Functional invadopodia formed in glioblastoma stem cells are important regulators of tumor angiogenesis

Abstract

Glioblastoma (GBM) represents the most common and lethal brain tumor. High vascularization, necrosis and invasiveness are hallmarks of GBM aggressiveness with recent data suggesting the important role of glioblastoma stem cells (GSCs) in these processes. It is now well established that cancer cells employ specialized structures termed invadosomes to potentiate invasion. However, the role of these structures in GBM dissemination remains poorly investigated. In this study, we showed that GBM-isolated GSCs form invadopodia-like protrusions endowed with degradative action. Interestingly, their formation depends on extracellular matrix (ECM) sensing via the CD44 receptor. We also found that GSCs invasive migration occurring during tubes assembly is promoted through invadopodia-mediated-ECM remodeling and LIM kinases signaling. Moreover, our study demonstrates that GSCs are highly adaptable cells that are able not only to restore damaged endothelial-derived tubes but also to generate in cooperation with normal endothelial cells (ECs) intact vascular channels. Taken together, our data provide new insights in GBM microvasculature and suggest that GSCs targeting in combination with anti-VEGF therapy may block tumor progression.

Podoplanin in Inflammation and Cancer

“…Interestingly, CD44 was also identified as a component of invadopodia in breast cancer cells, where it appears to be involved in their formation and recruitment of MMP14 [220,221]. In addition, CD44 was implicated in the formation of invadopodia-like protrusions in glioblastoma CSCs by mediating ECM sensing [222]. Since glioblastoma CSCs express podoplanin [180,181], CD44 is present in SCCs [33], and podoplanin binds both CD44 [33] and MMP14 [211] at the surface of cancer cells, it should be of great interest to explore the role of the podoplanin–CD44 interaction in invadopodia assembly and maturation, and the recruitment of MMP14 to these membrane structures.…”

Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells

“…It rarely metastasises outside the brain but actively migrates through two types of extracellular spaces in the brain: The perivascular space around all blood vessels, and spaces between the neurons and glial cells (2). In order to invade through these spaces, GBM cells have to undergo several biological changes, including gaining mobility, the ability to degrade the extracellular matrix (EcM) and the ability to acquire stem cell phenotype (4). Invasion involves a complicated mechanism comprising cross-talk between canonical pathways in cancer (2).…”

TKS5-positive invadopodia-like structures in human tumor surgical specimens

“…Invadopodia are cancer cell protrusions with localized pericellular proteolytic activity (Chen 1989). These structures are functionally linked to processes involving active extracellular matrix remodeling, such as invasive migration (Murphy and Courtneidge, 2011), proliferation in a three-dimensional protein matrix (Blouw et al, 2015;Iizuka et al, 2016), and angiogenesis (Petropoulos et al, 2018;Blouw et al, 2008). Accordingly, invadopodia are regulated in vitro by proinvasive signals such as EGFR ligands and TGFβ (Diaz et al, 2013;Zhou et al, 2014;Mandal et al, 2008), adhesion to the extracellular matrix (Branch et al, 2012), hypoxia (Diaz et al, 2013;Lucien et al, 2011;Hanna et al, 2013), and extracellular matrix rigidity (Alexander et al, 2008) among other signals.…”