What Happens to Serum Levels of Visinin-Like Protein-1, Caveolin-1 and Neuron-Specific Enolase after Supratentorial Glioma Resection: A Pilot Study.

AIM: To observe changes in the serum levels of visinin-like protein-1 (VILIP-1), caveolin-1 (Cav-1) and neuron-specific enolase (NSE) after glioma resection. MATERIAL AND METHODS: Consecutive 14 glioma patients with different histologic grade and 14 age and gender-matched healthy subjects were included in this pilot study. From the patients serum samples were taken in preoperative and on day 2 and 10 of postoperative periods. Healthy subjects provided serum sample once. The serum changes of three proteins were evaluated by ELISA. The results were compared between preoperative and postoperative periods and between patients and controls. RESULTS: Preoperative serum levels of VILIP-1 (p=0.008) and Cav-1 (p=0.012) were significantly higher in the patients. Mean serum levels of VILIP-1 (p=0.002) and Cav-1 (p=0.013) again were significantly higher than those of the controls. NSE did not show significant changes compared to controls in none of the periods. There was a steady decline regarding all three molecules from preoperative to postoperative day 10. However, statistical comparisons did not reveal any significant difference with respect the decline in any molecule. Significant positive correlation was detected between preoperative serum levels of VILIP-1 and Cav-1 (p=0.00001) in the patients and the controls (p=0.0000). CONCLUSION: This pilot study suggested that Cav-1 and particularly VILIP-1 may be used as a valuable serum biomarker for follow-up and for early detection of recurrence in high-grade gliomas. Future studies including larger cohort of patients with homogeneous group of glioma is required.

Clinical evidence for elevated levels of caveolin-1 in circulation of patients with diabetic foot ulcers.

Caveolin-1 directly interacts vascular endothelial growth factor receptor-2 (VEGFR2) and therefore prevents VEGF-induced angiogenesis. In addition, the production of nitric oxide (NO), which is effective in reducing ischemia in diabetic foot ulcers (DFU), is suppressed by caveolin-1 in endothelial cells. The present study was designed to investigate the change of caveolin-1 concentrations in DFU patients. A total of 150 participants were consecutively enrolled, including 40 DFU patients (DFU group), 40 diabetes patients without DFU (type 2 diabetes mellitus [T2DM] group), and 70 participants without diabetes (control group). Significant increased levels of plasma caveolin-1, accompanied with decreased concentration of plasma VEGF-A (vascular endothelial growth factor-A) and NO, were detected in DFU patients. Moreover, Pearson's correlation analysis revealed a negative correlation between plasma caveolin-1 and VEGF-A as well as NO levels in DFU patients. Furthermore, DFU patients had higher expression of caveolin-1 in the popliteal artery, compared to those in control and T2DM groups. Simultaneously, the amounts of eNOS (an enzyme responsible for the production of NO) and VEGFR2 were attenuated in the popliteal artery of DFU patients. Taken together, our study provided clinical evidence for the possible association of elevated caveolin-1 levels and the development of DFU. This may be induced by the suppressed VEGF-A/VEGFR2 and eNOS/NO signalling axis.

Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer.

Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.

Simvastatin delays castration­resistant prostate cancer metastasis and androgen receptor antagonist resistance by regulating the expression of caveolin­1.

