chondroitin-sulfates and Prostatic-Neoplasms

The aim of this study was to evaluate the impact of Ialuril Soft Gels in reducing acute genito-urinary (GU) toxicity in patients with prostate cancer treated with volumetric-modulated arc radiotherapy.. Forty patients were prospectively recruited. A moderate hypofractionation in 28 fractions ("hypo-moderate") was prescribed in 20 patients, while an extreme hypofractionation ("hypo-extreme") in 5 fractions was prescribed in 20 patients. The International Prostate Symptom Score (IPSS) questionnaire was administered in all cases before and after radiotherapy (RT). GU toxicity was evaluated according to CTCAE v4.0. Patients of each group ("hypo-moderate" and "hypo-extreme") were randomized (1:1) to receive RT alone or RT combined with Ialuril Soft Gels.. In "hypo-moderate" patients treated with Ialuril Soft Gels the following GU toxicity was reported: G0 3, G1 6, G2 1, G3 0. In the arm treated without Ialuril Soft Gels: G0 0, G1 7, G2 2, G3 1. In "hypo-extreme" arm treated with Ialuril Soft Gels the following GU toxicity was recorded: G0 7, G1 2, G2 1, G3 in 0; while in the arm treated without Ialuril Soft Gels: G0 5, G1 2, G2 2, G3 1. IPSS was unchanged in "hypo-moderate" and "hypo-extreme" groups and patients treated with Ialuril Soft Gels, with a median value of 6 and 5 respectively. In patients treated without Ialuril Soft Gels an increased IPSS was reported in "hypo-moderate" and "hypo-extreme" from 6 to 8 and from 3.5 to 4.5, respectively. At statistical analysis (Fisher's exact text) Ialuril Soft Gels was associated with IPSS improvement (P=0.03).. Ialuril Soft Gels seems to have a beneficial role in reducing GU toxicity without worsening the IPSS.

Topics: Administration, Oral; Aged; Chondroitin Sulfates; Drug Combinations; Humans; Hyaluronic Acid; Male; Neoplasm Grading; Prospective Studies; Prostatic Neoplasms; Radiation Injuries; Radiotherapy Planning, Computer-Assisted; Surveys and Questionnaires; Treatment Outcome; Urogenital System

Radiotherapy is one of the treatment options for prostate cancer (PCa) but up to 25% of men report about severe nocturia (nocturnal voiding). The combination of hyaluronic acid (HA) and chondroitin sulfate (CS) resembles glycosaminoglycan (GAG) replenishment therapy. The aim of our study was to evaluate the impact of HA and CS on nocturia, in men with nocturia after PCa radiotherapy.. Twenty-three consecutive patients with symptomatic cystitis after external radiotherapy for PCa were enrolled. Patients underwent bladder instillation therapy with HA and CS weekly for the first month and, afterwards, on week 6, 8 and 12. Nocturnal voiding frequency was assessed by item 3 (Q3) of the Interstitial Cystitis Symptoms Index (ICSI) and item 2 (Q2) of the Interstitial Cystitis Problem Index (ICPI). Data were analyzed with paired-samples T-test and adjusted for age.. Eighteen patients (78%) reported about nocturia. Pre- and post-treatment ICSI-Q3 was 2.13 ± 0.28 and 1.61 ± 0.21 (-24.4%, p = 0.001). With logistic regression analysis, both age and baseline ICSI-Q3 had a significant impact on nocturnal voiding frequency (r = 0.293, p = 0.011 and r = 0.970, p < 0.001). Pre- and post-treatment ICPI-Q2 was 1.87 ± 0.26 and 1.30 ± 0.25 (-30.5%, p = 0.016); logistic regression analysis was without significant findings.. Bladder instillation treatment with a combination of HA and CS was effective in reducing nocturnal voiding frequency in men with post-radiation bladder pain for PCa. Randomized, controlled trials with sham treatment are needed to confirm our result.

