Bone metastasis most commonly occurs in castration-resistant prostate cancer(CRPC).The TRPV6 calcium channel is absent in healthy prostate tissue,but its expression increases considerably during cancer progression.We ...Bone metastasis most commonly occurs in castration-resistant prostate cancer(CRPC).The TRPV6 calcium channel is absent in healthy prostate tissue,but its expression increases considerably during cancer progression.We hypothesized that cancer cells induce TRPV6 expression de novo to directly benefit from tightly regulated calcium intake via TRPV6 while providing cancer cells with a selective advantage for metastasis in the calcium-abundant niche,such as bone.Using a cohort of prostate cancer tissue biopsies from patients with a clinical history of at least 10 years after biopsy,we report that TRPV6 expression directly correlates with CRPC tumor aggressiveness and increased risk of metastasis development.The TRPV6 channel is involved in the acquisition of both mesenchymal and invasive phenotypes through increased phosphorylation of CaMK2 followed by the translocation of the transcription factor NF-κB to the nucleus and the expression of EMT markers,MMPs,and transcription factors such as Twist,Snail,and Slug.Moreover,TRPV6 expression was accompanied by increased formation of CXCR4/TRPV6 complexes.In vivo,mice bearing trpv6^(+/+)tumors presented increased metastasis,notably bone metastasis,whereas trpv6^(−/−)mice developed no metastasis.Targeting TRPV6 with a monoclonal antibody resulted in a significant reduction in the metastatic burden and an increase in overall survival.When AMD3100,a selective inhibitor of the CXCR4 receptor,was combined with AMD3100,a synergistic effect on the suppression of metastasis development was achieved.Thus,the suppression of CRPC metastasis to bone can be achieved via simultaneous targeting of TRPV6/CXCR4,demonstrating that combined therapy is a proof-of-concept approach in vivo.展开更多
基金supported by the French“Ligue Contre le Cancer”.
文摘Bone metastasis most commonly occurs in castration-resistant prostate cancer(CRPC).The TRPV6 calcium channel is absent in healthy prostate tissue,but its expression increases considerably during cancer progression.We hypothesized that cancer cells induce TRPV6 expression de novo to directly benefit from tightly regulated calcium intake via TRPV6 while providing cancer cells with a selective advantage for metastasis in the calcium-abundant niche,such as bone.Using a cohort of prostate cancer tissue biopsies from patients with a clinical history of at least 10 years after biopsy,we report that TRPV6 expression directly correlates with CRPC tumor aggressiveness and increased risk of metastasis development.The TRPV6 channel is involved in the acquisition of both mesenchymal and invasive phenotypes through increased phosphorylation of CaMK2 followed by the translocation of the transcription factor NF-κB to the nucleus and the expression of EMT markers,MMPs,and transcription factors such as Twist,Snail,and Slug.Moreover,TRPV6 expression was accompanied by increased formation of CXCR4/TRPV6 complexes.In vivo,mice bearing trpv6^(+/+)tumors presented increased metastasis,notably bone metastasis,whereas trpv6^(−/−)mice developed no metastasis.Targeting TRPV6 with a monoclonal antibody resulted in a significant reduction in the metastatic burden and an increase in overall survival.When AMD3100,a selective inhibitor of the CXCR4 receptor,was combined with AMD3100,a synergistic effect on the suppression of metastasis development was achieved.Thus,the suppression of CRPC metastasis to bone can be achieved via simultaneous targeting of TRPV6/CXCR4,demonstrating that combined therapy is a proof-of-concept approach in vivo.
