Cancer Stem Cell-Specific Scavenger Receptor CD36 Drives Glioblastoma Progression

Abstract

Glioblastoma (GBM) contains a self-renewing, tumorigenic cancer stem cell (CSC) population which contributes to tumor propagation and therapeutic resistance. While the tumor microenvironment is essential to CSC self-renewal, the mechanisms by which CSCs sense and respond to microenvironmental conditions are poorly understood. Scavenger receptors are a broad class of membrane receptors that are well characterized on immune cells and instrumental in sensing apoptotic cellular debris and modified lipids. Here we provide evidence that CSCs selectively utilize the scavenger receptor CD36 to promote their maintenance using patient-derived CSCs and in vivo xenograft models. We detected CD36 expression in GBM cells in addition to previously described cell types including endothelial cells, macrophages and microglia. CD36 was enriched in CSCs and was able to functionally distinguish self-renewing cells. CD36 was co-expressed with integrin alpha 6 and CD133, previously described CSC markers, and CD36 reduction resulted in concomitant loss of integrin alpha 6 expression, self-renewal and tumor initiation capacity. We confirmed that oxidized phospholipids, ligands of CD36, were present in GBM and found that the proliferation of CSCs, but not non-CSCs, increased with exposure to oxidized low-density lipoprotein. CD36 was an informative biomarker of malignancy and negatively correlated to patient prognosis. These results provide a paradigm for CSCs to thrive by the selective enhanced expression of scavenger receptors, providing survival and metabolic advantages.

The role of cancer stem cells in glioblastoma

“…47,66 Additional biomarkers that have been studied in GBM include CD15, CD36, A2B5, L1CAM, CD44, and CXCR4. 2,6,24,35,47,51,73,78,95 Although these markers are useful in furthering our understanding of CSC function and regulation and may be involved in targets for therapies against CSCs, no single marker can definitively identify or define CSCs (Table 1).…”

Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

“…As such, malignant glioma regrowth following alkylating agent therapy (temozolomide) in mice is due to the relative resistance of CSCs to this agent (Chen et al, 2012). Moreover, many of the markers expressed by CSCs also serve as independent predictors of survival in patients with these malignancies (Hale et al, 2014; Lathia et al, 2014; Pietras et al, 2014). …”

Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization

“…Indeed, selective targeting seems feasible as it was found with isolated rat cardiomyocytes that sulfo-N-succinimidyl oleate (SSO) does block CD36-mediated palmitate uptake while both hexarelin, a synthetic growth-hormone releasing peptide that binds to CD36, and EP 80317, a CD36 selective ligand that inhibits cholesterol transport, each had no effect on palmitate uptake (47). Still, intervening in the CD36 subcellular recycling machinery is expected to allow a more specific approach because, in general, the proteins involved in vesicular trafficking occur in tissue-specific types.A final interesting direction of CD36 research is the field of cancer and metastasis, as there is emerging evidence that in certain types of cancer, CD36 expression drives tumor progression by increasing the availability of fatty acids and lipids (e.g., see (78,79)). In addition, in a recent study Pascual and co-workers (80) observed that a subpopulation of cancer cells with unique metastasis-initiating potential could be marked by CD36, highlighting a key role of lipid metabolism in metastatic colonization.…”