High Levels Of Caveolin-1 Research Articles

Caveolin-1 protein expression as a prognostic biomarker of gastrointestinal tumours: A systematic review and meta-analysis.

Gastrointestinal (GI) cancers remain a major threat worldwide, accounting for over 30% of cancer deaths. The identification of novel prognostic biomarkers remains a challenge despite significant advances in the field. The CAV1 gene, encoding the caveolin-1 protein, remains enigmatic in cancer and carcinogenesis, as it has been proposed to act as both a tumour promoter and a tumour suppressor. To analyse the differential role of caveolin-1 expression in both tumour cells and stroma in relation to prognosis in GI tumours, we performed a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines; PROSPERO registration number: CRD42022299148. Our analysis showed that high levels of caveolin-1 in tumour cells were associated with poor prognosis and inferior overall survival (OS) in oesophageal and pancreatic cancer and hepatocellular carcinoma (HCC), but not in gastric and colorectal cancer. Importantly, our study showed that higher stromal caveolin-1 expression was associated with significantly longer OS and disease-free survival in colorectal cancer. Analysis of stromal caveolin-1 expression in the remaining tumours showed a similar trend, although it did not reach statistical significance. The data suggest that caveolin-1 expression in the tumour cells of oesophageal, pancreatic cancer and HCC and in the stroma of colorectal cancer may be an important novel predictive biomarker for the clinical management of these diseases in a curative setting. However, the main conclusion of our analysis is that caveolin-1 expression should always be assessed separately in stroma and tumour cells.

Suppression of ACADM-Mediated Fatty Acid Oxidation Promotes Hepatocellular Carcinoma via Aberrant CAV1/SREBP1 Signaling.

Lipid accumulation exacerbates tumor development, as it fuels the proliferative growth of cancer cells. The role of medium-chain acyl-CoA dehydrogenase (ACADM), an enzyme that catalyzes the first step of mitochondrial fatty acid oxidation, in tumor biology remains elusive. Therefore, investigating its mode of dysregulation can shed light on metabolic dependencies in cancer development. In hepatocellular carcinoma (HCC), ACADM was significantly underexpressed, correlating with several aggressive clinicopathologic features observed in patients. Functionally, suppression of ACADM promoted HCC cell motility with elevated triglyceride, phospholipid, and cellular lipid droplet levels, indicating the tumor suppressive ability of ACADM in HCC. Sterol regulatory element-binding protein-1 (SREBP1) was identified as a negative transcriptional regulator of ACADM. Subsequently, high levels of caveolin-1 (CAV1) were observed to inhibit fatty acid oxidation, which revealed its role in regulating lipid metabolism. CAV1 expression negatively correlated with ACADM and its upregulation enhanced nuclear accumulation of SREBP1, resulting in suppressed ACADM activity and contributing to increased HCC cell aggressiveness. Administration of an SREBP1 inhibitor in combination with sorafenib elicited a synergistic antitumor effect and significantly reduced HCC tumor growth in vivo. These findings indicate that deregulation of fatty acid oxidation mediated by the CAV1/SREBP1/ACADM axis results in HCC progression, which implicates targeting fatty acid metabolism to improve HCC treatment. SIGNIFICANCE: This study identifies tumor suppressive effects of ACADM in hepatocellular carcinoma and suggests promotion of β-oxidation to diminish fatty acid availability to cancer cells could be used as a therapeutic strategy.

Elevated Expression of CAV1 is Associated with Unfavorable Prognosis of Patients with Breast Cancer Who Undergo Surgery and Neoadjuvant Chemotherapy.

IntroductionNeoadjuvant chemotherapy (NACT), which is standard treatment for locally advanced breast cancer, improves the resectability of patients with early breast cancer and reduces the extent of breast and axillary surgery. Caveolin-1 (CAV1) is implicated in human cancers, although its utility for cancer prognosis is unknown. Here, we investigated the expression of CAV1 in breast cancer tissues to evaluate its prognostic significance on patients with breast cancer administered NACT.MethodsCAV1 expression in 80 breast cancer tissue samples was evaluated using immunohistochemistry (IHC). The association between CAV1 levels and clinical factors was analyzed using the chi-square test and that between CAV1 and prognosis was evaluated using multivariate Cox regression and Kaplan–Meier analyses.ResultsHigh levels of CAV1 were significantly associated with survival, and patients with overexpression of CAV1 had a poor prognosis. Adjusted multivariate Cox regression analyses revealed that a high level of CAV1 expression was an independent, significant prognostic factor for patients with breast cancer treated with NACT.DiscussionOverexpression of CAV1 in patients with breast cancer administered NACT was associated with shorter disease-free survival and overall survival. Therefore, high levels of CAV1 may serve as a prognostic biomarker for such patients.

