Wnt Signaling in the Development of Bone metastisis
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.
Keywords: Wnt signaling, β-catenin, cancer, bone metastasis, osteolysis, osteogenesis
https://www.ncbi.nlm.nih.gov/pmc/articl ... the%20bone.
Wnt Signaling in the Development of Bone Metastasis
Re: Wnt Signaling in the Development of Bone Metastasis
3. Bone Metastasis
Metastasis is the primary cause of mortality in patients with cancer. During cancer development, cancer cells detach from the primary tumor and penetrate the nearby blood and lymphatic vasculature, a process that is called intravasation. From there, they circulate in the blood or lymphatic system while evading the immune system, eventually extravasating the circulation to enter other tissues or organs, where they create a secondary tumor [51]. The ability of cancer cells to metastasize involves changes in adhesion molecules, such as cadherins and integrins that change cell–matrix interactions and the upregulation and activation of extracellular proteases that degrade the extracellular matrix (ECM) and thus facilitate invasion. Termed the “epithelial-mesenchymal transition” (EMT), cancer cells exploit this process to acquire the mesenchymal phenotype that enables them to migrate and invade distant tissues [52,53].
Bone constitutes one of the most frequent sites of metastases arising from breast, prostate, lung, thyroid, bladder, melanoma and kidney cancer [54]. This usually occurs in the metaphysis and diaphysis of long bones [55,56,57]. Once cancer cells reach the bone, it can rarely be cured, and therefore, it is a major cause of morbidity associated with severe pain, which can lead to skeletal-related events (SREs), such as impaired mobility, pathologic fractures, hypercalcemia, spinal cord compression and bone marrow aplasia [54]. The common treatment for bone metastases is mainly palliative, including pain control, the prevention and treatment of fractures, and the maintenance of patient function. The efficacy of anticancer drugs is associated with dose-limiting side effects in healthy tissues, and therefore, they do not always achieve therapeutic concentrations. In particular, these limiting factors take place within the complex structure of bone containing dense minerals, ECM and delicate niches that safeguard and control the development of crucial stem cells [58]. The only systemic chemotherapy options for prostate cancer patients are mitotic inhibitors known as taxanes. For patients with breast cancer bone metastasis, treatment relies on chemotherapeutic compounds in the armamentarium, which are inhibitors of DNA synthesis and RNA synthesis, the microtubule disruptor vinorelbine and the thymidylate synthase inhibitor capecitabine [59].
2. Wnt in Bone Development and Maintenance-
**chondrogenic and adipogenic
**https://cureasps.org/forum/viewtopic.php?p=15389#p15389
Metastasis is the primary cause of mortality in patients with cancer. During cancer development, cancer cells detach from the primary tumor and penetrate the nearby blood and lymphatic vasculature, a process that is called intravasation. From there, they circulate in the blood or lymphatic system while evading the immune system, eventually extravasating the circulation to enter other tissues or organs, where they create a secondary tumor [51]. The ability of cancer cells to metastasize involves changes in adhesion molecules, such as cadherins and integrins that change cell–matrix interactions and the upregulation and activation of extracellular proteases that degrade the extracellular matrix (ECM) and thus facilitate invasion. Termed the “epithelial-mesenchymal transition” (EMT), cancer cells exploit this process to acquire the mesenchymal phenotype that enables them to migrate and invade distant tissues [52,53].
Bone constitutes one of the most frequent sites of metastases arising from breast, prostate, lung, thyroid, bladder, melanoma and kidney cancer [54]. This usually occurs in the metaphysis and diaphysis of long bones [55,56,57]. Once cancer cells reach the bone, it can rarely be cured, and therefore, it is a major cause of morbidity associated with severe pain, which can lead to skeletal-related events (SREs), such as impaired mobility, pathologic fractures, hypercalcemia, spinal cord compression and bone marrow aplasia [54]. The common treatment for bone metastases is mainly palliative, including pain control, the prevention and treatment of fractures, and the maintenance of patient function. The efficacy of anticancer drugs is associated with dose-limiting side effects in healthy tissues, and therefore, they do not always achieve therapeutic concentrations. In particular, these limiting factors take place within the complex structure of bone containing dense minerals, ECM and delicate niches that safeguard and control the development of crucial stem cells [58]. The only systemic chemotherapy options for prostate cancer patients are mitotic inhibitors known as taxanes. For patients with breast cancer bone metastasis, treatment relies on chemotherapeutic compounds in the armamentarium, which are inhibitors of DNA synthesis and RNA synthesis, the microtubule disruptor vinorelbine and the thymidylate synthase inhibitor capecitabine [59].
