Circulating cathepsin K and cystatin C in patients with cancer related bone disease: Clinical and therapeutic implications

The clinical significance of serum cathepsin K and cystatin C was assessed in patients with breast cancer (BCa) or prostate cancer (PCa) with confined disease (M0) or bone metastasis (BM). Cathepsin K and cystatin C circulating levels were determined by ELISAs in 63 cancer patients, in 35 patients with nonmalignant diseases and in 42 healthy blood donors (control group). In BCa patients, cathepsin K serum levels were sig- nificantly lower than in sex matched control group (HS; p ¼ 0.0008) or in patients with primary osteoporosis (OP; p ¼ 0.0009). On the contrary, cystatin C levels were significantly higher in BCa patients than in HS ( p ¼ 0.0001) or OP ( p ¼ 0.017). In PCa patients, cathepsin K concen- trations did not significantly differ from those measured in sex matched HS or in patients with benign prostatic hyperplasia (BPH). Conversely, cystatin C was more elevated in cancer patients than in controls ( p ¼ 0.0001) or BPH patients ( p ¼ 0.0078). Furthermore, in PCa patients, a pos- itive correlation was observed between cystatin C and cathepsin K (rS ¼ 0.34; p ¼ 0.047). No further relationship was highlighted between these molecules and the clinicobiological parameters of BCa or PCa progression including the number of bone lesions. Moreover, ROC curve analysis showed a poor diagnostic performance of cathepsin K and cystatin C in the detection of BM patients. Interestingly, the administration of zole- dronic acid (ZA), a bisphosphonate derivative endowed with a potent antiosteoclastic activity, induced in BM patients a marked increase of cathepsin K and cystatin C serum levels compared to baseline values. However, this phenomenon was statistically significant only in the PCa group. In conclusion Cystatin C and cathepsin K may be regarded as possible markers to monitor the therapeutic response to bisphosphonate treatments. Nevertheless, their clinical value as specific gauges of skeletal metastasis remains questionable

Cathepsin L in metastatic bone disease: therapeutic implications

Cathepsin L is a lysosomal cysteine proteinase primarily devoted to the metabolic turnover of intracellular proteins. However, accumulating evidence suggests this endopeptidase may be also 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 remodelling processes, may contribute to facilitate bone metastasis formation. In support of this hypothesis, recent studies indicate that cathepsin L may foster this process by triggering multiple mechanisms which, in part, differ from those of the major cysteine proteinase of osteoclast, namely cathepsin K. Therefore, cathepsin L may 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

Cathepsin D expression levels in nongynecological solid tumors: Clinical and therapeutic implications

Cathepsin D is a lysosomal acid proteinase which is involved in the malignant progression of breast cancer and other gynecological tumors. Clinical investigations have shown that in breast cancer patients cathepsin D overexpression was significantly correlated with a shorter free-time disease and overall survival, whereas in patients with ovarian or endometrial cancer this phenomenon was associated with tumor aggressiveness and a degree of chemoresistance to various antitumor drugs such as anthracyclines, cis-platinum and vinca alkaloids. Therefore, a lot of research has been undertaken to evaluate the role and the prognostic value of cathepsin D also in other solid neoplasms. However, conflicting results have been generated from these studies. The discrepancies in these results may, in part, be explained with the different methodological approaches used in order to determine the levels of expression of the enzyme in tumor tissues and body fluids. Further investigations using well-standardized techniques may better define the clinical significance of cathepsin D expression in solid tumors. Nevertheless, evidence emerging from these studies indicates that this proteinase seems to facilitate early phases of tumor progression such as cell proliferation and local dissemination. These findings support the concept that cathepsin D may be a useful marker for identifying patients with highly malignant tumor phenotypes who may need more aggressive clinical treatment; this enzyme may also be considered as a potential target for a novel therapeutic approach in the treatment of solid neoplasms

Follistatin as potential therapeutic target in prostate cancer

Follistatin is a single-chain glycosylated protein whose primary function consists in binding and neutralizing some members of the transforming growth factor-β 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

Activin A circulating levels in patients with bone metastasis from breast or prostate cancer

Recent studies have highlighted that Activin A, a member of the transforming growth factor-beta (TGF-beta) superfamily, may be involved in the regulation of osteoblastic activity and in osteoclast differentiation. Therefore, we have investigated the clinical significance of its circulating levels in patients with bone metastasis. Activin A serum concentrations were determined, by a commercially available enzyme-linked immunosorbent assay kit, in 72 patients with breast cancer (BC) or prostatic cancer (PC) with (BM+) or without (BM-) bone metastases, in 15 female patients with age-related osteoporosis (OP), in 20 patients with benign prostatic hypertrophy (BPH) and in 48 registered healthy blood donors (HS) of both sex (25 female and 23 male). Activin A serum concentrations were significantly increased in BC or PC patients as compared to OP (P < 0.0001) or BPH (P = 0.045), respectively, or to sex matched HS (P < 0.0001). Additionally, these levels resulted more elevated in PC patients as compared to BC patients (P = 0.032). Interestingly, Activin A was significantly higher in BM+ patients than in BM- patients (BC, P = 0.047; PC, P = 0.016). In BC patients, a significant correlation was observed only between Activin A and number of bone metastases (P = 0.0065) while, in PC patients, Activin A levels were strongly correlated with the Gleason score (P = 0.011) or PSA levels (P = 0.0001) and, to a lessen extent, with the number of bone metastases (P = 0.056). Receiver operating characteristic curve (ROC) analysis showed a fair diagnostic accuracy of Activin A to discriminate between BM+ and BM- patients (BC: AUC = 0.71 +/- 0.09, P = 0.03; PC: AUC = 0.73 +/- 0.081, P = 0.005). These findings indicate that Activin A may be implicated in the pathogenesis of bone metastasis. Therefore, this cytokine may be considered a novel potential target for a more selective therapeutic approach in the treatment of skeletal metastasis and may be also useful as additional biochemical marker of metastatic bone disease

