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CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis.

Ouellet V, Siegel PM - J Cell Commun Signal (2012)

Bottom Line: The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity.These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease.In contrast, CCN3 is known to promote chondrocyte differentiation.

View Article: PubMed Central - PubMed

Affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 513, Montreal, Quebec, Canada, H3A 1A3.

ABSTRACT
The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity. These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease. In this review, we focus on CCN3, a founding member of this family, and its role in regulating cells within the bone microenvironment. CCN3 impairs normal osteoblast differentiation through multiple mechanisms, which include the neutralization of pro-osteoblastogenic stimuli such as BMP and Wnt family signals or the activation of pathways that suppress osteoblastogenesis, such as Notch. In contrast, CCN3 is known to promote chondrocyte differentiation. Given these functions, it is not surprising that CCN3 has been implicated in the progression of primary bone cancers such as osteosarcoma, Ewing's sarcoma and chondrosarcoma. More recently, emerging evidence suggests that CCN3 may also influence the ability of metastatic cancers to colonize and grow in bone.

No MeSH data available.


Related in: MedlinePlus

Potential roles for CCN3 in promoting the formation of osteolytic breast cancer metastases. CCN3 expressed by breast cancer cells can block the differentiation of mature osteoblasts, utilizing the mechanisms outlined in Fig. 2. This would result in a tip towards higher levels of Receptor Activator of NF-κB Ligand (RANKL) produced by pre-osteoblasts and less Osteoprotegerin (OPG). The higher levels of RANKL would serve to induce the differentiation of monocytes into osteoclasts. In concert with its negative effects on osteoblast differentiation, CCN3 can also sensitize osteoclast precursors to respond to RANKL, enhancing osteoclastogenesis and bone resorption
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Fig3: Potential roles for CCN3 in promoting the formation of osteolytic breast cancer metastases. CCN3 expressed by breast cancer cells can block the differentiation of mature osteoblasts, utilizing the mechanisms outlined in Fig. 2. This would result in a tip towards higher levels of Receptor Activator of NF-κB Ligand (RANKL) produced by pre-osteoblasts and less Osteoprotegerin (OPG). The higher levels of RANKL would serve to induce the differentiation of monocytes into osteoclasts. In concert with its negative effects on osteoblast differentiation, CCN3 can also sensitize osteoclast precursors to respond to RANKL, enhancing osteoclastogenesis and bone resorption

Mentions: In our own work, we also have shown that CCN3 is expressed in bone metastasis samples from patients with breast cancer and have identified CCN3 as a gene highly expressed at the mRNA and protein levels in 4T1 murine breast cancer cells selected for their ability to metastasize to bone (Rose et al. 2007; Ouellet et al. 2011). We also demonstrated that CCN3 enhanced the bone metastatic ability of 66cl4 cells, which are known only to metastasize to the lungs, without altering their growth in the mammary fat pad (Ouellet et al. 2011). Our interest in CCN3 as a factor that could promote the formation of osteolytic bone metastases stemmed from its demonstrated roles in regulating the differentiation and activity of bone resident cells, as discussed above. During the formation of osteolytic lesions, the balance between bone formation and resorption is tipped in favor osteoclast differentiation and bone destruction. In agreement with previous studies, CCN3 was able to impair osteoblast differentiation from primary bone marrow cultures, resulting in higher RANKL/OPG ratios which would enhance osteoclastogenesis. Furthermore, we demonstrated that CCN3 promotes osteoclast differentiation from RANKL-primed monocyte precursors (RAW264.7) through a mechanism involving calcium oscillations and NFATc1 nuclear translocation (Ouellet et al. 2011). Interestingly, the ability of CCN3 to promote the formation of osteolytic bone metastases may reflect the fact that breast cancer cells colonizing the bone would contribute to significantly elevated levels of CCN3, which would tip the balance towards osteoclastogenesis (Fig. 3).Fig. 3


CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis.