Topics: Administration, Intravesical; Aged; Chondroitin Sulfates; Cystitis; Drug Combinations; Humans; Hyaluronic Acid; Male; Nocturia; Pilot Projects; Prospective Studies; Prostatic Neoplasms; Radiation Injuries; Radiotherapy, Conformal; Treatment Outcome

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Chondroitin Sulfates; Docetaxel; Drug Carriers; Half-Life; Humans; Hyaluronan Receptors; Inhibitory Concentration 50; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Nanoparticles; NIH 3T3 Cells; Particle Size; PC-3 Cells; Prostatic Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays; Zein

Prostate cancer (PCa) is a common cancer in men that is curable prior to metastasis, when its prognosis worsens. Chondroitin sulfate (CS) is found in the extracellular matrix of normal prostate tissue and PCa, with greater content in metastatic PCa. Biomaterial scaffolds containing CS have yet to be evaluated for tumor microenvironment applications. Three-dimensional porous chitosan-CS (C-CS) scaffolds were developed and evaluated for PCa culture. Three C-CS scaffold compositions were prepared with 4 w/v% chitosan and 0.1, 0.5, and 1.0 w/v% CS and named 4-0.1, 4-0.5, and 4-1, respectively. The C-CS scaffolds had 90-95% porosity, average pore sizes between 143 and 166 μm, and no significant difference in scaffold stiffness. PC-3 and 22Rv1 PCa cells were cultured on the C-CS scaffolds to study the effect of CS on PCa growth and epithelial to mesenchymal transition (EMT). All C-CS scaffold compositions supported PCa growth and the 4-1 scaffolds had the greatest cell numbers for both PC-3 and 22Rv1. The C-CS scaffolds promoted upregulated EMT marker expression compared to 2D cultures with the greatest EMT marker expression in 4-1 scaffolds. Increasing CS concentration promoted upregulated vimentin expression in PC-3 cultures and N-cadherin and MMP-2 expression in 22Rv1 cultures. C-CS scaffolds promoted docetaxel drug resistance in PC-3 and 22Rv1 cultures and the 4-1 scaffold cultures had the greatest drug resistance. These results indicate that C-CS scaffolds are a promising in vitro platform for PCa.

Topics: Cell Proliferation; Chitosan; Chondroitin Sulfates; Epithelial-Mesenchymal Transition; Humans; Male; Porosity; Prostatic Neoplasms; Tissue Scaffolds; Tumor Microenvironment

Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to be up-regulated when arylsulfatase B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously been reported to inhibit the activity of the ubiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism by which decline in ARSB leads to decline in SHP2 activity is unclear. Here, we show that SHP2 binds preferentially C4S, rather than chondroitin 6-sulfate, and confirm that SHP2 activity declines when ARSB is silenced. The reduction in ARSB activity, and the resultant increase in C4S, increased the expression of EGFR (Her1/ErbB1) in human prostate stem and epithelial cells. The increased expression of EGFR occurred after 1) the decline in SHP2 activity, 2) enhanced c-Jun N-terminal kinase (JNK) activity, 3) increased nuclear DNA binding by c-Jun and c-Fos, and 4) EGFR promoter activation. In response to exogenous EGF, there was increased bromodeoxyuridine incorporation, consistent with enhanced cell proliferation. These findings indicated that ARSB and chondroitin 4-sulfation affect the activation of an important dual phosphorylation threonine-tyrosine kinase and the mRNA expression of a critical tyrosine kinase receptor in prostate cells. Restoration of ARSB activity with the associated reduction in C4S may provide a new therapeutic approach for managing malignancies in which EGFR-mediated tyrosine kinase signaling pathways are active.

Topics: Chondroitin Sulfates; Epithelial Cells; ErbB Receptors; Humans; Male; MAP Kinase Kinase 4; N-Acetylgalactosamine-4-Sulfatase; Phosphorylation; Prostate; Prostatic Neoplasms; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Signal Transduction; Stem Cells

After radiotherapy (RT) for prostate cancer (PCa), several patients reported lower urinary tract symptoms (LUTS) due to damage and discontinuation of the glycosaminoglycan layer of the bladder. Instillation of hyaluronic acid and chondroitin sulfate (HA-CS) represents replenishment therapy of the glycosaminoglycan layer. The aim of the study is to evaluate the efficacy and safety of HA-CS in men with symptomatic cystitis after RT for PCa.. Eighty consecutive men were treated with RT for PCa; 30 of these (37.5%) reported clinically relevant LUTS and associated bother as measured by the Interstitial Cystitis Symptom Index and Problem Index (ICSI/ICPI) Questionnaire 3 months after RT. Symptomatic patients received instillation therapy with HA-CS weekly for the first month and then at weeks 6, 8, and 12. All patients completed the ICSI/ICPI questionnaire before and after RT and at the end of HA-CS treatment.. HA-CS significantly reduced postradiation LUTS (P < .001) and bother (P = .006). Age, Gleason score, and radiation dose were the main determinants of worsening of LUTS after radiation (ICSI score baseline vs. postradiation: P = .047, .043, and .023). In multivariate analysis, only age influenced LUTS worsening after RT (P = .01). Age, radiation dose, and radiation toxicity were related to recovery of LUTS (ICSI score postradiation vs. post-HA-CS P = .041, P = .050, and P = .046). In multivariate analysis, no factor was statistically significant.. A remarkable worsening of symptoms and bother was observed after RT. HA-CS instillation is a safe treatment and resulted in an improvement of LUTS irrespective of age and clinical features, with full recovery of urinary bother.

