Cyclin A binds to CDK2 and plays critical roles when cells proliferate; staining for Ki67 can monitor the proliferation. The cyclin A expression pattern remains unclear in colorectal carcinogenesis and remote metastasis, however, and no one has reported on the association of its expression with key clinicopathologic factors in primary cancer. p27(kip1) protein-an extremely important inhibitor of CDK2-seems unchanged as colorectal cancers metastasize to the lymph nodes, a result contrary to that seen in gastric and prostatic cancers. To clarify the role of cyclin A in multistage colorectal neoplasms, cyclin A, CDK2, and Ki67 were immunohistochemically stained in 22 normal mucosa, 9 hyperplastic polyps, 61 adenomas, 197 primary carcinomas, 21 lymph node metastases, and 10 hepatic metastases. To clarify the alteration of p27(kip1) during lymphatic invasion, p27(kip1) was also stained in 21 primary cancers and paired lymph node foci. Situated in nuclei, cyclin A expression gradually increased from mild through moderate to severe dysplasia in adenomas and from normal tissue through hyperplasia to adenoma to early carcinoma. Expression was significantly decreased in the hepatic metastases and in the primary cancers showing venous invasion, deep infiltration, lymph node metastasis, mucinous type, advanced stage, or short postoperative survival time. Elevated cyclin A not only was linked with elevated CDK2 in primary cancers, but also was associated with increased Ki67 in both adenomas and primary carcinomas. Lymph node metastases lost more p27(kip1) than primary foci and hepatic lesions. Thus, dysregulation of cyclin A and its control mechanisms may contribute to colorectal carcinogenesis; abatement of overexpression of cyclin A is associated with hepatic metastasis and cancerous invasion. Loss of p27(kip1) may promote lymph node metastasis.
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