Yamagishi S, Nakamura K, Inoue H, Kikuchi S, Takeuchi M
Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Med Hypotheses. 2005;64(6):1208-10. doi: 10.1016/j.mehy.2005.01.015.
Colorectal cancer is a major public health problem, being the second most common cause of cancer in developed countries. Several epidemiological studies have reported moderately increased risks of colorectal cancer in diabetic patients compared with general population. However, the underlying molecular link between diabetes and colorectal cancer remains to be elucidated. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs-their receptor (RAGE) interactions are involved in the development of atherosclerosis and diabetic microangiopathy. AGEs-RAGE interactions stimulated the growth of human pancreatic cancer cells through the autocrine induction of platelet-derived growth factor-B. Furthermore, we have recently found that AGEs stimulated the growth and migration of cultured human melanoma cells and that anti-RAGE antibodies inhibited tumor formation and lung metastasis of melanoma cell xenografts and subsequently improved survival in athymic mice. These observations let us to hypothesize that AGEs could explain the molecular link between diabetes and colorectal cancer. In this paper, we would like to propose the possible ways of testing our hypotheses. Is elevation of serum AGE levels a risk factor for colorectal cancer in patients with diabetes? Does treatment with metformin, which has a potential effect on the inhibition of glycation reactions in vivo, decrease the risk for colorecetal cancer in diabetic patients? If the answer is yes, is this beneficial effect of metformin superior to that of other anti-diabetic agents with equihypoglycemic properties? Does treatment with pyridoxamine, a post-Amadori inhibitor (so-called Amadorins) of AGE formation, reduce the risk for colorectal cancer as well? Furthermore, are increased levels of AGEs and RAGE in colorectal cancer associated with poor prognosis in patients with diabetes? These clinical studies could clarify whether the AGEs-RAGE interactions serve as a causal link between diabetes and colorectal cancer.
结直肠癌是一个重大的公共卫生问题，是发达国家第二大常见癌症病因。多项流行病学研究报告称，与普通人群相比，糖尿病患者患结直肠癌的风险适度增加。然而，糖尿病与结直肠癌之间潜在的分子联系仍有待阐明。在糖尿病中，晚期糖基化终产物（AGEs）的形成和积累不断进展。越来越多的证据表明，AGEs与其受体（RAGE）的相互作用参与了动脉粥样硬化和糖尿病微血管病变的发展。AGEs-RAGE相互作用通过自分泌诱导血小板衍生生长因子-B刺激人胰腺癌细胞的生长。此外，我们最近发现AGEs刺激培养的人黑色素瘤细胞的生长和迁移，并且抗RAGE抗体抑制黑色素瘤细胞异种移植的肿瘤形成和肺转移，随后提高无胸腺小鼠的存活率。这些观察结果使我们推测AGEs可以解释糖尿病与结直肠癌之间的分子联系。在本文中，我们想提出检验我们假设的可能方法。血清AGE水平升高是否是糖尿病患者患结直肠癌的危险因素？二甲双胍在体内对糖基化反应具有潜在的抑制作用，用其治疗是否能降低糖尿病患者患结直肠癌的风险？如果答案是肯定的，二甲双胍的这种有益作用是否优于其他具有同等降血糖特性的抗糖尿病药物？吡哆胺是一种AGE形成的阿马多里后抑制剂（所谓的阿马多里宁），用其治疗是否也能降低患结直肠癌的风险？此外，结直肠癌中AGEs和RAGE水平的升高是否与糖尿病患者的不良预后相关？这些临床研究可以阐明AGEs-RAGE相互作用是否是糖尿病与结直肠癌之间的因果联系。
