Open Access

Wnt signaling and tumors (Review)

  • Authors:
    • Huaishi Wang
    • Lihai Zhang
    • Chao Hu
    • Hui Li
    • Mingyan Jiang
  • View Affiliations

  • Published online on: May 15, 2024
  • Article Number: 45
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Wnt signaling is a highly conserved evolutionary pathway that plays a key role in regulation of embryonic development, as well as tissue homeostasis and regeneration. Abnormalities in Wnt signaling are associated with tumorigenesis and development, leading to poor prognosis in patients with cancer. However, the pharmacological effects and mechanisms underlying Wnt signaling and its inhibition in cancer treatment remain unclear. In addition, potential side effects of inhibiting this process are not well understood. Therefore, the present review outlines the role of Wnt signaling in tumorigenesis, development, metastasis, cancer stem cells, radiotherapy resistance and tumor immunity. The present review further identifies inhibitors that target Wnt signaling to provide a potential novel direction for cancer treatment. This may facilitate early application of safe and effective drugs targeting Wnt signaling in clinical settings. An in‑depth understanding of the mechanisms underlying inhibition of Wnt signaling may improve the prognosis of patients with cancer.

1. Introduction

A wingless gene was discovered during Drosophila embryonic development >40 years ago (1). In 1982, Nusse and Varmus (1) cloned int gene (Drosophila homolog of the mouse mammary oncogene) that is homologous to wingless during carcinogenesis induced by mouse papilloma virus. This was termed Wnt gene. Wnt proteins bind to receptors on the cell membrane in an autocrine or paracrine manner. They subsequently undergo cascade reactions to activate intracellular proteins and transcription factors to promote target gene transcription. Wnt signaling is associated with cell differentiation, polarization and migration. Moreover, abnormalities in Wnt signaling serve an important role in the development of many diseases, including lung and breast cancer (2). The present review describes the role of Wnt signaling abnormalities in tumorigenesis, tumor development, metastasis, cancer stem cells (CSCs), radiotherapy resistance and tumor immunity (Fig. 1), as well as inhibitors that target Wnt signaling to explore novel avenues for cancer treatment.

2. Classical and non-classical Wnt signaling

A total of 19 Wnt and 10 frizzled (FZD) proteins have been identified in mammalian cells (3). These proteins activate Wnt signaling when the receptor binds to its ligand. At least three Wnt pathways have been identified: Classical Wnt/β-catenin pathway and two non-classical Wnt/planar cell polarity (PCP) and Wnt/Ca2+ pathways.

Classical Wnt/β-catenin signaling pathway

Classical Wnt signaling, known as β-catenin-dependent signaling, has been extensively studied (4-7). This pathway comprises three primary components: Cell membrane proteins, degradation complexes and β-catenin. Cell membrane proteins include Wnt ligands (Wnt1, Wnt2, Wnt3a and Wnt8), seven transmembrane receptors (FZD), auxiliary receptors and low-density lipoprotein receptor-related proteins 5/6 (LRP5/6). The degradation complex is primarily composed of glycogen synthase kinase 3β (GSK-3β), adenomatous polyposis coli (APC), casein kinase 1α (CK1α) and scaffolding protein axin (4). GSK-3β is a serine/threonine protein kinase that phosphorylates residues Thr41, Ser33 and Ser37 on β-catenin. APC increases the affinity of other components of the complex to β-catenin, whereas CK1α is a tyrosine kinase that phosphorylates Thr45 on β-catenin. Furthermore, axin serves as a scaffolding protein that keeps the degradation complex tightly bound and stable. β-catenin is a member of the connexin family. Activation of the Wnt/β-catenin signaling pathway also involves transduction of Wnt signaling in the cell membrane, maintenance of β-catenin stability in the cytoplasm, and activation of Wnt-associated target genes in the nucleus (5). When Wnt ligands are absent from the cell surface, most β-catenin located at the cell membrane junctions forms a complex with epithelial-type calcium adhesion protein (E-cadherin) and α-catenin to regulate the cytoskeleton and maintain intercellular adhesion. A small amount of unbound β-catenin in the free state is ubiquitinated by the degradation complex via amino-terminal phosphorylation and recognized by the E3 ubiquitin ligase β-transducin repeat-containing protein, which eventually leads to its degradation by the proteasome. The cytoplasm contains low levels of β-catenin in the free state. Therefore, it cannot enter the nucleus to initiate transcription of T cell factor/lymphoid enhancer factor (TCF/LEF), blocking the expression of downstream target genes (6). This blockage inactivates the Wnt pathway. In the presence of extracellular Wnt ligands, Wnt proteins bind to FZD and LRP5/6 to activate disheveled (DVL) proteins in the cytoplasm. Activated DVL inhibits GSK-3β in the degradation complex. Inactive GSK-3β cannot phosphorylate β-catenin, which gradually accumulates in the cytoplasm. When β-catenin reaches a certain level, it is transferred to the nucleus and initiates the transcription of c-Myc, cyclin D1, Dickkopf-associated protein 1, matrix metalloproteinase (MMP)-7, axin 2 and other downstream target genes by binding to TCF/LEF in the nucleus, leading to abnormal cell proliferation and resistance to apoptosis, thereby inducing tumor formation (7). Tumors are induced during this process.

Non-classical Wnt signaling

By contrast with activation of the classical Wnt/β-catenin pathway, activation of non-classical Wnt signaling is not dependent on β-catenin. Activation of the Wnt/PCP pathway is initiated by binding of cell-secreted Wnt ligand proteins to the cell membrane receptor FZD and co-receptors receptor-like tyrosine kinase and receptor tyrosine-kinase-like orphan receptor. These co-receptors control activity of small GTPases and regulate cytoskeletal remodeling (8). The binding of Wnt proteins to FZD recruits DVL to the cell membrane for activation (8). DVL activates DVL-associated activator of morphogenesis 1. This process is followed by activation of ρGTPase, which further activates myosin and ρ-associated kinase, thereby altering actin and cytoskeletal rearrangement in the presence of activated Rac GTPase. Activated Rac stimulates c-Jun amino-terminal kinase activation, leading to downstream target gene expression (9). Moreover, Wnt/Ca2+ signaling is activated when Wnt binds to FZD, recruiting DVL to the cell membrane via guanine nucleotide-binding proteins. This activates phospholipase C and calmodulin-dependent kinase II, causing increased intracellular calcium ion release and further regulating downstream signaling pathways (10).

3. Role of Wnt signaling in tumors

Wnt signaling plays an important role in the development of many types of tumors, including non-small cell lung cancer (NSCLC). Smoking is a key risk factor for lung cancer and cigarette smoke can activate Wnt signaling (11). In a mouse lung cancer model with KRAS mutations, activation of the β-catenin pathway accelerates growth of lung cancer tumors (12). β-catenin, a key component of the classical Wnt/β-catenin pathway, is often aberrantly expressed in lung cancer (13). β-catenin levels in Wnt1-positive NSCLC are higher than those in Wnt1-negative NSCLC (14). Odd-skipped related 1 (OSR1) decreases Wnt signaling activity by inhibiting β-catenin expression in lung cancer OSR1-overexpressing H1299 cells (15). Furthermore, immunohistochemical staining shows that Wnt1 and Wnt5a are highly expressed in NSCLC. Overexpression of Wnt1 is causes more aggressive NSCLC by inducing expression of survivin (16), whereas Wnt7a is considerably decreased in NSCLC cell lines and lung tumors. Contrastingly, Wnt7a interacts directly with the Wnt receptor FZD9(17). The total DVL expression is high in NSCLC cells but negative in normal bronchial and alveolar epithelial cells, suggesting DVL could promote the progression of NSCLC (18). Pygopus2, a downstream functional protein in Wnt/β-catenin signaling, is more elevated in the nucleus of NSCLC compared with normal lung tissues (19). In addition to lung cancer, β-catenin abnormalities are found in some digestive system cancers, such as liver, gastric and colorectal cancer (20-22). The gene catenin beta 1 (CTNNB1), which encodes β-catenin, is commonly mutated in hepatocellular carcinoma (23), whereas CTNNB1, TCF7L2 and APC are mutated in gastric cancer (24). Similarly, APC is mutated in colorectal cancer (22). Overexpression of Wnt11 may antagonize classical Wnt signaling by phosphorylating β-catenin in human hepatocellular carcinoma cells (25). However, activation or inhibition of Wnt signaling in hepatocellular carcinoma depends on the differentiation status of hepatocellular carcinoma cells. Classical and non-classical Wnt signaling serve complementary roles, with classical signaling inducing tumors and non-classical signaling promoting tumor progression (26). Overexpression of Wnt and β-catenin nuclear translocation are observed in gastric cancer (27). The localization of β-catenin from the cell membrane to the cytoplasm and nucleus has also been observed during colorectal cancer development (28). Similarly, Wnt10a and Wnt6 mRNA are detected in gastric cancer cell lines. Furthermore, upregulation of Wnt10a expression activates Wnt/β-catenin/TCF signaling, which is involved in gastric carcinogenesis (29). The expression of runt-related transcription factor 1 (RUNX1) is upregulated in colorectal cancer tissue. RUNX1 directly interacts with β-catenin to activate Wnt/β-catenin signaling (30). Wnt signaling is also aberrant in tumors common in female patients, such as breast and ovarian cancers (31,32). One study used microarray analysis to compare molecular changes in Wnt signaling in triple-negative breast cancer (TNBC) and non-TNBC (33). FZD7, LRP6 and TCF7 are overexpressed in TNBC. In addition, classical Wnt signaling associated with TCF7 is essential for breast carcinogenesis (33). Yoshioka et al (34) examined all Wnt ligands in malignant ovarian tumors and normal ovarian tissue and found high expression of Wnt7a and Wnt7b and low expression of Wnt3 and Wnt4. Additionally, Wnt1, Wnt5a, and Frizzled-1 levels are markedly higher in ovarian cancer than in normal ovaries (35).

