ABSTRACT
Follistatin is a single-chain glycosylated protein whose primary function consists in binding and neutralizing some members of the transforming growth factor-ß superfamily such as activin and bone morphogenic proteins. Emerging evidence indicates that this molecule may also play a role in the malignant progression of several human tumors including prostate cancer. In particular, recent findings suggest that, in this tumor, follistatin may also contribute to the formation of bone metastasis through multiple mechanisms, some of which are not related to its specific activin or bone morphogenic proteins' inhibitory activity. This review provides insight into the most recent advances in understanding the role of follistatin in the prostate cancer progression and discusses the clinical and therapeutic implications related to these findings.
Subject(s)
Follistatin/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/therapy , Animals , Disease Progression , Follistatin/antagonists & inhibitors , Humans , Male , Molecular Targeted Therapy , Prostatic Neoplasms/pathologyABSTRACT
The clinical significance of circulating follistatin (FLST), an inhibitor of the multifunctional cytokine activin A (Act A), was investigated in patients with prostate cancer (PCa). The serum concentrations of this molecule were determined by an enzyme-linked immunosorbent assay (ELISA) in PCa patients with (M+) or without (M0) bone metastases, in patients with benign prostate hyperplasia (BPH) and in healthy subjects (HS). The effectiveness of FLST in detecting PCa patients with skeletal metastases was determined by the receiver operating characteristic (ROC) curve analysis. Serum FLST was significantly higher in PCa patients than in BPH patients (P = 0.001) or HS (P = 0.011). Conversely, in BPH patients, FLST levels resulted lower than in HS (P = 0.025). In cancer patients the serum concentrations of FLST significantly correlated with the presence of bone metastases (P = 0.0005) or increased PSA levels (P = 0.04). Interestingly, significant differences in the ratio between FLST and Act A serum concentrations (FLST/Act A) were observed between HS and BPH patients (P = 0.001) or PCa patients (P = 0.0005). Finally, ROC curve analysis, highlighted a sound diagnostic performance of FLST in detecting M+ patients (P = 0.0001). However, the diagnostic effectiveness of FLST did not result significantly superior to that of Act A or PSA. These findings suggest that FLST may be regarded as a potential, molecular target in the treatment of metastatic bone disease while its clinical role as soluble marker in the clinical management of PCa patients with bone metastases needs to be better defined.
Subject(s)
Bone Neoplasms/blood , Bone Neoplasms/secondary , Follistatin/blood , Prostatic Neoplasms/blood , Activins/blood , Aged , Humans , Male , Middle Aged , Prostate-Specific Antigen/blood , Sensitivity and SpecificityABSTRACT
Cathepsin L is a lysosomal cysteine proteinase primarily devoted to the metabolic turnover of intracellular proteins. However, accumulating evidence suggests that this endopeptidase might also be implicated in the regulation of other important biological functions, including bone resorption in normal and pathological conditions. These findings support the concept that cathepsin L, in concert with other proteolytic enzymes involved in bone remodeling processes, could contribute to facilitate bone metastasis formation. In support of this hypothesis, recent studies indicate that cathepsin L can foster this process by triggering multiple mechanisms which, in part, differ from those of the major cysteine proteinase of osteoclasts, namely cathepsin K. Therefore, cathepsin L can be regarded as an additional target in the treatment of patients with metastatic bone disease. This review discusses the clinical and therapeutic implications related to these findings.
Subject(s)
Bone Neoplasms/complications , Bone Neoplasms/metabolism , Bone and Bones/metabolism , Bone and Bones/pathology , Cathepsin L/metabolism , Animals , Cathepsin K/metabolism , Humans , Neoplasm MetastasisABSTRACT
BACKGROUND: The effects of the bisphosphonate derivative zoledronic acid (ZA) on the circulating levels of matrix metalloproteinase-2 (MMP-2), matrix metallo-proteinases-9 (MMP-9), cathepsin B (Cath B) and urokinase-type plasminogen activator (uPA) in patients with bone metastasis (BMTS) and the possible correlation with the symptomatic response induced by this drug in these patients were evaluated. PATIENTS AND METHODS: Proteinase levels were determined by enzyme-linked immunosorbent assay (ELISA) in the plasma of 30 patients with painful bone metastases from breast or prostate cancer undergoing multiple treatment with ZA (4 mg i.v., every 4 weeks). Healthy subjects (HS) of both genders (12 female and 30 male) served as the control group. The symptomatic response to ZA was assessed by the visual analog scale score (VAS). RESULTS: The median MMP-2 and MMP-9 pretreatment levels were more elevated in BMTS as compared to HS (p < or = 0.0001). Conversely, uPA levels were lower in BMTS p = 0.0033; no significant difference was observed for Cath B. ZA administration was associated with a symptomatic response (VAS score < or =4) in 25/30patients (83.3%) (p < 0.0001). This phenomenon paralleled a decrease of Cath B and MMP-2 plasma concentrations from baseline values on week 12 (p = 0.05). A similar trend, although not statistically significant, was also noted for MMP-9 and uPA. However, no direct relationship was observed between the analgesic effect induced by ZA and changes in the circulating levels of these enzymes. CONCLUSION: These data show that ZA administration may provide relief from bone pain in patients with diffuse skeletal metastases and confirm a possible implication of cysteine proteinases and matrix metalloproteinases in bone metastasis formation, but not in the pathogenesis of metastatic bone pain.