Absence of caveolin-1 alters heat shock protein expression in spontaneous mammary tumors driven by Her-2/neu expression

In a previous study, we measured caveolin-1 protein levels, both in the normal breast and in breast cancer. The study revealed no association between caveolin-1 expression in the epithelial compartment and clinical disease outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor associated strongly with reduced metastasis and improved survival. Using an animal model, we found that the onset of mammary tumors driven by Her-2/neu expression was accelerated in mice lacking caveolin-1. We have analysed the heat shock protein (Hsp) response in the tumors of mice lacking caveolin-1. In all cases, the mammary tumors were estrogen and progesterone receptor negative, and the levels of Her-2/neu (evaluated by immunohistochemistry) were not different between the caveolin-1 +/+ (n=8) and the caveolin-1 -/- (n=7) tumors. However, a significant reduction in the extent of apoptosis was observed in mammary tumors from animals lacking caveolin-1. While Bcl-2, Bax, and survivin levels in the tumors were not different, the amount of HSPA (Hsp70) was almost double in the caveolin-1 -/- tumors. In contrast, HSPB1 (Hsp27/Hsp25) levels were significantly lower in the caveolin-1 -/- tumors. The mammary tumors from caveolin-1 null mice expressed more HSPC4 (gp96 or grp94), but HSPC1 (Hsp90), HSPA5 (grp78), HSPD1 (Hsp60), and CHOP were not altered. No significant changes in these proteins were found in the stroma surrounding these tumors. These results demonstrate that the disruption of the Cav-1 gene can cause alterations of specific Hsps as well as tumor development.

Involvement of the TGFβ pathway in the regulation of α5β1 integrins by caveolin‐1 in human glioblastoma

Caveolin-1 plays a crucial role in the development of cancer and its progression. We previously reported that glioblastoma cells expressing low levels of caveolin-1 exerted a more aggressive phenotype than cells expressing high levels. Such phenotype was due to the induction of α(5) β(1) integrin subsequent to the depletion of caveolin-1. Caveolin-1 was identified as a transcriptional repressor of α(5) β(1) integrin. The current study was designed to identify in vitro, the molecular mechanisms by which caveolin-1 controls α(5) β(1) integrin expression and to determine if a negative correlation between caveolin-1 and α(5) β(1) integrins also exists in biopsies and xenografted human brain tumors. We showed that depletion of caveolin-1 lead to the activation of the TGFβ/TGFβRI/Smad2 pathway which in turn induced the expression of α(5) β(1) integrins. We showed that cells expressing the lowest levels of caveolin-1 but the highest levels of α(5) β(1) integrins and TGFβRI were the most sensitive to a α(5) β(1) integrin antagonist and a TGFβRI inhibitor. Screening human glioma biopsies and human glioblastoma xenografts, we isolated subgroups with either low levels of caveolin-1 but high levels of α(5) β(1) integrin and TGFβRI or high levels of caveolin-1 but low levels of α(5) β(1) integrin and TGFβRI. In conclusion, caveolin-1 controls α(5) β(1) integrin expression through the TGFβ/TGFβRI/Smad2 pathway. The status of caveolin-1/α(5) β(1) integrins/TGFβRI might be a useful marker of the tumor evolution/prognosis as well as a predictor of anti-TGFβ or anti-α(5) β(1) integrin therapies.

Altered cholesterol homeostasis contributes to enhanced excitotoxicity in Huntington’s disease

