A CTGF-RUNX2-RANKL Axis in Breast and Prostate Cancer Cells Promotes Tumor Progression in Bone

Abstract

Metastasis to bone is a frequent occurrence in patients with breast and prostate cancers and inevitably threatens the patient's quality of life and survival. Identification of cancer‐derived mediators of bone metastasis and osteolysis may lead to novel therapeutic strategies. In this study, we established highly bone‐metastatic PC3 prostate and MDA‐MB‐231 (MDA) breast cancer cell sublines by in vivo selection in mice. In bone‐metastatic cancer cells, the expression and secretion of connective tissue growth factor (CTGF) were highly upregulated. CTGF knockdown in bone‐metastatic cells decreased invasion activity and MMP expression. RUNX2 overexpression in the CTGF knockdown cells restored the invasion activity and MMP expression. In addition, CTGF increased RUNX2 protein stability by inducing its acetylation via p300 acetyl transferase. The integrin αvβ3 receptor mediated these effects of CTGF. Furthermore, CTGF promoted RUNX2 recruitment to the RANKL promoter, resulting in increased RANKL production from the tumor cells and subsequent stimulation of osteoclastogenesis from precursor cells. In addition, animal model with injection of CTGF knocked‐down prostate cancer cells into 6‐week old BALB/c male mice showed reduced osteolytic lesions. More importantly, the expression levels of CTGF and RANKL showed a strong positive correlation in human primary breast tumor tissues and were higher in bone metastases than in other site metastases. These findings indicate that CTGF plays crucial roles for osteolytic bone metastasis both by enhancing invasiveness of tumor cells and by producing RANKL for osteoclastogenesis. Targeting CTGF may lead to the development of effective preventive and therapeutic strategies for osteolytic metastasis. © 2019 American Society for Bone and Mineral Research.

Small extracellular vesicles deliver osteolytic effectors and mediate cancer‐induced osteolysis in bone metastatic niche

“…More than 90% of patients with metastatic prostate cancer will develop bone metastases and result in pathological bone destruction (Coleman, 1997). Molecular mechanism mediating the crosstalks between prostate cancer cells and bone cells leading to imbalanced bone remodelling has been an emphasis of recent research (Kim et al., 2020). Bone homeostasis is maintained and regulated by osteoblastic bone formation and osteoclastic bone resorption.…”

Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone

“…Accumulating evidence indicates the involvement of several transcription factors, Runx-2 [ 11 ] and Bach1 [ 12 ], in breast cancer metastasis to bone. RUNX-2 can promote breast cancer bone metastasis by increasing integrin α5-mediated colonization [ 20 ] or inducing RANKL-mediated osteoclast activation [ 21 ]. Bach1 can promote bone metastasis by enhancing the expression of metalloproteinase 1 and a chemokine receptor, CXCR4 [ 12 ].…”

<p>Role of αVβ3 in Prostate Cancer: Metastasis Initiator and Important Therapeutic Target</p>

“…39 However, pathologically, CCN2 is closely related to cancer bone metastasis. 40,41 It has been reported that αVβ3 act as a major receptor for CCN2 and mediates the migration and adhesion of endothelial and hepatic stellate cells (Figure 1). Based on this theory, Bongjun Kim et al assessed the relationship between CCN2 and αVβ3 in PCa.…”

“…102,103 DNA sequencing found that the receptor activator of nuclear factor kB ligand (RANKL) contains a Runx2 binding site in the promoter region. 40,104 Thus, αvβ3-induced bone matrix dissolution likely depends on the delivery of Runx2 to the nucleus to promote RANKL transcription. In terms of mechanism, Aditi Gupta et al did not provide evidence that αvβ3 could directly interact with Runx2, but they determined that αvβ3 activates Samd5.…”