Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

Abstract

Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and β-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to β-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers with immune evasion, although the context-dependent effects of WNT signaling on immunity should be carefully assessed. Omics monitoring, such as genome sequencing and transcriptome tests, immunohistochemical analyses on PD-L1 (CD274), PD-1 (PDCD1), ROR1 and nuclear β-catenin and organoid-based drug screening, is necessary to determine the appropriate WNT signaling-targeted therapeutics for cancer patients.

CD133 as a regulator of cancer metastasis through the cancer stem cells

“…A large body of evidence demonstrated that activation of Wnt signaling is involved in controlling the malignant features of CSC through increased EMT, which leads to cancer invasion and metastasis (Katoh, 2017, Webster et al, 2015, Zhan et al, 2017). Knockdown of CD133 by the virally delivered short hairpins of RNA in human metastatic melanoma FEMX-I cells impeded cell motility and their ability to form spheroids (Rappa et al, 2008).…”

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

“…In the canonical pathway (WNT/β-catenin/TCF), a WNT ligand forms a ternary complex with the seven-pass transmembrane receptor, Frizzled (Fzd) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6), which activates Dvl homolog 1 (Dvl1) (26,27). Activation of Dvl1 dismantles the β-catenin 'destruction' complex to which it is associated, composed of Axin1 (AXIN1), adenomatous polyposis coli (APC), GSK3β and casein kinase 1 (CK1), which promotes the recruitment of β-catenin and TCF to the WNT target-gene promoters in the nucleus, to subsequently induce the transcription of target genes, including c-Myc and cyclin D1 (28).…”

“…Therefore, targeted inhibition of Fzd represents a rational and promising novel approach for cancer therapy (39). An ongoing clinical trial is evaluating vantictumab and ipafricept (27).…”

In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention

“…Currently, cancer stem cells have been identified in a number of cancers including breast and colon (193). Pathways implicated in cancer stem cell renewal include Wnt (194), janus kinase (Jak), bone morphogeneic protein (BMP), and octamer-binding transcription (Oct-4) signaling pathways (193). Natural dietary compounds have been shown to regulate CSCs by increasing their sensitivity to chemotherapeutic agents, enhancing their differentiation, and inhibiting their self-renewal signaling (195, 196).…”