Wnt Signaling in the Development of Bone Metastasis

Abstract

Wnt signaling occurs through evolutionarily conserved pathways that affect cellular proliferation and fate decisions during development and tissue maintenance. Alterations in these highly regulated pathways, however, play pivotal roles in various malignancies, promoting cancer initiation, growth and metastasis and the development of drug resistance. The ability of cancer cells to metastasize is the primary cause of cancer mortality. Bone is one of the most frequent sites of metastases that generally arise from breast, prostate, lung, melanoma or kidney cancer. Upon their arrival to the bone, cancer cells can enter a long-term dormancy period, from which they can be reactivated, but can rarely be cured. The activation of Wnt signaling during the bone metastasis process was found to enhance proliferation, induce the epithelial-to-mesenchymal transition, promote the modulation of the extracellular matrix, enhance angiogenesis and immune tolerance and metastasize and thrive in the bone. Due to the complexity of Wnt pathways and of the landscape of this mineralized tissue, Wnt function during metastatic progression within bone is not yet fully understood. Therefore, we believe that a better understanding of these pathways and their roles in the development of bone metastasis could improve our understanding of the disease and may constitute fertile ground for potential therapeutics.

Molecular Subtyping and Survival Analysis of Osteosarcoma Reveals Prognostic Biomarkers and Key Canonical Pathways

“…However, no genes were found to be significantly differentially mutated between the two molecular subtypes. The pathway enrichment analysis of survival associated protein-coding genes (as identified in log-odd test and Cox-regression analysis, p -value < 0.05) using IPA identified WNT signaling and Axonal Guidance signaling pathways, which are related to the OS pathogenesis [ 50 , 51 , 52 ] ( Supplementary Figure S5 ). However, no significant difference was observed in the survival of patients between the two subtypes.…”

Bone Endosteal Mimics Regulates Breast Cancer Development and Phenotype

“…17,35 The high flux of calcium may further lead to enhanced activation of various signaling, transducing cascades such as CD44, Wnt, mTOR, cadherins, etc. 36,38,39 This possible calcium effect is of a particular importance within the endosteal niche, where calcium, Wnt ligands, BMPs, and other trapped growth factors can be released following the onset of the "vicious cycle," degradation of the ECM and also can be secreted by the natural hub niche cells that are harnessed by the invading cells. 36,39 Cells in tissues and organs reside within a three-dimensional microenvironment composed of ECM and surrounding cells that play a crucial role in normal development and homeostasis.…”

“…36,38,39 This possible calcium effect is of a particular importance within the endosteal niche, where calcium, Wnt ligands, BMPs, and other trapped growth factors can be released following the onset of the "vicious cycle," degradation of the ECM and also can be secreted by the natural hub niche cells that are harnessed by the invading cells. 36,39 Cells in tissues and organs reside within a three-dimensional microenvironment composed of ECM and surrounding cells that play a crucial role in normal development and homeostasis. However, the physical and organic landscapes also play a pivotal role in shaping cellular activities, notably with respect to tumor progression.…”

“…In addition to physical traits, stemming from the aragonite, porous, complex, and large surface area, the strong effects of the BMM also may be explained by calcium flux, which is driven by the pH of the culturing media. The slow dissolution of Ca 2+ is then consumed by the cells and may affect different cellular activities. ,,,− These results are also in agreement with former findings demonstrating indirect effects of the BMM-biomaterial on cellular behavior. , …”

The ways Fusobacterium nucleatum translocate to breast tissue and contribute to breast cancer development

“…Bone is a common site of metastases from breast cancer, which usually occurs in the metaphysis and diaphysis of long bones. Upon their arrival to the bone, cancer cells enter a prolonged dormant phase hauled by the activation of Wnt signaling (Ben‐Ghedalia‐Peled & Vago, 2022). As mentioned above, F. nucleatum induces EMT, promotes the regulation of ECM, and allows cancer cells to metastasize and multiply in the bone.…”