Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden.
Theme Cancer, Oncology, Karolinska University Hospital, 17176 Solna, Sweden.
Int J Mol Sci. 2021 Jan 20;22(3):1025. doi: 10.3390/ijms22031025.
Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the "canonical" Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future.
Hedgehog (Hh) 信号通路调节肠道发育和稳态。多年来，人们一直在研究 Hh 信号通路在癌症中的作用；然而，其在结直肠癌 (CRC) 中的作用仍存在争议。越来越明显的是，“经典”Hh 途径，其中配体与受体 PTCH1 结合启动信号级联反应，最终导致 GLI 转录因子的激活，主要以旁分泌方式在健康结肠和 CRC 中组织。这种经典的 Hh 信号在很大程度上充当肿瘤抑制因子。此外，间质 Hh 信号在肠道中具有复杂的免疫调节作用，可能对癌变产生影响。相比之下，非经典 Hh 激活可能在 CRC 肿瘤细胞的亚群中具有促进肿瘤的作用。在这篇综述中，我们试图总结 Hh 通路在 CRC 中的最新知识，重点关注经典 Hh 信号在基质中的肿瘤抑制作用。尽管使用 Hh 抑制剂在 CRC 和其他实体瘤中的临床试验结果令人沮丧，但我们认为，对 Hh 信号的更精细理解可能允许将来在癌症治疗中利用这一关键的形态发生途径。
