wow, CCL5 (RANTES) in prostate cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463189/
4. The Role of CCL5 as an Upstream Mediator of Androgen/AR Signaling
Skeletal metastases occur in approximately 80% of patients with advanced prostate cancer, for which no curative treatment is available [28]. We previously reported that bone stromal cells and SaOS-2 osteoblast-like cells promote prostate cancer metastasis via activation of transforming growth factor-β1 (TGF β1) [29], which in turn induces the development of an immune suppressive microenvironment [30]. CCL2 is reported to increase bone metastasis through recruitment of TAMs and osteoclasts to the tumor site and blood vessel formation through vascular endothelial growth factor-A [31,32]. Therefore, we investigated whether further chemokines could be involved in the activation of prostate cancer cells within prostate cancer bone metastases. Migration of LNCaP cells (an AR-positive prostate cancer cell line) increased significantly when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned media from bone stromal cell cultures subsequently identified CCL5, a high-affinity ligand of CCR5, as a concentration-dependent promoter of LNCaP cell migration [12]. LNCaP cell migration was observed to be suppressed by the addition of a CCL5-neutralizing antibody to cocultures with bone stromal cells, while AR knockdown using siRNA was observed to increase LNCaP cell migration compared with control cells [12]. As CCL5 was unable to promote migration of LNCaP siAR cells, it was concluded that elevated CCL5 secretion by bone stromal cells from metastatic lesions induced prostate cancer cell migration in a CCL5-dependent manner, upstream of AR signaling [12]. Upregulation of CCL5 has previously been reported to increase the aggressive potential of breast cancer cells and the invasiveness of prostate cancer cells [33,34,35]. In addition, Luo et al. found that CCL5 upregulation in bone marrow mesenchymal stem cells increased the metastatic potential of prostate cancer cells, and subsequently downregulated AR signaling, due to inhibition of AR nuclear translocation [36]. Furthermore, CCL5 has been found to suppress prolyl hydroxylase expression, leading to suppression of VHL-mediated HIF2α ubiquitination and suppression of AR signaling [37]. Results obtained using LNCaP siAR cells indicate that CCL5 activity is located upstream of AR signaling. Moreover, SaOS-2 did not promote the migration of PC-3 AR-negative prostate cancer cells [12]. These results suggest that the migratory potential of AR-positive prostate cancer cells in bone metastases is increased by CCL5, secreted by bone stromal cells via the suppression of androgen/AR signaling. CCL5 is also secreted by prostate cancer-associated fibroblasts and recruited macrophages into the prostate cancer microenvironment [38]. Estrogen receptor α could reduce prostate cancer cell invasion through reduction of CCL5 secretion from fibroblasts and macrophage infiltration prostate cancer [38].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463189/
4. The Role of CCL5 as an Upstream Mediator of Androgen/AR Signaling
Skeletal metastases occur in approximately 80% of patients with advanced prostate cancer, for which no curative treatment is available [28]. We previously reported that bone stromal cells and SaOS-2 osteoblast-like cells promote prostate cancer metastasis via activation of transforming growth factor-β1 (TGF β1) [29], which in turn induces the development of an immune suppressive microenvironment [30]. CCL2 is reported to increase bone metastasis through recruitment of TAMs and osteoclasts to the tumor site and blood vessel formation through vascular endothelial growth factor-A [31,32]. Therefore, we investigated whether further chemokines could be involved in the activation of prostate cancer cells within prostate cancer bone metastases. Migration of LNCaP cells (an AR-positive prostate cancer cell line) increased significantly when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned media from bone stromal cell cultures subsequently identified CCL5, a high-affinity ligand of CCR5, as a concentration-dependent promoter of LNCaP cell migration [12]. LNCaP cell migration was observed to be suppressed by the addition of a CCL5-neutralizing antibody to cocultures with bone stromal cells, while AR knockdown using siRNA was observed to increase LNCaP cell migration compared with control cells [12]. As CCL5 was unable to promote migration of LNCaP siAR cells, it was concluded that elevated CCL5 secretion by bone stromal cells from metastatic lesions induced prostate cancer cell migration in a CCL5-dependent manner, upstream of AR signaling [12]. Upregulation of CCL5 has previously been reported to increase the aggressive potential of breast cancer cells and the invasiveness of prostate cancer cells [33,34,35]. In addition, Luo et al. found that CCL5 upregulation in bone marrow mesenchymal stem cells increased the metastatic potential of prostate cancer cells, and subsequently downregulated AR signaling, due to inhibition of AR nuclear translocation [36]. Furthermore, CCL5 has been found to suppress prolyl hydroxylase expression, leading to suppression of VHL-mediated HIF2α ubiquitination and suppression of AR signaling [37]. Results obtained using LNCaP siAR cells indicate that CCL5 activity is located upstream of AR signaling. Moreover, SaOS-2 did not promote the migration of PC-3 AR-negative prostate cancer cells [12]. These results suggest that the migratory potential of AR-positive prostate cancer cells in bone metastases is increased by CCL5, secreted by bone stromal cells via the suppression of androgen/AR signaling. CCL5 is also secreted by prostate cancer-associated fibroblasts and recruited macrophages into the prostate cancer microenvironment [38]. Estrogen receptor α could reduce prostate cancer cell invasion through reduction of CCL5 secretion from fibroblasts and macrophage infiltration prostate cancer [38].
