Wnt what does it stand for

In addition to performing normal developmental processes, EMT also plays a key role in tumor growth and progression if it goes unchecked 53 , The tumor microenvironment TME plays a crucial role in assisting cancer metastasis by inducing EMT in the tumor cells.

Besides Wnt ligands, the growth factors secreted by stromal cells of TME are also responsible for the activation of Wnt signaling in the nucleus For example, c-Met overexpression is significantly correlated with cervical cancer progression A study by Yang et al.

The vascular endothelial growth factor VEGF is another growth factor that is regarded as the archetype molecule in malignant phenotype VEGF expression and micro-vessel density are regarded as the prognostic factors for poor outcomes in various cancers Cancer-associated fibroblasts CAFs are also known to play a vital role in shaping the immunosuppressive environment within the tumor, specifically in oral squamous cell carcinoma OSCC , wherein CAF-educated cells suppress the T cell population more efficiently than the control cells CAFs are also considered to be a main source of Wnt2 in colorectal cancer where FZD8 acts as a putative receptor of Wnt2 and is responsible for tumor growth, invasions, and metastasis The interaction of inflammatory cells with cancer cells is well-studied.

In colorectal cancer, the infiltrating macrophages express high levels of Wnt2 and Wnt5a in progression from normal colorectal adenoma to carcinoma. This suggests that paracrine Wnt activation by macrophages may result in cancer progression Wnt7b is another Wnt ligand that is produced by macrophages residing in the tumor One study proposed a mechanism wherein macrophages produced Wnt7b and initiated canonical the Wnt signaling pathway in vascular endothelial cells VECs expressing LRP5 and Frizzled in a paracrine fashion.

Also, Wnt ligands secreted by tumor cells could stimulate the polarization of TAMs to M2 subtype via the canonical Wnt signaling pathway, resulting in tumor growth and migration Moreover, macrophage-derived soluble factors also induced canonical Wnt signaling pathway and promoted tumor growth and metastasis.

This results in higher expression of Wnt target genes in cancer cells. Components of the extracellular matrix ECM also regulate tumor cells, particularly of the colon. Wnt ligands are expressed in both epithelial and mesenchymal cells of the colon. Moreover, aberrant Wnt signaling is also associated with the development of colorectal cancer Mesenchymal forkhead transcription factors, Foxf1 and Foxf2 , can promote ECM production in the gut and can limit paracrine Wnt signaling.

A study by Ormestad et al. This resulted in over-proliferation of intestinal cells, which are also resistant to apoptosis Figure 3. WNT signaling works in a context-dependent manner. Under different physiological conditions, it can positively or negatively regulate immunosurveillance mechanisms in the tumor microenvironment. Wnt signaling is an important pathway for immune cell maintenance and renewal. It regulates the progenitor cell homeostasis, thereby controlling hematopoiesis.

Various Wnt ligands such as Wnt5a, Wnt10b, and Wnt16 have been reported in regulating hematopoiesis 73 — Apart from Wnt ligands, downstream molecules of Wnt signaling also control the development and differentiation of various hematopoietic cells. Besides its role in hematopoiesis, Wnt signaling is also demonstrated to play a role in thymocyte development where it helps in proliferation of immature thymocytes Wnt signaling is involved in consecutive thymic selection events leading to maturation of naive T cells.

Wnt inactivation by Dickkopf-related protein 1 DKK1 in postnatal mice resulted in the loss of progenitor thymic epithelial cells and thymic degeneration 79 , highlighting the importance of the presence of Wnt in the microenvironment. Wnt signaling also plays a crucial role in the B-cell development where it controls proliferation and survival of progenitor B-cells.

Lefdeficient mice showed defects in progenitor B-cell proliferation and survival Recently, it has been shown that the canonical and non-canonical Wnt signaling could contribute to the maintenance and differentiation of B-1 cells, a subpopulation of B cells localized in the peritoneum Thus, Wnt signaling plays a pivotal role in maintenance of hematopoiesis and renewal of immune cells in circulation and thereby positively regulates the anticancer immune response.

Wnt signaling also play a crucial role in dampening antitumor immune response in tumor microenvironment. There are several reports, which suggest that Wnt signaling encourages tumor progression by promoting tolerance and the immune-escape mechanism. The cumulative anti-tumor immune response mediated by T cells, dendritic cells, B cells, macrophages, neutrophils, and NK cells results in tumor regression caused by elimination of cancer cells Mutations and epigenetic changes developed by tumors due to continuous stimulation by carcinogens or the environmental factors alter the signaling cascade in the tumor microenvironment 1.

These changes alter the phenotypic expression of chemokines, cytokines, and some important ligands for the immune cells in the tumor microenvironment resulting in tolerance and immune escape.

