Paulsen Jan Erik, Bjørheim Jens, Røe Janne, Eide Tor Jacob, Alexander Jan, Gaudernack Gustav
Department of Environmental Medicine, The National Institute of Public Health, Oslo, Norway.
Anticancer Res. 2002 Jan-Feb;22(1A):171-5.
Rat colon carcinogenesis induced by 2 x 15 mg/kg body weight of azoxymethane (AOM) is a standard model, widely used to evaluate the role of nutritional components and chemopreventive agents at various stages of tumorigenesis. In this model, KRAS mutations have been frequently observed in aberrant crypt foci (ACF), putative preneoplastic lesions, as well as in tumours. Therefore we used this model and vaccinated F344 rats with a mixture of synthetic mutant KRAS peptides (MT KRAS) corresponding to frequent KRAS exon 1 mutations before AOM treatment in order to study the role of KRAS mutations in the development of ACF and subsequently tumours. The controls were sham-vaccinated with KRAS exon 1 wild-type KRAS peptides (WT KRAS). MT KRAS vaccination suppressed the number of ACF by 42% at week 13 (p=0.001). The subpopulation of ACF suppressed by MT KRAS vaccination had higher focal crypt multiplicity than the control ACF population (p=0.001). At week 26, vaccination reduced the KRAS mutation frequency in ACF from 50% in the MT KRAS group to 13% in the WT KRAS (p=0.038). However, at this phase of carcinogenesis, vaccination did not have significant effects on the ACF number and focal crypt multiplicity. Surprisingly, the KRAS mutation frequency was only 5% in the colonic tumours of the controls (1 out of 20 tumours). Although there were no tumours with KRAS mutations in the MT KRAS group, the possible effect of vaccination could not be evaluated. These data indicate that KRAS mutations play a minor role in colonic tumorigenesis and that ACF with KRAS mutations could hardly be the precursors of the AOM-induced tumours in rats. Hence, the cancer protective potential of a KRAS vaccine in the early phase of AOM-induced colon carcinogenesis in the rat appeared minuscule. Additional studies in a model with a high outcome of KRAS mutations in colonic tumours are needed to evaluate the effects of a KRAS vaccine at later stages of tumorigenesis.
用2×15毫克/千克体重的氧化偶氮甲烷（AOM）诱导大鼠结肠癌发生是一种标准模型，被广泛用于评估营养成分和化学预防剂在肿瘤发生各个阶段的作用。在这个模型中，在异常隐窝灶（ACF）、假定的癌前病变以及肿瘤中经常观察到KRAS突变。因此，我们使用这个模型，在AOM处理前用对应于常见KRAS第1外显子突变的合成突变KRAS肽混合物（MT KRAS）对F344大鼠进行疫苗接种，以研究KRAS突变在ACF以及随后肿瘤发生中的作用。对照组用KRAS第1外显子野生型KRAS肽（WT KRAS）进行假疫苗接种。MT KRAS疫苗接种在第13周时使ACF数量减少了42%（p = 0.001）。MT KRAS疫苗接种所抑制掉的ACF亚群，其灶性隐窝多倍性高于对照ACF群体（p = 0.001）。在第26周时，疫苗接种使ACF中的KRAS突变频率从MT KRAS组的50%降至WT KRAS组的13%（p = 0.038）。然而，在致癌作用的这个阶段，疫苗接种对ACF数量和灶性隐窝多倍性没有显著影响。令人惊讶的是，对照组结肠肿瘤中的KRAS突变频率仅为5%（20个肿瘤中有1个）。虽然MT KRAS组没有出现KRAS突变的肿瘤，但疫苗接种的可能效果无法评估。这些数据表明，KRAS突变在结肠肿瘤发生中起的作用较小，并且具有KRAS突变的ACF几乎不可能是AOM诱导的大鼠肿瘤的前体。因此，KRAS疫苗在AOM诱导的大鼠结肠癌发生早期阶段的癌症保护潜力似乎微乎其微。需要在结肠肿瘤中KRAS突变发生率高的模型中进行更多研究，以评估KRAS疫苗在肿瘤发生后期阶段的效果。