4. Wnt signaling and CSCs

Tumors comprise a heterogeneous population of tumor cells, a small group of which are CSCs. Similar to normal SCs, CSCs have a self-renewal capacity and differentiation potential, two properties that make tumor cell populations heterogeneous. CSCs have high oncogenic potential and serve a major role in tumor initiation, metastasis, drug resistance and tumor recurrence (36). Wnt signaling maintains stemness in CSCs (37-39).

Wnt signaling and lung CSCs

SOX2 participates in various stages of embryonic development by activating Wnt signaling and maintaining CSC stemness. Colon cancer-associated transcript 1 (CCAT1) elevates the expression of SOX2 and activates Wnt signaling in A549 and H460 lung cancer cells. However, the self-renewal capacity of lung CSCs is lost when microRNA (miR)-Let-7c binds CCAT1(40). In NSCLC cell lines, nuclear-enriched abundant transcript 1 may activate the Wnt pathway and promote the CSC phenotype by inhibiting epigallocatechin gallate-upregulated copper transporter 1(41). Octamer binding transcription factor 4 (OCT-4) is a lung cancer surface marker of SCs whose expression is regulated by Wnt signaling. When cisplatin-resistant human lung adenocarcinoma A549/DDP cells are stimulated with lithium chloride, an inhibitor of GSK-3β, expression of Wnt signaling target genes Cyclin D1 and OCT-4 is upregulated. Moreover, the proliferation, clonogenic ability, migration and drug resistance of A549/DDP cells is enhanced (42).

Wnt signaling and gastric CSCs

Wnt signaling is also involved in the maintenance of gastric cancer stemness. Stable overexpression of Wnt1 increases proliferation and tumor sphere formation in the human gastric adenocarcinoma cell line AGS. Additionally, AGS cells express the CSC surface markers OCT-4 and CD44. Activation of Wnt1 accelerates gastric CSC proliferation, suggesting that Wnt signaling contributes to self-renewal of gastric CSCs (37). Human epidermal growth factor 2 (HER2)-overexpressing gastric cancer cells induce increased stemness by regulating Wnt/β-catenin signaling (43). Placental growth factor (PlGF) is associated with gastric carcinogenesis. Thus, knockdown of PlGF expression induces apoptosis through Wnt signaling in gastric CSCs (44). Ring finger protein 43 is a member of the E3 ubiquitin ligase family and was originally identified in SCs. It attenuates the stemness of gastric CSC-like cells via Wnt/β-catenin signaling (45). The expression of bromodomain and extra-terminal domain protein is frequently upregulated in gastric cancer tissue and also promotes the stemness of gastric cancer cells by activating Wnt/β-catenin signaling (46).

Wnt signaling and colorectal CSCs

Colorectal carcinogenesis and disease progression are caused by progressive accumulation of genetic mutations. APC or β-catenin mutations activate Wnt/β-catenin signaling and initiate tumor formation. This suggests that Wnt signaling serve a central role in the regulation of colorectal CSCs (47-49). Markers on the surface of colon CSCs include CD44, CD133, CD24, CD29, CD26, CD166, leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) and aldehyde dehydrogenase 1 (ALDH1) (50). ALDH1B1 is a member of the ALDH1 family that is highly expressed in colon cancer cells. It can activate Wnt/β-catenin signaling and may be involved in tumorigenesis of colon CSCs (51). Higher β-catenin expression levels induce the expansion of Lgr5(+) cells in colonic crypts and the formation of crypts (52). The transcription factor GATA6 is a key regulator of Wnt signaling in colorectal cancer. It directly drives Lgr5 expression in adenoma SCs. Moreover, GATA6 achieves CSC self-renewal by competing with β-catenin/TCF4 to bind the distal regulatory region of the bone morphogenetic protein locus (38). Homeobox A5 abrogates the self-renewal properties of CSC and blocks tumor growth and metastasis by inhibiting Wnt signaling in colon cancer (53).

Wnt signaling and breast CSCs

Wnt/β-catenin signaling contributes to the maintenance of breast CSC stemness. B cell lymphoma factor 11A (BCL11A) is overexpressed in TNBC cells and participates in tumorigenesis and invasion (54). The high expression of this transcription factor causes SC-like characteristics and maintains stemness in breast CSCs by activating Wnt/β-catenin signaling (39). Similarly, Lgr4 is frequently overexpressed in BC and is associated with poor prognosis. Lgr4 regulates Wnt/β-catenin signaling by mediating breast CSC maintenance (55). The expression of calmodulin 11 (CDH11), a type II calmodulin and mesenchymal protein marker, is positively correlated with β-catenin and Wnt2 in breast cancer (56). When CDH11 is inhibited, it may suppress the mammary CSC-like phenotype by regulating the Wnt/β-catenin pathway (56).

Wnt signaling and ovarian CSCs

The surface markers of ovarian CSCs include CD24, CD44, CD117, CD133, ALDH, SOX2, OCT-4, NANOG and epithelial cell adhesion molecule, also known as CD326, a single channel type I membrane glycoprotein. Increased expression of these markers enables ovarian CSCs to become sphere-forming in vitro and tumorigenic in vivo, promoting development of epithelial ovarian cancer (EOC). This makes these cells more resistant to drugs and produces tumor progenitor cells that lead to tumor progression, metastasis and recurrence (57). Mounting evidence demonstrates Wnt/β-catenin signaling involvement in the acquisition of stemness in ovarian cancer cells (57-59). In one study, ALDH1A1 was overexpressed in cultured ovarian cancer spheres in vitro and was directly associated with key components of β-catenin signaling. This suggests that β-catenin-regulated ALDH1A1 maintains the sphere-forming ability of ovarian cancer cells (58). Another study confirmed that miR-1207 overexpression increases ovarian CSC-like properties in vitro and in vivo. The effects of miR-1207 are caused by Wnt/β-catenin signaling activation via inhibition of negative regulators of this pathway, such as secreted Frizzled-related protein 1 (SFRP1), axin 2, β-catenin inhibitor and TCF4(59).

5. Wnt signaling and tumor metastasis

Metastasis is a characteristic of advanced cancer and a major challenge in cancer treatment. Epithelial-mesenchymal transition (EMT) refers to loss of intercellular adhesion and acquisition of mesenchymal cell characteristics by epithelial cells. This enhances cancer cell invasion and metastasis (60). Activation of Wnt/β-catenin signaling can increase expression of adhesion molecule suppressors by reducing E-cadherin and increasing Snail, Slug, Twist, zinc finger E-box-binding homeobox (ZEB)1 and ZEB2 expression (61). Several molecules, such as forkhead box protein P3 (FOXP3), long non-coding RNA (lncRNA) JPX and WD repeat-containing protein 74 (WDR74) contribute to lung cancer metastasis via Wnt signaling (62-64). In previous in vitro and in vivo studies, FOXP3 promoted lung tumor growth and metastasis via FOX3-mediated Wnt/β-catenin signaling activation (62,65). Some biomolecules, such as serpin family H member 1 (SERPINH1), lncRNA miR-4435-2HG and LINC01606, cyclin G2 and Zic family member 1 contribute to EMT and invasive metastasis of gastric cancer via Wnt/β-catenin signaling (66-70). SERPINH1 is a member of the serine protease inhibitor H subfamily. Furthermore, expression of Wnt/β-catenin signaling proteins β-catenin, Wnt2, GSK-3β, Snail, Slug and Twist is downregulated in the SERPINH1-silenced gastric cell line SGC-7901. This suggests that SERPINH1 regulates gastric cancer progression via Wnt/β-catenin signaling (66). Tumor metastasis in female patients is associated with Wnt/β-catenin signaling abnormalities. Overexpression of SFRP attenuates Wnt signaling in cervical cancer CaSki cells and increases E-cadherin expression by repressing Slug, Twist, and Snail (71). By contrast, cysteine-rich intestinal protein 1 activates Wnt/β catenin signaling and promotes cervical cancer cell migration and invasion by increasing expression of c-Myc, cyclin D1 and cytoplasmic β-catenin (72). The early dissemination and metastasis of HER2(+) breast cancer depends on non-classical Wnt (Wnt5a, Wnt5b and Wnt11) signaling (73). In addition, Wnt/β-catenin signaling is involved in remodeling of the EOC extracellular matrix, a MMP-mediated process. MMP-2 expression is upregulated in ovarian cancer and promotes cancer cell invasion and metastasis (74).

6. Wnt signaling and chemoradiotherapy resistance

Chemoradiotherapy resistance often leads to tumor treatment failure. The causes of chemoradiotherapy resistance are complex and associated with tumor heterogeneity, drug efflux/inactivation and survival pathway activation (75). Wnt signaling can enhance tumor resistance to chemotherapeutic agents or radiotherapy. Furthermore, inhibitors of Wnt signaling can reverse this resistance and restore treatment sensitivity (76,77).

