Metabolic management of microenvironment acidity in glioblastoma

Abstract

Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.

Integrated analysis of fecal metagenomics and metabolomics reveals the role of gut microbiota in the pathogenesis of primary central nervous system lymphoma

“…Succinic acid is a crucial metabolic intermediate involved in a variety of metabolic pathways, which are closely related to tumorigenesis. Previous studies have demonstrated the accumulation of succinic acid in malignancies such as pituitary adenomas (31), ovarian cancers (32), and glioblastomas (33). However, the results of metabolomics showed that the proportion of succinic acid decreased in the PCNSL patient group.…”

Engineering the glioblastoma microenvironment with bioactive nanoparticles for effective immunotherapy

“…73 Acidication of the tumor prompts signicantly higher levels of immunosuppression and GSC migration and proliferation. [74][75][76] Molecular building blocks such as amino acids and nucleosides also have increased concentrations within the TME, contributing to greater aggression, invasion, and immunosuppression. Adenosine, a potent immunosuppressant produced in large quantities in hypoxic conditions by GBM cells and exported into the extracellular space, increases cancer aggressiveness and dampens the immune response through A2A receptors (A2AR) on immune cells.…”

“…73 Acidification of the tumor prompts significantly higher levels of immunosuppression and GSC migration and proliferation. 74–76…”

Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells

“…Malignant glioma is often diagnosed in older patients but can occur at any age with rising cases in children (Phillips et al, 2006; Tamimi and Juweid, 2017). Median survival is between 8-15 months with overall survival after 5 years remains below 10% (Omuro and DeAngelis, 2013; Fatehi et al, 2018; Seyfried et al, 2022). Patient outcome remains poor due in large part to the invasive characteristics in gliomas making complete surgical resection difficult (McCutcheon and Preul, 2021; Seyfried et al, 2022).…”

“…Median survival is between 8-15 months with overall survival after 5 years remains below 10% (Omuro and DeAngelis, 2013; Fatehi et al, 2018; Seyfried et al, 2022). Patient outcome remains poor due in large part to the invasive characteristics in gliomas making complete surgical resection difficult (McCutcheon and Preul, 2021; Seyfried et al, 2022). Gliomas encompass numerous cell types that express glial, stem cell, and mesenchymal markers (Aum et al, 2014; Sidaway, 2017).…”