APLN/APLNR Signaling Controls Key Pathological Parameters of Glioblastoma

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM-expansion depends on a dense vascular network and, coherently, GBMs are highly angiogenic. However, new intratumoral blood vessels are often aberrant with consequences for blood-flow and vascular barrier function. Hence, the delivery of chemotherapeutics into GBM can be compromised. Furthermore, leaky vessels support edema-formation, which can result in severe neurological deficits. The secreted signaling peptide Apelin (APLN) plays an important role in the formation of GBM blood vessels. Both APLN and the Apelin receptor (APLNR) are upregulated in GBM cells and control tumor cell invasiveness. Here we summarize the current evidence on the role of APLN/APLNR signaling during brain tumor pathology. We show that targeting APLN/APLNR can induce anti-angiogenic effects in GBM and simultaneously blunt GBM cell infiltration. In addition, we discuss how manipulation of APLN/APLNR signaling in GBM leads to the normalization of tumor vessels and thereby supports chemotherapy, reduces edema, and improves anti-tumorigenic immune reactions. Hence, therapeutic targeting of APLN/APLNR signaling offers an interesting option to address different pathological hallmarks of GBM.

Keywords: APLNR; Apelin (APLN); Glioblastoma (GBM); angiogenesis; invasion; pericytes; tumor associated myeloid cells (TAM); tumor microenvironment (TME); tumor parenchyma; vascular normalization.

Figure 1

APLN/APLNR upregulation in primary GBM. In situ hybridization (ISH) against APLN or APLNR mRNA was performed on horizontal sections in a GBM implantation model (A) using murine proneural-like p53^KOPDGFB GBM cells [42] or in patient primary GBM samples (B). (A) The picture on the left shows the aggressively invasive tumor (Tu) as stained by H&E, the arrowhead points to the invasive tumor border. The pictures on the right indicate APLN or APLNR mRNA (in pink) in tumor vessels (arrows) and tumor cells (arrowheads) using APLN/APLNR antisense ISH probes. (B) Patient biopsies were stained by H&E and APLN ISH was performed on consecutive sections. Note that APLN expression is high in vascular proliferates (arrows) and in the neighboring hypoxic areas of pseudopalisading necroses (asterisks). Micrographs of Figure 1B are adapted from Mastrella et al., 2019 [42]. Scale size is indicated in individual micrographs.

Figure 2

APLNR expression in neurons and astrocytes of the GBM-bearing mouse. Expression levels of APLNR in a healthy brain are compared to the immunoreactivity found in U87MG tumor cells. Magnifications and the region of the healthy brain structures are indicated in the individual panels.

Figure 3

The multimodal action of APLN/APLNR targeting therapy in GBM. In phase 1 of the disease, DEX treatment improves neurological symptoms; after resection, DEX may reduce options for targeted therapy (e.g., immunotherapy) in phase 2. In phase 3, during chemotherapy and tumor recurrence, DEX shows no change. For Apelin-F13A (F13A) therapy, there is evidence that it could improve life quality by reducing edema, that anti-angiogenic combination treatment moderately increases survival, and that vascular normalization could improve temozolomide chemotherapy.