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Purpose: High LET including alpha radiation-based approaches have been proved as a promising mode for cancer therapy owing to their biophysical and radiobiological advantages compared to photon beams. Studies pertaining to effect of α-radiation on cancer cells are limited to cytotoxic high doses., Materials and Methods: In this study, human lung adenocarcinoma (A549) cells were α-irradiated using 241 Am α-irradiator and effects of low dose of alpha radiation on these cells was studied under in vitro and in vivo conditions., Results: Clonogenic and other assays showed increased cellular proliferation at lower doses (1.36 and 6.8 cGy) but killing at higher doses (13.6-54.4 cGy). Further studies at low dose of alpha (1.36 cGy) showed increased TGF-β1 in the conditioned medium (CM) at early time point (24 h) but CM replacement did not affect the clonogenic survival. In these cells, increased phosphorylation of connexin 43 was correlated with decrease in gap-junction communication observed by dye transfer co-culture experiment. A decrease in caveolin-1 but increase in survivin expression was observed in low dose α-irradiated cells. An increase in cyclinD1 and decrease in Bcl-2, the target proteins of survivin, was observed in these cells. Low dose α-irradiated cancer cells transplanted in SCID mice showed significantly higher tumor volume, which was accompanied with an increased fraction of mitotic and PCNA/Ki67 positive cells in these tumor tissues., Conclusions: Taken together, our results suggest an increase in proliferation and tumor volume at in vitro and in vivo levels, respectively, when A549 cells were irradiated with low dose of α-radiation. These findings may be relevant for a better understanding of radiobiological processes during high LET-based cancer radiotherapy.

In this study we aim to demonstrate the value of monoclonal Caveolin 1 expression in distinguishing between malignant pleural mesothelioma and pulmonary adenocarcinoma. Total of 129 cases, consisting of 68 cases of malignant pleural mesothelioma (51 epitheloid, 12 biphasic, and 5 sarcomatoid type) and 61 cases of pulmonary adenocarcinoma were examined and stained with monoclonal Caveolin-1. Caveolin 1 expression with a membranous and /or cytoplasmic pattern was detected only in 32.35% (n:22/68) of malignant pleural mesothelioma and 6.5% (n:4/61) of pulmonary adenocarcinoma cases. This finding suggests that the choice of poly/monoclonal antibody for Caveolin 1 in the differential diagnosis of malignant pleural mesothelioma and pulmonary adenocarcinoma is important.

Malignant mesothelioma (MM) continues to be a disease with poor prognosis and limited treatment options. Calretinin and caveolin-1 expression by tumour in MM have recently been described to be associated with tumour histology, differentiation and consequently survival. In a large, well annotated cohort, we studied both of these biomarkers and explored their association with clinicopathological parameters and survival. A retrospective search of patients with MM who underwent surgery at the Austin Hospital in Melbourne, Australia, was conducted. Clinical history and outcome data were retrieved from patient records. Tissue microarrays (TMAs) were constructed and stained for calretinin and caveolin-1. 'H scores' were derived, taking intensity and distribution of staining, and the cohort was dichotomised using median values for both markers. In the 329 patients evaluated, median age was 67 years. Males outnumbered females by 5:1. Epithelioid histology 202/319 (62.9%) was the most common, followed by biphasic 72/319 (21.8%) and sarcomatoid 45/319 (13.6%); histology could not be confirmed in 10 patients. Calretinin expression was detected in 246 of the 324 (76%) evaluable patients and high expression was associated with epithelioid histology (p < 0.0001). Caveolin-1 was expressed in 298 (94%) of 317 evaluable patients which was much higher compared to its expression in a cohort of lung adenocarcinomas (8/58, 13.7%). However, no association with histology was found (p = 0.409). When taken as a continuous variable, calretinin expression was found to be an independent predictor of survival, alongside histology, neutrophil-lymphocyte ratio, weight loss and stage. No prognostic value was demonstrable for caveolin-1 expression and calretinin/caveolin-1 ratio. There was no relationship between calretinin and caveolin-1 expression. In MM, increased calretinin expression is associated with epithelioid histology and better survival. Caveolin-1 is a sensitive MM marker and is expressed in a high proportion of cases but lacks association with histology and survival., (Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Caveolin-1 (Cav-1) may act as a prognostic biomarker in human cancers. This study is prepared to clarify the prognostic value of Cav-1 in patients with non-small cell lung cancer (NSCLC). All eligible articles from China National Knowledge Infrastructure, Pubmed, Highvire, and Science Direct systems were incorporated into this study. We extracted the patients' clinical characteristics and survival outcomes and performed a meta-analysis to demonstrate the prognostic role of Cav-1 and the correlations between Cav-1 expression and clinical characteristics. Thirteen articles met the inclusion/exclusion criteria. Cav-1 is deregulated in human lung cancers (NSCLC and small cell lung cancer) compared to noncancerous tissues (χ(2) = 200.478, p < 0.005), but the difference of expression level of Cav-1 is not significant (χ(2) = 2.248, p > 0.005) among different types of NSCLC, such as adenocarcinomas (ADs), squamous cell carcinoma (SCC) and miscellaneous cancers. Cav-1 expression could predict the poor prognosis of patients with NSCLC. The combined hazard ratio (HR, 95 % CI) was 2.00 (1.54, 2.60) for overall survival (OS) and 3.14 (1.68, 5.88) for progression free survival or disease free survival. The combined HR (95 % CI) of OS was 2.29 (1.26, 4.17) for ADs and 3.21 (1.69, 6.09) for SCC. The Cav-1 expression was associated with age, differentiation, primary tumor stage, tumor node metastasis stage, lymph node metastasis, chemotherapeutic response, and other clinical characteristics. We also analyzed the odds ratios of Cav-1 expression in AD and SCC patients by subgroups. Cav-1 plays a duplex role in tumorigenesis and tumor progression. Cav-1 may be another biomarker to predict the prognosis of lung cancers.