Recognition and elimination of the cancer cells is largely dependent on antigen presenting cells APCs , such as dendritic cells DCs , macrophages, and B cells, which have the ability to present tumor associated antigens TAAs Suppressor cells present in the tumor microenvironment, such as Treg, myeloid-derived suppressor cells MDSC , DC suppressor cells, etc.

Despite MDSCs suppression by Wnt signaling, its presence in the Wnt active tumor microenvironment is highly contradictory. This was partially explained with the presence of Dkk1 secreted by the tumor stroma, which inhibits Beta-catenin in MDSCs To understand this puzzle of interplay between Wnt signaling and MDSCs, further study is needed that can correlate various driving factors working in different context.

Wnt signaling shows a negative correlation with TAA presentation. Canonical Wnt signaling can potentially regulate DC activation and maturation This phenotype of DC exhibits a positive correlation with antitumor immunity. Therefore, a combinatorial therapy of the Wnt inhibitor specifically targeting DCs along with PD1 and CTLA4 immune therapy can work better for patients not responding to cancer immune therapy. However, the challenge here lies in identifying effective agents that can target the Wnt pathway without tampering the normal cellular functions like tissue repair and homeostasis, the renewal of stem cells, and survival.

The detailed action of Wnt signaling in both canonical and non-canonical pathway has been summarized in the prior sections. Wnt pathway is observed to be upregulated in cancers. Activation of Wnt leads to the loss of function of APC, which is a negative regulator of cell proliferation.

Inhibitors of the Wnt signaling pathway can therefore have therapeutic values in cancer treatment, and multiple such targets have been identified wherein inhibitors act at different steps of Wnt signaling pathway.

Broadly, these inhibitors can be classified into two categories: 1. Inhibitors of Wnt-receptor complex, and 2. The detailed mechanism of action of these inhibitors and their subtypes has been briefed below. Also, a list summarizing such drugs and their clinical trial status has been appended in Table 2. Table 2. List of drugs for specific diseases under clinical trials and their targets.

It recently became a highly druggable target for inhibiting Wnt signaling pathways 97 , Moreover, PORCN is the only enzyme specific to the Wnt cascade that is found to be upregulated in mouse cancer models, and it is often regarded as a poor prognosis marker for head and neck squamous cell cancers This molecule is now undergoing phase 1 and phase 2 clinical trials.

Another promising molecule for PORCN inhibition is an oral, selective small molecule inhibitor, ETC, of porcupine, which has shown favorable results in preclinical studies and has now entered phase 1 of clinical trials This specific interaction is also an attractive target, and many groups are working on antibodies that can act at this point and lead to the inhibition of further downstream signaling. Monoclonal antibodies MAbs designed to bind Wnt1 and Wnt2 have shown to lead to tumor suppression in a plethora of malignancies, including, but not limited to, melanoma, colorectal cancers, and non-small cell lung carcinoma Its safety and efficacy in many cancers are being evaluated alone or combined with other chemotherapeutic regimes.

A first-in-human phase I study of this decoy receptor for Wnt ligands is presently being carried out in patients with advanced stages of solid tumors It binds to the Wnt ligand through the adomain present in the extracellular part of the human Frizzled 8 receptor fused to a human IgG1 Fc fragment. This also binds to Wnt ligands and blocks the downstream signaling. In xenograft models of ovarian cancer, Ipafricept has shown a reduction in the frequency of stem cells, suppressed tumor formation, and stimulate differentiation.

Also in a combinatorial approach, treatment with OMPF28 prior to taxane chemotherapy displays synergy and, therefore, superior antitumor efficacy The setback of this study lies in the trepidations of gastrointestinal toxicity associated with these inhibitors, and further studies are needed to verify their safety and efficacy.

Selective tankyrase inhibitors, MN and CMP8, with the capacity to bind to the nicotinamide subsite of tankyrases are amongst the best inhibitors and have demonstrated nanomolar potencies Disheveled binds to the frizzled receptor on its C-terminal region via its PDZ domain. This Frizzled—disheveled interaction is a target for some notable inhibitors like NSC, FJ9, and —, leading to inhibition of the Wnt signal transduction pathway and thereby causing cancer regression Sulindac is a FDA approved disheveled inhibitor which can inhibit the proliferation of lung cancer A cells , Wnt signaling involves a plethora of intermediate steps, and there is therefore a constantly evolving pursuit to find agents that can target the downstream steps of this pathway.

LF3, a 4-thioureido-benzenesulfonamide derivative, possesses the capacity to perturb this interaction in colon cancer However, this interaction is not very specific, causing many off-target effects.

Small molecule antagonists that have the capacity to inhibit this interaction can serve as a potential therapeutic agent. This molecule has shown promising results in the preclinical stage with pancreatic cancer cells. It has been proven to promote differentiation of CSCs, inhibition of stroma formation, and decrease the metastatic potential of cancer cells Wnt5a acts as a tumor suppressor in various cancers, and its downregulation is often associated with lower disease-free survival in primary breast cancers and also in hematopoietic, prostate, and colon cancers.

