Lee J J, Liu D, Lee J S, Kurie J M, Khuri F R, Ibarguen H, Morice R C, Walsh G, Ro J Y, Broxson A, Hong W K, Hittelman W N
Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
J Natl Cancer Inst. 2001 Jul 18;93(14):1081-8. doi: 10.1093/jnci/93.14.1081.
Lung cancer risk remains elevated for many years after quitting smoking. To assess using proliferation indices in bronchial tissues as an intermediate endpoint biomarker in lung cancer chemoprevention trials, we determined the relationship between the extent, intensity, and cessation of tobacco smoking and proliferative changes in bronchial epithelial biopsy specimens.
Bronchial biopsy specimens were obtained from up to six epithelial sites in 120 current smokers (median pack-years, 42) and 207 former smokers (median pack-years, 40; median quit-years, 8.1). Sections from the paraffin-embedded specimens were stained with hematoxylin--eosin to determine the metaplasia index and with an antibody to Ki-67 to determine the proliferative (labeling) index for the basal and parabasal (Ki-67 PLI) layers. All statistical tests were two-sided.
Biopsy sites with metaplasia had statistically significantly higher Ki-67-labeling indices than those without metaplasia (P<.001) in both current and former smokers. Increased proliferation was observed in multiple biopsy sites, with the average Ki-67 PLI of the subject strongly correlating with the metaplasia index (r =.72 for current smokers; P<.001), even in sites without metaplasia (r =.23 for current smokers; P<.001). In current smokers, the Ki-67 PLI was associated with the number of packs smoked/day (P =.02) but not with smoking years or pack-years. In subjects who had quit smoking, the Ki-67 PLI dropped statistically significantly within 1 year (P =.008) but remained detectable for more than 20 years, even in the absence of squamous metaplasia.
Smoking appears to elicit a dose-related proliferative response in the bronchial epithelia of active smokers. Although the proliferative response decreased gradually in former smokers, a subset of individuals had detectable proliferation for many years and may benefit from targeted chemoprevention. Bronchial epithelial proliferation, measured by Ki-67, may provide a useful biomarker in the assessment of lung cancer risk and in the response to chemopreventive interventions.
戒烟多年后肺癌风险仍持续升高。为了评估在肺癌化学预防试验中使用支气管组织中的增殖指数作为中间终点生物标志物，我们确定了吸烟程度、强度和戒烟与支气管上皮活检标本增殖变化之间的关系。
从120名当前吸烟者（中位吸烟包年数为42）和207名既往吸烟者（中位吸烟包年数为40；中位戒烟年数为8.1）的多达六个上皮部位获取支气管活检标本。将石蜡包埋标本的切片用苏木精-伊红染色以确定化生指数，并用抗Ki-67抗体确定基底和副基底（Ki-67增殖标记指数）层的增殖（标记）指数。所有统计检验均为双侧检验。
在当前吸烟者和既往吸烟者中，有化生的活检部位的Ki-67标记指数在统计学上显著高于无化生的部位（P<0.001）。在多个活检部位观察到增殖增加，受试者的平均Ki-67增殖标记指数与化生指数密切相关（当前吸烟者r = 0.72；P<0.001），即使在无化生的部位也是如此（当前吸烟者r = 0.23；P<0.001）。在当前吸烟者中，Ki-67增殖标记指数与每日吸烟包数相关（P = 0.02），但与吸烟年限或吸烟包年数无关。在戒烟者中，Ki-67增殖标记指数在1年内显著下降（P = 0.008），但即使在无鳞状化生的情况下，20多年内仍可检测到。
吸烟似乎在现吸烟者的支气管上皮中引发剂量相关的增殖反应。虽然既往吸烟者的增殖反应逐渐降低，但一部分个体多年来仍可检测到增殖，可能从靶向化学预防中获益。通过Ki-67测量的支气管上皮增殖可能为评估肺癌风险和化学预防干预反应提供有用的生物标志物。