Wnt signaling and chemoradiotherapy resistance in lung cancer

Cancer cells expressing Wnt1 resist drug-induced apoptosis. Moreover, Wnt/β-catenin signaling induces transcription of drug resistance factors such as multidrug resistance 1 (MDR-1) that is a membrane glycoprotein encoded by the MDR gene, survivin and livin (76). Platinum-based chemotherapy is the first-line treatment option for advanced NSCLC. However, acquired cisplatin resistance is prevalent in patients with NSCLC (78). One study reported that cytoplasmic inhibition of GSK-3β activates Wnt/β-catenin signaling and upregulates survivin expression, leading to cisplatin resistance in NSCLC (79). In another study, c-Myc, a downstream target gene of β-catenin, regulated A549/DDP resistance to cisplatin (80). Examination of β-catenin expression in NSCLC cell line PC9 and gefitinib-resistant cell line PC9/AB (2) revealed increased nuclear translocation of β-catenin in PC9/AB (2) compared with PC9. In addition, expression of certain components of β-catenin signaling (phosphorylated-GSK-3β, DVL1, c-Myc, c-JUN) increases (81). GDK-100017, a 2,3,6-trisubstituted quinoxaline derivative, inhibits Wnt/β-catenin signaling, blocks β-catenin-TCF/LEF interactions and increases sensitivity of A549/Wnt2 cells to radiotherapy (82). FZD8 is a member of the frizzled Wnt ligand-receptor family. Disruption of FZD8 increases the sensitivity of lung cancer cells to the chemotherapeutic drug paclitaxel (83).

Wnt signaling and chemoradiotherapy resistance in gastric cancer

Several molecules are involved in resistance to chemoradiotherapy in gastric cancer. Caveolin-1 (Cav-1) increases cisplatin resistance in gastric cancer cells by activating Wnt signaling (84). Similarly, DOCK6, a guanine nucleotide exchange factor, promotes radiotherapy resistance in gastric cancer by regulating Wnt signaling (85). ICG-001, an inhibitor of β-catenin, reduces the chemoresistance of gastric cancer cells by binding to CREB-binding protein (CBP) and interfering with its interaction with β-catenin, thereby inhibiting Wnt signaling (86). Cheng et al (87) investigated the mechanisms underlying regulation of cisplatin resistance by homologous cassette gene transcript antisense RNA (HOTAIR) in gastric cancer cells. Low HOTAIR expression attenuates cisplatin resistance in gastric cancer cells by inhibiting Wnt signaling. The long noncoding RNA FAM83H-antisense RNA 1 silencing also increases the chemosensitivity of gastric cancer cells via Wnt signaling (88). Similarly, basic leucine zipper ATF-like transcription factor 2, a member of the type I activator protein-1 family, reverses multidrug resistance in gastric cancer cells by inactivating Wnt signaling (89).

Wnt signaling and chemoradiotherapy resistance in BC

Wnt signaling plays a key role in chemoradiotherapy resistance in BC. The MDR1 gene encodes permeability glycoprotein, a transmembrane transporter glycoprotein that is a member of the ATP-binding cassette (ABC) transporter protein superfamily. This protein superfamily mediates drug efflux and is associated with tumor drug resistance. Pygo2 expression is upregulated in drug-resistant BC cells and activates MDR1 via Wnt signaling, thereby mediating chemoresistance in BC (90). The expression of the membrane transporter protein Cav-1 is upregulated in BC chemoresistance. Cav-1 promotes drug resistance in breast CSCs via β-catenin/ABCG2 signaling (91). Activation of classical and non-classical Wnt signaling pathways is detected in the tamoxifen-resistant estrogen receptor (ER)(+) breast cancer cell line MCF7. Furthermore, Wnt3a increases tamoxifen resistance in MCF7 cells (92). Follistatin like protein 1, an extracellular matrix glycoprotein, is associated with regulation of cellular signaling pathways. Its expression is considerably upregulated in drug-resistant BC cells. Moreover, this gene can act through integrin β3-induced activation of Wnt signaling (93). Similarly, lncAFAP1-AS1 can induce radiotherapy resistance in TNBC via Wnt signaling (94).

Wnt signaling and chemoradiotherapy resistance in ovarian cancer

In addition to its involvement in BC resistance, abnormal ABCG2 expression is associated with drug resistance in ovarian cancer. The SC-associated receptor tyrosine kinase c-kit promotes ovarian cancer drug resistance via the Wnt/β-catenin/ABCG2 signaling axis. Low c-kit expression increases ovarian cancer cell sensitivity to chemotherapeutic agents such as cisplatin and paclitaxel (95). One study showed that chemoresistance in high-grade plasma ovarian cancer is associated with Wnt signaling activation. In addition, the sensitization of ovarian cancer-initiating cells to cisplatin is restored by a Wnt signaling inhibitor (96). Human copper transporter 1 is a transmembrane transporter that allows copper and cisplatin to enter cells through the membrane barrier. Wnt/β-catenin signaling inhibits expression of this protein in cisplatin-resistant EOC cells (97). MMP-10 is highly expressed in cancer stem-like/carcinoma-initiating cells in EOC and is associated with platinum resistance. It acts by inhibiting Wnt5a activation during Wnt signaling (98).

Wnt signaling and cervical cancer chemoradiotherapy resistance

Several studies have shown that Wnt signaling is associated with chemoradiotherapy resistance in cervical cancer (99-102). Therefore, β-catenin nuclear expression can be used as a predictive marker of chemoradiotherapy resistance in cervical squamous carcinoma (99). Fat mass and obesity-associated protein, an N6-methyladenine demethylase with upregulated mRNA expression in cervical squamous carcinoma tissue, enhances radiotherapy resistance by regulating β-catenin (100). One study showed that chemotherapeutic drugs activate Wnt/β-catenin signaling in a eukaryotic translation initiation factor 4 E (eIF4E)-dependent manner. This suggests that eIF4E/β-catenin signaling serves a positive regulatory role in chemoresistance in cervical cancer (101). Similarly, LGR5 acts as a cancer-promoting factor by activating Wnt signaling in cervical cancer. Thus, high LGR5 expression in cervical cancer cells promotes cisplatin resistance (102).

7. Wnt signaling and tumor immunity

The tumor microenvironment (TME) consists of immune cells, peripheral blood vessels, fibroblasts, signaling molecules and extracellular matrix (103). The overexpression of immune checkpoint molecules in the TME serves a key role in tumor immune escape and progression. Tumor immunotherapy is a novel approach for treating tumors and it activates or reactivates tumor immune circuits (104). Several immune checkpoint inhibitors (ICIs), such as ibritumomab, nabumab, pembrolizumab and atezumab, have been approved for cancer therapy. Ibritumomab is an anti-cytotoxic T lymphocyte-associated protein 4 antibody (anti-CTLA4), whereas nabumab and pembrolizumab are anti-programmed death receptor 1 antibodies (anti-PD-1). By contrast, atezumab is an anti-PD ligand 1 antibody (anti-PD-L1). Anti-PD-1/PD-L1 antibodies have clinical utility in 15 types of cancer (lung cancer, cervical cancer, gastric cancer, etc.). However, most patients with advanced cancers do not derive clinical benefits from these agents (105). This suggests that immunosuppressive mechanisms in the TME may limit the efficacy of ICIs (105).

Growing evidence demonstrates that Wnt signaling blocks all steps of the tumor immune cycle, including tumor antigen release and presentation, T cell initiation, activation and infiltration and clearance of tumor cells (106,107). The first step in the tumor immune cycle is processing of tumor antigens by dendritic cells (DCs) for presentation to effector T cells. Wnt signaling regulates maturation and activity of these DCs. One study on lung adenocarcinoma found that Wnt1 causes transcriptional silencing of CC/CXC chemokines, T cell rejection and cross-tolerance in classical DCs. Furthermore, Wnt1 target gene expression is upregulated in classical DCs within tumors and downregulated when Wnt1 is silenced through enhanced T cell toxicity (108). Another study revealed that Wnt5a suppresses CD14 (+/low) monocyte-derived myeloid DC production and promotes CD14+/++CD16+ monocyte production (109). CD8+ T cells are the primary effector cells in the tumor immune cycle and can be activated by DCs and costimulatory molecules that infiltrate the tumor site to kill cancer cells (110). However, tumor cells evade immune clearance and reject or inactivate CD8+ T cells to prevent CD8+ T cell infiltration during tumor progression (111). Therefore, Wnt signaling is essential for T cell differentiation, polarization, effector function and migration (112). Tumor-infiltrating T cells substantially overexpress Wnt3a and β-catenin, leading to dysfunction and memory T cell depletion (113). In addition, Wnt-mediated β-catenin/TCF1 activation inhibits naïve T cell and terminal differentiation of effector CD8+ T cells (113). Helper T (Th) cells mainly contribute to CD8+ T cell antitumor responses by releasing cytokines. Wnt signaling also regulates Th cell development and function (114) by suppressing Th cells and impairing antitumor immunity. In colorectal cancer, β-catenin is activated and attenuates CD4+ T antitumor immunity by suppressing interferon γ and elevating IL-17a expression (115). Autoimmune encephalomyelitis-induced endothelial Wnt signaling limits CD4+ T cell infiltration, which is restored when signaling is suppressed (116). These findings demonstrate that Wnt signaling serves a non-negligible role in immune cell function. Therefore, the influence of this pathway warrants consideration in tumor immunotherapy, especially when efficacy is poor.

