Malkinson Alvin M, Radcliffe Richard A, Bauer Alison K
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Carcinogenesis. 2002 Mar;23(3):411-7. doi: 10.1093/carcin/23.3.411.
We have reported previously [Bauer,A.K. et al. (2001) Exp. Lung Res., 27, 197-216] that the 13 CXB recombinant inbred mouse strains derived from BALB/cByJ and C57BL/6J progenitors vary in their responsiveness to both lung tumor promotion and pulmonary inflammation induced by chronic administration of butylated hydroxytoluene (BHT). Herein we have applied these data, along with markers known to be polymorphic among these strains, to conduct linkage analysis of these susceptibilities. This enabled us to assign provisional quantitative trait loci (QTL) that govern these strain variations in susceptibility as a genetic approach to assessing the influence of inflammation on tumorigenesis. A Chr 15 (39.1-55.6 cM) QTL regulated susceptibility to two-stage carcinogenesis, a protocol in which chronic BHT exposure followed a single urethane injection; a similar QTL on Chr 15 (46.7-61.7 cM) influenced BHT induction of cyclooxygenase-2 (COX-2) expression. A Chr 18 (37-41 cM) QTL modulated both the number of lung tumors induced by 3-methylcholanthrene (MCA) injection with subsequent treatment with BHT as well as BHT-induced ingress of macrophages into airways. Other chromosomal sites that affected either the degree of BHT-elicited macrophage infiltration, Chr 9 (48-61 cM), or COX-2 induction, Chr 10 (59-65 cM), were reported to influence susceptibility to lung tumorigenesis in other strains. The fact that common chromosomal locations regulate both inflammation and carcinogenesis suggests a pathogenic role of inflammatory mediators in tumor development that may be exploited for chemoprevention of lung cancer.
我们之前报道过[鲍尔，A.K.等人（2001年）《实验肺研究》，27卷，第197 - 216页]，源自BALB/cByJ和C57BL/6J祖系的13种CXB重组近交小鼠品系，在对由长期给予丁基羟基甲苯（BHT）诱导的肺肿瘤促进作用和肺部炎症的反应性方面存在差异。在此，我们应用这些数据以及已知在这些品系中具有多态性的标记，对这些易感性进行连锁分析。这使我们能够确定临时的数量性状基因座（QTL），这些基因座控制着这些品系在易感性方面的差异，作为一种评估炎症对肿瘤发生影响的遗传学方法。位于15号染色体（39.1 - 55.6厘摩）的一个QTL调节对两阶段致癌作用的易感性，该方案是在单次注射乌拉坦后长期暴露于BHT；15号染色体上一个类似的QTL（46.7 - 61.7厘摩）影响BHT诱导的环氧化酶 - 2（COX - 2）表达。位于18号染色体（37 - 41厘摩）的一个QTL调节注射3 - 甲基胆蒽（MCA）并随后用BHT处理诱导的肺肿瘤数量，以及BHT诱导的巨噬细胞进入气道的情况。据报道，影响BHT引发的巨噬细胞浸润程度的其他染色体位点（9号染色体，48 - 61厘摩）或COX - 2诱导的位点（10号染色体，59 - 65厘摩）会影响其他品系对肺肿瘤发生的易感性。共同的染色体位置调节炎症和致癌作用这一事实表明，炎症介质在肿瘤发展中具有致病作用，这可能被用于肺癌的化学预防。
