Justin Chen

Background: Glioblastomas (GBM), the most common primary brain cancer, is classified as grade IV diffuse astrocytoma.¹ Patients have a median post-diagnosis survival of 14-16 months.¹ Pathologically, the aggressive, spindle-shaped tumor cells are arranged in a pseudopalisading pattern around an oxygen and nutrient-deprived necrotic center.² Due to poor prognosis, considerable efforts have been dedicated to identifying therapeutic interventions. Recently, galectins have been linked to unfavorable glioblastoma outcomes. Galectins comprise a protein family featuring a carbohydrate recognition domain capable of binding to β-galactosides. They are present both extracellularly, facilitating cellular communication, and intracellularly, where they regulate protein trafficking and signaling.³ In this review, the roles of galectin-1 and galectin-3 were explored in the context of facilitating tumor cell macropinocytosis, reversal of the Warburg effect, and M2 macrophage recruitment.

Objective: In this review, the mechanism in which galectin-1, galectin-3, and other binding partners confer worse glioblastoma prognosis is examined, and whether the inhibition of said galectins can reduce tumor size.

Search Methods: A search for primary research articles in PubMed published within the past five years was performed. MeSH search terms constituting “glioblastoma” and “galectins” were used, and five primary research publications were identified and reviewed.

Results: Macropinocytosis, a process by which cells engulf extracellular material, is seen in rapidly dividing glioma cells. Whether this occurs in glioma stem cells, which divide less rapidly, has not previously been characterized. In a human glioblastoma stem cell (GSC) model, different subsets of GSCs were identified. The mesenchymal GSCs, which had the highest galectin-3 protein and galectin-3 mRNA expression of all GSC subsets, had significantly increased micropinocytosis activity, measured by fluorescent TMR-dextran uptake.⁴ In another GBM biopsy experiment, galectin-1 expression promoted the Warburg effect, an important anabolic pathway in tumor cells to build nucleic acids, proteins, lipids, and carbohydrates. An immunoblot assay of lactate dehydrogenase A and B demonstrated that galectin-1 knockouts had reduced expression of Warburg substrates.⁵ The galectin-1 knockout GSCs also had significantly decreased tumor cell viability.⁵ Galectin-1, galectin-3, and chitinase-3-like 1 (a galectin-3 binding partner) have been associated with dampening the immune response against tumor cells by recruiting M2 macrophages. In an in vitro C57B/6 mice experiment, recombinant chitinase-3-like 1 attracted a significantly greater amount of M2 macrophages than M1 macrophages.⁶ When rCHi3l1 was knocked out in the C57BM/6J immunocompetent mice, there was a reduction in tumor size.⁶ In contrast, rCHi3l1-knockout in the immunocompromised SCID mice model had no difference in tumor, suggesting rChi3l1’s role in immune modulation.⁶ In another clinical experiment, patients with GBM had higher serum extracellular vesicle galectin-3 binding protein, which can serve as a potential GBM diagnostic marker.⁷

Conclusion: Galectin-3, galectin-1, and its binding partners are associated with poorer glioblastoma prognosis. In this review, galectins have been demonstrated to regulate tumor cell energy uptake, substrate anabolism, and host immune dampening. Inhibitors in galectin signaling have decreased tumor cell load in vitro, presenting immense therapeutic possibilities in the relatively nascent field of galectin-GBM medicine.

Works Cited:

1. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ. 2021;374:n1560. Published 2021 Jul 14. doi:10.1136/bmj.n1560
2. Brat DJ, Castellano-Sanchez AA, Hunter SB, et al. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res. 2004;64(3):920-927. doi:10.1158/0008-5472.can-03-2073
3. Cummings RD, Liu FT. Galectins. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Chapter 33. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1944/
4. Seguin L, Odouard S, Corlazzoli F, et al. Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells. Commun Biol. 2021;4(1):718. Published 2021 Jun 10. doi:10.1038/s42003-021-02258-z
5. Guda MR, Tsung AJ, Asuthkar S, Velpula KK. Galectin-1 activates carbonic anhydrase IX and modulates glioma metabolism. Cell Death Dis. 2022;13(6):574. Published 2022 Jun 30. doi:10.1038/s41419-022-05024-z
6. Chen A, Jiang Y, Li Z, et al. Chitinase-3-like 1 protein complexes modulate macrophage-mediated immune suppression in glioblastoma. J Clin Invest. 2021;131(16):e147552. doi:10.1172/JCI147552
7. Dufrusine B, Capone E, Ponziani S, et al. Extracellular LGALS3BP: a potential disease marker and actionable target for antibody-drug conjugate therapy in glioblastoma. Mol Oncol. 2023;17(8):1460-1473. doi:10.1002/1878-0261.13453