8. Wnt signaling and tumor therapy

Numerous studies have confirmed involvement of Wnt signaling in onset, progression, metastasis and drug resistance of various cancers (75,117,118). Moreover, strategies targeting this pathway for cancer treatment are gaining attention (75,118). Preclinical research has revealed four approaches that target Wnt signaling: i) Blocking ligand-receptor interactions, ii) blocking FZD/LRP5/6 signaling [porcupine (PORCN) inhibitors], iii) promoting β-catenin degradation (tankyrase (TNKS) enzymes or inhibitors) and iv) blocking β-catenin-TCF interactions (β-catenin inhibitors) (119).

Blocking Wnt ligand-receptor interactions

Different tumors express specific Wnt ligands. Therefore, blocking specific Wnt ligand-receptor interactions can inhibit tumor cell proliferation (120,121). In one study, addition of anti-Wnt1 monoclonal antibodies to human NSCLC, BC, mesothelioma and sarcoma cell lines led to apoptosis. In addition, the antibodies inhibited tumor growth in vivo (122). Another study showed that Wnt2 inhibitors decrease clone formation and transplanted tumor volume in NSCLC cell lines (123). After transferring interfering RNA of Wnt5a into the human lung squamous carcinoma cell line H157 and human lung adenocarcinoma cell line A549, the proliferative capacity of both cell lines was decreased (124). The recombinant fusion protein ipafricept (known as OMP-54F28) is formed by fusing the cysteine-rich structural domain of FZD8 with the structural domain of immunoglobulin Fc, which blocks Wnt signaling by binding to Wnt ligands. Preclinical studies have shown that OMP-54F28 slows tumor growth and has a synergistic effect when combined with chemotherapeutic agents (125,126). This human monoclonal antibody interacts with five FZD receptors to block classical Wnt signaling and clinical trials have shown that it has good tolerability (125,127).

Blocking FZD-LRP5/6 signaling

PORCN is a membrane-bound O-acetyltransferase that modifies Wnt proteins via palmitoylation; only such modified Wnt proteins can be secreted outside the cellular membrane to activate Wnt signaling by interacting with its co-receptors LRP5/6 and FZD (128). LGK974 is a small-molecule PORCN inhibitor that blocks Wnt signaling and induces tumor regression in MMTV-Wnt1 mice. In addition, LGK974 considerably attenuates clone formation in human head and neck cancer cell line HN30(129). ETC-159 is another PORCN inhibitor that blocks secretion and activation of Wnt proteins. Preclinical studies have shown that ETC-159 is highly effective in treating mouse-transplanted tumors with R-spondin translocations in patients with colon cancer (127,130). In another preclinical study, combination of the PORCN inhibitor RX004 and anti-PD-1 enhanced antitumor immune effects (131). PORCN inhibitors have shown therapeutic potential in colorectal, pancreatic, hepatocellular and head and neck tumors. To date, no PORCN inhibitors have entered clinical use; only LGK974, ETC159, CGX1321 and RXC004 have been investigated in phase I clinical trials (132-135).

Promotion of β-catenin degradation

End-anchored polymerase (TNKS) is a member of the poly ADP-ribose polymerase (PARP) family, which includes two isoforms, TNKS1 (PARP5a) and TNKS2 (PARP5b). These isoforms regulate classical Wnt signaling via poly ADP-ribosylated axin proteins. TNKS inhibitors promote β-catenin degradation by increasing axin levels (120). Treatment of the NSCLC cell line A549 with XAV939 inhibits cell proliferation and migratory capacity. Furthermore, it decreases TNKS, β-catenin and c-Myc protein levels (136). This TNKS inhibitor also decreases proliferative capacity of the SCLC cell line H446 by inhibiting Wnt signaling (137). The combination of XAV939 and chemotherapeutic agent paclitaxel induces apoptosis and inhibits Wnt signaling in BC cells. In addition, this treatment suppresses EMT and angiogenesis. Similarly, combined XAV939 and low-dose (20 nM) paclitaxel results in comparable therapeutic effects in BC cell lines compared with high-dose (200 nM) paclitaxel alone (138). NVP-TNKS656, another TNKS inhibitor, decreases β-catenin protein expression in the nucleus of colorectal cancer cells when combined with PI3K or AKT inhibitors, thereby reversing resistance to PI3K or AKT inhibitors and inhibiting tumor growth (139). Moreover, the TNKS inhibitor G007-LK has a sensitizing effect on anti-PD-1 antitumor therapy (140).

Blocking β-catenin and TCF interactions

An effective way of targeting the classical Wnt signaling pathway is to block the interaction of β-catenin with downstream transcription factors (120,121). TCF4 is a member of the TCF/LEF family and binds to β-catenin to initiate target gene transcription when Wnt signaling is activated. Inhibitors of β-catenin-TCF4 interactions include PKF115-584, CGP049090, PKF222-815, PKF118-744, PKF118-310, ZTM000990, iCRT3/5/14, NC043, LF3 and UU-T02/03(141). PKF115-584 inhibits β-catenin transcription and proliferation in the adrenocortical tumor cell line H295R in a dose-dependent manner (142). Similarly, CGP049090 and PKF115-584 effectively kill chronic lymphocytic leukemia cells (143). Three inhibitors, PKF118-310, PKF115-584 and CGP049090, downregulate the expression of TCF4/β-catenin target genes c-Myc, cyclin D1 and survivin in hepatocellular carcinoma. These inhibitors also induce apoptosis and cell cycle arrest and inhibit the growth of transplanted tumors in mice (144).

In addition, β-catenin can also interact with p300/CBP and BCL9(141). Thus, pharmacological blockade of Wnt signaling seems promising in preclinical models (141-144).

9. Conclusion

The dysregulation of classical and non-classical Wnt signaling pathways in tumors has been extensively studied in recent years (117,118,132-134). The present review provides an overview of the role of Wnt signaling in tumorigenesis, progression, metastasis, CSCs, chemoradiotherapy resistance and antitumor immunity as well as inhibitors targeting Wnt signaling. Wnt signaling is increasingly recognized as an anticancer therapeutic target and several studies have demonstrated the effectiveness of Wnt signaling inhibitors alone or in combination with other chemotherapeutic agents and ICIs in antitumor therapy (118,132-134,138). Furthermore, some Wnt signaling inhibitors (LGK974, ETC159, CGX1321, and RXC004) have been tested in phase I clinical trials (132,134,145,146). However, Wnt signaling serves an important role in physiological processes and the possible side effects after blockade are not well understood. Therefore, pharmacological effects and mechanisms underlying Wnt signaling and its inhibitors for early clinical application warrant further study. An in-depth understanding of these processes may improve prognosis in patients with cancer.


Not applicable.


Funding: The present study was supported by the Medical Scientific Research Project in Xiangtan City (grant. no. 2022-xtyx-16) and Guiding Science and Technology Program of Xiangtan City (grant. no. ZP-ZDJH2022006).

Availability of data and materials

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Authors' contributions

HW and MJ designed the review and edited the manuscript. HW and LZ wrote the manuscript. HW, CH and HL collected and analyzed data. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



Nusse R and Varmus HE: Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 31:99–109. 1982.PubMed/NCBI View Article : Google Scholar


Johnson ML and Rajamannan N: Diseases of Wnt signaling. Rev Endocr Metab Disord. 7:41–49. 2006.PubMed/NCBI View Article : Google Scholar


Janda CY, Dang LT, You C, Chang J, de Lau W, Zhong ZA, Yan KS, Marecic O, Siepe D, Li X, et al: Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling. Nature. 545:234–237. 2017.PubMed/NCBI View Article : Google Scholar


van Kappel EC and Maurice MM: Molecular regulation and pharmacological targeting of the β-catenin destruction complex. Br J Pharmacol. 174:4575–4588. 2017.PubMed/NCBI View Article : Google Scholar


Huang P, Yan R, Zhang X, Wang L, Ke X and Qu Y: Activating Wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities. Pharmacol Ther. 196:79–90. 2019.PubMed/NCBI View Article : Google Scholar


Wang D, Zhang Q, Li F, Wang C and Yang C: β-TrCP-mediated ubiquitination and degradation of Dlg5 regulates hepatocellular carcinoma cell proliferation. Cancer Cell Int. 19(298)2019.PubMed/NCBI View Article : Google Scholar


Lin CH, Ji T, Chen CF and Hoang BH: Wnt signaling in osteosarcoma. Adv Exp Med Biol. 804:33–45. 2014.PubMed/NCBI View Article : Google Scholar


Kohn AD and Moon RT: Wnt and calcium signaling: Beta-catenin-independent pathways. Cell Calcium. 38:439–446. 2005.PubMed/NCBI View Article : Google Scholar


Topol L, Jiang X, Choi H, Garrett-Beal L, Carolan PJ and Yang Y: Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation. J Cell Biol. 162:899–908. 2003.PubMed/NCBI View Article : Google Scholar


Krishnamurthy N and Kurzrock R: Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat Rev. 62:50–60. 2018.PubMed/NCBI View Article : Google Scholar


Lemjabbar-Alaoui H, Dasari V, Sidhu SS, Mengistab A, Finkbeiner W, Gallup M and Basbaum C: Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer. PLoS One. 1(e93)2006.PubMed/NCBI View Article : Google Scholar


Pacheco-Pinedo EC, Durham AC, Stewart KM, Goss AM, Lu MM, Demayo FJ and Morrisey EE: Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium. J Clin Invest. 121:1935–1945. 2011.PubMed/NCBI View Article : Google Scholar


