Cobb Stephanie, Wood Thomas, Ceci Jeffrey, Varro Andrea, Velasco Marco, Singh Pomila
Department of Anatomy & Neurosciences, University of Texas Medical Branch, Galveston, Texas 77555-1043, USA.
Cancer. 2004 Mar 15;100(6):1311-23. doi: 10.1002/cncr.20094.
The authors recently reported that transgenic mice (hGAS) expressing pharmacologic levels of progastrin (PG) (> 10 nM to 100 nM) exhibited increased susceptibility to colon carcinogenesis in response to azoxymethane (AOM). It is not known whether PG functions as a cocarcinogen at the concentrations observed in patients with hypergastrinemia (approximately 1.0 nM).
The authors generated transgenic mice that overexpressed either wild-type (wtPG) or mutant (mtPG) human PG in the intestinal mucosa using the murine fatty acid binding protein (Fabp) promoter. Fabp-PG mice and their wild-type littermates were treated with AOM, and their colons were examined for preneoplastic (aberrant crypt foci [ACF]) and neoplastic (adenomas [Ads] and adenocarcinomas [AdCas]) lesions after 2 weeks and 6 months of treatment.
ACF and tumors were significantly more common (by a factor of approximately 2) in colon specimens from both Fabp-wtPG mice and Fabp-mtPG mice relative to wild-type mice. It is noteworthy that the multiplicity of ACF and the total number of small and large Ads and AdCas were significantly greater in colon specimens from Fabp-PG mice compared with colon specimens from wild-type mice, irrespective of gender.
The results of the current study suggest that at concentrations (approximately 1.0 nM) far lower than the ones observed in hGAS mice, PG functions as an equally potent cocarcinogen and significantly increases the risk of colon carcinogenesis in response to AOM. Thus, PG may represent a clinically relevant target molecule in patients with hypergastrinemia or colon carcinoma.
作者最近报道，表达药理水平胃泌素原（PG）（>10 nM至100 nM）的转基因小鼠（hGAS）对乙基亚硝脲（AOM）诱导的结肠癌发生易感性增加。尚不清楚在高胃泌素血症患者中观察到的浓度（约1.0 nM）下，PG是否作为一种促癌剂发挥作用。
作者使用小鼠脂肪酸结合蛋白（Fabp）启动子，构建了在肠黏膜中过表达野生型（wtPG）或突变型（mtPG）人PG的转基因小鼠。用AOM处理Fabp-PG小鼠及其野生型同窝仔鼠，在处理2周和6个月后检查其结肠的癌前病变（异常隐窝灶[ACF]）和肿瘤病变（腺瘤[Ads]和腺癌[AdCas]）。
相对于野生型小鼠，来自Fabp-wtPG小鼠和Fabp-mtPG小鼠的结肠标本中，ACF和肿瘤明显更常见（约为2倍）。值得注意的是，与野生型小鼠的结肠标本相比，来自Fabp-PG小鼠的结肠标本中ACF的数量、大小腺瘤和腺癌的总数均显著更多，且与性别无关。
本研究结果表明，在远低于hGAS小鼠中观察到的浓度（约1.0 nM）下，PG作为一种同样有效的促癌剂发挥作用，并显著增加了对AOM诱导的结肠癌发生风险。因此，PG可能是高胃泌素血症或结肠癌患者临床相关的靶分子。