The failure of androgen deprivation therapy in prostate cancer treatment mainly results from drug resistance to androgen receptor antagonists. Although an aberrant caveolin­1 (Cav­1) expression has been reported in multiple tumor cell lines, it is unknown whether it is responsible for the progression of castration­resistant prostate cancer (CRPC). Thus, the aim of the present study was to determine whether Cav­1 can be used as a key molecule for the prevention and treatment of CRPC, and to explore its mechanism of action in CRPC. For this purpose, tissue and serum samples from patients with primary prostate cancer and CRPC were analyzed using immunohistochemistry and enzyme­linked immunosorbent assay, which revealed that Cav­1 was overexpressed in CRPC. Furthermore, Kaplan­Meier survival analysis and univariate Cox proportional hazards regression analysis demonstrated that Cav­1 expression in tumors was an independent risk factor for the occurrence of CRPC and was associated with a shorter recurrence­free survival time in patients with CRPC. Receiver operating characteristic curves suggested that serum Cav­1 could be used as a diagnostic biomarker for CRPC (area under the curve, 0.876) using a cut­off value of 0.68 ng/ml (with a sensitivity of 82.1% and specificity of 80%). In addition, it was determined that Cav­1 induced the invasion and migration of CRPC cells by the activation of the H­Ras/phosphoinositide­specific phospholipase Cε signaling cascade in the cell membrane caveolae. Importantly, simvastatin was able to augment the anticancer effects of androgen receptor antagonists by downregulating the expression of Cav­1. Collectively, the findings of this study provide evidence that Cav­1 is a promising predictive biomarker for CRPC and that lowering cholesterol levels with simvastatin or interfering with the expression of Cav­1 may prove to be a useful strategy with which to prevent and/or treat CRPC.

Downregulated Caveolin-1 expression in circulating monocytes may contribute to the pathogenesis of psoriasis.

Caveolin-1 (CAV-1) is the principal component of caveolae that regulates a variety of signaling molecules and receptors. Our previous study revealed CAV-1 reduction in the epidermis of patients with psoriasis, which leads to enhanced Janus kinase/signal transducer and activator of transcription activation and cytokine production, suggesting that aberrant CAV-1 expression may contribute to psoriatic inflammation. This study aimed to investigate whether abnormal modulation of CAV-1 on immune cells is involved in the pathogenesis of psoriasis. We observed that CAV-1 level in psoriasis patients was apparently reduced in peripheral blood mononuclear cells (PBMCs) and it was prominent in CD14+ monocytes. CAV-1 silencing in monocytes represented elevated levels of interleukin (IL)-1ß and IL-6, and those had enhanced chemotaxis activity. In a murine model of psoriasis-like inflammation induced by imiquimod, we observed a significant CAV-1 reduction in PBMCs. Systemic administration of CAV-1 scaffolding domain peptide significantly improved the skin phenotype with less macrophage infiltration. Taken together, aberrant CAV-1 expression in monocytes may be involved in the pathogenesis of psoriasis.

Maternal chronic intermittent hypoxia in rats causes early atherosclerosis with increased expression of Caveolin-1 in offspring.

OBJECTIVE: The objective of our research was to explore the effects of maternal and postpartum chronic intermittent hypoxia (CIH) exposure on atherosclerosis in adulthood offspring of rats, and the role of Caveolin-1 in the course. METHODS: Sixteen rats were assigned to two groups (n = 8), maternal normoxia and CIH group. After delivery, two male pups per litter were selected and breastfed for 1 month, which then randomly received postpartum normoxia or CIH. Thus, 4 groups were created as follows (n = 8): (1) maternal normoxia and postpartum normoxia group, (2) maternal CIH and postpartum normoxia group, (3) maternal CIH and postpartum CIH group, and (4) maternal normoxia and postpartum CIH group. The offspring were weighed at birth and weaning. After the duration of 12-week experiment, morphological changes, the expression of Caveolin-1 and NF-κB p65 in the aorta were detected. RESULTS: Maternal CIH resulted in significantly lower body weight and thicker intima (P < 0.001). CIH upregulated the expression of Caveolin-1 and NF-κB p65 significantly (P < 0.01). There was a synergistic effect of maternal and postpartum CIH on the thickening of intima (P < 0.05), also on the expression of Caveolin-1 and NF-κB p65 (P < 0.01). CONCLUSIONS: The results demonstrate that maternal CIH exposure causes a postpartum catch-up growth and early atherosclerotic changes followed by upregulating Caveolin-1 expression. Besides, maternal CIH enhances the atherosclerotic changes caused by postpartum CIH. Oxidative stress probably implicates in above effects.

Clinical significance of serum caveolin-1 levels in gastric cancer patients.