Topics: Administration, Intravesical; Aged; Chondroitin Sulfates; Cystitis; Drug Therapy, Combination; Humans; Hyaluronic Acid; Male; Middle Aged; Neoplasm Grading; Pilot Projects; Prospective Studies; Prostatic Neoplasms; Surveys and Questionnaires; Treatment Outcome

Arylsulfatase B (N-acetylgalactosamine-4-sulfatase; ARSB) removes 4-sulfate groups from chondroitin-4-sulfate (C4S) and dermatan sulfate and is required for their degradation. In human prostate stromal and epithelial cells, when ARSB was silenced, C4S, versican and versican promoter activity increased, and the galectin-3 that co-immunoprecipitated with C4S declined. Galectin-3 silencing inhibited the ARSB-silencing-induced increases in versican and versican promoter due to effects on the AP-1-binding site in the versican promoter. These findings demonstrate for the first time the transcriptional mechanism whereby ARSB can regulate expression of an extracellular matrix proteoglycan with C4S attachments. In addition, following ARSB silencing, C4S that co-immunoprecipitated with versican increased, whereas co-immunoprecipitated EGFR declined, total EGFR increased and exogenous EGF-induced cell proliferation increased, suggesting profound effects of ARSB on vital cell processes.

Topics: Amino Acid Sequence; Animals; Blood Proteins; Cell Line, Tumor; Chondroitin Sulfates; ErbB Receptors; Galectin 3; Galectins; Gene Expression Regulation, Neoplastic; Genes, fos; Genes, jun; Humans; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; N-Acetylgalactosamine-4-Sulfatase; Promoter Regions, Genetic; Prostatic Neoplasms; Transcription Factor AP-1; Versicans

Previous studies from our laboratory demonstrated a strong association between an elevated level of chondroitin sulfate (CS) in peritumoral stroma and PSA-relapse in patients with early stage disease. In this study we determined whether CS levels could predict overall survival in men diagnosed with advanced prostate cancer subsequently treated by orchiectomy alone.. CS was localized in archived prostatic tissues by immunohistochemistry, and the level of CS expression as measured by video image analysis was compared in cohorts of 157 and 60 men with early stage or advanced disease, respectively.. The CS levels in the peritumoral stroma of patients without relapse after treatment for early stage disease was significantly reduced compared to levels in prostate tissue from patients who either relapsed (P = 0.003) or were diagnosed with advanced prostate cancer (P < 0.00001). There was no difference between the median CS level in the peritumoral prostatic stroma of early stage patients that relapsed after treatment and patients diagnosed with advanced prostate cancer. Increased CS levels (P < 0.0001) and high Gleason score (P < 0.0001) were associated with an increased rate of PSA-relapse in the cohort of patients with early stage disease. However, neither CS level nor Gleason score alone or in combination could predict survival outcome in patients with advanced prostate cancer following androgen deprivation therapy.. Although peritumoral CS levels and Gleason score are strong predictors of relapse-free survival in early stage prostate cancer patients, neither peritumoral CS levels nor Gleason score can predict survival outcome in patients with advanced disease.

Topics: Aged; Aged, 80 and over; Chondroitin Sulfates; Cohort Studies; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Orchiectomy; Predictive Value of Tests; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies

TENB2 encodes a putative transmembrane proteoglycan, related to the EGF/heregulin family of growth factors and follistatin, which has been identified through the application of a differential display technique to a xenograft model of prostate cancer. Northern analysis and competitive PCR were used to demonstrate significantly increased TENB2 expression (p = 0.0003) on the acquisition of androgen independence in the model system. TENB2 is also overexpressed in clinical prostate carcinoma vs. its benign counterpart (p < 0.0001), with particular prominence in high-grade tumours, and shows a high degree of tissue specificity, being detected on a multitissue Northern array exclusively in brain and prostate material. Studies of recombinant protein expression demonstrate that TENB2 is a chondroitin sulphate proteoglycan. The presence of an EGF and 2 follistatin domains suggests a role in the regulation of growth factor signalling either as a ligand precursor, a membrane-bound receptor or as a binding protein for growth factors. These data are indicative of a significant role for TENB2 in the progression of poorly differentiated tumour types, with implications for prostate cancer detection, prognosis and therapy.

