Monocarboxylate transporters in the brain and in cancer.

Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1-4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou

Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function

Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, we report that long-term in vivo antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronic T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronic T cells appeared to rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to produce ATP for IFNγ synthesis. Check-point blockade, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1-mediated inhibition appears essential for limiting oxidative metabolism linked to effector function in chronic T cells, thereby promoting survival and functional fitness.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Metabolic Adaptations and Targets in Cancer

The metabolism of cancer cells differs from that of their normal counterparts in a spectrum of attributes, including imbalances in diverse metabolic arms and pathways, metabolic plasticity and extent of adaptive responses, levels, and activities of metabolic enzymes and their upstream regulators and abnormal fluxes of metabolic intermediates and products. These attributes endow cancer cells with the ability to survive stressors of the tumor microenvironment and enable them to landscape and exploit the host terrain, thereby facilitating cancer progression and therapy resistance. Understanding the molecular and physiological principles of cancer metabolism is one of the key prerequisites for the development of better anticancer treatments. Therefore, various aspects of cancer metabolism were addressed at the 5th annual meeting of the International Society of Cancer Metabolism (ISCaM) in Bratislava, Slovakia, on October 17\u201320, 2018. The meeting presentations and discussions were traditionally focused on mechanistic, translational, and clinical characteristics of metabolism and pH control in cancer, at the level of molecular pathways, cells, tissues, and organisms. In order to reflect major healthcare challenges of the current era, ISCaM has extended its scope to metabolic disorders contributing to cancer, as well as to opportunities for their prevention, intervention, and therapeutic targeting

Gut microbiota-derived propionate reduces cancer cell proliferation in the liver

Peer reviewedPublisher PD

RRx-001, an epigenetic-based radio- and chemosensitizer, has vascular normalizing effects on SCCVII and U87 tumors

BACKGROUND: The tumor-specific microregional effects of the anticancer agent RRx-001, a novel epigenetic-based radio/chemosensitizer with nitrogen oxide-donating properties in phase II clinical trials, were investigated with whole tissue section quantitative immunohistological staining in mouse SCCVII and human U87 tumors. RESULTS: SCCVII tumors exhibited regions of intermittent perfusion exemplified by co-localization of vessels with the hypoxia marker pimonidazole commonly occurring throughout the tissue. A moderate increase in perfusion (21 to 28 %) was observed after a bolus dose of the perivascular stain DiOC(7)(3), however, with the absence of an increase in tissue oxygenation. U87 tumors showed an absence of blood flow over large areas of treated tumors after dosing with RRx-001. However, these areas did not become necrotic and returned to near normal levels after 12 h. No significant change in tumor hypoxia was seen at 90 min or 12 h. For both tumor types, RRx-001 treatment resulted in the loss of perfusion in the large regions of the tumor; however, at the 12-h time point, both tumor types showed an increase in vessel perfusion but no significant decrease in hypoxia. CONCLUSIONS: These data suggest a redistribution of blood flow within the tumor for both tumor types akin to vascular normalization. Differences between the tumors were related to tumor architecture and distribution of alpha-smooth muscle actin (α-SMA). RRx-001 shows promise for short-term blood flow redistribution in tumors with a pericyte- and α-SMA-rich vasculature. Expression of α-SMA in tumor vasculature could therefore be useful for predicting tumor response to RRx-001

Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis

Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities

Quiescience as a mechanism for cyclical hypoxia and acidosis

Tumour tissue characteristically experiences fluctuations in substrate supply. This unstable microenvironment drives constitutive metabolic changes within cellular populations and, ultimately, leads to a more aggressive phenotype. Previously, variations in substrate levels were assumed to occur through oscillations in the hæmodynamics of nearby and distant blood vessels. In this paper we examine an alternative hypothesis, that cycles of metabolite concentrations are also driven by cycles of cellular quiescence and proliferation. Using a mathematical modelling approach, we show that the interdependence between cell cycle and the microenvironment will induce typical cycles with the period of order hours in tumour acidity and oxygenation. As a corollary, this means that the standard assumption of metabolites entering diffusive equilibrium around the tumour is not valid; instead temporal dynamics must be considered

Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Cancer Metabolism

Tumors are metabolic entities wherein cancer cells adapt their metabolism to their oncogenic agenda and microenvironmental influences. Metabolically different cancer cell subpopulations collaborate to optimize nutrient delivery with respect to immediate bioenergetic and biosynthetic needs. They can also metabolically exploit host cells. These metabolic networks are directly linked with cancer progression, treatment, resistance, and relapse. Conversely, metabolic alterations in cancer are exploited for anticancer therapy, imaging, and stratification for personalized treatments. These topics were addressed at the 4th annual meeting of the International Society of Cancer Metabolism (ISCaM) in Bertinoro, Italy, on 19–21 October 201