Caveolin-1 plays a significant role in the pathogenesis of various carcinomas and its expression affects the survival of cancer patients. However, the molecular function of caveolin-1 and its possible clinical importance has remained uncertain in gastric cancer. No clinical trial has examined serum caveolin-1 levels in gastric cancer patients so far, instead all available results were provided from studies conducted on tissue samples. In the current study, we analyzed the soluble serum caveolin-1 levels in gastric cancer patients, and specified its associations with the clinical factors and prognosis. MATERIAL AND METHODS: Sixty-three patients with pathologically confirmed gastric cancer were enrolled into the trial. Serum caveolin-1 concentrations were detected by ELISA method. Thirty healthy subjects were also included in the study. RESULTS: The median age of patients was 62 years, ranging from 28 to 82 years. The serum caveolin-1 levels in gastric cancer patients were significantly higher than those in control group (p < 0.001). The common clinical parameters including patient age, sex, lesion localization, histopathology, histological grade, disease stage, and various serum tumor markers (e.g. LDH, CEA, and CA 19.9) were not found to be associated with serum caveolin-1 levels (p > 0.05). Similarly, no correlation existed between serum caveolin-1 concentration and chemotherapy responsiveness (p = 0.93). Furthermore, serum caveolin-1 level was not found to have a prognostic role (p = 0.16). CONCLUSION: Even though it is neither predictive nor prognostic, serum caveolin-1 level may be a valuable diagnostic indicator in patients with gastric cancer.

Baseline and longitudinal plasma caveolin-1 level as a biomarker in active surveillance for early-stage prostate cancer.

OBJECTIVES: To evaluate the role of caveolin-1 (Cav-1) as a predictor of disease reclassification (DR) in men with early prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: We analysed archived plasma samples prospectively collected from patients with early prostate cancer in a single-institution AS study. Of 825 patients enrolled, 542 had ≥1 year of follow-up. Baseline and longitudinal plasma Cav-1 levels were measured using an enzyme-linked immunosorbent assay. Tumour volume or Gleason grade increases were criteria for DR. Logistic regression analyses were used to assess associations between clinicopathological characteristics and reclassification risk. RESULTS: In 542 patients, 480 (88.6%) had stage cT1c disease, 542 (100.0%) had a median prostate-specific antigen level of 4.1 ng/mL, and 531 (98.0%) had a median Cancer of the Prostate Risk Assessment score of 1. In all, 473 (87.3%) had a Gleason score of 3+3. After a median of 3.1 years of follow-up, disease was reclassified in 163 patients (30.1%). The mean baseline Cav-1 level was 2.2 ± 8.5 ng/mL and the median 0.2 ng/mL (range, 0-85.5 ng/mL). In univariate analysis, baseline Cav-1 was a significant predictor for risk of DR (odds ratio [OR] 1.82, 95% confidence interval [CI] 1.24-2.65; P = 0.002). In multivariate analysis, with adjustments for age, tumour length, group risk stratification and number of positive cores, reclassification risk associated with Cav-1 remained significant (OR 1.91, 95% CI 1.28-2.84; P = 0.001). CONCLUSION: Baseline plasma Cav-1 level was an independent predictor of disease classification. New methods for refining AS and intervention may result.

The influence of caveolin-1 gene polymorphisms on hepatitis B virus-related hepatocellular carcinoma susceptibility in Chinese Han population: A case-control study.

