As early as 2006, Liao et al. demonstrated that elevated extracellular Ca2+ facilitated skeletal metastasis of prostate cell lines and that this effect was associated with an up-regulated CaSR which mediated the influx of extracellular Ca2+ triggering the AKT signalling pathway, but extracellular Ca2+ influx had no effect in prostate cancer cells derived from a lymph node metastasis [57]. This evidence concerns the gene CASR and Familial prostate cancer.