Kren L, Hermanová M, Goncharuk VN, Kaur P, Ross JS, Pavlovský Z and Dvorák K: Downregulation of plasma membrane expression/cytoplasmic accumulation of beta-catenin predicts shortened survival in non-small cell lung cancer. A clinicopathologic study of 100 cases. Cesk Patol. 39:17–20. 2003.PubMed/NCBI


Huang CL, Liu D, Ishikawa S, Nakashima T, Nakashima N, Yokomise H, Kadota K and Ueno M: Wnt1 overexpression promotes tumour progression in non-small cell lung cancer. Eur J Cancer. 44:2680–2688. 2008.PubMed/NCBI View Article : Google Scholar


Wang Y, Lei L, Zheng YW, Zhang L, Li ZH, Shen HY, Jiang GY, Zhang XP, Wang EH and Xu HT: Odd-skipped related 1 inhibits lung cancer proliferation and invasion by reducing Wnt signaling through the suppression of SOX9 and β-catenin. Cancer Sci. 109:1799–1810. 2018.PubMed/NCBI View Article : Google Scholar


Nakashima N, Huang CL, Liu D, Ueno M and Yokomise H: Intratumoral Wnt1 expression affects survivin gene expression in non-small cell lung cancer. Int J Oncol. 37:687–694. 2010.PubMed/NCBI View Article : Google Scholar


Winn RA, Marek L, Han SY, Rodriguez K, Rodriguez N, Hammond M, Van Scoyk M, Acosta H, Mirus J, Barry N, et al: Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation. J Biol Chem. 280:19625–19634. 2005.PubMed/NCBI View Article : Google Scholar


Wei Q, Zhao Y, Yang ZQ, Dong QZ, Dong XJ, Han Y, Zhao C and Wang EH: Dishevelled family proteins are expressed in non-small cell lung cancer and function differentially on tumor progression. Lung Cancer. 62:181–192. 2008.PubMed/NCBI View Article : Google Scholar


Liu Y, Dong QZ, Wang S, Fang CQ, Miao Y, Wang L, Li MZ and Wang EH: Abnormal expression of Pygopus 2 correlates with a malignant phenotype in human lung cancer. BMC Cancer. 13(346)2013.PubMed/NCBI View Article : Google Scholar


Khalaf AM, Fuentes D, Morshid AI, Burke MR, Kaseb AO, Hassan M, Hazle JD and Elsayes KM: Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J Hepatocell Carcinoma. 5:61–73. 2018.PubMed/NCBI View Article : Google Scholar


Flanagan DJ and Vincan E: Wnt signaling in cancer: Not a binary On:Off switch. Cancer Res. 79:5901–5906. 2019.PubMed/NCBI View Article : Google Scholar


Christie M, Jorissen RN, Mouradov D, Sakthianandeswaren A, Li S, Day F, Tsui C, Lipton L, Desai J, Jones IT, et al: Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis. Oncogene. 32:4675–4682. 2013.PubMed/NCBI View Article : Google Scholar


Russell JO and Monga SP: Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology. Annu Rev Pathol. 13:351–378. 2018.PubMed/NCBI View Article : Google Scholar


Molaei F, Forghanifard MM, Fahim Y and Abbaszadegan MR: Molecular signaling in tumorigenesis of gastric cancer. Iran Biomed J. 22:217–230. 2018.PubMed/NCBI View Article : Google Scholar


Toyama T, Lee HC, Koga H, Wands JR and Kim M: Noncanonical Wnt11 inhibits hepatocellular carcinoma cell proliferation and migration. Mol Cancer Res. 8:254–265. 2010.PubMed/NCBI View Article : Google Scholar


Yuzugullu H, Benhaj K, Ozturk N, Senturk S, Celik E, Toylu A, Tasdemir N, Yilmaz M, Erdal E, Akcali KC, et al: Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells. Mol Cancer. 8(90)2009.PubMed/NCBI View Article : Google Scholar


Cheng XX, Wang ZC, Chen XY, Sun Y, Kong QY, Liu J and Li H: Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumour dissemination. Cancer Lett. 223:339–347. 2005.PubMed/NCBI View Article : Google Scholar


Bhattacharya I, Barman N, Maiti M and Sarkar R: Assessment of beta-catenin expression by immunohistochemistry in colorectal neoplasms and its role as an additional prognostic marker in colorectal adenocarcinoma. Med Pharm Rep. 92:246–252. 2019.PubMed/NCBI View Article : Google Scholar


Kirikoshi H, Sekihara H and Katoh M: Up-regulation of WNT10A by tumor necrosis factor alpha and Helicobacter pylori in gastric cancer. Int J Oncol. 19:533–536. 2001.PubMed/NCBI


Li Q, Lai Q, He C, Fang Y, Yan Q, Zhang Y, Wang X, Gu C, Wang Y, Ye L, et al: RUNX1 promotes tumour metastasis by activating the Wnt/β-catenin signalling pathway and EMT in colorectal cancer. J Exp Clin Cancer Res. 38(334)2019.PubMed/NCBI View Article : Google Scholar


Xu X, Zhang M, Xu F and Jiang S: Wnt signaling in breast cancer: Biological mechanisms, challenges and opportunities. Mol Cancer. 19(165)2020.PubMed/NCBI View Article : Google Scholar


Wu R, Zhai Y, Fearon ER and Cho KR: Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res. 61:8247–8255. 2001.PubMed/NCBI


Yang L, Wu X, Wang Y, Zhang K, Wu J, Yuan YC, Deng X, Chen L, Kim CCH, Lau S, et al: FZD7 has a critical role in cell proliferation in triple negative breast cancer. Oncogene. 30:4437–4446. 2011.PubMed/NCBI View Article : Google Scholar


Yoshioka S, King ML, Ran S, Okuda H, MacLean JA II, McAsey ME, Sugino N, Brard L, Watabe K and Hayashi K: WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway. Mol Cancer Res. 10:469–482. 2012.PubMed/NCBI View Article : Google Scholar


Badiglian Filho L, Oshima CT, De Oliveira Lima F, De Oliveira Costa H, De Sousa Damião R, Gomes TS and Gonçalves WJ: Canonical and noncanonical Wnt pathway: A comparison among normal ovary, benign ovarian tumor and ovarian cancer. Oncol Rep. 21:313–320. 2009.PubMed/NCBI


Ahmed N, Abubaker K and Findlay JK: Ovarian cancer stem cells: Molecular concepts and relevance as therapeutic targets. Mol Aspects Med. 39:110–125. 2014.PubMed/NCBI View Article : Google Scholar


Mao J, Fan S, Ma W, Fan P, Wang B, Zhang J, Wang H, Tang B, Zhang Q, Yu X, et al: Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis. 5(e1039)2014.PubMed/NCBI View Article : Google Scholar


Whissell G, Montagni E, Martinelli P, Hernando-Momblona X, Sevillano M, Jung P, Cortina C, Calon A, Abuli A, Castells A, et al: The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression. Nat Cell Biol. 16:695–707. 2014.PubMed/NCBI View Article : Google Scholar


Zhu L, Pan R, Zhou D, Ye G and Tan W: BCL11A enhances stemness and promotes progression by activating Wnt/β-catenin signaling in breast cancer. Cancer Manag Res. 11:2997–3007. 2019.PubMed/NCBI View Article : Google Scholar


Chaudhary S, Islam Z, Mishra V, Rawat S, Ashraf GM and Kolatkar PR: Sox2: A regulatory factor in tumorigenesis and metastasis. Curr Protein Pept Sci. 20:495–504. 2019.PubMed/NCBI View Article : Google Scholar


Lin S, Zhen Y, Guan Y and Yi H: Roles of Wnt/β-catenin signaling pathway regulatory long non-coding RNAs in the pathogenesis of non-small cell lung cancer. Cancer Manag Res. 12:4181–4191. 2020.PubMed/NCBI View Article : Google Scholar


Teng Y, Wang X, Wang Y and Ma D: Wnt/beta-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochem Biophys Res Commun. 392:373–379. 2010.PubMed/NCBI View Article : Google Scholar


Jung DH, Bae YJ, Kim JH, Shin YK and Jeung HC: HER2 regulates cancer stem cell activities via the Wnt signaling pathway in gastric cancer cells. Oncology. 97:311–318. 2019.PubMed/NCBI View Article : Google Scholar


Akrami H, Mehdizadeh K, Moradi B, Borzabadi Farahani D, Mansouri K and Ghalib Ibraheem Alnajar S: PlGF knockdown induced apoptosis through Wnt signaling pathway in gastric cancer stem cells. J Cell Biochem. 120:3268–3276. 2019.PubMed/NCBI View Article : Google Scholar


Gao Y, Cai A, Xi H, Li J, Xu W, Zhang Y, Zhang K, Cui J, Wu X, Wei B and Chen L: Ring finger protein 43 associates with gastric cancer progression and attenuates the stemness of gastric cancer stem-like cells via the Wnt-β/catenin signaling pathway. Stem Cell Res Ther. 8(98)2017.PubMed/NCBI View Article : Google Scholar


Song H, Shi L, Xu Y, Xu T, Fan R, Cao M, Xu W and Song J: BRD4 promotes the stemness of gastric cancer cells via attenuating miR-216a-3p-mediated inhibition of Wnt/β-catenin signaling. Eur J Pharmacol. 852:189–197. 2019.PubMed/NCBI View Article : Google Scholar