2. Wnt in Bone Development and Maintenance-
**chondrogenic and adipogenic
**https://cureasps.org/forum/viewtopic.php?p=15389#p15389
Last edited by D.ap on Sat Apr 13, 2024 7:15 am, edited 2 times in total.
Debbie
Re: Wnt Signaling in the Development of Bone Metastasis
2. Wnt in Bone Development and Maintenance
As mentioned above, Wnt signaling is a key regulator of developmental and postnatal processes [1,2]. One such process is postnatal bone homeostasis regulation, which is maintained by the delicate balance between bone formation and resorption, which are controlled by the dynamics between bone cells. The three main cellular players involved in bone homeostasis comprise one of hematopoietic origin, the osteoclasts, responsible for bone resorption, while the others are of mesenchymal origin. These comprise osteoblasts, which are responsible for bone mineralization and formation, and osteocytes, which are derived from osteoblasts and responsible for bone maintenance by regulating the activities of osteoclasts and osteoblasts. Osteocytes are mechanosensory cells that can produce different molecules and transmit signals in response to physical forces [34,35]. In recent years, the role of Wnt signaling in bone biology has become evident, and there is an increased understanding that aberrant Wnt signaling activity/regulation may cause different bone pathologies [34,36]. Canonical Wnt ligands have been found to promote the differentiation of mesenchymal stem cells (MSCs) into the osteoblast lineage and to inhibit chondrogenic and adipogenic cell fates [35,37]. The activity of this pathway in mature osteoblasts leads to their terminal differentiation into osteocytes and regulates the apoptosis of osteoblastic cells [38]. Moreover, Wnt-β catenin pathway activity in osteoblasts and osteocytes upregulates the expression of the osteoclastogenesis inhibitory factor osteoprotegerin (OPG), which binds to RANKL and inhibits the RANK-RANKL interaction, eventually reducing osteoclastic activity and hampering bone resorption [34,36,39]. Canonical Wnt pathway activity in bone thus leads to increased bone mass, and Wnt inhibition may cause a decrease in bone mass. For example, Bennett et al. showed that Wnt10b facilitates osteogenesis via the expression of RUNX2 and Dlx5, osteoblastogenic transcription factors, and that it increases bone mass in transgenic mice [40]. In addition, in vitro studies showed that different Wnt ligands, such as Wnt 1, 2, 3, 6, 7 and 10, promote osteogenesis and inhibit chondrogenesis and adipogenesis via the canonical Wnt pathway [36,41]. On the other hand, loss-of-function mutations in the canonical Wnt co-receptors LRP5/6 have been identified as a cause of osteoporosis pseudoglioma syndrome [39]. In addition, the aberrant regulation of Wnt inhibitors such as Sclerostin (SOST) and Dickkopf (DKK), which bind to LRP5/6, was found to cause different bone diseases, such as sclerosteosis and osteoporosis [42]. Though SOST dysregulation was identified as the gene responsible for sclerosteosis, its upregulation suppresses bone formation via canonical Wnt inhibition [34,39]. Recently, a SOST inhibition agent was introduced as a new osteoporosis therapy [43,44]. In other research, mice in which the Wnt ligand secretory system was inhibited were shown to have increased bone resorption and diminished bone formation that led to severe osteoporosis [45].
As described above, the role of canonical Wnt signaling in bone formation and resorption has been extensively investigated. Less well understood, however, are the roles that the non-canonical Wnt pathways fulfill in bone homeostasis and the crosstalk between the pathways, but work in recent years has made some progress. Liu et al. found that the non-canonical Wnt receptor ROR2 promotes osteoblast differentiation via the expression of osterix, an osteogenic transcription factor, resulting in bone formation [46]. In addition, the binding of Wnt5a, a non-canonical Wnt ligand, to ROR2 activates JNK, regulates the expression of RUNX2 and inhibits adipogenesis through the repression of the transcription factor PPAR-γ [34,47]. Yu et al. showed that the expression of a non-canonical Wnt ligand, Wnt4, in osteoblasts correlates with a high-bone-mass phenotype [48]. Non-canonical Wnt was found to have a role in osteoclast differentiation and function. Maeda et al. demonstrated that non-canonical Wnt promotes the expression of RANK, resulting in osteoclastogenesis and bone resorption [49]. Wnt16, however, was shown to activate the non-canonical pathway and to inhibit osteoclast differentiation through the suppression of RANKL [50]. Nevertheless, all branches of Wnt signaling, the crosstalk and the delicate balance between all of the Wnt components, are essential for the regulation of bone homeostasis and proper bone remodeling, However, a better understanding of the crosstalk between the pathways is needed.