Foxy-5 is a hexapeptide mimic of Wnt5a which is synthesized to possess Wnt5a-like properties that can impair cancer cell migration. Also, peptides derived by modifying the Wnt5a ligand sequence have shown the capability to mimic the Wnt5a molecule. It can bind to the Fzd-5 receptor in a human breast tumor cell line and impair metastatic ability Wnt signaling has now been shown to be closely associated with other pathways, like the Notch signaling pathway, and Notch1 is thought to be acting as a connecting link between them.

MK in combination with ridaforolimus MK is currently in phase I trial of patients with solid tumors MK with docetaxel has entered phase II trials in breast cancer patients Another selective GSI, PF, showed a reduction in tumor cell migration and mammosphere formation in vitro , and a marked decrease in tumor cell self-renewal ability in vivo The phase I trials in triple negative breast cancer patients in combination with docetaxel, however, showed gastrointestinal toxicity.

Another pathway involved in crosstalk with the Wnt pathway is the sonic hedgehog pathway with sFRP-1 being the mediator between them.

It is also being studied in the context of other cancers, like gastric and prostate cancer, and is currently undergoing phase I and II trials.

Erismodegib is also being studied in phase I and II clinical trials for other cancer types. Apart from different chemical inhibitors, many natural compounds have shown to target the Wnt pathway directly or indirectly.

To conclude, Wnt signaling can be targeted at various steps to develop potential therapy against cancer, and this is summarized in Figure 4. Figure 4. Targeting Wnt signaling to combat cancer. The Wnt pathway has multiple players that can be effectively targeted to modulate the signaling cascade, thereby inhibiting cancer proliferation.

The targets that are showing promising results are highlighted in the figure. Inhibiting cancer by targeting the Wnt signaling pathway has been a hotspot for the last four decades. Various molecules involved in this pathway have been studied in depth and proposed as innovative targets for anti-tumor therapy, and some have also found uses in the treatment of neurodegenerative disease, such as Parkinson's disease.

Despite showing promising results, no such drugs have been approved for clinical use. Thus, tweaking this pathway can also affect the normal Wnt-dependent activities. Some of the drugs targeting Wnt signaling have shown dose-limiting gastrointestinal toxicity and upregulation of markers for bone formation and growth. Apart from direct roles, Wnt signaling is also known to cross functions with other pathways that are involved in cell signaling.

A better understanding of these crosstalks and the development of combination therapy that can target specific molecules without disrupting normal cellular functions or using natural compounds may be the choice of future research. Tumor cells require a milieu of growth factors, secretory molecules, and crosstalk between different cells present in the tumor microenvironment for their growth and proliferation.

Each of these secreted inhibitors are tightly regulated during embryogenesis and serve to limit or likely create a gradient of Wnt signaling for pattern formation. Mutations in either of these genes result in wingless-like phenotypes in Drosophila, and both genes promote Wnt signaling in mammalian cell culture experiments. In adults, mis-regulation of the Wnt pathway also leads to a variety of abnormalities and degenerative diseases Table1. Tetra-amelia, also called autosomal recessive tetraamelia, is an extremely rare autosomal recessive congenital disorder characterized by the absence of all four limbs.

Other areas of the body are also affected by malformations, such as the face, skull, reproductive organs, anus and pelvis. The disorder has been proposed to result from WNT3 loss-of-function mutations. The mutation is a single amino-acid substitution that makes LRP5 insensitive to Dkk-mediated Wnt pathway inhibition, indicating that the phenotype results from overactive Wnt signaling in the bone.

In addition, a hereditary disorder, called familial exudative vitreopathy FEVR , is caused by mutations in both LRP5 and the Fz4 receptor, which results in defective vasculogenesis in the peripheral retina.

A nonsense mutation in Axin2 has been shown to produce severe tooth agenesis, or oligodontia, a condition inwhichmultiple permanent teeth aremissing. In addition to tooth defects, individuals with Axin2 mutations display a prediposition to colon cancer.

Moreover, the best-known example of a disease involving a Wnt pathway mutation that produces tumors is familial adenomatous polyposis FAP , an autosomal, dominantly inherited disease in which patients display hundreds or thousands of polyps in the colon and rectum. This disease is caused most frequently by truncations in APC, which promote aberrant activation of the Wnt pathway leading to adenomatous lesions owing to increased cell proliferation.

Yuko Komiya, Raymond Habas. Wnt signal transduction pathways [J]. Landes Bioscience, ,, Beverly D. Smolich, Jill A. McMahon, Andrew P. Wnt family proteins are secreted and associated with the cell surface. Molecular Biology of the Cell,,4, Wnt and the Wnt signaling pathway in bone development and disease [J].

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