Increased CAV1 expression has been reported to be associated with progression of papillary carcinoma of the thyroid, high-grade bladder cancer, poor prognosis of pancreas cancer, and lymph node metastasis in esophageal squamous cell carcinoma. Moreover, increased CAV1 expression has been reported to be associated with various pathological parameters, including higher Gleason score in prostate cancer, lymph node metastasis and positive surgical margins, and it has been shown to be an independent prognostic marker for progression in clinically localized prostate cancer [23
]. These studies indicate that CAV1 functions as a tumor metastasis and progression-promoting molecule. On the other hand, CAV1 has also been implicated in the inhibition of cancer progression. For example, CAV1 expression is frequently lost in colon cancer, ovarian cancer, lung cancer and sarcoma [9
]. Therefore, the physiological role of CAV1 in cancer cells is quite complicated depending e.g. on the type of cancer and the tumor origin. Several studies using tissue microarry (TMA) and immunostaining have shown similar associations between the increased expression of CAV1 and clinicopathological parameters in RCC as described in prostate cancer. A major difference between prostate and kidney tissue is that CAV1 is present at high levels in normal kidney tissue independent of CAV1 levels in tumor tissue but not in normal prostate tissue [23
Several groups of investigators have studied the prognostic significance of caveolin-1 protein expression. Horiguchi et al. [28
] reported that in clear cell RCC patients increased caveolin-1 expressions also correlated with tumor aggressiveness. Campbell et al. [13
] also described that higher caveolin-1 expression was correlated with shorter survival in 69 patients with clear cell histology.
Previously, we were able to show that CAV1
mRNA expression is higher in RCC compared to normal renal tissue and increases with tumour stage [29
]. In the present study, which until today is the largest study cohort with a sufficient follow-up period, Caveolin 1 protein expression was correlated with clinico-pathological parameters and survival in patients with clear cell RCC. Kaplan-Meier analysis disclosed significant differences in overall and tumor specific 5-year survival for patients with higher and lower than average cytoplasmic CAV1 expression levels, i.e. 51.4% vs. 75.2% for overall survival and 55.3% vs. 80.1% for disease specific survival, respectively. This supports the hypothesis that CAV1 plays a potential role in renal carcinogenesis or at least RCC progression. In contrast, a study by Tamaskar et al. with 22 RCC patients there was no correlation between membranous or cytoplasmic caveolin-1 expression and other clinical parameters, with membranous caveolin-1 expression being detected predominantly in clear cell RCC. Mete et al. [30
] studied 112 renal tumors with different histological subtypes also using polyclonal rabbit antihuman CAV1 antibody and observed that staining was mainly cytoplasmic in all tumor groups. Also Campbell et al. [13
] showed in that staining is predominantly found in the tumor cell cytoplasm of RCC patients. We were able to confirm these results as CAV1 expression was detected in the tumor cell cytoplasm of 242 (83.7%) and the cell membrane of 232 (80.3%) patients with clear cell RCC, the cell nuclei were negative in all patients' tumor specimens. Furthermore, high CAV1 protein expression level in the tumor cell cytoplasm could be identified as an independent poor prognostic marker.
The reasons for these findings are still unclear, as CAV1 expression would be expected to be mainly found on the cell surface. Tahir et al. [31
] where able to show that in prostate cancer cell lines CAV1 is secreted in response to androgens and glucocorticoids leading to survival and clonal growth of these cells and thereby contributing to their metastatic potential and androgen insensitivity. Tahir et al was able to show that elevated preoperative levels of serum CAV1 predicts decreased time to cancer recurrence [32
]. Adapted from these results, one explanation for the cytoplasmatic expression of CAV1 in clear cell RCC might be that within the transformed cells, CAV1 is rerouted into the secretory pathway of these cells, and that the cytoplasmatic CAV1 accumulation may contribute to the transformed phenotype. Furthermore, Puyraimond et al. [33
] have shown that CAV1 interacts and potentiates the activity of metalloproteinases; other studies have shown the same effect on urokinase receptors leading to the conclusion that CAV1 may serve as an important intercellular signaling molecule that is capable of inducing progression, invasiveness and vascularisation of renal tumors.
A further important fact is that the etiology of most cancers does not reflect alterations in a single gene, but rather the functional loss or induction of a series of key regulatory proteins that, in combination, disrupts the normal regulation of the cell cycle and subsequently leads to uncontrolled cell growth [34
]. CAV1 has been recognized to potentiate AKT activity in a variety of model systems. Campbell et al. [35
] revealed that when CAV1 is co expressed with pAKT, pmTOR, pS6 or p4E-BP1 within the primary tumor, time to relapse was significantly reduced compared with when either of the individual variables were expressed alone. They have suggested that the co expression of CAV1 and activated components of the AKT/mTOR pathway represents a 'linked molecular signature' that identifies patients with localized RCC that are at high risk of developing metastatic disease that warrants greater postoperative surveillance. Evaluation of the expression status of both CAV1 and mTOR pathway components in these tumors may help to predict tumor response to novel pathway specific therapies, hence allowing appropriate selection of treatment for individual patients. Interestingly, CAV1 has been identified as a molecular target of bortezomib, which has many molecular targets including proteins related to apoptosis, growth signaling/cell cycle heat-shock proteins, and the proteasome pathway. A Phase II trial in patients with advanced RCC showed moderate clinical efficacy for bortezomib [36