Ouellet V, Siegel PM - J Cell Commun Signal (2012)

Potential roles for CCN3 in promoting the formation of osteolytic breast cancer metastases. CCN3 expressed by breast cancer cells can block the differentiation of mature osteoblasts, utilizing the mechanisms outlined in Fig. 2. This would result in a tip towards higher levels of Receptor Activator of NF-κB Ligand (RANKL) produced by pre-osteoblasts and less Osteoprotegerin (OPG). The higher levels of RANKL would serve to induce the differentiation of monocytes into osteoclasts. In concert with its negative effects on osteoblast differentiation, CCN3 can also sensitize osteoclast precursors to respond to RANKL, enhancing osteoclastogenesis and bone resorption
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
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Fig3: Potential roles for CCN3 in promoting the formation of osteolytic breast cancer metastases. CCN3 expressed by breast cancer cells can block the differentiation of mature osteoblasts, utilizing the mechanisms outlined in Fig. 2. This would result in a tip towards higher levels of Receptor Activator of NF-κB Ligand (RANKL) produced by pre-osteoblasts and less Osteoprotegerin (OPG). The higher levels of RANKL would serve to induce the differentiation of monocytes into osteoclasts. In concert with its negative effects on osteoblast differentiation, CCN3 can also sensitize osteoclast precursors to respond to RANKL, enhancing osteoclastogenesis and bone resorption
Mentions: In our own work, we also have shown that CCN3 is expressed in bone metastasis samples from patients with breast cancer and have identified CCN3 as a gene highly expressed at the mRNA and protein levels in 4T1 murine breast cancer cells selected for their ability to metastasize to bone (Rose et al. 2007; Ouellet et al. 2011). We also demonstrated that CCN3 enhanced the bone metastatic ability of 66cl4 cells, which are known only to metastasize to the lungs, without altering their growth in the mammary fat pad (Ouellet et al. 2011). Our interest in CCN3 as a factor that could promote the formation of osteolytic bone metastases stemmed from its demonstrated roles in regulating the differentiation and activity of bone resident cells, as discussed above. During the formation of osteolytic lesions, the balance between bone formation and resorption is tipped in favor osteoclast differentiation and bone destruction. In agreement with previous studies, CCN3 was able to impair osteoblast differentiation from primary bone marrow cultures, resulting in higher RANKL/OPG ratios which would enhance osteoclastogenesis. Furthermore, we demonstrated that CCN3 promotes osteoclast differentiation from RANKL-primed monocyte precursors (RAW264.7) through a mechanism involving calcium oscillations and NFATc1 nuclear translocation (Ouellet et al. 2011). Interestingly, the ability of CCN3 to promote the formation of osteolytic bone metastases may reflect the fact that breast cancer cells colonizing the bone would contribute to significantly elevated levels of CCN3, which would tip the balance towards osteoclastogenesis (Fig. 3).Fig. 3

Bottom Line: The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity.These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease.In contrast, CCN3 is known to promote chondrocyte differentiation.

View Article: PubMed Central - PubMed

Affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 513, Montreal, Quebec, Canada, H3A 1A3.

ABSTRACT
The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity. These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease. In this review, we focus on CCN3, a founding member of this family, and its role in regulating cells within the bone microenvironment. CCN3 impairs normal osteoblast differentiation through multiple mechanisms, which include the neutralization of pro-osteoblastogenic stimuli such as BMP and Wnt family signals or the activation of pathways that suppress osteoblastogenesis, such as Notch. In contrast, CCN3 is known to promote chondrocyte differentiation. Given these functions, it is not surprising that CCN3 has been implicated in the progression of primary bone cancers such as osteosarcoma, Ewing's sarcoma and chondrosarcoma. More recently, emerging evidence suggests that CCN3 may also influence the ability of metastatic cancers to colonize and grow in bone.

No MeSH data available.


Related in: MedlinePlus