Mathonnet Muriel, Perraud Aurelie, Christou Niki, Akil Hussein, Melin Carole, Battu Serge, Jauberteau Marie-Odile, Denizot Yves
Muriel Mathonnet, Aurelie Perraud, Niki Christou, Carole Melin, Department of Digestive Surgery, Limoges University Hospital, 87042 Limoges, France.
World J Gastroenterol. 2014 Apr 21;20(15):4189-96. doi: 10.3748/wjg.v20.i15.4189.
Carcinogenesis is a multistep process that requires the accumulation of various genetic and epigenetic aberrations to drive the progressive malignant transformation of normal human cells. Two major hallmarks of carcinogenesis that have been described are angiogenesis and the stem cell characteristic of limitless replicative potential. These properties have been targeted over the past decade in the development of therapeutic treatments for colorectal cancer (CRC), one of the most commonly diagnosed and lethal cancers worldwide. The treatment of solid tumor cancers such as CRC has been challenging due to the heterogeneity of the tumor itself and the chemoresistance of the malignant cells. Furthermore, the same microenvironment that maintains the pool of intestinal stem cells that contribute to the continuous renewal of the intestinal epithelia also provides the necessary conditions for proliferative growth of cancer stem-like cells. These cancer stem-like cells are responsible for the resistance to therapy and cancer recurrence, though they represent less than 2.5% of the tumor mass. The stromal environment surrounding the tumor cells, referred to as the tumor niche, also supports angiogenesis, which supplies the oxygen and nutrients needed for tumor development. Anti-angiogenic therapy, such as with bevacizumab, a monoclonal antibody against vascular-endothelial growth factor, significantly prolongs the survival of metastatic CRC patients. However, such treatments are not completely curative, and a large proportion of patient tumors retain chemoresistance or show recurrence. This article reviews the current knowledge regarding the molecular phenotype of CRC cancer cells, as well as discusses the mechanisms contributing to their maintenance. Future personalized therapeutic approaches that are based on the interaction of the carcinogenic hallmarks, namely angiogenic and proliferative attributes, could improve survival and decrease adverse effects induced by unnecessary chemotherapy.
癌症发生是一个多步骤过程，需要积累各种基因和表观遗传异常，以驱动正常人类细胞的渐进性恶性转化。已描述的癌症发生的两个主要标志是血管生成和具有无限复制潜能的干细胞特征。在过去十年中，这些特性已成为全球最常见且致命的癌症之一——结直肠癌（CRC）治疗方法开发的靶点。由于肿瘤本身的异质性和恶性细胞的化疗耐药性，实体肿瘤如CRC的治疗一直具有挑战性。此外，维持有助于肠上皮持续更新的肠干细胞池的相同微环境，也为癌干细胞样细胞的增殖生长提供了必要条件。这些癌干细胞样细胞虽然在肿瘤组织中所占比例不到2.5%，却导致了对治疗的抵抗和癌症复发。肿瘤细胞周围的基质环境，即肿瘤微环境，也支持血管生成，为肿瘤发展提供所需的氧气和营养。抗血管生成疗法，如使用抗血管内皮生长因子的单克隆抗体贝伐单抗，可显著延长转移性CRC患者的生存期。然而，此类治疗并非完全治愈性的，很大一部分患者的肿瘤仍保留化疗耐药性或出现复发。本文综述了关于CRC癌细胞分子表型的当前知识，并讨论了其维持的机制。基于致癌标志（即血管生成和增殖属性）相互作用的未来个性化治疗方法，可能会提高生存率并减少不必要化疗引起的不良反应。
