Cytoskeleton protein adducin 3 dysregulation in modulating tumor growth and angiogenesis in glioblastoma multiforme

Abstract

Among the primary malignancies in the central nervous system, glioblastoma multiforme (GBM) is the most aggressive subtype in adults. Although current multimodal therapy offers survival advantage, GBM almost invariably relapses. In contrast to the growing knowledge on cancer-specific signaling pathways, relatively less is known about the fundamental molecular basis that underlies the rapid disease progression and highly invasive behaviour of GBM.

The actin cytoskeleton represents the basic apparatus in modulating cell growth and survival signals while also acting as the basic engine in driving cell motility. As such, dysregulation of the actin cytoskeleton has been implicated in cancer pathogenesis. Several studies have reported aberrant expression of an important actin interacting protein, namely adducin 3 or -adducin (ADD3), in different types of cancers. However, the role of ADD3 in cancer remains controversial and its role in determining GBM malignant phenotypes is unclear.

In this study, this candidate had first confirmed downregulation of ADD3 in human GBM, but not in less malignant gliomas, when compared to its normal controls, suggesting that actin-remodeling might represent a critical event in malignant progression of GBM. Moreover, ADD3 expression level was found to be of prognostic significance in predicting GBM patient survival. To validate whether ADD3 acts as a tumor suppressor in GBM, the candidate hypothesized that ADD3 gain-of-function would suppress tumor growth and abrogate the malignant phenotypes, whereas ADD3 loss-of-function would have oncogenic effects.

Preliminary studies yielded contradictory results. On the one hand, although ADD3 depletion resulted in morphological alterations of cytoskeletal re-organization and generation of multinucleated cell population, it did not yield the anticipated findings on functional assays - ADD3 depletion was found to have tumor-suppressive effects in vitro. On the other hand, in vivo findings were consistent with the candidate’s initial hypothesis in that ADD3-depletion would promote tumor growth in both subcutaneous and orthotopic xenograft mice models. The discrepancies observed between a simple cell-based system and in vivo animal model suggested a possible interplay between tumor microenvironment and ADD3 functions. Indeed, further studies revealed that GBMs with ADD3 deficiency were associated with alterations in extracellular matrix (ECM)-protein profile that favoured angiogenesis and epithelial mesenchymal transition (EMT). Consistently, ADD3 depletion was associated with a significant increase in intratumoral blood vessel density and diameter. Furthermore, it was found that ADD3 deficient GBM cells were able to elicit pro-angiogenic signals to stimulate endothelial cells in both ECM-dependent and ECM-independent manner, possibly through -catenin- and LOX-mediated pathways, thus providing growth advantage. This study provides the first in vivo evidence on the putative tumor suppressive role of ADD3 in modulating GBM growth and angiogenesis. It also provides possible explanations on the current controversies between different reported studies and novel insights into the translational implications of targeting the cytoskeleton for the treatment of malignancies. It would deserve further investigations into the mechanisms of cytoskeletal dysregulation-mediated cancer progression.