gms | German Medical Science

Objective: Caveolae are 50-100 nm large uncoated invaginations of the plasma membrane which exist in numerous tissue types. The major protein component of Caveolae is Caveolin (Cav), a 21-24 kDa integral membrane protein. Several members of the Caveolin gene family have been identified, namely Cav-1, Cav-2 and Cav-3. In contrast to Cav-1 and -2 which are expressed in a wide variety of tissues, Cav-3 was predominantly described in muscle fibers. However, several reports demonstrated the expression of Cav-3 within cells of the brain, mainly glial fibrillary acidic protein (GFAP) positive astrocytes. Caveolins play an important role in a variety of cellular functions including endocytosis, calcium signalling and different signal transduction events. They directly regulate the Caveolae-localized tyrosine kinase receptor, the epidermal growth factor receptor (EGFR). A hallmark of high grade gliomas is EGFR overexpression and recent studies demonstrated a strong inhibitory effect of Cav-1 on EGFR. So far nothing is known about the expression of Cav-3 within gliomas.

Method: In the present study we examined expression pattern of Cav-3 in 40 glioma brain biopsies. Out of these 10 were glioblastoma WHO grade IV, 10 were anaplastic astrocytoma WHO grade III, 10 were diffuse astrocytoma WHO grade II and 10 were pilocytic astrocytyoma WHO grade I. In a human glioblastoma-derived cell line U87MG the effect of Cav-3 on EGFR was analyzed using immunoblots, qPCR and proliferation assays.

Results: We found high Cav-3 expression in 80% (16 out of 20) of low-grade gliomas (WHO grade I and II) and in 11% (2 out of 20) of high-grade gliomas (WHO grade III and IV). The high-grade gliomas with low levels of Cav-3 showed high levels of EGFR. Moreover, the expression of Cav-3 and EGFR was mutually exclusive in these gliomas. After transfection with Cav-3, U87MG cells which express EGFR showed reduced levels of EGFR and decreased activation of downstream signaling factors. Accordingly, in these cells reduced proliferation was observed.

Conclusions: Cav-3 negatively regulates cell growth due to its inhibitory effects on EGFR and its transduction factors. This correlates with the observation that high-grade gliomas with low levels of Cav-3 show high expression of EGFR. Taken together, these findings suggest Cav 3 as an effective biomarker pointing out gliomas with low EGFR-levels. Moreover this study could help to develop a drug mimicking Cav-3 to elevate the impact of EGFR-targeted therapies.