González Nieves, Prieto Isabel, Del Puerto-Nevado Laura, Portal-Nuñez Sergio, Ardura Juan Antonio, Corton Marta, Fernández-Fernández Beatriz, Aguilera Oscar, Gomez-Guerrero Carmen, Mas Sebastián, Moreno Juan Antonio, Ruiz-Ortega Marta, Sanz Ana Belen, Sanchez-Niño Maria Dolores, Rojo Federico, Vivanco Fernando, Esbrit Pedro, Ayuso Carmen, Alvarez-Llamas Gloria, Egido Jesús, García-Foncillas Jesús, Ortiz Alberto
Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.
Oncotarget. 2017 Mar 14;8(11):18456-18485. doi: 10.18632/oncotarget.14472.
Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.
在过去20年中，全球糖尿病（DM）和结直肠癌导致的死亡人数分别增加了90%和57%。据估计，2型糖尿病患者患结直肠癌的风险比非糖尿病对照组高27%。然而，存在潜在的混杂因素，来自低收入国家的信息匮乏，全球范围内糖尿病患病率与结直肠癌发病率之间没有相关性，且这种关联随时间而演变，这表明存在其他环境因素的影响。这些关联的临床相关性取决于对其中涉及机制的理解。尽管证据有限，但胰岛素的使用与结直肠癌发病率增加有关，而二甲双胍与结直肠癌发病率降低有关。此外，结直肠癌与糖尿病靶器官损伤（如糖尿病肾病）有一些共同的细胞和分子途径。这些包括上皮细胞损伤、炎症和Wnt/β-连环蛋白途径的激活以及铁稳态缺陷等。事实上，一些药物已针对癌症和糖尿病肾病进行了临床试验。全基因组关联研究已经确定了与糖尿病相关的基因（如TCF7L2），这些基因可能也与结直肠癌有关。我们综述了糖尿病与结直肠癌关联的流行病学证据、潜在的病理生理机制及治疗意义。进一步的研究应阐明全球范围内糖尿病与结直肠癌之间的关联，通过对所涉及分子途径的表征来加强因果关系的生物学合理性，寻找糖尿病条件下结直肠癌的特定分子特征，并最终探索预防或治疗结直肠癌的糖尿病特异性策略。
