Role of exosomes in the progression, diagnosis, and therapy targeting of malignant brain gliomas

Glioblastoma, the most aggressive primary brain tumor, is characterized by infiltrative growth, resistance to therapy, and a dismal prognosis, with median survival rarely exceeding 16 months post-diagnosis. Despite advancements in treatments like temozolomide (TMZ) and radiotherapy, recurrence is nearly inevitable, highlighting the urgent need for innovative therapeutic strategies. Recent research has unveiled the pivotal role of exosomes—nanoscale extracellular vesicles—in glioblastoma progression, diagnosis, and therapy. These vesicles carry bioactive molecules, including proteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), which facilitate intercellular communication, modulate the tumor microenvironment (TME), and drive chemoresistance. This review synthesizes current knowledge on exosomal contributions to glioblastoma pathogenesis, their potential as diagnostic biomarkers, and their emerging role as therapeutic carriers.

Exosomes in Glioblastoma Progression
Exosomes secreted by glioblastoma cells are laden with oncogenic cargo that promotes tumor proliferation, invasion, and immune evasion. Key molecules include:

• Proteins: PSMD2, EGFR, and PDGFR amplify tumor invasiveness and TMZ resistance.

• miRNAs: miR-21, miR-221/222, and miR-374b-3p inhibit apoptosis and enhance angiogenesis. For instance, miR-374b-3p suppresses PTEN, polarizing macrophages to the pro-tumor M2 phenotype.

• lncRNAs: Remodel the TME and foster chemoresistance by altering DNA repair pathways (e.g., XRCC4 downregulation via exosomal miR-151a).

These exosomal components collectively sustain glioblastoma’s aggressive phenotype, making them critical targets for intervention.

Diagnostic Potential of Exosomes
Exosomes offer a non-invasive source of glioblastoma-specific biomarkers, enabling early detection and molecular stratification:

• Protein Markers: Overexpression of ANXA1, ANXA2, and EGFRvIII in exosomes correlates with tumor grade and invasiveness.

• miRNAs: Elevated serum levels of miR-210 and miR-21 distinguish glioblastoma patients from healthy controls and predict poor prognosis.

• lncRNAs: Exhibit high specificity for glioblastoma, aiding in early diagnosis and monitoring therapeutic response.

Standardizing exosome isolation and profiling techniques remains a challenge, but advances in nanotechnology and deep learning are enhancing detection sensitivity.

Therapeutic Applications
Exosomes’ ability to cross the blood-brain barrier (BBB) makes them ideal drug carriers:

• Drug Delivery: Exosomes loaded with schimethub or TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) selectively target tumor cells, sparing healthy tissue. For example, Exo-iNSC-TRAIL induces apoptosis in TMZ-resistant glioblastoma.

• Chemosensitization: Exosomal miR-151a restores TMZ sensitivity by inhibiting DNA repair mechanisms.

• Immunomodulation: Engineered exosomes can reprogram the TME, countering immunosuppressive M2 macrophages.

Challenges and Future Directions
Despite their promise, exosome-based therapies face hurdles:

• Standardization: Lack of uniform protocols for exosome isolation and cargo loading.

• Scalability: Manufacturing clinical-grade exosomes is complex and costly.

• Safety: Long-term effects of exosomal therapies require further validation.

Future research should focus on integrating multi-omics data, optimizing exosome engineering, and conducting large-scale clinical trials.

Conclusion
Exosomes are central to glioblastoma’s pathogenesis, offering dual utility as diagnostic biomarkers and therapeutic vehicles. Their capacity to transport oncogenic molecules and penetrate the BBB positions them as transformative tools in neuro-oncology. While challenges persist, leveraging exosomes for early detection and targeted therapy holds immense potential to improve outcomes for glioblastoma patients.

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https://www.xiahepublishing.com/2996-3427/OnA-2024-00023

The study was recently published in the Oncology Advances.

Oncology Advances is dedicated to improving the diagnosis and treatment of human malignancies, advancing the understanding of molecular mechanisms underlying oncogenesis, and promoting translation from bench to bedside of oncological sciences. The aim of Oncology Advances is to publish peer-reviewed, high-quality articles in all aspects of translational and clinical studies on human cancers, as well as cutting-edge preclinical and clinical research of novel cancer therapies.

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