Chung Jon H, Bunz Fred
Department of Radiation Oncology and Molecular Radiation Sciences, The Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Oncotarget. 2013 Dec;4(12):2208-11. doi: 10.18632/oncotarget.1651.
Hedgehog (Hh) signaling is largely suppressed in the normal differentiated tissues of the adult but activated in many cancers. The Hh pathway can either be activated by the expression of Hh ligands, or by mutations that cause constitutive, ligand-independent signaling. Colorectal cancer cells frequently express Hh ligands that are believed to exert paracrine effects on the stromal component of the tumor. Evidence for a more direct role of Hh signaling on the growth and evolution of colorectal cancer cell clones has been lacking. Here, we report a loss-of-function mutation of PTCH1, a tumor suppressor in the Hh pathway, in a colorectal cancer that exhibits transcriptional upregulation of the downstream Hh gene GLI1. This finding demonstrates that autocrine Hh signaling can provide a selective advantage to evolving tumors that arise in the colorectal epithelia, and suggests a definable group of colorectal cancer patients that could derive enhanced benefit from Hh pathway inhibitors.
刺猬信号通路（Hh）在成体正常分化组织中大多受到抑制，但在许多癌症中被激活。Hh通路可通过Hh配体的表达激活，也可通过导致组成型、不依赖配体信号传导的突变激活。结肠直肠癌细胞经常表达Hh配体，据信这些配体对肿瘤的基质成分发挥旁分泌作用。一直缺乏Hh信号在结肠直肠癌细胞克隆生长和演变中发挥更直接作用的证据。在此，我们报告了在一例结肠直肠癌中发现的Hh通路肿瘤抑制因子PTCH1的功能缺失突变，该肿瘤表现出下游Hh基因GLI1的转录上调。这一发现表明自分泌Hh信号可为结肠直肠上皮中发生的肿瘤进化提供选择性优势，并提示了一组可从Hh通路抑制剂中获得更大益处的结肠直肠癌患者。
