Glutathione (GSH) is the most abundant antioxidant found in living organisms and has multiple functions, most of which maintain cellular redox homeostasis. GSH preserves sufficient levels of cysteine ...and detoxifies xenobiotics while also conferring therapeutic resistance to cancer cells. However, GSH metabolism plays both beneficial and pathogenic roles in a variety of malignancies. It is crucial to the removal and detoxification of carcinogens, and alterations in this pathway can have a profound effect on cell survival. Excess GSH promotes tumor progression, where elevated levels correlate with increased metastasis. In this review, we discuss recent studies that focus on deciphering the role of GSH in tumor initiation and progression as well as mechanisms underlying how GSH imparts treatment resistance to growing cancers. Targeting GSH synthesis/utilization therefore represents a potential means of rendering tumor cells more susceptible to different treatment options such as chemotherapy and radiotherapy.
Molecular oxygen (O
) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen ...concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine-tuning the responses to hypoxic stress.
Solid tumors reside in harsh tumor microenvironments (TMEs) together with various stromal cell types. During tumor progression and metastasis, both tumor and stromal cells undergo rapid metabolic ...adaptations. Tumor cells metabolically coordinate or compete with their “neighbors” to maintain biosynthetic and bioenergetic demands while escaping immunosurveillance or therapeutic interventions. Here, we provide an update on metabolic communication between tumor cells and heterogeneous stromal components in primary and metastatic TMEs and discuss emerging strategies to target metabolic communications for improved cancer treatments.
Growing solid tumors consist of malignant cancer cells and heterogeneous stromal cell components. This Review from Simon and Li provides an updated overview of metabolic communication between tumor cells and stromal cells in primary and metastatic tumor microenvironments and discusses emerging strategies to target metabolic interactions for improved cancer therapies.
The tumor microenvironment Anderson, Nicole M.; Simon, M. Celeste
CB/Current biology,
08/2020, Volume:
30, Issue:
16
Journal Article
Peer reviewed
Open access
A tumor is not simply a group of cancer cells, but rather a heterogeneous collection of infiltrating and resident host cells, secreted factors and extracellular matrix. Tumor cells stimulate ...significant molecular, cellular and physical changes within their host tissues to support tumor growth and progression. An emerging tumor microenvironment is a complex and continuously evolving entity. The composition of the tumor microenvironment varies between tumor types, but hallmark features include immune cells, stromal cells, blood vessels, and extracellular matrix. It is believed that the “tumor microenvironment is not just a silent bystander, but rather an active promoter of cancer progression” (Truffi et al., 2020). Early in tumor growth, a dynamic and reciprocal relationship develops between cancer cells and components of the tumor microenvironment that supports cancer cell survival, local invasion and metastatic dissemination. To overcome a hypoxic and acidic microenvironment, the tumor microenvironment coordinates a program that promotes angiogenesis to restore oxygen and nutrient supply and remove metabolic waste. Tumors become infiltrated with diverse adaptive and innate immune cells that can perform both pro- and anti- tumorigenic functions (Figure 1). An expanding literature on the tumor microenvironment has identified new targets within it for therapeutic intervention.
The tumor microenvironment is a complex entity. Here, Anderson and Simon introduce this complex collection of cells, metabolites and extracellular matrix, and the role it plays in cancer progression.
Deregulated cell proliferation is an established feature of cancer, and altered tumor metabolism has witnessed renewed interest over the past decade, including the study of how cancer cells rewire ...metabolic pathways to renew energy sources and “building blocks” that sustain cell division. Microenvironmental oxygen, glucose, and glutamine are regarded as principal nutrients fueling tumor growth. However, hostile tumor microenvironments render O2/nutrient supplies chronically insufficient for increased proliferation rates, forcing cancer cells to develop strategies for opportunistic modes of nutrient acquisition. Recent work shows that cancer cells overcome this nutrient scarcity by scavenging other substrates, such as proteins and lipids, or utilizing adaptive metabolic pathways. As such, reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid-mediated signaling during cancer progression. In this review, we highlight more recently appreciated roles for lipids, particularly cholesterol and its derivatives, in cancer cell metabolism within intrinsically harsh tumor microenvironments.
In this special issue of Molecular Cell, Riscal et al. highlight recent breakthroughs and studies showing that Western diets, lipids, and particularly cholesterol and its derivatives directly influence cancer cell metabolism as well as the tumor microenvironment, suggesting that even cancer cells have to watch their cholesterol.
The growing field of tumor metabolism has greatly expanded our knowledge of metabolic reprogramming in cancer. Apart from their established roles, various metabolic enzymes and metabolites harbor ...non-canonical (“moonlighting”) functions to support malignant transformation. In this article, we intend to review the current understanding of moonlighting functions of metabolic enzymes and related metabolites broadly existing in cancer cells by dissecting each major metabolic pathway and its regulation of cellular behaviors. Understanding these non-canonical functions may broaden the horizon of the cancer metabolism field and uncover novel therapeutic vulnerabilities in cancer.
In this review article, we review the current understanding of moonlighting functions of metabolic enzymes and related metabolites broadly existing in cancer cells by dissecting each major metabolic pathway and its regulation of cellular behaviors.
Hypoxia and dysregulated metabolism are defining features of solid tumors. How cancer cells adapt to low O2 has been illuminated by numerous studies, with “reprogrammed” metabolism being one of the ...most important mechanisms. This metabolic reprogramming not only promotes cancer cell plasticity, but also provides novel insights for treatment strategies. As the most studied O2 “sensor,” hypoxia-inducible factor (HIF) is regarded as an important regulator of hypoxia-induced transcriptional responses. This minireview will summarize our current understanding of hypoxia-induced changes in cancer cell metabolism, with an initial focus on HIF-mediated effects, and will highlight how these metabolic alterations affect malignant phenotypes.
Hypoxia is a prominent characteristic of many acute or chronic inflammatory diseases, and exerts significant influence on their progression. Macrophages and neutrophils are major cellular components ...of innate immunity and contribute not only to O2 deprivation at the site of inflammation, but also alter many of their functions in response to hypoxia to either facilitate or suppress inflammation. Hypoxia stabilizes HIF-αs in macrophages and neutrophils, and these O2-sensitive transcription factors are key regulators of inflammatory responses in myeloid cells. In this review, we will summarize our current understanding of the role of HIF-αs in shaping macrophage and neutrophil functions in the pathogenesis and progression of multiple inflammatory diseases.
Oxygen availability, along with the abundance of nutrients (such as glucose, glutamine, lipids and albumin), fluctuates significantly during tumour evolution and the recruitment of blood vessels, ...leukocytes and reactive fibroblasts to complex tumour microenvironments. As such, hypoxia and concomitant nutrient scarcity affect large gene expression programmes, signalling pathways, diverse metabolic reactions and various stress responses. This Review summarizes our current understanding of how these adaptations are integrated in hypoxic tumour cells and their role in disease progression.
Low levels of oxygen (O2) occur naturally in developing embryos. Cells respond to their hypoxic microenvironment by stimulating several hypoxia-inducible factors (and other molecules that mediate O2 ...homeostasis), which then coordinate the development of the blood, vasculature, placenta, nervous system and other organs. Furthermore, embryonic stem and progenitor cells frequently occupy hypoxic 'niches' and low O2 regulates their differentiation. Recent work has revealed an important link between factors that are involved in regulating stem and progenitor cell behaviour and hypoxia-inducible factors, which provides a molecular framework for the hypoxic control of differentiation and cell fate. These findings have important implications for the development of therapies for tissue regeneration and disease.
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