Recent findings suggest that altered cholesterol homeostasis may contribute to the pathophysiology of Huntington's disease (HD). To understand the underlying mechanisms, here we used a combination of two-photon microscopy, epifluorescence, and biochemical methods to visualize and quantify lipid distribution in cell cultures expressing mutant huntingtin. Such expression promotes lipid imbalance, and cholesterol accumulation in cellular and murine models and in HD-affected human brains. Interestingly, cells expressing mutant huntingtin also showed higher content of ordered domains in their plasma membranes. These findings correlated with high levels of caveolin-1 and glycosphingolipid GM1, two well-defined markers of cholesterol-enriched domains, at the cell surface. In addition, cells expressing mutant huntingtin showed increased localization of NMDA receptors with cholesterol-enriched domains, contributing to increased NMDA receptor susceptibility to excitotoxic insults. Treatment with simvastatin or β-cyclodextrin, two cholesterol-lowering drugs, reduced the content of ordered domains at the cell surface, which in turn, protected cells against NMDA-mediated excitotoxicity. Taken together, our results indicate that mutant huntingtin produces accumulation of cholesterol and alters its cellular distribution that contributes to NMDA-mediated excitotoxicity. Administration of drugs that recover this effect, such as simvastatin could be beneficial for the treatment of HD.

Caveolin-1 Modifies the Immunity to Pseudomonas aeruginosa

The inflammatory response to Pseudomonas aeruginosa is not properly regulated in the lungs of patients with cystic fibrosis (CF). In the lung epithelium of individuals with wild-type CF transmembrane conductance regulator, lipid rafts containing CF transmembrane conductance regulator are rapidly formed in response to P. aeruginosa infection, and this response is closely linked to resistance to infection and disease. We found these rafts also contained high levels of caveolin-1 and thus examined the sensitivity of cav1 knockout (KO) mice to P. aeruginosa challenge in both acute and chronic P. aeruginosa infection models. We found that cav1 KO mice had increased sensitivity to P. aeruginosa infection, as represented by an increased mortality rate, elevated bacterial burdens recovered from lungs and spleens, and elevated inflammatory responses. These findings correlated with the decreased ability of cav1-deficient neutrophils to phagocytose P. aeruginosa. In addition, P. aeruginosa colonized cav1 KO mice much better compared with the wild-type controls in a model of chronic infection, indicting an important contribution of Cav-1 to innate host immunity to P. aeruginosa infection in the setting of both acute pneumonia and chronic infection typical of CF.

Stromal Cell Expression of Caveolin-1 Predicts Outcome in Breast Cancer

Caveolin-1 has been linked to tumor progression and clinical outcome in breast cancer, but a clear resolution of its role as a prognostic marker is lacking. We assessed caveolin-1 levels in normal breast tissue and two breast cancer cohorts for which outcome data were available. We found that caveolin-1 was not expressed in normal breast luminal epithelium but was present in the epithelial compartment of some tumors. We found no association between caveolin-1 expression in the epithelial compartment and clinical outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor, rather than within tumor cells, associated strongly with reduced metastasis and improved survival (P < 0.0001). The onset of mammary tumors driven by Her2/neu overexpression was accelerated in mice lacking caveolin-1, thereby supporting the observation that the presence of caveolin-1 in the tumor microenvironment modulates tumor development. These studies suggest that stromal caveolin-1 expression may be a potential therapeutic target and a valuable prognostic indicator of breast cancer progression.

The overexpression of caveolin-1 and caveolin-2 correlates with a poor prognosis and tumor progression in esophageal squamous cell carcinoma

Caveolin-1 (CAV1) and caveolin-2 (CAV2) are the major structural proteins of caveolae. We investigated the relationship between the clinicopathological factors of esophageal squamous cell carcinoma (ESCC) and the expression of CAV1 and CAV2. CAV1 and CAV2 expression were analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 15 esophageal cancer cell lines (TE1-15) and a normal esophageal epithelium cell line (Het-1A). CAV1 and CAV2 expression was examined by RT-PCR and immunohistochemical analysis in 47 ESCC specimens. High levels of CAV1 and CAV2 mRNA were detected in TE1-15, but neither CAV1 nor CAV2 mRNA were detected in Het-1A. In the ESCC samples CAV1 and CAV2 mRNA expression in the ESCC samples were significantly higher than in the corresponding normal esophageal mucosa (CAV1, P=0.0024; CAV2, P=0.0136). However, we could not find any significant relationship between CAV1 or CAV2 mRNA expression and clinicopathological factors. Immunostaining for CAV1 was positive in 13 of 47 patients (27.7%), whereas CAV2 was positive in 22 of 47 patients (46.8%). A significant correlation was observed between CAV1 and CAV2 immunostaining and T factor, lymphatic invasion, vein invasion and differentiation. The patients with positive staining for CAV1 or CAV2 had a significantly shorter survival than those with negative staining (P=0.0105 and 0.0424 for CAV1 and CAV2, respectively). These results suggest that positive staining for CAV1 and CAV2 could be a potentially useful prognostic marker of ESCC.

