Hedgehog Signaling in the Maintenance of Cancer Stem Cells

Abstract

Cancer stem cells (CSCs) represent a rare population of cells with the capacity to self-renew and give rise to heterogeneous cell lineages within a tumour. Whilst the mechanisms underlying the regulation of CSCs are poorly defined, key developmental signaling pathways required for normal stem and progenitor functions have been strongly implicated. Hedgehog (Hh) signaling is an evolutionarily-conserved pathway essential for self-renewal and cell fate determination. Aberrant Hh signaling is associated with the development and progression of various types of cancer and is implicated in multiple aspects of tumourigenesis, including the maintenance of CSCs. Here, we discuss the mounting evidence suggestive of Hh-driven CSCs in the context of haematological malignancies and solid tumours and the novel strategies that hold the potential to block many aspects of the transformation attributed to the CSC phenotype, including chemotherapeutic resistance, relapse and metastasis.

Low folate metabolic stress reprograms DNA methylation‐activated sonic hedgehog signaling to mediate cancer stem cell‐like signatures and invasive tumour stage‐specific malignancy of human colorectal cancers

“…LFMS‐induced CSC‐like potentials of human CRC was consistent with few studies on the xenograft mouse model of liver cancers, antifolate‐treated non‐small cell lung cancers and colonic cancers . In line with the robust activation of the Shh‐Gli pathway required for expressing stemness potentials in different cancer contexts, blockage of FD‐activated Shh signaling by CYC abolished FD‐promoted SOX2 gene expression, EMT trans‐differentiation, oncosphere formation and subsequently abrogated FD‐enhanced invasion of human adenocarcinoma cells. Our data established the causal effects of LFMS‐enhanced CSC‐like potentials were in part, if not all, mediated by the activation of the Shh signaling pathway.…”

Anti-Cancer Phytometabolites Targeting Cancer Stem Cells

“…Furthermore, evidence implicates the Hh pathway in CSCs in a variety of cancer models, including hematological malignancies and solid tumors [182-195]. The Hedgehog signaling pathway entails two transmembrane receptors, Patched-1 (PTCH1) and Smoothened (SMO).…”

Stemness-related markers in cancer

“…Hedgehog ligands (Desert Hedgehog, Sonic Hedgehog and Indian Hedgehog) bind to Ptch, activating a cascade of downstream signals that lead to the activation and nuclear localization of TFs, consequently followed by expression of genes that are involved in survival, proliferation, and angiogenesis [120]. Hedgehog signaling has been widely implicated in CSC self-renewal and cell fate determination [120], and is considered a potential therapeutic target in breast cancer and pancreatic cancer [121-123],…”