This study aimed to explore the genetic association of polymorphisms in caveolin-1 gene (CAV1) with hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) susceptibility in a Chinese Han population.The genotyping of polymorphism was conducted using polymerase chain reaction-restriction fragment length polymorphism method. Whether the genotype distribution of polymorphisms in the healthy controls was consistent with Hardy-Weinberg equilibrium (HWE) was detected. The genotype and allele frequency difference between the 2 groups was compared by chi-square test. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated to show the relative risk of HCC which resulted from genetic variants in CAV1. Moreover, the linkage disequilibrium of CAV1 polymorphisms was analyzed by Haploview.The AG genotype and A allele of rs1049334 showed significantly higher frequency in HCC patients than that of chronic HBV patients and the healthy controls (P < .05); so their carriage obviously increased the susceptibility to HBV-related HCC, irrespective of the fact whether individuals were infected with hepatitis B virus or not (AG vs GG: OR 1.958, 95% CI 1.050-3.650, OR 1.899, 95% CI 1.034-3.487; A vs G: OR 1.667, 95% CI 1.033-2.689, OR 1.777, 95% CI 1.103-2.863). Additionally, A-G haplotype of rs3807989-rs1049334 showed the protective role for HBV-related HCC (OR 0.102, 95% CI 0.035-0.293; OR 0.135, 95% CI 0.046-0.395).CAV1 rs1049334 polymorphism is significantly associated with the occurrence risk of HBV-related HCC, and the interaction of polymorphisms should not be neglected.

Is plasma caveolin-1 level a prognostic biomarker in metastatic pancreatic cancer?

BACKGROUND/AIMS: To evaluate the prognostic significance of plasma caveolin (CAV)-1 and its association with survival and treatment response rates in metastatic pancreatic cancer (MPC). PATIENTS AND METHODS: Plasma samples were prospectively collected from 41 patients with newly diagnosed MPC. Moreover, plasma samples were collected from 48 patients with chronic pancreatitis and 41 healthy individuals (control groups) for assessing Cav-1 levels. Plasma Cav-1 levels were evaluated at baseline and after three cycles of chemotherapy in the patients with MPC. RESULTS: The median Cav-1 level was 13.8 ng/mL for the patients with MPC and 12.2 ng/mL for healthy individuals (P = 0.009). The Cav-1 cut-off level was calculated as 11.6 ng/mL by using the receiver operating characteristic curve. The median overall survival and progression-free survival rates were 5 and 2.4 months, respectively, for participants with a high basal plasma Cav-1 level; the corresponding values were 10.5 and 9.4 months for participants with a low plasma Cav-1 level (P = 0.011 and P= 0.003, respectively). Of the 41 patients with MPC, 23 completed at least three cycles of chemotherapy. The median Cav-1 level was 13 ng/mL for post-treatment MPC (r2: 0.917; P= 0.001). High basal plasma caveolin-1 level have continued to remain at high levels even after chemotherapy, showing a trend toward worse response rates (P = 0.086). CONCLUSION: High basal plasma Cav-1 levels seem to be associated with poor survival and tend to yield worse therapeutic outcomes in patients with MPC. This study is the first to evaluate the prognostic significance of plasma Cav-1 levels as a prognostic factor in patients with MPC. However, larger prospective clinical trials are warranted.

TLR4 and Caveolin-1 in Monocytes Are Associated With Inflammatory Conditions in Diabetic Neuropathy.

The purpose of this study was to investigate the expression of TLR4 and caveolin-1 in monocytes among healthy volunteers as well as those with type-2 diabetes mellitus (T2DM) and diabetic peripheral neuropathy (DPN). Nineteen healthy control subjects, 18 patients with T2DM, and 20 patients with DPN were enrolled. Toll-like receptor (TLR)4, caveolin-1, MyD88, phosphorylated IκB, and plasma TNF-α and interleukin (IL)-6 were measured using real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. Compared with the other two groups, the DPN group had higher expression of TLR4, MyD88, phosphorylated IκB, TNF-α, and IL-6, but significantly lower levels of caveolin-1 and total IκB in monocytes. Plasma concentrations of TNF-α and IL-6 were positively correlated with TLR4 and negatively correlated with caveolin-1 in patients with DPN. Plasma concentration of TLR4 was negatively correlated with caveolin-1 in patients with DPN. Reduced expression of caveolin-1 in monocytes could aggravate the TLR4-mediated inflammatory cascade.

Is Serum Caveolin-1 a Useful Biomarker for Progression in Patients with Colorectal Cancer?.

