3抗体，包括白细胞和危险因素数据；2)开发一种新的分析方法，以量化CA125(或CA15.3)与WBC亚类的结合；3)研究CA125与WBC结合的功能免疫效应；以及4)开始“下一代”病例对照研究，在治疗前纳入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，我一直试图通过流行病学和生物标记物研究来推进卵巢癌的预防和早期发现，并获得了与癌症常见危险因素、粘液肿瘤抗原以及对它们的体液和细胞免疫反应相互关联的广泛视野。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.