Topics: Amino Acid Sequence; Animals; CHO Cells; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Cricetinae; Humans; Male; Mice; Molecular Sequence Data; Polymerase Chain Reaction; Prostatic Neoplasms

The disease course of localized prostate cancer is highly variable, and patients potentially curable by aggressive management are not readily identified by current clinical practice. Chondroitin sulfate (CS) glycosaminoglycan is a candidate biomarker as elevated levels of CS in peritumoral stroma of prostate cancer have been associated with prostate-specific antigen (PSA) failure. Immunoreactive CS was measured using image analysis of archived radical prostatectomy tissues, obtained from 157 men with a median of 47 months (range, 16-111 months) clinical follow-up. CS level, Gleason score, and preoperative serum PSA levels were independent predictors of PSA failure by Cox's multivariate analysis. Patients with low CS levels had significantly fewer PSA failures after radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot; 32% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 50% for CS > or = 7.0, P = 0.0001). In the subgroup of patients with preoperative serum PSA levels < 10 ng/ml, CS was particularly useful in discriminating retrospectively those patients most suited for surgery (Kaplan-Meier plot; 14% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 47% for CS > or = 7.0, P = 0.0001). We conclude that measurements of CS level can assist in predicting patient outcome after surgery. Additionally, our data suggest that the combination of CS and PSA measurements may improve outcome prediction for patients with intermediate Gleason scores.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Chondroitin Sulfates; Cohort Studies; Disease Progression; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Life Tables; Male; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Severity of Illness Index; Survival Analysis

To investigate changes in glycosaminoglycan (GAG) profiles in human prostatic tissue.. Seventeen human prostatic samples were examined; five were normal, six hyperplastic and six were cancerous. Prostatic proteoglycans were extracted with 4 mol/L guanidine-HCl containing protease inhibitors. After digestion of the freeze-dried proteoglycan extract with papain, the prostatic GAGs were purified. Total GAGs were measured by a modified dimethylmethylene blue (DMB) method. High-performance liquid chromatography (HPLC) was used to quantify the extracted GAGs.. Six types of GAGs, i.e. chondroitin 4-sulphate (Ch-4S), chondroitin 6-sulphate (Ch-6S), dermatan sulphate (DS), chondroitin, heparan sulphate and hyaluronic acid, were analysed qualitatively and quantitatively. The total amount of GAGs was increased in hyperplastic and cancerous prostates, with the predominant components being DS and Ch-6S in these specimens. The Ch-S:DS ratio in cancerous prostate was significantly higher than that in normal and BPH tissue (P < 0.05). Moreover, chondroitin was increased in hyperplastic prostatic tissue (P < 0.01).. These results suggest that an increase in chondroitin levels may be associated with hyperplastic change and an increase in the Ch-S:DS ratio may be related to the development of malignancy.

Topics: Adult; Aged; Chondroitin Sulfates; Chromatography, High Pressure Liquid; Dermatan Sulfate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Male; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms

Curative therapies for clinically localized prostate cancer have significant morbidity, and those patients who might be cured by aggressive management are not easily identified using current clinical information. Better biomarkers of tumor behavior need to be identified to improve clinical outcome. Chondroitin sulfate (CS), a glycosaminoglycan, may be a potentially useful biomarker as it is known to influence cell growth and differentiation and might influence malignant progression. In this study, CS was immuno-localized to the periacinar and peritumoral fibromuscular stromal tissue of nonmalignant and malignant prostates. The CS concentration was increased in the prostate tissue of men with early-stage prostate cancer compared with tissue from men without cancer (P < 0.0001). Using Cox's univariate analysis, CS concentration, tumor grade, preoperative serum prostate-specific antigen (PSA), extracapsular extension of disease, positive surgical margins, and patient age were associated with an increased risk of PSA failure. The CS concentration was compared with the other features in two-variable regression analyses. CS and preoperative serum PSA concentrations were independent predictors of PSA failure. CS was a stronger prognostic feature than tumor grade and could predict outcome for patients with moderately differentiated tumors. Patients with a low CS concentration had significantly better progression-free survival following radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot, 91% versus 49% PSA progression free at 5 years, respectively, P = 0.0038). Only postoperative pathological indices (extracapsular extension, surgical margins) were stronger predictors than CS. We conclude that measurement of prostatic CS concentrations at diagnosis may allow stratification of patients with early-stage prostate cancer for adjunctive or alternate therapies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Biomarkers, Tumor; Cell Differentiation; Cell Division; Chondroitin Sulfates; Disease Progression; Disease-Free Survival; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Stromal Cells; Survival Analysis; Time Factors

