The Multifaceted Therapeutic Role of the Low-Density Lipoprotein Receptor Family in High-Grade Glioma

Academic Background

High-grade gliomas (HGG) are the most aggressive and prevalent primary brain tumors in the central nervous system (CNS), accounting for approximately 80% of all malignant brain tumors. Among them, glioblastoma (GBM) is the most malignant form, with a median survival of only 12 months. The poor prognosis of GBM is mainly attributed to the blood-brain barrier (BBB), which hinders the entry of therapeutic drugs into the tumor site. Therefore, identifying drug delivery systems that can effectively cross the BBB and target tumor signaling pathways is crucial.

The low-density lipoprotein receptor family (LDLR) plays a critical role in maintaining CNS health and is implicated in neurological diseases or cancer. The high expression of LDLR family members in tumor cells is closely related to the pathophysiology and progression of tumors. This review explores the multifaceted roles of the LDLR family in high-grade gliomas, delving into its molecular mechanisms in tumorigenesis, proliferation, migration, and invasion, and evaluates its potential as a therapeutic target.

Source of the Paper

This paper was co-authored by Elisa Mastrantuono, Matilde Ghibaudi, Diana Matias, and Giuseppe Battaglia. The authors are affiliated with the João Lobo Antunes Institute of Molecular Medicine at the Faculty of Medicine, University of Lisbon, Portugal; the Institute for Bioengineering of Catalonia at the Barcelona Institute of Science and Technology, Spain; the Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN) in Madrid, Spain; and the Catalan Institution for Research and Advanced Studies in Barcelona, Spain. The paper was published online on September 14, 2024, in the journal Molecular Oncology, with the DOI: 10.¹⁰⁰²⁄₁₈₇₈-0261.13730.

Main Content of the Paper

1. The Key Role of the LDLR Family in Glioma Progression

Members of the LDLR family, particularly LDLR and LRP1, are overexpressed in GBM tissues, indicating their critical role in regulating tumor aggressiveness and malignant potential. The LDLR family is involved in glioma progression by regulating cellular uptake and molecular transport, as well as activating signaling pathways related to tumor proliferation, migration, and invasion.

1.1 Cellular Uptake and Molecular Transport

One of the primary functions of the LDLR family is to regulate cholesterol homeostasis and metabolism. In tumor cells, cholesterol uptake and metabolism are often dysregulated to support their growth and proliferation. The high expression of LDLR and LRP1 in GBM cells suggests that they are the main importers of cholesterol. Studies have shown that the overexpression of LDLR and LRP1 leads to higher LDL uptake, providing more energy for tumor cell growth.

1.2 Regulation of Signaling Pathways

Members of the LDLR family also influence glioma progression by regulating various signaling pathways. For example, LRP1 affects tumor cell proliferation and invasion by modulating the ERK and JNK signaling pathways. LRP8 (also known as ApoER2) is overexpressed in various cancers and is associated with poor patient prognosis. LRP5 and LRP6, as coreceptors of the Wnt/β-catenin signaling pathway, play important roles in cell proliferation, migration, and invasion.

2. Applications of the LDLR Family in Targeted Glioma Therapy

The multifunctionality of the LDLR family makes it a potential target for glioma therapy. The high expression of LDLR and LRP1 in glioma and brain capillary endothelial cells provides new strategies for drug delivery systems.

2.1 LDLR-Targeted Therapy

Studies have shown that nanoparticles targeting LDLR can significantly enhance drug uptake and cytotoxicity. For example, polymeric micelles loaded with sorafenib and targeting LDLR significantly increased drug uptake and cytotoxicity. Additionally, gold nanoparticles (AuNP) have been used to enhance the anticancer effects of proton therapy.

2.2 LRP1-Targeted Therapy

The high expression of LRP1 in glioma cells makes it an ideal target for therapy. The interaction between the Angiopep-2 (Ang2) peptide and the LRP1 receptor has been used to enhance the uptake of various carriers, improving therapeutic efficacy. For instance, Ang2-decorated polymersomes loaded with doxorubicin (Dox) significantly increased tumor cell uptake and overall survival rates.

3. Conclusions and Future Perspectives

The LDLR family plays a crucial role in glioma progression, influencing tumor cell proliferation, migration, and survival. Current research focuses on leveraging LDLR family members as targets to facilitate drug delivery across biological barriers (such as the BBB) or to directly impact glioma cells. The application of nanoparticles offers new hope for glioma treatment, particularly polymeric nanoparticles due to their easily customizable design features.

Although LDLR and LRP1 show great potential in targeted glioma therapy, the roles of LRP5/6 and LRP8 require further exploration. Future research should focus on elucidating the specific roles of these receptors in glioma and developing new therapeutic strategies. Additionally, the immunomodulatory role of the LDLR family in the tumor microenvironment warrants further investigation, which may provide new directions for glioma treatment.

Significance and Value of the Paper

This review summarizes the multifaceted roles of the LDLR family in high-grade gliomas, emphasizing its importance in tumorigenesis, progression, and therapy. By synthesizing current research findings, this paper provides a theoretical foundation and practical guidance for developing new glioma treatment strategies. The LDLR family, as a target for drug delivery systems, holds significant clinical potential, particularly in overcoming BBB limitations and improving therapeutic efficacy. Future research will further reveal the complex roles of the LDLR family in glioma, offering new directions for personalized and immunomodulatory therapies.

Highlights

1. Multifaceted Roles of the LDLR Family in Glioma: This paper elaborates on the molecular mechanisms by which the LDLR family influences glioma cell proliferation, migration, and invasion, highlighting its critical role in tumor progression.
2. Potential for Targeted Therapy: By leveraging LDLR and LRP1 as targets, this paper demonstrates the application prospects of nanoparticles in glioma therapy, particularly in overcoming BBB limitations and enhancing drug delivery efficiency.
3. Future Research Directions: This paper proposes future research directions, including exploring the roles of LRP5/6 and LRP8 in glioma and the immunomodulatory role of the LDLR family in the tumor microenvironment.

Through this review, readers can gain a deeper understanding of the complex roles of the LDLR family in glioma and obtain important references for developing new therapeutic strategies.