Zhao H, Han R, Wang Z, Xian J and Bai X: Colorectal cancer stem cells and targeted agents. Pharmaceutics. 15(2763)2023.PubMed/NCBI View Article : Google Scholar


D'Antonio L, Fieni C, Ciummo SL, Vespa S, Lotti L, Sorrentino C and Di Carlo E: Inactivation of interleukin-30 in colon cancer stem cells via CRISPR/Cas9 genome editing inhibits their oncogenicity and improves host survival. J Immunother Cancer. 11(e006056)2023.PubMed/NCBI View Article : Google Scholar


Liao W, Zhang L, Chen X, Xiang J, Zheng Q, Chen N, Zhao M, Zhang G, Xiao X, Zhou G, et al: Targeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer. Phytomedicine. 108(154524)2023.PubMed/NCBI View Article : Google Scholar


Hatano Y, Fukuda S, Hisamatsu K, Hirata A, Hara A and Tomita H: Multifaceted interpretation of colon cancer stem cells. Int J Mol Sci. 18(1446)2017.PubMed/NCBI View Article : Google Scholar


Singh S, Arcaroli J, Chen Y, Thompson DC, Messersmith W, Jimeno A and Vasiliou V: ALDH1B1 is crucial for colon tumorigenesis by modulating Wnt/β-catenin, notch and PI3K/Akt signaling pathways. PLoS One. 10(e0121648)2015.PubMed/NCBI View Article : Google Scholar


Hirata A, Utikal J, Yamashita S, Aoki H, Watanabe A, Yamamoto T, Okano H, Bardeesy N, Kunisada T, Ushijima T, et al: Dose-dependent roles for canonical Wnt signalling in de novo crypt formation and cell cycle properties of the colonic epithelium. Development. 140:66–75. 2013.PubMed/NCBI View Article : Google Scholar


Ordóñez-Morán P, Dafflon C, Imajo M, Nishida E and Huelsken J: HOXA5 counteracts stem cell traits by inhibiting wnt signaling in colorectal cancer. Cancer Cell. 28:815–829. 2015.PubMed/NCBI View Article : Google Scholar


Khaled WT, Choon Lee S, Stingl J, Chen X, Raza Ali H, Rueda OM, Hadi F, Wang J, Yu Y, Chin SF, et al: BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells. Nat Commun. 6(5987)2015.PubMed/NCBI View Article : Google Scholar


Yue Z, Yuan Z, Zeng L, Wang Y, Lai L, Li J, Sun P, Xue X, Qi J, Yang Z, et al: LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells. FASEB J. 32:2422–2437. 2018.PubMed/NCBI View Article : Google Scholar


Satriyo PB, Bamodu OA, Chen JH, Aryandono T, Haryana SM, Yeh CT and Chao TY: Cadherin 11 inhibition downregulates β-catenin, deactivates the canonical WNT signalling pathway and suppresses the cancer stem cell-like phenotype of triple negative breast cancer. J Clin Med. 8(148)2019.PubMed/NCBI View Article : Google Scholar


Nguyen VHL, Hough R, Bernaudo S and Peng C: Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis. J Ovarian Res. 12(122)2019.PubMed/NCBI View Article : Google Scholar


Condello S, Morgan CA, Nagdas S, Cao L, Turek J, Hurley TD and Matei D: β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. Oncogene. 34:2297–2308. 2015.PubMed/NCBI View Article : Google Scholar


Wu G, Liu A, Zhu J, Lei F, Wu S, Zhang X, Ye L, Cao L and He S: MiR-1207 overexpression promotes cancer stem cell-like traits in ovarian cancer by activating the Wnt/β-catenin signaling pathway. Oncotarget. 6:28882–28894. 2015.PubMed/NCBI View Article : Google Scholar


Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009.PubMed/NCBI View Article : Google Scholar


Rapp J, Jaromi L, Kvell K, Miskei G and Pongracz JE: WNT signaling-lung cancer is no exception. Respir Res. 18(167)2017.PubMed/NCBI View Article : Google Scholar


Yang S, Liu Y, Li MY, Ng CSH, Yang SL, Wang S, Zou C, Dong Y, Du J, Long X, et al: FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer. Mol Cancer. 16(124)2017.PubMed/NCBI View Article : Google Scholar


Pan J, Fang S, Tian H, Zhou C, Zhao X, Tian H, He J, Shen W, Meng X, Jin X and Gong Z: lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/β-catenin signaling. Mol Cancer. 19(9)2020.PubMed/NCBI View Article : Google Scholar


Li Y, Chen F, Shen W, Li B, Xiang R, Qu L, Zhang C, Li G, Xie H, Katanaev VL and Jia L: WDR74 induces nuclear β-catenin accumulation and activates Wnt-responsive genes to promote lung cancer growth and metastasis. Cancer Lett. 471:103–115. 2020.PubMed/NCBI View Article : Google Scholar


Qi H, Wang S, Wu J, Yang S, Gray S, Ng CSH, Du J, Underwood MJ, Li MY and Chen GG: EGFR-AS1/HIF2A regulates the expression of FOXP3 to impact the cancer stemness of smoking-related non-small cell lung cancer. Ther Adv Med Oncol. 11(1758835919855228)2019.PubMed/NCBI View Article : Google Scholar


Tian S, Peng P, Li J, Deng H, Zhan N, Zeng Z and Dong W: SERPINH1 regulates EMT and gastric cancer metastasis via the Wnt/β-catenin signaling pathway. Aging (Albany NY). 12:3574–3593. 2020.PubMed/NCBI View Article : Google Scholar


Wang H, Wu M, Lu Y, He K, Cai X, Yu X, Lu J and Teng L: LncRNA MIR4435-2HG targets desmoplakin and promotes growth and metastasis of gastric cancer by activating Wnt/β-catenin signaling. Aging (Albany NY). 11:6657–6673. 2019.PubMed/NCBI View Article : Google Scholar


Luo Y, Tan W, Jia W, Liu Z, Ye P, Fu Z, Lu F, Xiang W, Tang L, Yao L, et al: The long non-coding RNA LINC01606 contributes to the metastasis and invasion of human gastric cancer and is associated with Wnt/β-catenin signaling. Int J Biochem Cell Biol. 103:125–134. 2018.PubMed/NCBI View Article : Google Scholar


Gao J, Zhao C, Liu Q, Hou X, Li S, Xing X, Yang C and Luo Y: Cyclin G2 suppresses Wnt/β-catenin signaling and inhibits gastric cancer cell growth and migration through Dapper1. J Exp Clin Cancer Res. 37(317)2018.PubMed/NCBI View Article : Google Scholar


Ge Q, Hu Y, He J, Chen F, Wu L, Tu X, Qi Y, Zhang Z, Xue M, Chen S, et al: Zic1 suppresses gastric cancer metastasis by regulating Wnt/β-catenin signaling and epithelial-mesenchymal transition. FASEB J. 34:2161–2172. 2020.PubMed/NCBI View Article : Google Scholar


Chung MT, Lai HC, Sytwu HK, Yan MD, Shih YL, Chang CC, Yu MH, Liu HS, Chu DW and Lin YW: SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway. Gynecol Oncol. 112:646–653. 2009.PubMed/NCBI View Article : Google Scholar


Zhang LZ, Huang LY, Huang AL, Liu JX and Yang F: CRIP1 promotes cell migration, invasion and epithelial-mesenchymal transition of cervical cancer by activating the Wnt/β-catenin signaling pathway. Life Sci. 207:420–427. 2018.PubMed/NCBI View Article : Google Scholar


Harper KL, Sosa MS, Entenberg D, Hosseini H, Cheung JF, Nobre R, Avivar-Valderas A, Nagi C, Girnius N, Davis RJ, et al: Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature. 540:588–592. 2016.PubMed/NCBI View Article : Google Scholar


Kenny HA and Lengyel E: MMP-2 functions as an early response protein in ovarian cancer metastasis. Cell Cycle. 8:683–688. 2009.PubMed/NCBI View Article : Google Scholar


Vasan N, Baselga J and Hyman DM: A view on drug resistance in cancer. Nature. 575:299–309. 2019.PubMed/NCBI View Article : Google Scholar


Stewart DJ: Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 106(djt356)2014.PubMed/NCBI View Article : Google Scholar


Zhong Z and Virshup DM: Wnt signaling and drug resistance in cancer. Mol Pharmacol. 97:72–89. 2020.PubMed/NCBI View Article : Google Scholar


Geng P, Zhao J, Li Q, Wang X, Qin W, Wang T, Shi X, Liu X, Chen J, Qiu H and Xu G: Z-Ligustilide combined with cisplatin reduces PLPP1-mediated phospholipid synthesis to impair cisplatin resistance in lung cancer. Int J Mol Sci. 24(17046)2023.PubMed/NCBI View Article : Google Scholar


Gao Y, Liu Z, Zhang X, He J, Pan Y, Hao F, Xie L, Li Q, Qiu X and Wang E: Inhibition of cytoplasmic GSK-3β increases cisplatin resistance through activation of Wnt/β-catenin signaling in A549/DDP cells. Cancer Lett. 336:231–239. 2013.PubMed/NCBI View Article : Google Scholar


