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Lactate in Sarcoma Microenvironment: Much More than just a Waste Product.

ABSTRACT: Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.

SUBMITTER: Taddei ML

PROVIDER: S-EPMC7072766 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Lactate in Sarcoma Microenvironment: Much More than just a Waste Product.

Taddei Maria Letizia ML Pietrovito Laura L Leo Angela A Chiarugi Paola P

Cells 20200224 2

Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict int ...[more]

PMID: 32102348

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Project description:Objectives: Ewing sarcoma (EWS) is an aggressive tumor of bone and soft tissue. Growing evidence indicated lactate as a pivotal mediator of crosstalk between tumor energy metabolism and microenvironmental regulation. However, the contribution of lactate-related genes (LRGs) in EWS is still unclear. Methods: We obtained the transcriptional data of EWS patients from the GEO database and identified differentially expressed-LRGs (DE-LRGs) between EWS patient samples and normal tissues. Unsupervised cluster analysis was utilized to recognize lactate modulation patterns based on the expression profile of DE-LRGs. Functional enrichment including GSEA and GSVA analysis was conducted to identify molecular signaling enriched in different subtypes. ESTIMATE, MCP and CIBERSORT algorithm was used to explore tumor immune microenvironment (TIME) between subtypes with different lactate modulation patterns. Then, lactate prognostic risk signature was built via univariate, LASSO and multivariate Cox analysis. Finally, we performed qPCR analysis to validate candidate gene expression. Result: A total of 35 DE-LRGs were identified and functional enrichment analysis indicated that these LRGs were involved in mitochondrial function. Unsupervised cluster analysis divided EWS patients into two lactate modulation patterns and we revealed that patients with Cluster 1 pattern were linked to poor prognosis and high lactate secretion status. Moreover, TIME analysis indicated that the abundance of multiple immune infiltrating cells were dramatically elevated in Cluster 1 to Cluster 2, including CAFs, endothelial cells, Macrophages M2, etc., which might contribute to immunosuppressive microenvironment. We also noticed that expression of several immune checkpoint proteins were clearly increased in Cluster 1 to Cluster 2. Subsequently, seven genes were screened to construct LRGs prognostic signature and the performance of the resulting signature was validated in the validation cohort. Furthermore, a nomogram integrating LRGs signature and clinical characteristics was developed to predict effectively the 4, 6, and 8-year prognosis of EWS patients. Conclusion: Our study revealed the role of LRGs in immunosuppressive microenvironment and predicting prognosis in EWS and provided a robust tool to predict the prognosis of EWS patients.

Project description:John Newsom-Davis was born in 1932 and died, aged 74, in 2007. After national service in the Royal Air Force, he read Natural Sciences at Cambridge. Following clinical studies at the Middlesex Hospital, he began research into respiratory neurophysiology with Tom Sears at the National Hospital, Queen Square, in London, and spent 1 year with Fred Plum at Cornell University in New York. After neurology specialist training at Queen Square, he became the director of the Batten Unit, continuing his interest in respiratory physiology. There he began to work on myasthenia gravis in collaboration with Ricardo Miledi at University College London and in 1978, after performing the first studies on plasma exchange in that disease, he established a myasthenia gravis research group at the Royal Free Hospital. There he investigated the role of the thymus in this disease and demonstrated an autoimmune basis for the Lambert Eaton myasthenic syndrome and 'seronegative' myasthenia. He was awarded the first Medical Research Council Clinical Research Professorship in 1979 but moved to Oxford in 1987 when he was elected Action Research Professor of Neurology. While at Oxford, he continued to run a very successful multidisciplinary group, researched further into the thymic abnormalities and cellular immunology of myasthenia, identified antibody-mediated mechanisms in acquired neuromyotonia, and began the molecular work that identified the genetic basis for many forms of congenital myasthenic syndrome. Meanwhile, he was also involved in university and college governance and contributed widely to the Medical Research Council, government committees, research charities and the Association of British Neurologists. Among many honours, he was elected Fellow of the Royal Society in 1991, appointed Commander of the British Empire in 1996 and made a Foreign Associate Member of the Institute of Medicine of the United States in 2001. Nearing and following retirement from Oxford, where he continued to see patients with myasthenia, he was the President of the Association of British Neurologists and Editor of Brain, and led a National Institutes of Health-funded international trial of thymectomy.

Project description:BackgroundHemozoin is considered a waste byproduct of heme detoxification following hemoglobin digestion; consequently, the biological functions of hemozoin in hemozoin-producing organisms have often been overlooked. However, recent findings indicate that Schistosoma hemozoin facilitates the transfer of iron from erythrocytes to eggs through its formation and degradation, thereby increasing interest in the role of malarial hemozoin.MethodsUsing transmission electron microscopy, we compared the formation of Schistosoma hemozoin and malaria hemozoin. Through transcriptome analysis of different stages of P. falciparum 3D7WT and P. falciparum 3D7C580Y,- where the latter serves as a control with reduced hemozoin production, -we analyzed expression patterns of genes related to DNA synthesis, iron, and heme utilization. Using light microscopy, we observed hemozoin aggregation following artemether treatment, and macrophage morphology after ingesting hemozoin in vivo and in vitro.ResultsSimilar to Schistosoma hemozoin, malaria hemozoin consists of heme aggregation and a lipid matrix, likely involved in lipid processing and the utilization of heme and iron. Transcriptome analysis reveals that during the trophozoite stage, the expression levels of these genes in P. falciparum 3D7WT and P. falciparum 3D7C580Y are higher than those during the schizont stage. Correspondingly, less hemozoin was detected at the trophozoite stage, while more was observed during the schizont stage. These results suggest that when more heme and iron are utilized, less heme is available for hemozoin formation. Conversely, when less heme and iron are utilized, they can accumulate for hemozoin formation during the schizont stage, likely benefiting lipid remodeling. Disruption of heme utilization and hemozoin aggregation may lead to parasite death. In addition, the hemozoin released by schizonts can impair macrophage functions, potentially protecting merozoites from phagocytosis. Furthermore, it may be carried by gametocytes into the next host, fulfilling their requirements for iron and heme during their development in mosquitoes.ConclusionsHemozoin is not a waste byproduct of heme detoxification but instead plays a crucial role in the parasite's life cycle.

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Lactate in Sarcoma Microenvironment: Much More than just a Waste Product.

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Lactate in Sarcoma Microenvironment: Much More than just a Waste Product.

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