Laminin alpha 2 enables glioblastoma stem cell growth

Abstract

Objective Glioblastomas (GBMs) are lethal cancers that display cellular hierarchies parallel to normal brain. At the apex are GBM stem cells (GSCs), which are relatively resistant to conventional therapy. An important driver of malignancy and self-renewal in GSCs are interactions with the adjacent perivascular niche. Extracellular matrix (ECM) cues instruct neural stem/progenitor cell-niche interactions and the objective of our study was to elucidate its composition and contribution to GSC maintenance in the perivascular niche. Methods We interrogated human tumor tissue for immunofluorescence analysis and derived GSC from tumor tissues for functional studies. Bioinformatics analyses were conducted by mining publicly available databases. Results We find that laminin ECM proteins are localized to the perivascular GBM niche and inform negative patient prognosis. To identify the source of laminins, we characterized cellular elements within the niche and found that laminin α chains were expressed by non-stem tumor cells and tumor associated endothelial cells (ECs). RNA interference targeting laminin α2 inhibited GSC growth and self-renewal. In co-culture studies of GSCs and ECs, laminin α2 knockdown in ECs resulted in decreased tumor growth. Interpretation Our studies highlight the contribution of non-stem tumor cell-derived laminin juxtracrine signaling. As laminin α2 has recently been identified as a molecular marker of aggressive ependymoma, we propose that the brain vascular ECM promotes tumor malignancy through maintenance of the GSC compartment providing not only a molecular fingerprint but also a possible therapeutic target.

Cerebrospinal fluid and serum IL-8, CCL2, and ICAM-1 concentrations in astrocytic brain tumor patients

“…Moreover, enhanced secretion of IL-8 by glioma cells was also reported by Yeung et al [29]. IL-8 was also inversely correlated with GBM patients' survival [30]. GBM cells, which secrete IL-8, promote angiogenesis and microvascular endothelial permeability [9].…”

Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy

“…For instance, non-CSCs support the tumor vasculature (Cheng et al 2013), secrete extracellular matrix components (Lathia et al 2012), and provide survival signals back to enhance CSC maintenance ). This suggests that within a given tumor, there is a balance of differentiation and self-renewal to continuously generate differentiated progeny while maintaining the CSC population.…”

“…Differentiated cell populations are not strictly responsible for tumor propagation, but these cells may serve as components of the microenvironment to maintain the CSCs, suggesting a potential drive toward continuous creation of a hierarchy. In brain tumors, differentiated tumor cells secrete cytokines such as interleukin-6 ) and extracellular matrix (laminins) (Lathia et al 2012) that stimulate CSC survival and tumor growth. A similar relationship is found in the normal colon, where Lgr5-positive crypt cells act as a highly proliferative stem cell pool in direct proximity with CD24 + Paneth cell progeny that provide ligands for stem cell proliferation (Sato et al 2011).…”

Brevican knockdown reduces late-stage glioma tumor aggressiveness

“…This portends a unique interaction between glioma cells, the TME and the normal brain environment facilitates glioma invasion. The TME also provides a niche for establishing and maintaining the heterogeneity of cellular subpopulations within glioma tumors, including the treatment-resistant glioma initiating cell (GIC) population [5–7]. The broad functionality of the glioma TME in mediating aspects of glioma progression makes it an attractive therapeutic target [8].…”