BACKGROUND: Colorectal cancer (CRC) is the third most common cause of cancer diagnosed in males and the second in females. Survival is strongly related to stage at diagnosis. There is an urgent need to find a noninvasive biomarker that can be commonly applied for screening diagnosis, early detection of recurrence, and monitoring of metastatic CRC. Protein caveolin-1 (CAV-1) has been known to be expressed abnormally in colon cancer and appears to contribute to aberrant signaling and protein trafficking. There are controversial results regarding the role of CAV-1 in cancer. We hypothesized that levels of CAV-1 in serum of patients with CRC might be important to estimate the progression of the disease. Therefore, the purpose of this study is to investigate whether serum CAV-1 might be used as a factor determining progression of CRC. METHODS: A total of 61 patients with CRC (26 male, 35 female) and 46 controls (38 male, 8 female) were enrolled. Serum CAV-1 levels were measured by ELISA. The relationship between CAV-1 and progression-free survival (PFS) was analyzed with use of receiver operating characteristic (ROC) and Kaplan-Meier analysis. Results were given as median (95% CI). Mann-Whitney test was used for the comparison of groups. RESULTS: CAV-1 levels were found to be 11.5 ng/mL (10.4-12.9) in CRC and 11.9 ng/mL (10.7-14.4) in controls (p = 0.465). The serum CAV-1 levels in CRC patients with disease progression and without progression were respectively 10.0 ng/mL (8.5-11.3) and 12.2 ng/mL (11.1-14.8) (p = 0.023). In ROC analysis, if CAV-1 levels are equal or lesser than 10.73 ng/mL, it might show presence of progression with a sensitivity 73.3% and specificity 66.7% in patients with CRC (area under the ROC curve (AUC) = 0.697, p = 0.005). The mean PFS time was found to be 29.7 months (19.8-39.7, 95% CI for the mean) in patients who have CAV-1 level ≤ 10.73 ng/mL and 61.9 months (44.2-79.6) in patients who have CAV-1 level > 10.73 ng/mL [hazard ratios (HR) with 95% CI = 3.49 (1.26 - 9.68) (p = 0.017)]. CONCLUSIONS: Our results strongly suggest that CAV-1 levels might be used as a marker to determine progression of CRC. When considered in combination with other biomarkers of CRC, CAV-1 is clinically informative and instructive.

Clinical significance of serum caveolin-1 levels in melanoma patients.

BACKGROUND: Caveolin-1 plays an important role in the pathogenesis of multiple malignancies, and its expression also strongly affects the outcomes of patients with cancer. The objective of this study was to determine the clinical significance of the serum levels of caveolin-1 in patients with melanoma. MATERIALS AND METHODS: A total of 60 patients with a pathologically confirmed diagnosis of melanoma were enrolled into this study. Serum caveolin-1 concentrations were determined by the solid-phase sandwich enzyme-linked immunosorbent assay method. Thirty age- and sex-matched healthy controls were included in the analysis. RESULTS: The median age at diagnosis was 53.5 years, range 16-88 years. The baseline serum caveolin-1 levels of the patients with melanoma were significantly higher than in those in the control group (0.47 vs. 0.37 ng/ml, respectively, P = 0.05). Known clinical variables, including age of patient, gender, site of lesion, histology, stage of disease, serum lactic dehydrogenase levels, and response to chemotherapy, were not found correlated with serum caveolin-1 concentrations (P > 0.05). Moreover, serum caveolin-1 concentration was found to have no prognostic role on survival (P = 0.44). CONCLUSIONS: Serum levels of caveolin-1 may have a diagnostic marker in melanoma patients. However, its predictive and prognostic value was not determined.

Significant Association of Caveolin-1 and Caveolin-2 with Prostate Cancer Progression.