Xie C, Pan Y, Hao F, Gao Y, Liu Z, Zhang X, Xie L, Jiang G, Li Q and Wang E: C-Myc participates in β-catenin-mediated drug resistance in A549/DDP lung adenocarcinoma cells. APMIS. 122:1251–1258. 2014.PubMed/NCBI View Article : Google Scholar


Fang X, Gu P, Zhou C, Liang A, Ren S, Liu F, Zeng Y, Wu Y, Zhao Y, Huang B, et al: β-Catenin overexpression is associated with gefitinib resistance in non-small cell lung cancer cells. Pulm Pharmacol Ther. 28:41–48. 2014.PubMed/NCBI View Article : Google Scholar


Lee SB, Gong YD, Park YI and Dong MS: 2,3,6-Trisubstituted quinoxaline derivative, a small molecule inhibitor of the Wnt/beta-catenin signaling pathway, suppresses cell proliferation and enhances radiosensitivity in A549/Wnt2 cells. Biochem Biophys Res Commun. 431:746–752. 2013.PubMed/NCBI View Article : Google Scholar


Wang HQ, Xu ML, Ma J, Zhang Y and Xie CH: Frizzled-8 as a putative therapeutic target in human lung cancer. Biochem Biophys Res Commun. 417:62–66. 2012.PubMed/NCBI View Article : Google Scholar


Wang X, Lu B, Dai C, Fu Y, Hao K, Zhao B, Chen Z and Fu L: Caveolin-1 promotes chemoresistance of gastric cancer cells to cisplatin by activating WNT/β-catenin pathway. Front Oncol. 10(46)2020.PubMed/NCBI View Article : Google Scholar


Chi HC, Tsai CY, Wang CS, Yang HY, Lo CH, Wang WJ, Lee KF, Lai LY, Hong JH, Chang YF, et al: DOCK6 promotes chemo- and radioresistance of gastric cancer by modulating WNT/β-catenin signaling and cancer stem cell traits. Oncogene. 39:5933–5949. 2020.PubMed/NCBI View Article : Google Scholar


Liu Y, Chen H, Zheng P, Zheng Y, Luo Q, Xie G, Ma Y and Shen L: ICG-001 suppresses growth of gastric cancer cells and reduces chemoresistance of cancer stem cell-like population. J Exp Clin Cancer Res. 36(125)2017.PubMed/NCBI View Article : Google Scholar


Cheng C, Qin Y, Zhi Q, Wang J and Qin C: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3K/Akt and Wnt/β-catenin signaling pathways by up-regulating miR-34a. Int J Biol Macromol. 107:2620–2629. 2018.PubMed/NCBI View Article : Google Scholar


Wang B, Guan G and Zhao D: Silence of FAM83H-AS1 promotes chemosensitivity of gastric cancer through Wnt/β-catenin signaling pathway. Biomed Pharmacother. 125(109961)2020.PubMed/NCBI View Article : Google Scholar


Yang W, Wu B, Ma N, Wang Y, Guo J, Zhu J and Zhao S: BATF2 reverses multidrug resistance of human gastric cancer cells by suppressing Wnt/β-catenin signaling. In Vitro Cell Dev Biol Anim. 55:445–452. 2019.PubMed/NCBI View Article : Google Scholar


Zhang ZM, Wu JF, Luo QC, Liu QF, Wu QW, Ye GD, She HQ and Li BA: Pygo2 activates MDR1 expression and mediates chemoresistance in breast cancer via the Wnt/β-catenin pathway. Oncogene. 35:4787–4797. 2016.PubMed/NCBI View Article : Google Scholar


Wang Z, Wang N, Li W, Liu P, Chen Q, Situ H, Zhong S, Guo L, Lin Y, Shen J and Chen J: Caveolin-1 mediates chemoresistance in breast cancer stem cells via β-catenin/ABCG2 signaling pathway. Carcinogenesis. 35:2346–2356. 2014.PubMed/NCBI View Article : Google Scholar


Loh YN, Hedditch EL, Baker LA, Jary E, Ward RL and Ford CE: The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer. BMC Cancer. 13(174)2013.PubMed/NCBI View Article : Google Scholar


Cheng S, Huang Y, Lou C, He Y, Zhang Y and Zhang Q: FSTL1 enhances chemoresistance and maintains stemness in breast cancer cells via integrin β3/Wnt signaling under miR-137 regulation. Cancer Biol Ther. 20:328–337. 2019.PubMed/NCBI View Article : Google Scholar


Bi Z, Li Q, Dinglin X, Xu Y, You K, Hong H, Hu Q, Zhang W, Li C, Tan Y, et al: Nanoparticles (NPs)-meditated LncRNA AFAP1-AS1 silencing to block Wnt/β-catenin signaling pathway for synergistic reversal of radioresistance and effective cancer radiotherapy. Adv Sci (Weinh). 7(2000915)2020.PubMed/NCBI View Article : Google Scholar


Chau WK, Ip CK, Mak ASC, Lai HC and Wong AST: c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/β-catenin-ATP-binding cassette G2 signaling. Oncogene. 32:2767–2781. 2013.PubMed/NCBI View Article : Google Scholar


Nagaraj AB, Joseph P, Kovalenko O, Singh S, Armstrong A, Redline R, Resnick K, Zanotti K, Waggoner S and DiFeo A: Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance. Oncotarget. 6:23720–23734. 2015.PubMed/NCBI View Article : Google Scholar


Chiu WT, Huang YF, Tsai HY, Chen CC, Chang CH, Huang SC, Hsu KF and Chou CY: FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells. Oncotarget. 6:2349–2365. 2015.PubMed/NCBI View Article : Google Scholar


Mariya T, Hirohashi Y, Torigoe T, Tabuchi Y, Asano T, Saijo H, Kuroda T, Yasuda K, Mizuuchi M, Saito T and Sato N: Matrix metalloproteinase-10 regulates stemness of ovarian cancer stem-like cells by activation of canonical Wnt signaling and can be a target of chemotherapy-resistant ovarian cancer. Oncotarget. 7:26806–26822. 2016.PubMed/NCBI View Article : Google Scholar


Zhang Y, Liu B, Zhao Q, Hou T and Huang X: Nuclear localizaiton of β-catenin is associated with poor survival and chemo-/radioresistance in human cervical squamous cell cancer. Int J Clin Exp Pathol. 7:3908–3917. 2014.PubMed/NCBI


Zhou S, Bai ZL, Xia D, Zhao ZJ, Zhao R and Wang YY: FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β-catenin through mRNA demethylation. Mol Carcinog. 57:590–597. 2018.PubMed/NCBI View Article : Google Scholar


Xu H, Wang Z, Xu L, Mo G, Duan G, Wang Y, Sun Z and Chen H: Targeting the eIF4E/β-catenin axis sensitizes cervical carcinoma squamous cells to chemotherapy. Am J Transl Res. 9:1203–1212. 2017.PubMed/NCBI


Cao HZ, Liu XF, Yang WT, Chen Q and Zheng PS: LGR5 promotes cancer stem cell traits and chemoresistance in cervical cancer. Cell Death Dis. 8(e3039)2017.PubMed/NCBI View Article : Google Scholar


Joyce JA and Fearon DT: T cell exclusion, immune privilege, and the tumor microenvironment. Science. 348:74–80. 2015.PubMed/NCBI View Article : Google Scholar


Chen DS and Mellman I: Oncology meets immunology: The cancer-immunity cycle. Immunity. 39:1–10. 2013.PubMed/NCBI View Article : Google Scholar


Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R, Kaplan JB, Chae YK and Giles FJ: Wnt/beta-catenin pathway: Modulating anticancer immune response. J Hematol Oncol. 10(101)2017.PubMed/NCBI View Article : Google Scholar


Ganesh S, Shui X, Craig KP, Park J, Wang W, Brown BD and Abrams MT: RNAi-mediated β-catenin inhibition promotes T cell infiltration and antitumor activity in combination with immune checkpoint blockade. Mol Ther. 26:2567–2579. 2018.PubMed/NCBI View Article : Google Scholar


Luke JJ, Bao R, Sweis RF, Spranger S and Gajewski TF: WNT/β-catenin pathway activation correlates with immune exclusion across human cancers. Clin Cancer Res. 25:3074–3083. 2019.PubMed/NCBI View Article : Google Scholar


Kerdidani D, Chouvardas P, Arjo AR, Giopanou I, Ntaliarda G, Guo YA, Tsikitis M, Kazamias G, Potaris K, Stathopoulos GT, et al: Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma. Nat Commun. 10(1405)2019.PubMed/NCBI View Article : Google Scholar


Bergenfelz C, Janols H, Wullt M, Jirström K, Bredberg A and Leandersson K: Wnt5a inhibits human monocyte-derived myeloid dendritic cell generation. Scand J Immunol. 78:194–204. 2013.PubMed/NCBI View Article : Google Scholar


Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, Lee H, Arthur CD, White JM, Kalinke U, et al: Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med. 208:1989–2003. 2011.PubMed/NCBI View Article : Google Scholar


Sharma P, Hu-Lieskovan S, Wargo JA and Ribas A: Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 168:707–723. 2017.PubMed/NCBI View Article : Google Scholar


Gattinoni L, Ji Y and Restifo NP: Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy. Clin Cancer Res. 16:4695–4701. 2010.PubMed/NCBI View Article : Google Scholar


Schinzari V, Timperi E, Pecora G, Palmucci F, Gallerano D, Grimaldi A, Covino DA, Guglielmo N, Melandro F, Manzi E, et al: Wnt3a/β-catenin signaling conditions differentiation of partially exhausted T-effector cells in human cancers. Cancer Immunol Res. 6:941–952. 2018.PubMed/NCBI View Article : Google Scholar