Background: Exposure to inadequate chemotherapy may alter cancer cell behavior including their metastatic potential. Because the molecular basis of such a phenomenon is largely unclear, we investigated the possible impact of cisplatin on anoikis response on human lung carcinoma cells., Materials and Methods: Using molecular and pharmacological tools, Caveolin-1 (CAV1) overexpressing and knock-down H460 cells were generated by stable transfection. The levels of CAV1 were determined by western blotting and reactive oxygen species (ROS) were detected by specific probes., Results: Sub-toxic concentrations of cisplatin suppressed anoikis response in H460 cells. The anoikis attenuation observed, was found to be caused by CAV1 up-regulation. Exposure to cisplatin induced superoxide anion and hydrogen peroxide generation; however, only hydrogen peroxide was found to be responsible for the CAV1 elevation., Conclusion: Exposure to cisplatin at sub-toxic concentrations induced hydrogen peroxide generation and the subsequent increase of ROS further regulated CAV1 levels and anoikis resistance. Our findings demonstrate a novel effect of cisplatin treatment on cancer cells which may lead to a better understanding of cancer biology and in the improvement of chemotherapy.

Background: Anoikis is a key inhibitory step in the process of cancer cell metastasis. Knowledge regarding the adaptive response resulting in resistance to anoikis may benefit the development of new therapies., Materials and Methods: Anoikis-resistant cells were generated from anoikis-sensitive lung carcinoma cells and the underlying mechanism for this process was investigated., Results: Culturing H460 cells under suspended conditions caused spontaneous generation of anoikis-resistant H&#95;AR1 and H&#95;AR2 cells. We found that anoikis resistance in these cells caused caveolin-1 (CAV1) up-regulation. Using short hairpin RNA (shRNA), we confirmed that depletion of CAV1 rendered anoikis-resistant H&#95;AR2 cells sensitive to anoikis. Furthermore, this study revealed that the acquisition of anoikis resistance induced CAV1 up-regulation through induction of CAV1 mRNA transcription., Conclusion: Our findings show CAV1 to be a key player in anoikis resistance and provide a novel mechanism regarding cancer cell adaptation, resulting in acquisition of anoikis resistance in lung cancer cells.

