Tanaka Shinji
Department of Molecular Oncology Tokyo Medical and Dental University Tokyo Japan.
Ann Gastroenterol Surg. 2018 Jan 24;2(2):106-115. doi: 10.1002/ags3.12059. eCollection 2018 Mar.
Accumulated evidence suggests that multiple molecular and cellular interactions promote cancer evolution in vivo. Surgical oncology is of growing significance to a comprehensive understanding of the malignant diseases for therapeutic application. We have analyzed more than 1000 clinical samples from surgically resected tissue to identify molecular biomarkers and therapeutic targets for advanced malignancies. Cancer stemness and mitotic instability were then determined as the essential predictors of aggressive phenotype with poor prognosis. Recently, whole genome/exome sequencing showed a mutational landscape underlying phenotype heterogeneity in caners. In addition, integrated genomic, epigenomic, transcriptomic, metabolic, proteomic and phenomic analyses elucidated several molecular subtypes that cluster in liver, pancreatic, biliary, esophageal and gastroenterological cancers. Identification of each molecular subtype is expected to realize the precise medicine targeting subtype-specific molecules; however, there are obstacle limitations to determine matching druggable targets or synthetic lethal interactions. Current breakthroughs in genome editing technology can provide us with unprecedented opportunity to recapitulate subtype-specific pathophysiology in vitro and in vivo. Given a great potential, on-demand editing system can design actionable strategy and revolutionize precision cancer medicine based on surgical oncology.
越来越多的证据表明，多种分子和细胞相互作用促进了体内癌症的演变。外科肿瘤学对于全面理解恶性疾病以用于治疗应用的意义日益重大。我们分析了1000多个手术切除组织的临床样本，以确定晚期恶性肿瘤的分子生物标志物和治疗靶点。癌症干性和有丝分裂不稳定性随后被确定为预后不良的侵袭性表型的重要预测指标。最近，全基因组/外显子组测序显示了癌症中表型异质性背后的突变图谱。此外，综合基因组、表观基因组、转录组、代谢组、蛋白质组和表型组分析阐明了在肝癌、胰腺癌、胆管癌、食管癌和胃肠癌中聚类的几种分子亚型。识别每种分子亚型有望实现针对亚型特异性分子的精准医学；然而，确定匹配的可药物化靶点或合成致死相互作用存在障碍限制。基因组编辑技术目前的突破可以为我们提供前所未有的机会，在体外和体内重现亚型特异性病理生理学。鉴于其巨大潜力，按需编辑系统可以设计可行的策略，并基于外科肿瘤学彻底改变精准癌症医学。
