Uchida K, Samma S, Momose H, Kashihara N, Rademaker A, Oyasu R
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611.
J Urol. 1990 Mar;143(3):618-21. doi: 10.1016/s0022-5347(17)40041-3.
There is evidence to suggest that control mechanisms, either growth-stimulatory, inhibitory or inductive, may play a role in carcinogenesis. To test the hypothesis that treatment of rat urinary bladder with carcinogen induces alterations in the stroma which result in modified epithelial-stromal interactions, experiments were conducted using a rat model specifically designed for the study. Following exposure of Fischer F344 rats in drinking water to the urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN) for four weeks, bladders were removed and subjected to a brief detergent treatment to completely remove epithelium. The bladders without epithelium ("stroma" bladder) were heterotopically transplanted to syngeneic recipients. Four days later, the denuded mucosa surface was resurfaced with intraluminal instillation of urothelial cells, either untreated or treated with BHBN for six weeks (6w-BHBN) or 10 weeks (10w-BHBN). Examination at 12 weeks posttransplant of the "stroma" bladders that had received 6w-BHBN urothelial cells showed a higher tumor incidence of carcinoma in the BHBN-exposed "stroma" bladders as compared with the incidence in the carcinogen-unexposed "stroma" bladders (p less than 0.05). Examination at 18 weeks posttransplant showed 100% incidence of tumors in all "stroma" bladders irrespective of the lengths of BHBN exposure of urothelial cells. However, among the bladders that had received 6w-BHBN urothelial cells, carcinogen-exposed "stroma" bladders proved to be better "soil" for neoplastic cells to proliferate; the mean tumor volume as well as the mean total tumor volume per bladder were significantly higher than in the control "stroma" bladders (p less than 0.01 for each comparison). Similarly, among the bladders that had been resurfaced with 10w-BHBN urothelial cells, the mean total tumor volume per bladder was greater in the carcinogen-treated "stroma" bladders than in the controls (p less than 0.05). No proliferative or neoplastic changes were observed in the BHBN exposed "stroma" bladders which had been resurfaced with normal urothelial cells. Our data indicate that neoplastic growth of carcinogen treated urothelium is enhanced when such cells interact with the stroma which has also been exposed to carcinogen.
有证据表明，无论是生长刺激、抑制还是诱导的控制机制，都可能在致癌过程中发挥作用。为了验证用致癌物处理大鼠膀胱会诱导基质发生改变，从而导致上皮-基质相互作用改变这一假说，我们使用专门设计用于该研究的大鼠模型进行了实验。将Fischer F344大鼠的饮用水中加入膀胱致癌物N-丁基-N-(4-羟基丁基)亚硝胺（BHBN），持续四周，然后取出膀胱，进行短暂的去污剂处理以完全去除上皮。将无上皮的膀胱（“基质”膀胱）异位移植到同基因受体中。四天后，通过向腔内滴注尿路上皮细胞使裸露的黏膜表面重新覆盖上皮，这些上皮细胞要么未经处理，要么用BHBN处理六周（6w-BHBN）或十周（10w-BHBN）。对接受6w-BHBN尿路上皮细胞的“基质”膀胱在移植后12周进行检查发现，与未接触致癌物的“基质”膀胱相比，接触BHBN的“基质”膀胱中癌的肿瘤发生率更高（p小于0.05）。移植后18周的检查显示，所有“基质”膀胱无论尿路上皮细胞接触BHBN的时长如何，肿瘤发生率均为100%。然而，在接受6w-BHBN尿路上皮细胞的膀胱中，接触致癌物的“基质”膀胱被证明是肿瘤细胞增殖的更好“土壤”；每个膀胱的平均肿瘤体积以及平均总肿瘤体积均显著高于对照“基质”膀胱（每次比较p均小于0.01）。同样，在重新覆盖10w-BHBN尿路上皮细胞的膀胱中，经致癌物处理的“基质”膀胱中每个膀胱的平均总肿瘤体积大于对照组（p小于0.05）。在用正常尿路上皮细胞重新覆盖的接触BHBN的“基质”膀胱中未观察到增殖或肿瘤性变化。我们的数据表明，当致癌物处理过的尿路上皮细胞与同样接触过致癌物的基质相互作用时，其肿瘤生长会增强。
