The Tumor Metabolic Microenvironment: Lessons from Lactate

García-Cañaveras, Juan Carlos; Chen, Li; Rabinowitz, Joshua D.

doi:10.1158/0008-5472.can-18-3726

Cited by 171 publications

(119 citation statements)

References 82 publications

(101 reference statements)

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“…The inverted pH gradient (decreased extracellular and increased intracellular pH) is a feature of many neoplasms, including gliomas in the rodent model in vivo [123]. The acidic pH in the tumor and surrounding tissue was shown in human patients [124] and rat glioma in vivo [125][126][127].…”

Section: Reversing Lactate Effectsmentioning

confidence: 99%

Targeting Glutamine Addiction in Gliomas

Obara-Michlewska

Szeliga

2020

Cancers

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The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas.

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Section: Reversing Lactate Effectsmentioning

confidence: 99%

Targeting Glutamine Addiction in Gliomas

Obara-Michlewska

Szeliga

2020

Cancers

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“…However, this seems to be an epiphenomenon seen in many cancers from different tissues of origin which harbor a variety of driver mutations (3). While a driver mutation such as oncogenic KRAS directly alters metabolic pathways, cancers that successfully grow and evade the immune system undergo selective pressures from hypoxia, limited precursor availability, and secondary stimulation of pro-and anti-inflammatory responses by metabolic by-products (4)(5)(6)(7)(8). Given that metabolic pathways are tightly linked, alterations in one pathway have consequences in many others.…”

Section: Introductionmentioning

confidence: 99%

“…Energy coupling between tumor cells and their surrounding stroma has also come under close study. Tissue hypoxia and glycolysis lead to a buildup of lactic acid and thus an acidic, hypoglycemic microenvironment (8). This microenvironment has been shown to have a number of tumor-permissive and immune-suppressive effects, including promoting angiogenesis, invasion, and metastasis (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Amino Acid Oncometabolism and Immunomodulation of the Tumor Microenvironment in Lung Cancer

2020

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The observation that cancer acquires significant changes in its metabolism dates back nearly a century, to Otto Warburg noting that cancer cells preferentially utilize glycolysis even when there are no hypoxic conditions in the growth media. Altered energetics are thus considered a hallmark of cancer. However, it has become clear that altered metabolism is not limited to cellular energetic pathways. Alterations in amino acid synthesis and catabolism, lipid biogenesis, and other pathways such as polyamine processing are commonly seen in cancer. Additionally, alterations in metabolism do not only have profound effects for cancer cells but also affect their surrounding microenvironment. With new cancer therapeutics targeting the immune microenvironment, these effects may have implications on cancer growth and response to therapy. These interactions are profound in lung cancer, further demonstrating the manifold interactions between developing tumors and the inflammatory microenvironment. Here, we discuss how dysregulation of metabolism in cancer alters its microenvironment and how this newfound knowledge can be exploited for anticancer treatment.

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“…5 Later in his life, he changed his side of view and claimed that tumor cells are characterized by a damaged respiration. 6,7 In contrast to these observations and numerous studies since, two recent publications stated that the tumor environment contains no elevated lactate levels in the interstitial fluid, 8,9 and lactate may accumulate preferentially in tumor cells. In this case, the tumor stroma, for example, immune cells, would not face high-lactate concentrations.…”

Section: His Toric Al Timeline-the Warburg Effec T Then and Nowmentioning

confidence: 90%

The immunological Warburg effect: Can a metabolic‐tumor‐stroma score (MeTS) guide cancer immunotherapy?

Siska

Singer

Evert

et al. 2020

Immunological Reviews

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The "glycolytic switch" also known as the "Warburg effect" is a key feature of tumor cells and leads to the accumulation of lactate and protons in the tumor environment.Intriguingly, non-malignant lymphocytes or stromal cells such as tumor-associated macrophages and cancer-associated fibroblasts contribute to the lactate accumulation in the tumor environment, a phenomenon described as the "Reverse Warburg effect." Localized lactic acidosis has a strong immunosuppressive effect and mediates an immune escape of tumors. However, some tumors do not display the Warburg phenotype and either rely on respiration or appear as a mosaic of cells with different metabolic properties. Based on these findings and on the knowledge that T cell infiltration is predictive for patient outcome, we suggest a metabolic-tumor-stroma score to determine the likelihood of a successful anti-tumor immune response: (a) a respiring tumor with high T cell infiltration ("hot"); (b) a reverse Warburg type with respiring tumor cells but glycolytic stromal cells; (c) a mixed type with glycolytic and respiring compartments; and (d) a glycolytic (Warburg) tumor with low T cell infiltration ("cold"). Here, we provide evidence that these types can be independent of the organ of origin, prognostically relevant and might help select the appropriate immunotherapy approach. K E Y W O R D Sacidification, GLUT, immunotherapies, lactate, T cell, Warburg

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The Tumor Metabolic Microenvironment: Lessons from Lactate

Cited by 171 publications

References 82 publications

Targeting Glutamine Addiction in Gliomas

Targeting Glutamine Addiction in Gliomas

Amino Acid Oncometabolism and Immunomodulation of the Tumor Microenvironment in Lung Cancer

The immunological Warburg effect: Can a metabolic‐tumor‐stroma score (MeTS) guide cancer immunotherapy?

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