Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options

Abstract

Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

“…Among them, the WNT pathway is deregulated in epithelial-mesenchymal transition (EMT) and CSCs (13). Mutations in WNT signaling components, such as APC, AXIN, β-catenin, and WNT ligands were first observed in colorectal cancers, but have also been reported in other solid tumors (14)(15)(16)(17)(18)(19)(20)(21) and hematological malignancies, including leukemia and Multiple Myeloma (MM) (22)(23)(24).…”

<p>Bioactive Compounds from <em>Abelmoschus manihot L</em>. Alleviate the Progression of Multiple Myeloma in Mouse Model and Improve Bone Marrow Microenvironment</p>

“…[26][27][28] The aberrant activation of the Wnt/β-catenin pathway with nonphosphorylated active β-catenin expression in the nucleus could sensitize MM cells to autocrine Wnt ligands and paracrine Wnt emanating from the BMM, thus may contribute to the proliferation, migration, and drug resistance of MM cells (see recent review). 29 The results presented in Figure 5C revealed that β-catenin protein levels were downregulated following HK-11 treatment and that this suppressive effect could be reversed by LiCl, which stabilized β-catenin by inhibiting the kinase activity of Glycogen Synthase Kinase-3, a crucial mediator of the Wnt/β-catenin signaling. 24,30 It has been suggested that the inhibitory effect of HK-11 on β-catenin signaling may be utilized as a potential target for treating MM, as the majority of MM patients exhibit hallmarks of Wnt activation in a ligand- dependent manner, irrespective of the complex genetic heterogeneity.…”

“…24,30 It has been suggested that the inhibitory effect of HK-11 on β-catenin signaling may be utilized as a potential target for treating MM, as the majority of MM patients exhibit hallmarks of Wnt activation in a ligand- dependent manner, irrespective of the complex genetic heterogeneity. 29 Furthermore, β-catenin is dynamically stored and cleared in MM. 31 Further studies are required to investigate the most effective strategy for targeting canonical Wnt signaling in MM, potentially by inhibiting Wnt/βcatenin activation in the BMM of MM cells.…”

Wnt5a/CaMKII/ERK/CCL2 axis is required for tumor-associated macrophages to promote colorectal cancer progression

“…International Publisher processes through activation of canonical Wnt/βcatenin pathway and non-canonical pathways [9,10]. Wnt5a, a member of Wnt family, plays various physiological roles in tumor growth, invasion and metastasis, mainly by activating the non-canonical pathways such as planar cell polarity (PCP), JNK and Ca2 + /CaKMII pathways [11,12].…”