DEVELOPMENT OF BIOLOGICAL MARKERS FOR INDIVIDUAL CANCER RISK AND CANCER PREVENTION ON THE BASIS OF A PROSPECTIVE COHORT STUDY

我们在普通人群(总共3625名年龄在40岁以上的人)中进行了一项前瞻性队列研究，使用各种生物标记物和关于生活方式的问卷，调查了与人类癌症发生有关的宿主与环境的相互作用。一项对队列成员长达11年的跟踪调查发现，共有192例癌症病例，显示以K562为靶细胞的基线同位素释放法评估的外周血淋巴细胞(PBL)NK(自然杀伤)活性与癌症发病率呈负相关。以NK活性低者的风险为参照，所有部位癌症发病的年龄调整相对危险度分别为0.62(95%CI，0.38~1.03)和0.72(0.45~1.16)，女性分别为0.56(0.31~1.01)和0.52(0.28~0.95)。NK活性中等和高度的两性分别为0.59(0.40~0.87)和0.63(0.43~0.92)。虽然我们发现NK活性与选定的生活方式因素有关，但即使在调整这些因素后，结果也几乎没有变化。在我们的前瞻性队列研究中，我们进一步研究了105名健康人PBL的两种不同细胞毒性(穿孔素/颗粒酶依赖和Fas配体依赖)，以及NK细胞、NK细胞上KIR(杀伤细胞抑制受体)和KAR(杀伤细胞激活受体)的表达以及细胞因子的产生。我们发现，即使对高表达MHC-I类分子的靶细胞，PBL也表现出很强的FasL非依赖性NK活性，并且这种NK活性与我们以K562为靶细胞的队列研究中测得的结果有很好的相关性。

We investigated host-environmental interaction involved in human carcinogenesis in terms of a prospective cohort study among a general population (a total of 3,625 individuals aged over 40 years), using various biological markers along with a questionnaire on lifestyle. An eleven-year follow-up survey on cohort members found a total of 192 cancer cases, revealing that NK (natural killer) activity of peripheral blood lymphocytes (PBL), which was assessed at baseline by isotope-release assay using K562 as target cells, showed a negative association with cancer incidence. Categorizing the NK activity of PBL by tertiles, age-adjusted relative risk of cancer incidence (all sites) is 0.62 (95%CI, 0.38-1.03) and O.72 (0.45-1.16) for men with medium and high NK activity, respectively, taking the risk of those with low NK activity as reference ; 0.56 (0.31-1.01) and 0.52 (0.28-0.95) for women with medium and high NK activity, respectively ; 0.59 (0.40-0.87) and 0.63 (0.43-0.92) for both sexes with medium and high NK activity, respectively. Although NK activity was found to be associated with selected lifestyle factors, the results almost unchanged even after adjusting for these factors.The findings in our prospective cohort study were followed by a further study to compare the two different cytotoxicities of PBL (perforin/granzyme-dependent and Fas ligand-dependent) among 105 healthy individuals, along with measurement of NK cells, expression of KIR (killer-cell inhibitory receptor) and KAR (killer-cell activating receptor) on NK cells, and production of cytokines. We found that PBL showed a strong FasL-independent NK activity even towards the target cells which highly express MHC class I, and that this NK activity was well correlated to that measured in our cohort study using K562 as target cells..