BACKGROUND/AIM: Up-regulation of caveolin (CAV)-1 is associated with aggressive prostate cancer. Recently, it has been inferred that CAV2, a co-factor sub-type of CAV1, cross-talks with CAV1 and promotes tumor growth. We previously reported that plasma CAV1 levels are elevated in patients with castration-resistant prostate cancer (CRPC), but not in hormone-sensitive prostate cancer (non-CRPC), implying that CAV1 may be a therapeutic target for CRPC. However, a correlation of CAV1 and CAV2 expression in PC has not yet been reported. Herein, we analyzed associations between PC progression and plasma CAV1 and -2 in Japanese men, and expression of CAV1 and -2 in PC3 (CRPC) and LNCaP (non-CRPC) cell lines. MATERIALS AND METHODS: We investigated plasma samples from 36 patients with CRPC and 22 with non-CRPC. We used enzyme-linked immunosorbent assay (ELISA) to determine plasma levels of CAV1 and -2, and examined correlations with clinicopathological characteristics such as Gleason grade and clinical T stage. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate CAV1 and CAV2 mRNA in PC cell lines. We also introduced CAV1- and CAV2-specific small interfering (siRNA) into PC3 cells to knock-down (KD) both molecules, and examined its influence on the expression of these genes between PC3 CAV1 and -2 KD cells and control cells. RESULTS: Plasma CAV1 and -2 levels in patients with CRPC were significantly higher than in those with non-CRPC (CAV1, p=0.003; CAV2, p<0.001). Plasma levels of CAV1 and -2 were significantly correlated (p<0.001). However, we did not find any significant relationship between CAV1 or CAV2 expression and clinicopathological factors. ELISA and real-time qRT-PCR showed that both proteins and mRNAs in PC3 cells were significantly over-expressed compared to LNCaP cells (p<0.001). In PC3 CAV1 KD cells, expression of CAV2 was suppressed and confirmed the linkage of CAV2 KD and suppression of CAV1 expression. CONCLUSION: There was a significant correlation between plasma CAV-1 and -2 levels and progression of PC. CAV1 and -2 were highly expressed in the PC3 compared to the LNCaP cell line. Our findings support the potential of these molecules as therapeutic targets for CRPC.

Increased plasma caveolin-1 levels are associated with progression of prostate cancer among Japanese men.

AIM: Up-regulation of caveolin-1 (CAV1) is associated with aggressive prostate cancer. Among Caucasian and African-American patients, plasma CAV1 levels are elevated in patients with castration-resistant prostate cancer (CRPC), but not in those with hormone-sensitive prostate cancer (non-CRPC), which implies that CAV1 could be a therapeutic target for CRPC. Here, we evaluated associations between plasma CAV1 levels and these types of cancer in Japanese men, and CAV1 expression in PC3 (CRPC) and LNCaP (non-CRPC) cell lines. MATERIALS AND METHODS: Plasma samples were obtained from 58 patients with prostate cancer: 36 with CRPC and 22 with non-CRPC. Enzyme-linked immuno sorbent assay (ELISA) kits were used to determine CAV1 plasma levels; qRT-PCR and western blots were used to evaluate the expression of CAV1 mRNA and protein in cell lines. RESULTS: Plasma CAV1 levels in patients with CRPC were greatly higher than in those with non-CRPC (1.46±1.37 ng/ml in CRPC; 0.56±0.32 ng/ml in non-CRPC, p<0.004). Western blot and real-time qRT-PCR showed CAV1 protein and mRNA in PC3 cells to be significantly overexpressed compared to its expression in LNCaP cells (p<0.0001). CONCLUSION: Our results showed a relationship between CAV1 expression and prostate cancer progression, and support the possibility of CAV1 as a therapeutic target for CRPC.

Serum caveolin-1, a biomarker of drug response and therapeutic target in prostate cancer models.

