Divergent Expression of Caveolin1 in Human Cancer The Case of Lung Cancer

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The expression of caveolin-1 in different cancer cell lines and tumor samples was documented in numerous studies, and the picture that emerges from these studies is that caveolin-1 expression is highly divergent [6]. Whereas in many cases caveolin-1 expression is down-regulated, in other cancer cells elevated caveolin-1 levels are maintained. High expression of caveolin-1 in cancer cells was initially demonstrated in human multidrug resistant (MDR) cancer cells [43-45] and in mouse metastatic prostate cancer cells [46]. Evidence that has accumulated since these early studies seems to indicate that the expression of caveolin-1 often depends on the tumor's stage and grade. In fact, in most cases where this relationship was examined explicitly, a positive correlation was found between a high expression of caveolin-1 and advanced tumor cell grade and/or progression stage. Such was the case in cancers from the breast [46], prostate [46,47], lung [48,49], bladder [50], kidney [51,52] and pancreas [53,54]. Furthermore, in some cases, high expression of caveolin-1 was shown to be an independent predictor of poor disease prognosis [47,49,51-53,55-58].

The divergent pattern of caveolin-1 in human cancer is well represented in studies of lung cancer tumors and cell lines. Human lung adenocarcinoma- and small cell carcinoma-derived cell lines exhibited little or no caveolin-1 expression, in contrast to high levels of caveolin-1 expression observed in CaLu-1 lung squamous carcinoma cells [59]. However, when compared with normal human lung epithelia, four other lung squamous cell carcinoma lines expressed reduced levels of cav-eolin-1 [60]. In another study, low-level caveolin-1 expression was similarly found in cell lines derived from two lung adenocarcinomas, a bronchioalveolar carcinoma and a large-cell lung carcinoma, whereas non-small-cell lung carcinoma cell lines (Hop-62, Hop-92) highly expressed caveolin-1 [61]. More recently, it was found that about 95 % of small-cell lung cancer (SCLC) cell lines exhibit low or no caveolin-1 expression, whereas a majority (76%) of non-SCLC lines retained high caveolin-1 expression [62].

The loss of caveolin-1 expression in SCLC and in primary non-SCLC was verified immunohistochemically in tumor samples [63,64]. Caveolin-1 expression was reported to be positively correlated with metastatic potential in a series of lung adenocarcinoma cell lines established by selection for increasing invasiveness [48]. The same study found that primary lung adenocarcinoma tumors are largely cav-eolin-1-negative, but there was a significant trend of increased caveolin-1 expression in metastatic lung tumors and in their lymph nodes metastases [48]. Caveolin-1 was prominently down-regulated in primary lung adenocarcinomas, as revealed by DNA microarray analysis [65,66].

Nevertheless, ~25% of lung adenocarcinomas still expressed high levels of caveolin-1 protein, although this study found no correlation of caveolin-1 expression with tumor stage or lymph node status [63]. Other analyses of primary lung squamous cell carcinoma specimens revealed that 26-30% were caveolin-1-posi-tive [49,67]. In these studies there was a significant correlation between caveolin-1 expression and advanced pathologic stage [49,67].

Furthermore, there was a statistically significant decrease in five-year survival after complete resection of patients with caveolin-1-positive tumors [49]. Together, the above data are consistent with a suppression of caveolin-1 gene expression in primary lung tumors (in particular, SCLC). However, some lung tumors and lung cancer cell lines are caveolin-1-positive (notably non-small cell lung carcinoma), and there seems to be a positive correlation between caveolin-1 expression and advanced cancer pathologic stage or metastatic potential. Thus, the status of caveolin-1 in lung cancer is as complex as it is in other forms of cancer.

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