Gazdar A F
Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas 75235-8590.
Anticancer Res. 1994 Jan-Feb;14(1B):261-7.
Lung cancer arises after a series of morphological changes, which take several years to progress from normal epithelium to invasive cancer. The morphological changes progress from hyperplasia, to metaplasia, to dysplasia, to carcinoma in situ, to invasive cancer and finally to metastatic cancer. Multiple molecular changes have been documented in lung cancers, both small cell (SCLC) and non-small cell (NSCLC) types. The number of changes has been estimated to be in double digits. How can so many changes develop in one cell? One possible explanation is the "field cancerization" theory, that states that all or much of the aerodigestive tract epithelium has been mutagenized, perhaps as the result of exposure to tobacco products or other carcinogens. The molecular changes include activation of dominant oncogenes (myc family, K-ras and HER/2/neu genes), as well as loss of recessive growth regulatory genes or anti-oncogenes (p53, and rb as well as unidentified gene or genes on chromosome 3). However, cytogenetic and molecular genetic studies indicate that multiple other specific sites of actual or potential DNA loss may be present in lung cancers. Many of the well characterized molecular changes may function as negative prognostic factors for survival in subsets of lung cancers. Other changes may include development of drug resistance, and production of growth factors and their receptors. It is tempting to associate specific molecular changes with specific morphological changes, as has been attempted in the colon. However, because of the difficulties in serially sampling the respiratory tract, only a modest amount of data has been collected to date. It appears that deletions of chromosome 3p, hyperproliferation and aneuploidy are early changes, while p53 mutations appear later in the preneoplastic cascade. Documentation of intermediate markers for lung cancer and prospective studies of their prognostic effects will be necessary for the design of rational chemoprevention trials.
肺癌是在一系列形态学变化之后发生的，从正常上皮细胞发展到浸润性癌需要数年时间。形态学变化从增生发展到化生，再到发育异常，到原位癌，再到浸润性癌，最后发展到转移性癌。在小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）中都记录到了多种分子变化。变化的数量估计为两位数。一个细胞怎么会发生这么多变化呢？一种可能的解释是“场癌化”理论，该理论认为，整个或大部分气消化道上皮细胞都已发生诱变，这可能是接触烟草制品或其他致癌物的结果。分子变化包括显性癌基因（myc家族、K-ras和HER/2/neu基因）的激活，以及隐性生长调节基因或抑癌基因（p53、rb以及3号染色体上未确定的一个或多个基因）的缺失。然而，细胞遗传学和分子遗传学研究表明，肺癌中可能还存在多个其他实际或潜在的DNA缺失的特定位点。许多特征明确的分子变化可能是肺癌亚组患者生存的不良预后因素。其他变化可能包括耐药性的产生，以及生长因子及其受体的产生。人们很想将特定的分子变化与特定的形态学变化联系起来，就像在结肠癌研究中所尝试的那样。然而，由于对呼吸道进行连续采样存在困难，迄今为止只收集到了少量数据。似乎3号染色体短臂缺失、过度增殖和非整倍体是早期变化，而p53突变则在癌前病变过程中出现得较晚。记录肺癌的中间标志物并对其预后影响进行前瞻性研究，对于合理设计化学预防试验是必要的。