We investigated the effect of dasatinib and sunitinib on tyrosine kinase (TK) signaling, caveolin-1 (Cav-1) expression and secretion and proliferation of PC-3 and DU145 prostate cancer cells in vitro and in vivo. Treatment of both cell lines with either dasatinib or sunitinib reduced phosphorylation of PDGFR, VEGFR2, Akt, FAK, Src (dasatinib only) and Cav-1, and reduced cellular and secreted levels of Cav-1. Both agents dose-dependently inhibited proliferation of these cells. In PC-3 and DU145 subcutaneous xenografts, treatment with dasatinib, sunitinib or anti-Cav-1 antibody (Ab) alone produced significant tumor regression compared with that by vehicle or IgG alone. Combined dasatinib and anti-Cav-1 Ab treatment or sunitinib and anti-Cav-1 Ab produced greater tumor regression than either treatment alone. Serum Cav-1 levels were lower in dasatinib- and sunitinib-treated mice than they were in vehicle-treated mice, and correlated positively with tumor growth in dasatinib- and sunitinib-treated groups (r = 0.48, p = 0.031; r = 0.554, p = 0.0065, respectively), compared with vehicle controls. Cav-1 knockdown, in combination with dasatinib or sunitinib treatment in PC-3 cells, caused a greater reduction in the phosphorylation of PDGFR-ß and VEGFR2, and expression and secretion of PDGF-B and VEGF-A than that in PC-3 cells treated with dasatinib or sunitinib alone in control siRNA cells, suggesting that Cav-1 is involved in an autocrine pathway that is affected by these drugs. Overall, our results suggest a role for Cav-1 as a biomarker of response to both dasatinib and sunitinib treatment and as a therapeutic target in prostate cancer.

Caveolin-1 as a potential high-risk prostate cancer biomarker.

Current diagnostic techniques of prostate cancer cannot efficiently distinguish the latent and low-risk forms from the high-risk significant forms of prostate cancer. Caveolin-1 (Cav-1), except other functions, plays an important role in cell transformation and the process of tumorigenesis. Furthermore, Cav-1 is involved in metastatic processes. It has also been shown that Cav-1 expression is induced under stress conditions, such as oxidative stress. The present study focused on the determination of prognostic markers of aggressive (high-grade) forms of prostate cancer. We determined serum Cav-1 and serum markers of antioxidant activity-glutathione (GSH), 2,2-diphenyl-1-picrylhydrazyl (DPPH), Trolox equivalent antioxidant capacity (TEAC), ferric-reducing antioxidant power (FRAP), N,N-dimethyl-1,4-diaminobenzene (DMPD), free radicals method (FRK) and blue chromium peroxide (Cro) in 97 serum samples (82 prostate cancer patients and 15 controls). We found insignificant differences in Cav-1 between the sera of patients and controls (5.69 in the cancer group vs. 5.42 ng/ml in the control group). However, we found a significant (p<0.004) 2.8-fold elevation of Cav-1 in high tumour stages (TNM T4) compared to lower stages and a significant positive association with histological grading (r=0.29, p=0.028). We also found that in patients with high serum Cav-1 the antioxidant capacity of the body is reduced. These findings indicate that Cav-1 may be an interesting tool for the prediction of disease burden.

Caveolin 1 protein expression in renal cell carcinoma predicts survival.

BACKGROUND: Caveolae play a significant role in disease phenotypes such as cancer, diabetes, bladder dysfunction, and muscular dystrophy. The aim of this study was to elucidate the caveolin-1 (CAV1) protein expression in renal cell cancer (RCC) and to determine its potential prognostic relevance. METHODS: 289 clear cell RCC tissue specimens were collected from patients undergoing surgery for renal tumors. Both cytoplasmic and membranous CAV1 expression were determined by immunohistochemistry and correlated with clinical variables. Survival analysis was carried out for 169 evaluable patients with a median follow up of 80.5 months (interquartile range (IQR), 24.5-131.7 months). RESULTS: A high CAV1 expression in the tumor cell cytoplasm was significantly associated with male sex (p = 0.04), a positive nodal status (p = 0.04), and poor tumor differentiation (p = 0.04). In contrast, a higher than average (i.e. > median) CAV1 expression in tumor cell membranes was only linked to male sex (p = 0.03). Kaplan-Meier analysis disclosed significant differences in 5-year overall (51.4 vs. 75.2%, p = 0.001) and tumor specific survival (55.3 vs. 80.1%, p = 0.001) for patients with higher and lower than average cytoplasmic CAV1 expression levels, respectively. Applying multivariable Cox regression analysis a high CAV1 protein expression level in the tumor cell cytoplasm could be identified as an independent poor prognostic marker of both overall (p = 0.02) and tumor specific survival (p = 0.03) in clear cell RCC patients. CONCLUSION: Over expression of caveolin-1 in the tumour cell cytoplasm predicts a poor prognosis of patients with clear cell RCC. CAV1 is likely to be a useful prognostic marker and may play an important role in tumour progression. Therefore, our data encourage further investigations to enlighten the role of CAV1 and its function as diagnostic and prognostic marker in serum and/or urine of RCC patients.