Retention of a differentiated endothelial phenotype by outgrowth endothelial cells isolated from human peripheral blood and expanded in long-term cultures

Rapid adequate vascularization by autologous human endothelial cells remains a limiting step in the treatment of ischemic tissues and the generation of new tissues. We have expanded outgrowth endothelial cells (OEC) from human peripheral blood and investigated their phenotypic stability in long-term cultures. Our goal has been to obtain suitable numbers of autologous endothelial cells for pro-angiogenic cell therapies. Mononuclear cells were isolated from human peripheral blood. During culture, cells were characterized for several endothelial and stem cell markers in mono- or in co-culture with mature endothelial cells. In cultures from peripheral blood, we observed cells with a variable ability to assume a differentiated endothelial phenotype. Most of the cells showed markers reported for endothelial progenitor cells or hemangioblasts (CD31, KDR, VE-cadherin, CD34, CD117, CD45) but failed to develop a differentiated phenotype. Caveolin-1 was not detectable in these cells by reverse transcription/polymerase chain reaction (RT-PCR) or immunofluorescence. Another cell type arising from the same cultures expressed a differentiated phenotype and was designated as an OEC. This subset as an OEC was expanded in long-term cultures and analyzed by immunofluorescence, flow-cytometry, and RT-PCR for a stable endothelial phenotype. OEC showed several markers of a differentiated endothelium, such as high levels of caveolin-1 throughout all tested passages, and the ability to form angiogenic sprouts in vitro. Thus, OEC in long-term expansion cultures from blood mononuclear cells are phenotypically highly stable, a feature that is an important prerequisite for using OEC from peripheral blood for autologous endothelial cell therapies.

Localization of the κ Opioid Receptor in Lipid Rafts

Lipid rafts are microdomains of plasma membranes enriched in cholesterol and sphingolipids in the outer layer. We determined whether kappa opioid receptors (KOR) in human placenta and FLAG (DYKDDDDK)-tagged human KOR (FLAG-hKOR) expressed in Chinese hamster ovary (CHO) cells are localized in lipid rafts and whether changes in cholesterol contents affect hKOR properties and signaling. Lipid rafts were prepared from placenta membranes and CHO cells expressing FLAG-hKOR using the Na2CO3 method and fractionation through a sucrose density gradient. The majority of the KOR in the placenta and FLAG-hKOR in CHO cells, determined by [3H]diprenorphine binding and/or immunoblotting with an anti-FLAG antibody, was present in low-density fractions, coinciding with high levels of caveolin-1 and cholesterol, markers of lipid rafts, which indicated that the KOR is localized in lipid rafts. Pretreatment with 2% methyl beta-cyclodextrin (MCD) reduced cholesterol content by approximately 48% and changed the cells from spindle-shaped to spherical. MCD treatment disrupted lipid rafts, shifted caveolin-1 and FLAG-hKOR to higher density fractions, increased the affinity of (-)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50,488H) for the hKOR, and greatly increased U50,488H-induced [35S]guanosine 5'-O-(3-thio)triphosphate binding and p42/44 mitogen-activated protein kinase phosphorylation. Cholesterol replenishment reversed all the MCD effects. Caveolin-1 immunoprecipitated with Galphai proteins and MCD treatment reduced caveolin-1 associated with Galphai proteins, which may contribute to the enhanced agonist-induced G protein activation. Caveolin-1 also immunoprecipitated with FLAG-hKOR, but MCD treatment had no effect on the association. Thus, the KOR is located in lipid rafts and its localization in the microdomains greatly affects coupling to G proteins.

Caveolin-1 is regulated by c-myc and suppresses c-myc-induced apoptosis.

Recent data indicating that overexpression of caveolin-1 as well as c-myc are relatively common features of advanced prostate cancer prompted us to test for potential cooperative interactions between caveolin-1 and c-myc that would be consistent with malignant progression. We used the well-characterized Rat1AmycERT cells to show that the caveolin-1 gene is down-regulated at the level of transcription by c-myc. By maintaining relatively high levels of caveolin-1 with an adenoviral vector or in stably transfected clones we show that caveolin-1 can suppress c-myc-induced apoptosis. Further we established human prostate cancer cell lines with the mycER construct and show that clones with increased caveolin-1 are more resistant to myc-induced apoptosis and have increased capacity for growth in soft agar when c-myc is activated.