Date Published: April 10, 2018
Author(s): Wladimir Gerstenberger, Michaela Wrage, Eeva Kettunen, Klaus Pantel, Sisko Anttila, Stefan Steurer, Harriet Wikman.
The expression of caveolin-1 (CAV1) in both tumor cell and cancer-associated fibroblasts (CAFs) has been found to correlate with tumor aggressiveness in different epithelial tumor entities, whereas less is known for caveolin-2 (CAV2). The aim of this study was to investigate the clinicopathological significance and prognostic value of stromal CAV1 and CAV2 expression in lung cancer. The expression of these two genes was investigated at protein level on a tissue microarray (TMA) consisting of 161 primary tumor samples. 50.7% of squamous cell lung cancer (SCC) tumors showed strong expression of CAV1 in the tumor-associated stromal cells, whereas only 15.1% of adenocarcinomas (AC) showed a strong CAV1 expression (p < 0.01). A strong CAV2 stromal expression was found in 46.0% of the lung tumor specimens, with no significant difference between the subtypes. Neither CAV1 nor CAV2 stromal expression was associated with any other clinicopathological factor including survival. When the stromal expression in matched primary tumors and lymph node metastases was compared, both CAV1 and CAV2 expressions were frequently found lost in the corresponding stroma of the lymph node metastasis (40.6%, p = 0.003 and 38.4%, p = 0.001, resp.). Loss of stromal CAV2 in the lymph node metastases was also significantly associated with earlier death (p = 0.011). In conclusion, in contrast to the expression patterns in the tumor tissue of lung cancer, stromal expression of CAV1 in primary tumors was not associated with clinical outcome whereas the stromal expression of especially CAV2 in the metastatic lymph nodes could be associated with lung cancer pathogenesis.
Caveolin-1 (CAV1) and caveolin-2 (CAV2) are integral membrane proteins found in the outer cell membrane called caveolae and in other intracellular membranes of the endoplasmic reticulum, Golgi apparatus, and transport vesicles [1, 2]. Both proteins are also found as soluble proteins [2, 3] and are expressed in fibroblasts, endothelial cells, lipocytes, and in type I pneumocytes [4, 5]. They are involved in various mechanisms like membrane trafficking as well as signal transduction and gene regulation of cell growth and apoptosis [2, 6–8]. Caveolins have also been implicated in many processes involved in cancer initiation and metastasis [6, 9]. It has been shown that CAV1 may possess both tumor suppressing and oncogenic functions, depending on progress and tumor type . In early stages of the disease, CAV1 has been shown to function mainly as a tumor suppressor, whereas at later stages, CAV1 expression has been associated with progression and metastasis [6, 11]. The role of CAV2 in carcinogenesis is less well documented. In our previous study, we analyzed the expression of both proteins in primary tumors from lung cancer patients . Loss of CAV1 protein expression was detected in 48% of the tumors, whereas 28% of the tumors did not express CAV2. CAV2 protein expression correlated with shorter survival whereas no such association was found for CAV1 .
Caveolins are known to play an important role in tumor initiation and progression. Several publications have already investigated the association between caveolin expression in primary and metastatic lung tumor tissue and cancer outcome [35–44]. In the last decades, it was shown that the cancer stroma has an important influence on tumor behavior. Whereas in the tumor tissue, high caveolin expression has usually been associated with a poor outcome; also, in other tumor entities, the inverse association has been found in cancer-associated stromal tissue [15–25].