Abstract
The importance of Wnt/β-catenin signaling in cancer stem cells (CSCs) has been acknowledged; however, the mechanism through which it regulates the biological function of CSCs and promotes cancer progression remains elusive. Hence, to understand the intricate mechanism by which Wnt controls stemness, the specific downstream target genes of Wnt were established by analyzing the genetic signatures of multiple types of metastatic cancers based on gene set enrichment. By focusing on the molecular function of Wnt target genes, the biological roles of Wnt were interpreted in terms of CSC dynamics from initiation to metastasis. Wnt signaling participates in cancer initiation by generating CSCs from normal stem cells or non-CSCs and augmenting persistent growth at the primary region, which is resistant to anti-cancer therapy. Moreover, it assists CSCs in invading nearby tissues and in entering the blood stream, during which the negative feedback of the Wnt signaling pathway maintains CSCs in a dormant state that is suitable for survival. When CSCs arrive at distant organs, another burst of Wnt signaling induces CSCs to succeed in re-initiation and colonization. This comprehensive understanding of Wnt target genes provides a plausible explanation for how Wnt allows CSCs variation during cancer progression.
Highlights
Wnt signaling is a highly complex and evolutionarily conserved pathway that maintains pluripotency during embryonic development and regulates homeostasis in somatic stem cells from various tissues [1]
Genetic mutations that activate Wnt signaling reportedly contribute to cancer initiation [2], and nuclear accumulation of the Wnt signaling molecules β-catenin and lymphoid enhancer-binding factor 1 (LEF1) have been shown to be positively correlated with poor clinical outcomes, such as cancer progression, invasion, metastasis, and recurrence, resulting in low survival rates [2,3,4]
We investigated Wnt-mediated mechanisms that control stemness by examining downstream target genes involved in the characteristic features of cancer stem cells (CSCs) from initiation to metastasis
Summary
Wnt signaling is a highly complex and evolutionarily conserved pathway that maintains pluripotency during embryonic development and regulates homeostasis in somatic stem cells from various tissues [1]. Multiple studies on Wnt signaling have reported specific mechanisms that promote cancer initiation and progression and can be investigated as therapeutic targets. In these studies, cancer stem cells (CSCs) have emerged as key players in Wnt-mediated carcinogenesis of various types. The specific antibody OMP-18R5 blocks the binding of Wnt ligands to FZD [11] and the small molecule inhibitor CWP23228 prevents the formation of β-catenin/T-cell factor (TCF)/LEF complexes, leading to significant suppression of cancer growth, metastasis, and chemo-resistance through CSC inhibition in breast [12] and liver cancers [8]. DM) iacnrodaorvraayriadnactaanocefrfo(GuSrEd21if0f9e)r,ewnetrceaanncaelry,zleidv.eGr e(nLeIsHuCp)r,ecgoulloatned(GbySEL1E4F3133w)e,rgeastric (STADs)igannidficoavnatlryiaennrciachnecderin(GmSeEta2s1ta0t9ic),cwanecreersa.nTahleyzdeedta.ilGedenmeesthuopdrsegaureladteesdcrbibyedLEinF1Suwpperleemseignntairfiycantly enricheMdaitnermialest.aTsCtaGtiAc;cTahneceCrasn.cTerhGe edneotmaieleAdtmlase,tLhEoFd1s; alyrme pdheoscidriebnehdainnceSru-bpinpdleinmgefnactatorry1M, GaEteOr;iaGlse.nTe CGA; The CaEnxcperreGsseionnomOme nAibtluass., LEF1; lymphoid enhancer-binding factor 1, GEO; Gene Expression Omnibus
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