Wang B, Tian T, Kalland KH, Ke X and Qu Y: Targeting Wnt/β-catenin signaling for cancer immunotherapy. Trends Pharmacol Sci. 39:648–658. 2018.PubMed/NCBI View Article : Google Scholar


Sun X, Liu S, Wang D, Zhang Y, Li W, Guo Y, Zhang H and Suo J: Colorectal cancer cells suppress CD4+ T cells immunity through canonical Wnt signaling. Oncotarget. 8:15168–15181. 2017.PubMed/NCBI View Article : Google Scholar


Lengfeld JE, Lutz SE, Smith JR, Diaconu C, Scott C, Kofman SB, Choi C, Walsh CM, Raine CS, Agalliu I and Agalliu D: Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis. Proc Natl Acad Sci USA. 114:E1168–E1177. 2017.PubMed/NCBI View Article : Google Scholar


Xu P, Xi Y, Kim JW, Zhu J, Zhang M, Xu M, Ren S, Yang D, Ma X and Xie W: Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis. Acta Pharm Sin B. 14:1241–1256. 2024.PubMed/NCBI View Article : Google Scholar


Hussain T, Alafnan A, Almazni IA, Helmi N, Moin A, Baeissa HM, Awadelkareem AM, Elkhalifa AO, Bakhsh T, Alzahrani A, et al: Aloe-emodin exhibits growth-suppressive effects on androgen-independent human prostate cancer DU145 cells via inhibiting the Wnt/β-catenin signaling pathway: An in vitro and in silico study. Front Pharmacol. 14(1325184)2024.PubMed/NCBI View Article : Google Scholar


Suryawanshi A, Hussein MS, Prasad PD and Manicassamy S: Wnt signaling cascade in dendritic cells and regulation of anti-tumor immunity. Front Immunol. 11(122)2020.PubMed/NCBI View Article : Google Scholar


Haseeb M, Pirzada RH, Ain QU and Choi S: Wnt signaling in the regulation of immune cell and cancer therapeutics. Cells. 8(1380)2019.PubMed/NCBI View Article : Google Scholar


Zhan T, Rindtorff N and Boutros M: Wnt signaling in cancer. Oncogene. 36:1461–1473. 2017.PubMed/NCBI View Article : Google Scholar


He B, You L, Uematsu K, Xu Z, Lee AY, Matsangou M, McCormick F and Jablons DM: A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia. 6:7–14. 2004.PubMed/NCBI View Article : Google Scholar


Bravo DT, Yang YL, Kuchenbecker K, Hung MS, Xu Z, Jablons DM and You L: Frizzled-8 receptor is activated by the Wnt-2 ligand in non-small cell lung cancer. BMC Cancer. 13(316)2013.PubMed/NCBI View Article : Google Scholar


Huang Y, Liu G, Zhang B, Xu G, Xiong W and Yang H: Wnt-5a regulates proliferation in lung cancer cells. Oncol Rep. 23:177–181. 2010.PubMed/NCBI


Dotan E, Cardin DB, Lenz HJ, Messersmith W, O'Neil B, Cohen SJ, Denlinger CS, Shahda S, Astsaturov I, Kapoun AM, et al: Phase Ib study of Wnt inhibitor ipafricept with gemcitabine and nab-paclitaxel in patients with previously untreated stage IV pancreatic cancer. Clin Cancer Res. 26:5348–5357. 2020.PubMed/NCBI View Article : Google Scholar


Le PN, McDermott JD and Jimeno A: Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. 146:1–11. 2015.PubMed/NCBI View Article : Google Scholar


Taciak B, Pruszynska I, Kiraga L, Bialasek M and Krol M: Wnt signaling pathway in development and cancer. J Physiol Pharmacol. 69:185–196. 2018.PubMed/NCBI View Article : Google Scholar


Suryawanshi A, Tadagavadi RK, Swafford D and Manicassamy S: Modulation of inflammatory responses by Wnt/β-catenin signaling in dendritic cells: A novel immunotherapy target for autoimmunity and cancer. Front Immunol. 7(460)2016.PubMed/NCBI View Article : Google Scholar


Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, et al: Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci USA. 110:20224–20229. 2013.PubMed/NCBI View Article : Google Scholar


Jimeno A, Gordon M, Chugh R, Messersmith W, Mendelson D, Dupont J, Stagg R, Kapoun AM, Xu L, Uttamsingh S, et al: A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin Cancer Res. 23:7490–7497. 2017.PubMed/NCBI View Article : Google Scholar


Bhamra I, Armer R, Bingham M, Eagle C, Cook A, Phillips C and Woodcock S: Abstract 3764: Porcupine inhibitor RXC004 enhances immune response in pre-clinical models of cancer. Cancer Res. 78 (Suppl 13)(S3764)2018.


Tabernero J, Van Cutsem E, Garralda E, Tai D, De Braud F, Geva R, van Bussel MTJ, Fiorella Dotti K, Elez E, de Miguel MJ, et al: A phase Ib/II study of WNT974 + encorafenib + cetuximab in patients with BRAF V600E-mutant KRAS wild-type metastatic colorectal cancer. Oncologist. 28:230–238. 2023.PubMed/NCBI View Article : Google Scholar


Goswami VG and Patel BD: Recent updates on Wnt signaling modulators: A patent review (2014-2020). Expert Opin Ther Pat. 31:1009–1043. 2021.PubMed/NCBI View Article : Google Scholar


Shah K, Panchal S and Patel B: Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol Res. 167(105532)2021.PubMed/NCBI View Article : Google Scholar


Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, et al: Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 110:12649–12654. 2013.PubMed/NCBI View Article : Google Scholar


Li C, Zheng X, Han Y, Lv Y, Lan F and Zhao J: XAV939 inhibits the proliferation and migration of lung adenocarcinoma A549 cells through the WNT pathway. Oncol Lett. 15:8973–8982. 2018.PubMed/NCBI View Article : Google Scholar


Pan F, Shen F, Yang L, Zhang L, Guo W and Tian J: Inhibitory effects of XAV939 on the proliferation of small-cell lung cancer H446 cells and Wnt/β-catenin signaling pathway in vitro. Oncol Lett. 16:1953–1958. 2018.PubMed/NCBI View Article : Google Scholar


Shetti D, Zhang B, Fan C, Mo C and Lee BH: Low dose of paclitaxel combined with XAV939 attenuates metastasis, angiogenesis and growth in breast cancer by suppressing Wnt signaling. Cells. 8(892)2019.PubMed/NCBI View Article : Google Scholar


Arqués O, Chicote I, Puig I, Tenbaum SP, Argilés G, Dienstmann R, Fernández N, Caratù G, Matito J, Silberschmidt D, et al: Tankyrase inhibition blocks Wnt/β-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clin Cancer Res. 22:644–656. 2016.PubMed/NCBI View Article : Google Scholar


Waaler J, Mygland L, Tveita A, Strand MF, Solberg NT, Olsen PA, Aizenshtadt A, Fauskanger M, Lund K, Brinch SA, et al: Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models. Commun Biol. 3(196)2020.PubMed/NCBI View Article : Google Scholar


Zhang X, Wang L and Qu Y: Targeting the β-catenin signaling for cancer therapy. Pharmacol Res. 160(104794)2020.PubMed/NCBI View Article : Google Scholar


Doghman M, Cazareth J and Lalli E: The T cell factor/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells. J Clin Endocrinol Metab. 93:3222–3225. 2008.PubMed/NCBI View Article : Google Scholar


Gandhirajan RK, Staib PA, Minke K, Gehrke I, Plickert G, Schlösser A, Schmitt EK, Hallek M and Kreuzer KA: Small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. Neoplasia. 12:326–335. 2010.PubMed/NCBI View Article : Google Scholar


Wei W, Chua MS, Grepper S and So S: Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int J Cancer. 126:2426–2436. 2010.PubMed/NCBI View Article : Google Scholar


Rodon J, Argilés G, Connolly RM, Vaishampayan U, de Jonge M, Garralda E, Giannakis M, Smith DC, Dobson JR, McLaughlin ME, et al: Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br J Cancer. 125:28–37. 2021.PubMed/NCBI View Article : Google Scholar


Phillips C, Bhamra I, Eagle C, Flanagan E, Armer R, Jones CD, Bingham M, Calcraft P, Edmenson Cook A, Thompson B and Woodcock SA: The Wnt pathway inhibitor RXC004 blocks tumor growth and reverses immune evasion in Wnt ligand-dependent cancer models. Cancer Res Commun. 2:914–928. 2022.PubMed/NCBI View Article : Google Scholar

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Wang H, Zhang L, Hu C, Li H and Jiang M: Wnt signaling and tumors (Review). Mol Clin Oncol 21: 45, 2024
Wang, H., Zhang, L., Hu, C., Li, H., & Jiang, M. (2024). Wnt signaling and tumors (Review). Molecular and Clinical Oncology, 21, 45.
Wang, H., Zhang, L., Hu, C., Li, H., Jiang, M."Wnt signaling and tumors (Review)". Molecular and Clinical Oncology 21.1 (2024): 45.
Wang, H., Zhang, L., Hu, C., Li, H., Jiang, M."Wnt signaling and tumors (Review)". Molecular and Clinical Oncology 21, no. 1 (2024): 45.