An expanded role for Caveolin-1 in brain tumors.

Glioblastoma multiforme (GBM) arises from cells in the brain called astrocytes and can form in many different parts of the brain, including the cerebellum and spinal cord. GBM is both the most frequent and also the most deadly adult brain tumor, with an incidence rate of between two to three per 1,000 people. Post-surgical standard of care usually consists of radiation combined with temozolomide and dexamethasone. However, even with aggressive intervention, GBM continues to be an aggressive, progressive disease with extremely high mortality rates. Because of the severity of the disease and the poor median and overall survival statistics for GBM patients, the need for identifying new and more effective targets and pathways to treat GBM is obvious and critical.

Caveolae are submicroscopic invaginations found in the cell membranes of a variety of tissue types and play an ever-expanding role in multiple cellular processes. The predominant structural components of caveolae is the trans-membrane-bound protein caveolin-1 (Cav-1). Cav-1 has been extensively studied and its activities characterized in a number of cancers, for which it has been shown to function as either a tumor suppressor or tumor promoter depending on tissue type and the underlying cellular proteome.

Cav-1 has only recently received increased attention in the brain cancer field, with approximately 25 published papers appearing in PubMed on Cav-1 and human brain cancers. The in vitro characterizations of the role of Cav-1 in GBM have largely been undertaken by Martin and colleagues, where Cav-1 was identified it as a tumor suppressor, affecting proliferation in part through modulating TGFB/SMAD signaling.

In a new study, Quann et al. expanded upon this previous work by creating a stable Cav-1-overexpressing cell line based on the common GBM-derived cell line U-87MG. Microarray analyses comparing Cav-1-overexpressing cells to control cells established that critical cell cycle genes and cell survival proteins and pathways, such as cyclin D1 and AKT/mTOR, respectively, were downregulated. Perhaps more importantly, using a mouse xenograft model, they found that Cav-1-overexpressing tumors were significantly less proliferative and less invasive when compared with control cells, with explanted tumors displaying marked silencing of cell cycle and protein biosynthetic pathways. Finally, Cav-1-overexpressing cells were found to be sensitized to the antitumor effects of the most commonly used chemotherapy agent, temozolomide, and were significantly more likely to undergo apoptosis after treatment as compared with controls cells. These results extend the role of Cav-1 into the prognosis and possibly the treatment of GBM.

Interestingly, one of the most frequent point mutants in GBM occurs in the tumor suppressor protein, p53. In certain p53-mutant tumors, glucose restriction, which induces oxidative stress, resulted in activation of autophagy and an autophagy-dependent degradation of mutant p53, leading to a feedforward acceleration of autophagy and tumor inhibition. Furthermore, in the tumor stroma, Cav-1 expression has been found to be similarly downregulated by oxidative stress when autophagy was activated, which, in turn, resulted in a feedforward upregulation of stromal autophagy. Termed the “reverse Warburg effect,” this tumor microenvironment is defined by enhanced stromal aerobic glycolysis, oxidative stress and localized inflammation, which, in turn, promotes tumor cell survival through cancer cell parasitism of nutrients released from the autophagic stromal cells. Collectively, these results suggest that the expression levels of Cav-1, and certain mutant forms of p53, may be regulated in a similar fashion by autophagy, leading, however, to different phenotypic outcomes depending upon whether their expression occurs in the tumor or in the stromal component. Thus, it will be very important to determine whether and how Cav-1 and mutant forms of p53 cross-talk with the stroma and define their relationship with autophagy and the metabolism of tumor cells.

While the current study was limited to one cell line and an ectopic xenograft mouse model, the observations are extremely interesting, and further investigations are clearly warranted and encouraged. Given the great advances in mouse modeling of brain malignancies and the recent focus on perfecting non-invasive imaging of drug sensitivity/responses, it is likely that more dynamic and comprehensive investigations into Cav-1 as an etiological mediator of GMB progression and treatment will be forthcoming. (Fig. 1)

Figure 1. Caveolin-1 plays a central role in Glioblastoma multiforme onset and progression and may be a biomarker for sensitivity to chemotherapy. Red lines denote genes or pathways inhibited by Cav-1, while green lines indicate those that are upregulated.