Vitamin D in cancer chemoprevention

Context: There is increasing evidence that Vitamin D (Vit D) and its metabolites, besides their well-known calcium-related functions, may also exert antiproliferative, pro-differentiating, and immune modulatory effects on tumor cells in vitro and may also delay tumor growth in vivo. Objective: The aim of this review is to provide fresh insight into the most recent advances on the role of Vit D and its analogues as chemopreventive drugs in cancer therapy. Methods: A systematic review of experimental and clinical studies on Vit D and cancer was undertaken by using the major electronic health database including ISI Web of Science, Medline, PubMed, Scopus and Google Scholar. Results and conclusion: Experimental and clinical observations suggest that Vit D and its analogues may be effective in preventing the malignant transformation and/or the progression of various types of human tumors including breast cancer, prostate cancer, colorectal cancer, and some hematological malignances. These findings suggest the possibility of the clinical use of these molecules as novel potential chemopreventive and anticancer agent

Effects of zoledronic acid on proteinase plasma levels in patients with bone metastases.

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¡Ü0.0001). 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¡Ü4) in 25/30 patients (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

A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for (1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and (2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. One hundred and thirty-seven models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs. docetaxel, carboplatin vs. paclitaxel and carboplatin vs. docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. Sixty-five eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3%, n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01, Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5%, n=88 compared to 49.4%, n=85 for paclitaxel combined with other agents (p<0.001, Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore, the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets

Effects of Oleuropein on colon cancer progression in vitro. A preliminary report

Introduction. Accumulating evidence highlights that Oleuropein (OLE), one of the main bioactive phenolic compound present in olives, olive oil and olive leaves, appears to exert chemo-preventive effects against several human malignancies including gastrointestinal tumors. As the cellular mechanisms underlying this phenomenon are still not fully elucidated, we have undertaken some in vitro studies to examine the effects of OLE on the growth, adhesion and invasion of HTC116 and SW480 human colon cancer cells and the influence of this molecule on the production of certain proteins that appear to be relevant to cancer progression namely, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β (TGF-β) Methods. The effects of OLE on HTC116 and SW480 colon cancer cells growth, adhesion and invasion were evaluated by i) the colorimetric MTT assay, ii) the fibronectin coated multi-well assay and iii) the Matrigel transwell invasion assay, respectively. The influence of OLE on the rate of MMP-2, MMP-9 and TGF-β secretion by tumor cells during adhesion and invasion were determined by enzyme-linked immunosorbent assay. Results. 1)Exposure of human HCT116 and SW480 cancer cells for 24 or 72h to different concentrations of OLE (10-500 µM) resulted in a dose- and time-dependent inhibition of cell proliferation. The calculated IC50 values were 323.1µM and 186.8µM at 24h and 72h respectively for HCT116 tumor cells and 317.6µM at 24h and 226.8 µM at 72h for SW480 tumor cells. 2) The adhesion of HTC116 tumor cells exposed to non-cytotoxic concentrations of OLE (50-250 µM) up to 4h was reduced by 30% as compared to untreated cells while, a 72h continuous exposure to OLE (10-100 µM) decreased HTC116 cell invasion by 40%. This molecule showed to inhibit also SW480 tumor cell adhesion (-25%) but only at the highest drug concentration (250 µM) while, its effects on SW480 invasion were negligible. 3) The secretion of MMP-2, MMP-9 and TGF-β by OLE-treated HCT116 cells during adhesion experiments was reduced (-39%,-19%,-48% respectively) as compared to unexposed cells while, in invasion experiments, the extracellular release of MMP-2 and MMP-9 resulted increased at 24h (+41% and +23%) and then decreased (~ -25%) after 72h. However, TGF-β secretion was not significantly influenced by drug treatments. Finally, in invasion experiments, MMP-9 and TGF-β secretion by OLE-treated SW480 cells resulted impaired (-32% and-74% respectively) while, MMP-2 levels were only slightly affected ( -10%) Conclusions. These data indicate that OLE might exert its chemo-preventive effects by interfering with some key steps of cancer progression, such as tumor cell proliferation, adhesion and invasion and by modulating the extracellular secretion of proteins that may foster these processes. Further studies to better assess the specific molecular mechanisms underlying these phenomena are warranted by these preliminary observations