Seventy five prostatic specimens from cancer, BPH and normal controls were studied by light microscopic histochemical methods for the demonstration of complex carbohydrates and some proteins: 1) alcian blue (AB) (pH 1.0), 2) alcian blue (AB) (pH 2.5), 3) Periodic Acid-Schiff (PAS), 4) peroxidase labelled-Ricinus communis agglutinin-diaminobenzidine (PO-RCA-DAB), 5) Concanavalin A-peroxidase-diaminobenzidine (ConA-PO-DAB), 6) ConA-PO-DAB-periodic acid-m-aminophenol Fast black salt K (ConA-PO-DAB-PA-AP-FBK). For identifying individual acidic and neutral carbohydrates, following procedures of enzyme digestion were performed upon some tissue sections prior to the above histochemical staining: a) sialidase (prior to staining with AB at pH 2.5), b) streptomyces hyaluronidase (prior to staining with AB at pH 2.5), c) testicular hyaluronidase (prior to staining with AB at pH 1.0 or pH 2.5), d) chondroitinase ABC (prior to staining with AB at pH 1.0 or pH 2.5), e) chondroitinase AC (prior to staining with AB at pH 1.0 or pH 2.5), f) alpha-amylase (prior to staining with PAS). In addition, the tissue specimens from prostatic cancer were stained immunohistochemically for demonstration of prostatic acid phosphatase (PAP) and the serum PAP levels were also measured by radioimmunoassay. The histochemical differences in the prostatic tissue among normal control, BPH and cancer as follows. In the tissue of prostatic cancer, chondroitin sulfate A, C and hyaluronic acid were present in the interstitium. Chondroitin sulfate, hyaluronic acid and sialic acid were present in the cytoplasm of cancer cells. In the tissue of BPH chondroitin sulfate B and hyaluronic acid was present in the interstitium and hyaluronic acid was present in the cytoplasm of epitherial cells. In the epithelial basement membrane of the tissue from BPH, chondroitin B and hyaluronic acid were present. 1,2-Glycol groups of neutral complex carbohydrates in the interstitium of prostatic cancer were shown to exist in smaller amounts than in that of BPH. In the cytoplasm of cancer cells the intensity of both PO-RCA-DAB and ConA-PO-DAB staining could be divided into three groups: strong, moderate and weak. In the prostatic cancer there was a good correlation between the intensity of PO-RCA-DAB staining and tumor grade, and intensity of ConA-PO-DAB staining was correlated well with serum PAP level. The cytoplasm of cancer cells showed a positive reaction to PAP immunostaining and no appreciable difference was ob

Topics: Acid Phosphatase; Aged; Carbohydrates; Chondroitin Sulfates; Humans; Hyaluronic Acid; Male; Middle Aged; N-Acetylneuraminic Acid; Prostatic Hyperplasia; Prostatic Neoplasms; Sialic Acids; Staining and Labeling

The glycosaminoglycans of normal, benign hyperplastic and cancerous prostate were studied. In both prostatic hyperplasia and cancer the chondroitin sulfate:dermatan sulfate ratio was increased. In prostatic cancer this increase correlated with both the differentiation and extent of cancer in the prostate. The percentages heparan sulfate and heparan sulfate sulfation were decreased in prostatic cancer. Hyaluronic acid increased with dedifferentiation of the cancer. Histochemically, sulfated glycosaminoglycans were concentrated in the prostatic stroma at the stromal-epithelial interface. The increased chondroitin sulfate:dermatan sulfate ratio may be a nonspecific response or requirement for epithelial growth.

Topics: Adult; Aged; Chondroitin Sulfates; Dermatan Sulfate; Glycosaminoglycans; Heparitin Sulfate; Histocytochemistry; Humans; Hyaluronic Acid; Male; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Uronic Acids