Association of caveolin-1 and -2 genetic variants and post-treatment serum caveolin-1 with prostate cancer risk and outcomes.

BACKGROUND: Caveolin-1 (cav-1) is overexpressed by metastatic prostate cancer (PC) cells. Pre-operative serum cav-1 levels have been shown to be a prognostic marker for PC recurrence. This study evaluated the relationship between post-treatment serum cav-1 levels and single nucleotide polymorphisms (SNPs) in the cav-1 and -2 genes with risk of PC, aggressive PC, PC recurrence or death. METHODS: Two case-control studies of PC among men in Washington State were combined for this analysis. Cases (n = 1,458) were diagnosed in 1993-1996 or 2002-2005 and identified via a SEER cancer registry. Age-matched controls (n = 1,351) were identified via random digit dialing. Logistic regression was used to assess the relationship between exposures (19 haplotype-tagging SNPs from all subjects and post-treatment serum cav-1 levels from a sample of 202 cases and 226 controls) and PC risk and aggressive PC. Cox proportional hazards regression was used to assess the relationship between exposures and PC recurrence and death. RESULTS: Rs9920 in cav-1 was associated with an increased relative risk of overall PC (OR(CT + CC) = 1.37, 95% CI = 1.12, 1.68) and aggressive PC (OR(CT + CC) = 1.57, 95% CI = 1.20, 2.06), but not with PC recurrence or death. High post-treatment serum cav-1 levels were not associated with PC risk, aggressive PC, or PC-specific death, but approached a significant inverse association with PC recurrence (hazard ratio = 0.69, 95% CI = 0.47, 1.00). CONCLUSIONS: We found modest evidence for an association with a variant in the cav-1 gene and risk of overall PC and aggressive PC, which merits further study. We found no evidence that higher post-treatment serum cav-1 is associated with risk of aggressive PC or adverse PC outcomes.

Overexpression of caveolin-1 in adult T-cell leukemia.

Caveolin-1 is implicated in the regulation of signal pathways. Adult T-cell leukemia (ATL) is a T-cell malignancy causatively associated with human T-cell leukemia virus type 1 (HTLV-1). To determine the role of caveolin-1 in leukemogenesis, we examined caveolin-1 expression levels in HTLV-1-infected T-cell lines and ATL cells. These cells expressed high levels of caveolin-1 compared with uninfected T-cell lines and normal peripheral blood mononuclear cells (PBMCs). Caveolin-1-positive ATL cells were detected in ATL lymph nodes and skin lesions, and caveolin-1 was also detected in the plasma of patients with ATL. Infection of a human T-cell line, an epithelial cell line, and normal PBMCs with HTLV-1 induced caveolin-1 expression. The viral protein Tax transcriptionally activated caveolin-1 gene through nuclear factor-kappaB and cAMP response element binding protein signal pathways. HTLV-1-infected T-cell lines, and ATL cells are known to be resistant to transforming growth factor beta (TGF-beta)-induced growth inhibition. Caveolin-1 was colocalized with TGF-beta type I receptor in HTLV-1-infected T-cell lines and suppressed TGF-beta signaling. Caveolin-1 knockdown in an HTLV-1-infected T-cell line exhibited susceptibility to TGF-beta. Thus, we describe a new function for Tax, repression of TGF-beta signaling through caveolin-1 expression, which may play a critical role in ATL leukemogenesis.