Caveolin-1 (cav-1) has been implicated in the development of human cancers. However, the distribution of cav-1 in non-small cell lung cancer (NSCLC) and its significance require further study. Real-time PCR and Western blot assays were performed to detect cav-1 mRNA and protein levels in tumor tissues (TT) and matched tumor-free tissues (TF). The protein expression in 115 paraffin-embedded blocks was examined by immunohistochemical staining (IHC). Correlations between cav-1 mRNA and protein expression by IHC and clinicopathological features were statistically evaluated. For the 136 patients examined, the levels of cav-1 mRNA and protein expression were significantly lower in lung TT compared to matched TF (P<0.05). High cav-1 expression was detected in 60 of 115 (52.2%) NSCLC tissues and this level was significantly lower than cav-1 expression in non-cancerous lung tissues (15 of 19, 78.9%, P<0.05). Up-regulation of cav-1 mRNA expression in lung adenocarcinoma (AC) (29.7%) was higher than that observed in lung squamous cell carcinoma (SCC) (15.8%). Statistical analysis of the correlation between cav-1 protein expression and clinical features showed a statistical association with poorer N-stage (P=0.032) and higher pathological TNM stage (P=0.012) in lung AC patients, that was not found in lung SCC patients. Moreover, lung AC patients with higher cav-1 expression showed significantly shorter life-spans than those with lower cav-1 expression (P=0.032, log-rank test). The levels of cav-1 mRNA and protein expression were significantly lower in lung cancers when compared to matched TF or non-cancerous lung tissues. The higher protein expression correlated with the advanced pathological stage and shorter survival rates in lung AC patients.

Caveolin-1 was up-regulated in different drug-resistant cancer cell lines and was suggested to confer drug resistance by different mechanisms. However, the relation of caveolin-1 expression and the clinical response to chemotherapy and prognosis in non-small cell lung cancer (NSCLC) remains unknown. Total 73 NSCLC (stages IIIB and IV) patients who received gemcitabine-based chemotherapy and also had tumour specimens available before treatment were assessed for caveolin-1 expression using immunohistochemistry. Immunoreactivity of caveolin-1 was correlated with the response to chemotherapy, the clinicopathologic features, and the progression-free survival (PFS) and overall survival (OS) of all patients. Positive caveolin-1 immunostaining was found in 12 (16.4%) of the 73 patients. Eight of the twelve had disease progression and the other four patients remained stable after chemotherapy. Patients with caveolin-1 expression had a significantly lower response rate (complete or partial response, 0% versus 37.7%; P=0.01) and a poor PFS and OS (median survival time: PFS, 4.6 months versus 6.1 months, P=0.005; OS, 7.0 months versus 14 months, P<0.001) than those without caveolin-1 expression. Moreover, multivariate analyses indicated that caveolin-1 positivity was an independent prognostic factor for disease-free survival (DFS) (P=0.003) and OS (P=0.008), respectively. Caveolin-1 expression significantly correlated with drug resistance and a poor prognosis in advanced NSCLC patients treated with gemcitabine-based chemotherapy.

The objectives of this study were firstly to compare the immunostaining patterns of antibodies against caveolin-1, thyroid transcription factor-1 (TTF-1), cytokeratin 7 (CK7) and cytokeratin 20 (CK20) in primary and secondary pulmonary adenocarcinomas of breast or colonic origin, and secondly, to investigate their use alone and in combination, in distinguishing between primary and secondary lung adenocarcinomas from breast or colonic origin. Of the 49 lung adenocarcinoma specimens that were enrolled in this study, 30 were primary pulmonary adenocarcinomas, and 19 (9, breast origin; 10, colonic origin) were metastatic pulmonary carcinomas. Immunohistochemical staining was used to detect the expression of caveolin-1, TTF-1, CK7, and CK20. Primary pulmonary adenocarcinoma most often had the CK7-positive/CK20-negative immunohistochemical phenotype and was either TTF-1 positive or caveolin-1 negative. Secondary pulmonary adenocarcinoma of breast origin most often had the CK7-positive/CK20-negative immunohistochemical phenotype and was either TTF-1 negative or caveolin-1 positive, while secondary pulmonary adenocarcinoma of colonic origin most often had the CK20-positive/CK7-negative immunohistochemical phenotype and was either TTF-1 negative or caveolin-1 positive. The results suggest that caveolin-1, TTF-1, or CK7/CK20 alone did not distinguish reliably between primary and secondary pulmonary adenocarcinomas originating from breast or colon. The use of a panel of antibodies that includes TTF-1, caveolin-1, and CK7/CK20 may have higher sensitivity in discriminating between primary adenocarcinomas and metastatic lung adenocarcinomas from breast or colonic origin.