Itoh F, Imai K
First Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
Hokkaido Igaku Zasshi. 1996 Jan;71(1):9-14.
Accumulating evidences that carcinogenesis requires multiple gene alterations of oncogenes and tumor suppressor genes have recently emerged. In addition, genes related to invasion and metastasis are also important in understanding development of colorectal cancer. In this study, clinical significance and application of tumor suppressor genes and invasion related genes such as APC (adenomatous polyposis coli), DCC (deleted in colorectal carcinoma) tumor suppressor genes and invasion related gene, matrilysin were studied. In the mouse tumor induced by mutagen contained in cooked food, PhIP (2-amino-1-methyl-6- phenylimidazo [4,5-b] pyridine), nonsense mutations of APC gene that is similar to human colorectal cancer have been observed. These results suggested the quite interesting issue of mutagen contained in daily food having etiological role of colorectal cancer. DCC gene alteration, decreased expression of DCC mRNA was detected in 60% of advanced colorectal cancer. In all cases with liver metastasis, DCC expression was absent or markedly decreased, a finding that detection of DCC expression have an clinical importance that predicts metastatic potential of colorectal cancer. Matrilysin, the member of MMPs (matrix metalloproteinases) which degrade matrix components such as type IV collagen, laminin or fibronectin. In most of colorectal cancer, matrilysin was overexpressed in tumor cells. Matrilysin-transfected colorectal cancer cells showed more invasive ability in vitro and gained metastatic potential in SCID mice. Suppression of matrilysin expression by treated with all-trans retinoic acid (ATRA) or introduction of anti-sense matrilysin decreased the invasive ability in vitro. This result suggests that matrilysin plays an important role in invasion and metastasis and have a possibility of new anti-invasion therapy.
越来越多的证据表明，致癌作用需要原癌基因和肿瘤抑制基因发生多种基因改变。此外，与侵袭和转移相关的基因在理解结直肠癌的发展过程中也很重要。在本研究中，对肿瘤抑制基因和侵袭相关基因，如APC（腺瘤性息肉病 coli）、DCC（结直肠癌缺失）肿瘤抑制基因以及侵袭相关基因基质溶解素的临床意义和应用进行了研究。在用熟食中含有的诱变剂诱导的小鼠肿瘤中，已观察到与人类结直肠癌相似的APC基因无义突变。这些结果提示了日常食物中含有的诱变剂对结直肠癌具有病因学作用这一相当有趣的问题。在60%的晚期结直肠癌中检测到DCC基因改变，DCC mRNA表达降低。在所有发生肝转移的病例中，均未检测到DCC表达或其表达明显降低，这一发现表明检测DCC表达对预测结直肠癌的转移潜能具有临床重要性。基质溶解素是基质金属蛋白酶（MMPs）的成员，可降解IV型胶原、层粘连蛋白或纤连蛋白等基质成分。在大多数结直肠癌中，肿瘤细胞中基质溶解素过度表达。转染基质溶解素的结直肠癌细胞在体外显示出更强的侵袭能力，并在SCID小鼠中获得了转移潜能。用全反式维甲酸（ATRA）处理或导入反义基质溶解素抑制基质溶解素表达可降低体外侵袭能力。这一结果表明基质溶解素在侵袭和转移中起重要作用，并且有可能成为新的抗侵袭治疗方法。