As mentioned above, Wnt signaling is a key regulator of developmental and postnatal processes [1,2]. One such process is postnatal bone homeostasis regulation, which is maintained by the delicate balance between bone formation and resorption, which are controlled by the dynamics between bone cells. The three main cellular players involved in bone homeostasis comprise one of hematopoietic origin, the osteoclasts, responsible for bone resorption, while the others are of mesenchymal origin. These comprise osteoblasts, which are responsible for bone mineralization and formation, and osteocytes, which are derived from osteoblasts and responsible for bone maintenance by regulating the activities of osteoclasts and osteoblasts. Osteocytes are mechanosensory cells that can produce different molecules and transmit signals in response to physical forces [34,35]. In recent years, the role of Wnt signaling in bone biology has become evident, and there is an increased understanding that aberrant Wnt signaling activity/regulation may cause different bone pathologies [34,36]. Canonical Wnt ligands have been found to promote the differentiation of mesenchymal stem cells (MSCs) into the osteoblast lineage and to inhibit chondrogenic and adipogenic cell fates [35,37]. The activity of this pathway in mature osteoblasts leads to their terminal differentiation into osteocytes and regulates the apoptosis of osteoblastic cells [38]. Moreover, Wnt-β catenin pathway activity in osteoblasts and osteocytes upregulates the expression of the osteoclastogenesis inhibitory factor osteoprotegerin (OPG), which binds to RANKL and inhibits the RANK-RANKL interaction, eventually reducing osteoclastic activity and hampering bone resorption [34,36,39]. Canonical Wnt pathway activity in bone thus leads to increased bone mass, and Wnt inhibition may cause a decrease in bone mass. For example, Bennett et al. showed that Wnt10b facilitates osteogenesis via the expression of RUNX2 and Dlx5, osteoblastogenic transcription factors, and that it increases bone mass in transgenic mice [40]. In addition, in vitro studies showed that different Wnt ligands, such as Wnt 1, 2, 3, 6, 7 and 10, promote osteogenesis and inhibit chondrogenesis and adipogenesis via the canonical Wnt pathway [36,41]. On the other hand, loss-of-function mutations in the canonical Wnt co-receptors LRP5/6 have been identified as a cause of osteoporosis pseudoglioma syndrome [39]. In addition, the aberrant regulation of Wnt inhibitors such as Sclerostin (SOST) and Dickkopf (DKK), which bind to LRP5/6, was found to cause different bone diseases, such as sclerosteosis and osteoporosis [42]. Though SOST dysregulation was identified as the gene responsible for sclerosteosis, its upregulation suppresses bone formation via canonical Wnt inhibition [34,39]. Recently, a SOST inhibition agent was introduced as a new osteoporosis therapy [43,44]. In other research, mice in which the Wnt ligand secretory system was inhibited were shown to have increased bone resorption and diminished bone formation that led to severe osteoporosis [45].
As described above, the role of canonical Wnt signaling in bone formation and resorption has been extensively investigated. Less well understood, however, are the roles that the non-canonical Wnt pathways fulfill in bone homeostasis and the crosstalk between the pathways, but work in recent years has made some progress. Liu et al. found that the non-canonical Wnt receptor ROR2 promotes osteoblast differentiation via the expression of osterix, an osteogenic transcription factor, resulting in bone formation [46]. In addition, the binding of Wnt5a, a non-canonical Wnt ligand, to ROR2 activates JNK, regulates the expression of RUNX2 and inhibits adipogenesis through the repression of the transcription factor PPAR-γ [34,47]. Yu et al. showed that the expression of a non-canonical Wnt ligand, Wnt4, in osteoblasts correlates with a high-bone-mass phenotype [48]. Non-canonical Wnt was found to have a role in osteoclast differentiation and function. Maeda et al. demonstrated that non-canonical Wnt promotes the expression of RANK, resulting in osteoclastogenesis and bone resorption [49]. Wnt16, however, was shown to activate the non-canonical pathway and to inhibit osteoclast differentiation through the suppression of RANKL [50]. Nevertheless, all branches of Wnt signaling, the crosstalk and the delicate balance between all of the Wnt components, are essential for the regulation of bone homeostasis and proper bone remodeling, However, a better understanding of the crosstalk between the pathways is needed.
Debbie